Am9780854042074 00001

 

1

Amino Acids B y G.C. BARRETT

1

Introduction

The 1994 literature covering the amino acids, from the point of view of their chemistry chemis try and bioche biochemistry mistry,, is dealt with in this Chapter. The appro approach ach adopted is identical to that th at us used ed in all previous Vol Volumes umes of this Special Specialist ist Periodical Report. The Chapter concentrates on the literature covering the natural occurrence, chemistry, and analysis methodology for amino acids. Routine literature covering the natural distribution of well-known amino acids is excluded. Patent literature deals with material that also finds its way into the conventional literature, and is therefore excluded from this Chapter. It is easily reached through the appropriate sections of Chemical Abstracts (Section 34 in particular). The flow flow o off Journal papers a and nd secondary literature continues to accelerate, as far as the amino acids are concerned, and papers have been collected for this Chapter from major Journals and from Chemical Abstracts [to Volume 122 (1995), issue 91. Where it is helpful to refer to earlier Volumes of this Specialist Periodical Report, Repo rt, the fformula ormula ‘(se ‘(see e Vol. 23, p. 3)’ is used. Most of the papers cited are only briefly described, so that adequate commentary can be offered for particular papers presenting significant advances in synthetic and analytical methodology relating to the amino acids, wi with th mechanistically-interesting chemis chemistry try being given promine prominence. nce. The coverage adopts the usual meaning of the term ‘amino acids’, i.e. aminoalkanoic acids H3N+ (R1R2C),C02-. Many conceivab conceivable le structural types (for example, benz benzen ene e derivatives carrying amino and carboxy groups) are excluded. exclud ed. Representative citations are offered offered,, o off analogues in which the carboxy group is replace replaced d by a phosphorus oxyaci oxyacid d equivalent, H3N+-(R1R2C),P(0)(OH)(O-),1-4 e.g. (1S,2S)-phosphothreonine$ have impor important tant research applications; even the boron analogue R3N(BHR1),,-C02R may hold some similar pro mi ~e .~

2

Textbooks and Reviews

A substantial source of information on instrumental and analytical protocols6 includes inclu des material on the amino acids. A similarly thorou thorough gh c coverage overage of top topics ics in the synthesis of amin amino o ac acids ids has been publ publish ished. ed.’’ 1

 

Amino A cids, Peptides and Proteins Proteins

2

Several reviews will be found in appropriate sections of this Chapter, though others of a more general general na natur turee are collected here; thes thesee cover a-aminoisobutyric a-aminoisobutyric acid,8 carbora carboranylalani nylalanine ne in neutron captu cap ture re ther therap apy y: cyclopropane-b cyclopropane-based ased ami amino no acids,1° 1-aminocyclopropanecarboxylic acid synthesis,' cyclobutane-based amino acids,I2 synthesis of heterocyclic amino acids,13 uses of amino acid esters as chiral auxiliaries in organic synthesi synthesis,14 s,14 uses of a-a a -ami mino no acids in aaminosugar minosugar synthesis,15and synthesis,15 and stereochemical details of metabo metabolic lic reactions of amino acids. 6 3

Naturally Occurring Amino Acids

3.1

Isolation of A mino Acids fr from om Natural Sources - All fermentative processes

for the production of amino acids require routine isolation of the product, and, like the production of amino acids through protein hydrolysis, the separation of mixtures is a common concluding stage to the process. This section is intended to select some less routine aspects of the isolation of amino acids, particularly those unexpected outcomes of otherwise straightforward procedures. Protein hydrolysis is most commonly accomplished using hydrochloric or methanesulfonic acids, but several alternative protocols have been suggested; mercaptoethanesulfonic acid (1 60- 18 180' 0') ha hass been found t o be effective. 7 Continuous concentration of amino acids using a liquid emulsion membrane with a cation extractant, di-2-ethylhexylphosphoricacid, has been described. 8 Preparative chromatographic isolation (gel filtration and partition) of pyridinoline' and of hydroxylysylhydroxylysyl- and an d lysyl-pyridinolines20 lysyl-pyridinolines20from from biological fluids, and preparative chromatography of benzyl esters of basic amino acids2' and Nbenzylox benz yloxycarb ycarbonyl onyl amino ami no acids (Z-ami (Z-amino no acids)22 acids)22 llustrate standar sta ndard d methods. 3.2 Occurrence of Known Amino Acids - Where common amino acids are found in meteorites, and in ancient fossils, an obvious first question, but one only recently recen tly addressed in a rational rationa l scientific scientific manner, is: is the ami a mino no acid indigen indigenous ous or has it been introduce introduced d subsequently? Furth Fur ther er studies (see Vo1.2 o1.25, 5, p.3) based on

sensitive GC-MS isotope-analytical techniques the indigeneity of amino acids through identical 613C and 615N values confirm for D- and L-enantiomers of a particular amino acid in thoroughly-cleaned 7000-1 O5 y samples, and in Pleistocene fossils.23Quaterna fossils.23Quaternary ry land snails give given n more detailed confirm this diagnostic test as far as neutral amino acids are concerned, but differing 613C values for D- and L-enantiomers of aspartic and glutamic acids introduce an element eleme nt of doubt doubt;; presu presumabl mably y these amin amino o acid acidss as a s constituents of she shell ll protein are subject to more m ore complex diagenesis. Contemporary natural sources that have been shown to contain unusually interesting, though known, amino acids include D-aspartic acid (supplied by intestinal bacteria) in appreciable quantities in Octopus v ~ l g a r i s ,he ~ ~antimicrobial and an d antioxidant ant ioxidant N-(p-coumary1)pipecolic N-(p-coumary1)pipecolic acid in rhizomes of Cirsium brevicaule.26 Both D- and L-tert-leucine appear, together with D-kynurenine, as constituents of discodermin E, from the marine sponge Discodermia k i i e n ~ i s . ~ ~ a-Methylcysteine appears in condensed form in the cryoprotective agent

 

1: Amino Acids

3

thiazohalostatin (1) from Actinomadura.28 Another peptide from Verticilliurn coccosporum has been discovered to contain 2-amino-8-oxo-9-hydroxydecanoic acid.29 The Th e presenc presence e of p p-alanine -alanine in Clitocybe acromelalga, as its L-glutamide deri derivavative tive30 30 ad adds ds another natural location to those already established for this P-amino P-amino acid. y-Hydroxy-L-glutamic acid occurs in bulbs of Hemerocallis longituba in the form of the amide, longitubanine (2; R = OH).31 Synthetic cis-4-methylproline cis-4-meth ylproline is physic physically ally different from the compound located over the years in various natural sources, calling for some reconsideration of the structural assignment^.^^ The assessment of crosslinks that develop in vivo in proteins of higher species, as a result of ageing or disease, has become an important diagnostic criterion, and pyridinium crosslink^^^ and dityrosine crosslinks have been identified in bovine t hyrog hyroglo lobulin.34

New Naturally Occurring Amino Acids - Mycestericins from Mycelia immunosuppressants ssants that have be been en shown to be hydro hydroxylated xylated sterilia are potent immunosuppre a-hydroxymethyl-a-aminoalkanoic cids (3 (3-5) of extra extraordi ordinary nary types.35Anot Another her 3.3

new acyclic aliphatic a-amino acid also owes its fascination to the functional group that it contains, the first natural azoxy-containing antifungal agent, L azoxybacilin ( 6 ) , from Bacillus cereus NR299 1 36 Sphingofungins (7) are a new family of antifungal metabolites from Aspergi Aspergill llus us fum iga tus ATC ATCC C 20857.37New opines (8) (8)38 38 and piperidine 2,4,5-tricarb 2,4,5-tricarboxylic oxylic acid (9), are ffurth urther er met metabolites abolites from C li Five en new ew compou compounds nds (e.g (e.g., ., 10 and li t o c y b e a ~ r o m e l a l g asee ~ ~ also Ref.30). Fiv stereoisomers) stereoisome rs) related tto o domoi domoic c acid have been isolated from mu muss ssels els.4 .40 0

3.4

New Amino Acids from Hydrolysates - y-Hydroxy-tert-leucine is a constituent of polytheonamides A-C from the marine sponge Theonella swinhoei?’ and Zwittermicin A from Bacillus cereus is (1 l).42 Th The e other ne new w amino acids are mostl mostly y lactams condensed into mor more e complex structur structures; es; the 2,5dihydrofuryl-y-lactams, fulvanines D and E (12), (1 3) from H em em eerr o c a lli s f ~ l v a , 4 ~ €5-D (14) from the sponge Anchinoe tenacior,44 the antibiotic anchinopeptolides magnesidin from V i b r i o g ~ z o g e n e s , ~nd A (15) ~ the novel siderophore vibrioferrin (1 6) that develops in Vibrio parahuemolyticus in response to limitation of Fe F e in the culture

4

Chem ical Synthesis an and d Resolution of Amino Acids

General Methods for the Synthesis of a-Amino Acids - The term ‘general methods’ has been attached to a group of reactions that have become familiar

4.1

through use for many years; these are covered in this Section as far as the a-amino acids are co concerned. ncerned. Relatively few novel ideas have been introduced under this heading in recent years, and those that have, have been concerned with the burgeoning area of ‘Asymmetric Synthesis’. Although gi given ven a Section of their own in this Chapter

 

Amino Acids, Peptides and Proteins

4

(3) R ’ = ( € , € , R)-CH=CH(CH2)&H =CHCH(OH)(CH2)5Me. R’ = OH (4) R’ = ( € ) - C H =CH(CH,)6CH(OH)(CH2)5Me; R 2 = O H

(5) R ’ = (CH2)8CO(CH2)5Me;R 2 = OH; or R ’ = ( € ) - C H Z C H =CH(CH2)6CO(CH2)5 CH2)5Me; Me; R 2 = H or R’ = (€ )-C H =CH(CH2)6CO(

+ Me’

N +

ey

4

N

H

3

coe-

Three-dimensional eatures at chiral centres of structures depicted depicted in this chapter follow the convention:(a) horizontally-rangedatoms, horizontally-rangedatoms, and their bonds, bonds , and atoms in rings, ring s, are are understood to be in the the plane plan e of the paper; b) atoms and groups attached to to these atoms in (a) are ABOVE the page if ranged LEFTWARDS and BELOW the page if ranged RIGHTWARDS:

Rx eans

R

R’

 

5

1: Amino Acids

+

R 4H 02-

OH

OH

(8) R ' = Pr', Bu', or Bus

(7) R = (CH2),CH(OH)(CH2),Me and

N -acetylated, for Sphingofungin D; N -non-acetylated, for Sphingofungin B ; NH3' replaced by NHC(= NH)NH2 or

Sphingofungin A

(9)

CONH2 0

$9,,

HO

OMe

OH OH

OH

 

Amino Acid s, Pep tides and Proteins Proteins

6

(1 4 various R

L

OH I

(1 6) R = ( C H Z ) ~ O C O C H ~ C C H ~ C O ~ H

(15)

Ph

OH

I C02H

Ar I PhCONHCHC02H

Ph

Reagents: i, A r p b ( 0 A ~ ) ~i,; NaOH in EtOH-H20; iii, H 30 +

Scheme 1

 

1 : Amino Aci

7

(Section 4.2 4.2)’ )’ asymmetric asymmetr ic synthesis methods are nearly near ly alwa always ys ‘general meth methods ods of synthesis’ too. Other general reactions by which one amino acid is used as starting material for the synthesis of another, are mostly covered in the later Section 6.3 (Specific Reactions of Amino Acids). Long-established methods continue to be revisited as reliable routes, and many of these are used in syntheses of labelled amino acids (see (see Section 4 4.1 .15). 5). The alkylation of diethyl phthalimidomalonate phthalimido malonate (see (see Refs.166 166,2 ,256) 56) and diethyl acetamidomalonate (see also Refs.254,258), e.g. for a synthesis of 2-amino-7,7dimethyloctanoic and 2-amino-8,8-dimethylnonanoiccids,47 cids,47and and the alkylation of oxazolones, e.g. in an aspartic acid synthesis (17 + 18),48 n a synthesis of a amino-P-phosphonopropionic cid,49 cid,49and and in an arylglycine synthesis (Scheme 1) 50 and corresponding vinylglycine synthesi~,~’re re typical long-established methods. Rearranged dimers that are well-known (usually unwanted) side-products from oxazolone alkylation, alkylation, can be hydrolysed to gi give ve a-alkyl-a-amino a-alkyl-a-amino acids.s2Addition of a thiol to 4-benzylidene-2-methyloxazolone, ollowed by routin ollowed routinee work-up work-up,, gives a threolerythro-mixture of N-acetyl S-(p-methylbenzy1)-P-phenylcysteinemethyl ester.s3 A novel variant of the oxazolone oxaz olone procedure is represented in the converconve rsion of a 4,4-bis(isopropylthio)oxazolone into amides or peptides, and its chlorinolysis (S (SO O$&) $&) to giv givee halogenoglycine halogenoglycin e derivatives that are easily converted into in to othe otherr ami amino no ac acid idss throug through h hal halog ogen en s u b ~ t i t u t i o n . ~ ~ These two general methods are essentially glycine alkylation procedures; other routes in this category include alkylation of glycine Schiff bases (phase-transfer catalysed alkylation of PhCH = NCH2C02Me + phenylalanine, mediated by microwave energy),55and energy),55and corresponding corresponding syntheses of leuc leucine, ine, seri serine ne and aspartic acid,56 acid ,56Mi Micha chael el additions additions,, of (R1 (R10) 0)2P 2P(0 (0)CH )CH= CH257 CH257and and a two-step alkylation (by R 1 H = CRCH2Br then y-elimination of Br) to give a-cyclopropylglycines.58 Similar approaches employing N-phena~yl-N-benzylglycine~~ nd N-(a-chloroalkyl)-N-Boc-glycin alkyl)-NBoc-glycine60 e60 as starting star ting materials lead tto o azetidineca azetidinecarboxylic rboxylic acids and higher homologues. The corresponding use of N-oxides of glycine Schiff basess to prepare m-(N base m-(N-hyd -hydroxy roxyamin amino) o) acids,61 acids,61 and of a-amidinoa a-amidinoalkanoates lkanoates (Scheme 2)62 2)62have have a good deal in common, mechanistically. of N-pro The [3,3]-rearrangement N-protect tected ed process glycine that ally ally1 1has este esters rs (19 20)63 exemplifies an alternative glycine alkylation been well studied from the 1960’s. Alkylation of a-ha a-halogenoglyci logenoglycine ne synthons (Scheme 3) is si significantl gnificantly y facilitated by Zn ZnC1 C12, 2, indi indicati cating ng a radical mechanism where the catalyst is both a radical initiator and chelates the substrate.@ Copper(1)-catalysed C1-transfer radical cyclization of N-(alk-3-enyl)-a-chloroglycines gives prolines via 2-aza-5-alken-lyl radicals.65A radicals.65A similar study of the generation of the glycine a-radical formed by stannanes from a-bromo-, -benzyloxycarbonyloxy-, -benzyloxycarbonyloxy-,and and -methoxy-gl -methoxy-glycine ycinederivatives, and its alkanesulfenylation with disulfides, has been described.66Xanthates described.66Xanthates MeO2CNHCH(S2C0Et)CO2Me MeO2CNHCH(S2C0E t)CO2Me similarl similarly y yiel yield d radicals that add to alkenes tto o offerr a valuable new offe new general general amino acid acid ~ ~yn ynth thes esis is.~ .~’’ -Protected a-hydroxyglycine esters are readily substituted, illustrated this year in a preparation of (p-vinylphenyl)glycine.68 a-Acetoxy analogues have been employed in syntheses of ~inyl glyci ne~~ nd propargyl h or no l~ gu es .~ ~

 

Amino Acids, Peptides and Proteins

8

0 ph/B\+JR’ -/

0

iii,iv

R2 Me2N

Me2N

Me2N

(+ epimer at B)

Reagents: i, K+ PhBF3-/Me3 PhBF3-/Me3SiCI; SiCI; ii, KOBU‘, KOBU‘, R2hal; iii, refluxing reflux ing MeOH; MeOH ; iv, ethylenediamine MeOH

Scheme 2

Reagents: i, CH2CH= CH2CH = CHSnBu3, ZnCI2.0Et2

Scheme 3

H3N

IR’ 2

 

I

Amino Acids

9

Isocyanoac etates CNCH2C Isocyanoacetates CNCH2C02R 02R (s (see ee also Ref.255) perform we well ll in aldol additions that show high diastereoselectivity to provide P-hydroxy-a-amino acids.71 a-Ni a-Nitroac troacetate etatess ar are e readi readily ly a alkyl lkylated ated,, Michael addition of al ally ly1 1 acry acrylate late followed by by reductive cyclization giv giving ing N-hy N-hydrox droxy-py y-pyrogl roglutam utamate ate derivative^.^^ Amination processes leading to amino acids constitute an establis established hed group of general methods that have been exemplified this year by some of the oldest variants: reductive amination of a-ketocarboxylic acids using NH3/Raney and of methyl (1S,2R,3R)-3-hydroxy-2-methoxycyclohexanecarboxylate; lat e;74 74 amm ammono onolys lysis is or me meth thyl ylam amin inol olys ysis is of tt-but butyl yl b r ~ m o a c e t a t e , ~nd ~ the correspo corr espondin nding g process wit with h diethy diethyll bis(2-methylthioethyl)malonate.76 Addition of ammonia, primary amines, or hydroxylamine to substituted fumaric acids leads to corresponding aspartic acid analogue^,^' and corresponding Michael addition of N-acylisoureas (formed from a carbodi-imide and a carboxylic acid) to methyl hydrogen maleate to give give N-carbamy N-carbamylaspartic laspartic acids.78 acids.78 Fur Further ther examples (see Vol. 26) of the formation of cyclic hydrazino-acids through cycloaddi cycl oaddition tion of dien dienes es to azod azodicar icarboxyl boxylates ates,, hav have e be been en p ~ b l i s h e d ’ ~see also Ref. 199) 199).. Conden Condensatio sation n of a primary amin amine e (T (TiC1 iC14) 4)with with a y-chloro-a y-chloro-a-ketoester -ketoesterto give a y-ch y-chloroloro-a-imi a-iminoes noester ter is fol followe lowed d by cyclization to give a 1 amino-2,2dialkylcyclopropanecarboxylic acid.80 Several examples of azidation, of enolatessl and of a-methoxyacrylonitriles (giving a-azidonitrates),82have a-azidonitrates),82have been described as stages in a-amino acid syntheses. Diazonium salts are electrophilic a-aminating agents towards esters in the form of their ketene si sily lyll ketals, yi yield elding ing a-azo a-azo-- o orr -h -hydra ydrazono zono-este -esters rs whic which h o on n hydrogenation yield a-amino acid esters.83Use esters.83Use of an alkyl sulfenimine R2S = N H as aminating agent towards a latent nucleophilic carboxy group equivalent has been g giiven a pr prel elim imin inar ary ya s s e ~ s m e n t . ~ ~ Amination through Stevens rearrangement of transient ammonium ylides formed between amines and diazoketones diaz oketones or diazoesters gi gives ves a-aminoketo a-aminoketones nes o orr a-amin a-a mino o esters esters,, rrespe especti ctivel vely, y, in on one e step.85 Amidocarbonylation - he introduction of both amino and carboxy groups in a one-pot process - has be been en illustrated in an N-acetylgl N-acetylglycine ycine synthesis (paraformaldehyde, CO, and H2, with cobalt-phosphine catalyst),86 the distantlyrelated equivalent process fr from om aaldehydes and CHC1catalyst),86and 3 continuesand to be stud studied.87 ied.87 Introduction of the carboxy function into a protected amine, to lead to the corresponding correspond ing a-amino acid, can be accomplis accomplished hed in certa certain in cases, e.g. e.g. by the oxidation of a phenyl group (CsH5- -+- C 0 2 H ) using R u O ~ . ~ ~ ‘Modificationss to an amino ac ‘Modification acid id side-chai side-chain’ n’ could be described as a general method of amino acid synthesi synthesis, s, although examples of this approach constitute a somewhat miscellaneous collection and are mostly located later in this Chapter (Section 6.3 6.3). ). However, an inte interesting resting set set of pr procedures ocedures for the alkylation of the dehydro-alanine derivative methyl 2-acetamidoacrylate)tricarbonyliron(O), has been described,89 leading to PbP-tri-alkyl amin amino o ac acids ids throu through gh succ successi essive ve treatment with 2 eq MeLi an and d an alkyl halid halide e ((se see e also Vo Vo1. 1.25 25,, p.9). Contraction of a p-amino ac acid id b backbone ackbone could also be described as a general synthesis synt hesis meth method od for a-am a-amino ino acids, and further furth er ex examples amples (se (see eV Vo o1.24, p.8) of th the e conversion of a-keto-&lactams into a-amino acid N-carboxylic acid anhydrides

 

Amino Acids, Peptides and Proteins

10

Reagents: i, Et2AICN; ii, 6M HCI, HCI, reflux Scheme 4

Reagents: i, PhCH2NH2, PhCH2NH2,K2 K2C0 C03, 3, CH2C1 CH2C12, 2, .t. 40 h; ii, NaOMe/ MeOH Scheme 5

+

L-aa NHOSiMe3

Reagents: i estab establishe lished d methods; ii, Me3SiN Me3SiNHOSiMe HOSiMe$CH2C1 $CH2C12, 2,22 "C, 18h

Scheme 6

epimer

 

I : Amino Acids

11

have been accomplished by Baeyer-Villiger oxidation,g0 a process that is applicable to homochiral substrates, leading to j3-alkylserine N-carboxylic anhydridesg1The anhydridesg1 The method has been also been illustrated in a synthesis of (R)-a,pdi-am diamino ino-y-y-hyd hydrox roxyac yacid id N-c N-carb arboxy oxyli licc anhydr anhydride idess ffrom rom p - l a ~ t a m s . ~ ~ 4.2

Asymmetric Synthesis of a-Amino Acids - Activity in this area continues to

increase, both in the provision of new methodology and in the development of established methods, including well-known standard general methods of synthesis, some of which which are described in the preceding section, and an d revisited here in ‘asymmetr ‘asy mmetric ic ver version sions’. s’. Two thorough reviews cover the overall topicg3vg4and topicg3vg4and another review deals with asymmetric asym metric synthesis of ‘2,3-methano’-amino ‘2,3-methano’-amin o acids (i.e., (i.e., 1 aminocyclop aminocycloproropanecarboxylic acids).95 Modifications of standard general methods of a-amino acid synthesis are represented in a Strecker procedure employing a chiral ketone as catalyst for the equilibration of aminonitriles R1R2C(CN)NHCHRCN,96 R1R2C(CN)NHCHRCN,96 and in an equivalent process using homochiral sulfinimines (illustrated for the (Ss)-configuration in Scheme 4).97 Amination reactions incorporating kinetic resolution (Scheme 5),98 and rela related ted hydroxylamination (Scheme 6),* illustrate further further standard methods. Several examples of the alkylation of glycine derivatives can be grouped together: Michael addition of MeCH(CN)C02Me to vinyl ketones or acrolein catalysed by a Rh(1)-chiral phosphine complex, giving (R)-RCOCH2CHZCHMe(C Me (CN) N)C0 C02M 2Mee in 8383-93 93% % e. e.e. e. and thence t o (R)-a-methyl-a-amino acids through routine elaboration; loo stereoselective alkylation of glycine Schiff bases Ph2C= NCH2C02But NCH2C02Butusin using g active methylene compounds compound s an and d a (-)-cinchoni (-)-cinchonidinedinederived chiral catalyst;lol aldolization of glycine with PhCHO, catalysed by supramolecular supramolecu lar bilayer assemblies assemblies containing L-alanine-lipid L-alanine-lipid peptides with pyridoxal and a nd Cu(I1) salts, to give give (S)+-phenyls (S)+-phenylserine erine in modest enantio enantiomeric meric excess; o2 alkylation of (-)-menthy1 N-acetyl a-bromo a-bromoglycine glycine by allyltrimethy allyltrimethylsilsilane catalysed by ZnC12 to give S)- +)-norvaline after hydrogenation (see also Scheme for r a synthesis ofglyoxalate (-)-menthy1 (-)-menthy+ 1 N-acetyl a-hydroxy a-hydroxyglycine glycine research 3);lo3 group grou pfo using ((-))-me menth nthy1 y1 MeCONH2, see Ref. 104. by this Addition of a glycine enolate to the carbonyl group of a-D-ribohexofuranos-3ulose gives the corresponding (S)-a-(glycos-2-yl)glycine.o 5 The asymmetric benzylation of the carbanion from (-)-menthy1 hippurate and similar glycine derivatives carrying chiral auxiliary groups, although thoroughly researched over many years, was recently found to be unsuccessful when only one equivalent of base is used.lo6 In a b broad road study, tthe he diastereoselectiv diast ereoselectivity ity of this proc process ess was shown to be dependent upon the amount of additives and the nature of the N-acyl group and of the chiral ester. Alkylation of homochiral glycinamides gives generally good diastereosele~tivity.~~~ -Boc-2-(tert-Butyldiethylsilyloxy)pyrrole is a glycine equivalent that underges aldol addition to homochiral aldehydes (Scheme 7) to give a-(polyhydroxyalky1)-a-amino cids. o* Further conventional approaches are described for phase transfer-catalysed Gabriel synthesis employing employing (-)-b (-)-borny ornyll a-bromoalkanoates a-bromoalk anoates (optical purities from

 

Amino AcidF, AcidF, Peptid es and Pro teins

12

1.7-47%);lo9 rather worse results are obtai 1.7-47%);lo9 obtained ned in this reaction with various heterogeneous phase-transfer catalysts.' l o Th The e conversion of lithiu lithium m (1 S,2R,4R)0-dicyclohexylsulfamyliso hexylsulfamylisobornyl-2-cyano-3,3-diphenyl propanoate into PP-di10-dicyclo phenyl-a-methylalanine phenyl-a-meth ylalanine (2 1 2) involves a Curt Curtius ius rearrangemen rearrangement. t. A related approach for a synthesis of (S)-3,4-dichlorophenylalanine' 2 is completed by a subtilisin resolution (see Section 4.17) in view of the disappointing optical purity of the product of the synthesis. Photochemical amination of chiral silyl enol esters (23 in Scheme 8) has been illustrated illustrate d in a synthesis of erythro-P-methyl-L-phenylalanine.3 The Schollkopf S chollkopf bis-lactim ether synthesis continues in use (se (see e also Ref.260) for the asymmetric synthesis of 2-amino-3-methyl-4-phosphonobutanoic cids,' l4 3fluoro-4-nitro-L-phenylalanine,' bicyclic lactams,' l 6 and (2S,3R)-3-methylglutamic acid. Alkylation of L-valine-derived piperazine-2,5-diones (24) ollowed by hydrolysis leads predomi predominantly nantly to (S)-a-amino acids. l 8 The S-configuration is induced by the chiral grouping in the substrate, during the hydrogenation of N-formyl-(Z)-dehydro-PBP-trifluorobutyrine -)-menthy1 ester (25 26).l19 The other main interest in the asymmetric hydrogenation of dehydro-amino acid derivatives over the years has concentrated on achiral substrates, and on the development of improved asymmetric hydrogenation

'

'

-,

catalysts. A clear enhancement of enantioselectivity (e.e.'s of L-amino acids up to 99%) accompanies the incorporation of electron-donating aromatic substituents in vic-diarylphosphonites derived from carbohydrates, as the chiral moiety in a Rh(1)-chiral phosphine catalyst. 2O The role of the protecting groups in cinnamates subjected t o this procedu procedure re h has as bee been n assessed.1 assessed.12' 2' The main focus of development of synthetic methodology continues to be the use of heterocyclic chiral auxiliaries, most of which have been favoured for several years now. Predominantly (2R)-syn-P-substituted serines are formed (d.e. 84100%) when the Ni(I1) complex of the Schiff base of N-benzyl-L-proline 0 benzoylanilide is aldolized by m-fluorobenzaldehyde or by a fluorine-substituted alkanal. 122 Alkylation of th the e Schi Schiff ff base using alky alkyll halides123 llustrates the approach employed by by this research group ffor or many years, though they have now established aldolization the Schiff base (27) by aldehydes efficient (better th than an 90%ofe.e .e. .) alte alchiral tern rnat ativ ive e ro rout ute e to ssub ubst stit itut uted ed ~ e r i n e to s . 'be ~se ~an of this synthon in a synthesis of the photoactivatable 4 -( 1 azi-2,2,2-trifluoroethyl)L-phenylalanine L-phenyla lanine has been descr described ibed as extreme extremely ly efficient efficient.. 25 N-Acryloyl and -crotonoyl-camphorsultams can be used for the synthesis of stereodefined aziridineaziridine-2-carboxylic 2-carboxylic acids th through rough bromination, dehydrob dehydrobromiromination, and aminolysis stages.126Construction stages.126Construction of a cyclopropane ring on the well-known aminoalkenyl synthon R*-CH = C(NHZ)C02Me [R*-CH is the S ) glyceraldehyde glyceralde hyde moiety] an and d subsequen subsequentt processing gi gives ves (1S,2R)- 1-amino-2-vinylcyclopropanecarboxylic cyclopropanec arboxylic acid (alias y5-dehydro-allocaoronamicacid).127 The use of chiral N-acyloxazolidinones in various contexts (see also Ref.64) continues to give excellent results, illustrated in the synthesis of (-)-pyrimidoblamic acid (Scheme 9) the early stages being based on [4 + 21-cycloaddition of 2,4,6-tris(ethoxycarbonyl)- 1,3,5-triazi 1,3,5-triazine ne to 1 (dibenzylami (dibenzylamino)no)-1-propyne);128 P-branched phenylalanine~;'~~ r y p t ~ p h a n s ; ' ~nd ~ c@-dimethyl-l,2,3,4-tetrahy-

 

I

Amino Acids

13

iii,iv

/ BocNH

protected 4-epi -polyoxamic acid Reagents: i, 0 O sop rop ylide ne -(R -2,3-d ihydro xypro pan al, SnCI,, Et20; ii, KMnO,, CH,CI,; iii, LiO H, TH F, th the e n NaIO, NaIO,;; iv, NaIO, NaIO,,, R u 0 2

Scheme 7

NC

KOH/MeOH then

Me02CNHXCHPhl

Curtius rearrangement

NHC02Et

-

eoYYPh I

TBDMSO

e

Reagents: i, ethyl azidoformate, hv

Scheme 8

Me

0

Me

 

14

Amino Acids, Peptides and Proteins Me

Qi:6”””.

OKNBZ

H

NHBoc CO,Et

rNdCONH2

I

I

Me

Me

I

Me

Reagents: i, C0,Et

- HO + Boc-Asp derivative;

iii, Bu3SnH hen HCLEtOAc

Scheme 9

Me ii

Evans Sn” enolate;

 

1: A mi min o A c i h

15

droisoquinoline-3-carboxylic cids;'

homoserine analogues (using the alte alternarnative Karady/Seebach oxazolidinone appr~ach);'~~ nd (2S,3S)-threoninol and related compounds using the (R)-glycidol-derived oxazolidinone (28). 133 Homologous chiral heterocycles u used sed in similar ways ways include oxa oxaziridines ziridines [reaction wit with h copper(1) salts to give products of N-centred radicals leading to cis-5-benzyl-Dp r ~ l i n e ] . ' is-4,5-Disu is-4,5-Disubstituted ~~ bstituted oxazolidin-2-on oxazolidin-2-ones es are epim epimeriz erized ed aatt C-5 via a N / C-5 di-anion. 135 Piperainones carrying a homochiral N-substit~ent'~~ rovide a new ne w variant of the well-est well-established ablished imidazolidin-5-one. imidazolidi n-5-one. An alternative to the oxazolidinones oxazolidin ones is the lactam (28; -CH -CH22- in place of ring -0- ,hown to be a useful chiral a~xi1iary.l~~-Acylated 5-substituted 3,3-dimethyl-2-pyrrolidinones created crea ted in in this study study have have bee been n used used in in illustrat illustrative ive asym asymmetr metric ic s y n t h e ~ e s . ' ~ ~ Routes based on recently-developed variants include the synthesis of yhydroxy-a-amino hydroxy-a-am ino acids, ill illustrated ustrated for ( + )-bulgecinine, based on aldolization of the Cr(0)-modified Cr(0)- modified acyloxa acyloxazoli zolidino dinone ne (Scheme 10; see Vo1. Vo1.26 26,, p. 16 16), ),"" a high highlylydiastereoselective aldol reaction of a Cr(0)-complexed benzaldehyde derivative starting a synthesis of (29), an analogue of the N-terminal amino acid of nikkomycin B,I4l synthesis o off (2S, (2S, 1'Sy2'S)-2-( 1'Sy2'S)-2-(carboxycyclo carboxycyclopropyl)glycin propyl)glycine e from the serine-der serine-derived ived oxazolidine oxazolidin e (e.g. (e.g. compound 107),142 nd a sy synthesis nthesis of (2s (2s)-N)-Nbenzoyl 2-t-butyl-4-methylene-oxazolidin-5-one Vo1,26, p. 16) for use in asymmetric synthesis, synthesis , by bromina bromination tion (Br2/hv) of the L-alanineL-alanine-derived derived heterocycl heterocycle, e, then dehydrobromina dehydrobromination tion (NaI)y143 nd synthesis of (2R73S)- and (2S73R)precursors (3 (30 0 an and d epimer, epime r, respectively; respectively; Scheme 11) illustrated for syntheses o off p methyl analogues of protein amino acids (Phe, Tyr, and His analogues; see also Vo1.26 Vo1 .26,, p. 13). 144 Alkylation of new heterocyclic 'chiral glycine derivatives' prepared from glycinamide (Scheme 12) follows the oxazolidinone philosophy, 145 and hydrogenation of homochiral3-ethyl-5-phenyl-3,4-didehydroorpholinones (see Vo1.26, p. 16) has led t o (R)- and (S)-2-aminobut (S )-2-aminobutanoic anoic acids from 2-oxobutanoic 2-ox obutanoic acid.'46 Particular examples, illustrating illustratin g new new synthons syntho ns that tha t aare re capable of being used in asymmetric syntheses more generally, have been reported; thus, the furan-2-one synthon (31), obtained from D-glucosamine, has been used in a synthesis of 147 4-hydroxy-L-pipecolic 4-hydroxy-L-pipecolicacid, acid,periodate and an d D-glucosamin D-glucosamine has been used used in aispreparatio preparation n of Boc-L-serinal through cleavage. 148eD-Mannosamine a starting material for a synthesis of sphingofungin D (7; Scheme 13).149Kinetic resolution induced by L-( + )-di-isopropy )-di-isopropyll tartrate ta rtrate accompanies ButOOH/ ButOOH/Ti(OiPr)4 Ti(OiPr)4 oxidation of a-furanylamines a-furanylami nes (3 (32 2 33 + 34) and ozonolysis of the residual L-afuranylaminee leads to the furanylamin the N-tolueneN-toluene-p-sulfonyl p-sulfonyl L-amino acid. Unconvention Unconventional al asymmetricc synthesis of amino acids features asymmetri features a homochiral a-amino a-a mino acid aass chiral auxiliary to generate an enantiomer of y-hydroglutamic acid,lS1 ring-contraction' ring-contraction' of 5-isonitroso-2,2-dimethyl-l,3-dioxan-4,6-dione hrough refluxing with ketones via a nitrosoketene (Sche (Scheme me 1 14) 4),, cycloaddition cycloaddition to t o alkenes and routine el elaboration aboration yielding L-a-amino acids,' 52 while ring-expansion is involved in a Coxoproline synthesis from a homochiral azetidinonecarboxylic azetidinon ecarboxylic acid (Sche (Scheme me 15). 15). 53

Synthesis of Protein Amino Acids and Other Naturally Occurring a-Amino Acids - This section continues the coverage of a-amino acid synthesis, showing 4.3

 

Amino Acids, Peptides and Proteins

16

R

h

OnPh xN& i

R

xNTR

rT

h

0

Cr(co),

+ diastereoisomer Reagents: i, BuLi, RCHO; ii, hv, CO[-Cr(CO),] Scheme 10

p -MeO-C,H,

AcO(CH& Me

Toyo NHAc

Me

Ph

Ph

Reagents: i, MeMgBr-CuBr.SMe2; ii, NBS Scheme 11

Reagents: i, LDA/THF,-78 "C; ii, RX; iii, TFNCH2C12 hen 0.2M HCI Scheme 12

 

17

I : Amino A c i h

I

( R -1,2-epoxyoctane

Me(CH2)5 iijii

\

RO Me(CH,),

A

CH+ NHAc

sphingofungin D 7) Reagents: i , 1 -heptyne, BuLi, BF3.0Et2; ii, Li, BU OK, H,N(CH,)3NH2; iii, Et02C-N = N-CO, N-CO,Et, Et, Ph 3P, PhC 0,H then TB SC I; iv, Bu3SnH, AIBN then then I ; v , synthon from N acetyl-D-mannosamine, CrCI2/NiCI2/DMSO; vi, routine steps Scheme 13

 

Am n o A cids, P ep tides and Proteins

18

o

..

-

O X 0

...

11,111

-0

R3

R

Reagents: i, R COR , reflux; ii, R3CH =CH2; aHC0 C0 3, then the n H2h0/O Pd-C iii, -amino acid by aq. N aH

-

Scheme 14

COZBZI

pLOc

0-

I

0-

0

J ii

Reagents: i, Me2SOCH2,DMSO; i, HX; iii, ML,(cat.)

Scheme 15

J

iii

COzMe NH

Reagents: i, TolSCH2N02, hen MeSOZCI, ii, Bu'COOK; iii, NH3 then ZCI

Scheme 16

 

I

Amino Acids

19

applications applicati ons of curre nt methodology f or the synthesi synthesiss of natu ral pr odu cts. Choice of route is usually tailored to the particular synthesis target, though alternative appro aches are occa occasi sional onally ly compared. Th e usual cr op f rom the primary literat literature ure dealing wit withh aspects of fermentative production of the common amino acids [L-lysine using Corynebacterium glutami~um;'~ -aspartic ~ acid using using intact co ryneform Brevibac Brevibacteri terium um fIavum M J233;'55 L-threonine using Brevibacterium l~ctofermentum;'~~-phenylalanine methyl ester ester from me thyl tr trans-cinnamate ans-cinnamate using phenylalanine am m on ia lyase;' lyase;' 57 L-DOPA using a cell suspension culture of Mucuna p r ~ r i e n s ; ' ~ *nd D-amino acids from enzymic hydrolysis of hydantoins by whole cells of Agrobacterium r ~ d i o b a c t e r ' ~ s~ ]supplemented by reviews [production of amino acids using genetically-engineered Serratia marcescens marcescens;';'60 60 using am inopeptidases an d aminoamidases;16' noamidases ;16' using hydantoinases; 162 L-aspartic acid using using immobilized m icroo r g a n i s m ~ ; ' ~n d~ L -D - D O P A uuss i n g ttyy ro ro ssii n e p hhee n ooll l y a ~ e ' ~ ~ etails ]. of routine studies of the biosynt biosynthesis hesis of am ino acids in plants have no t been collected collected in this Chapter over the years, though there has been the custom to mention unusual studies, e.g. e.g. the enzymic synthesis of P-substituted alan ines in plants,'65 an d of 5hydroxy-4-0x0-L-norvaline in S treptomyces akiyoshiensis. 66 A new synthesis of D-alloisoleucine from (S)-2-rnethylb~tanol'~~ ompares favourably with two standard procedures, viz. inversion at C-2 of L-isoleucine and racemization of N-acetyl-L-isoleucine and resolution with hog acylase. New syntheses o f protected D-threonine and L-allo-threonine'6g employ a lit little tle-used -used general method of a-amino acid synthesis (Scheme 16). Extraordinary syntheses of L -glutamic acid acid and L-a-am inoadipic acid'69 use chiral equivalents of cyclopentadienone an d cyclohexadienone respective respectively ly (Scheme 17). Th e labor ato ry synthesis synthesis of 'MeBmt', the threonine derivati derivative ve present in cyclosporin, has been reviewed.' reviewed.'70 70 A new synthes synthesis is iinn fou r ste ps'7 1 from (22,4R)4-methyloct-6-yn-2-en-1-01Sharpless epoxidation and ring-opening with M eN H 2 are the essenti essential al step steps) s),, offer offerss an improvement on the heroic multist multistage age first synthesis o f M eBm t (see Vol. 17, p.8). A synthesis of 2-amino-4-hydroxy-3,3dimethylbutyric acid (alias pantonine) from 3-chloro-2,2-dimethylpropanol, 7 72 2 P-hydroxyhomoserine P-hydroxyhomoseri ne (an intermediate in mugeneic aci acidd syntheses) in constituent 12 steps173 from cis-2-butene- 1,4-diol, (2S,3R)-2-amino-4-hydroxyadipic cid (ain of theonellamide F) by asymmetric reduction of the corresponding P-ketoester obtained from L-aspartic acid,'74 quisqualic acid from L-ser L-serine ine vi viaa the G ar ne r aldehyde (107, R = H ; -C H O -+ - C H = N O H -CH2N(OH)CONHC02Et, e t ~ ) , ' tizolobic ~~ acid through a biomimetic route starting with a catechol aldehyde, 176 and the alicyclic relatives anticapsin and bacilysin starting with a Diels-Alder adduct of dehydroalanine with O-TMS-cyclohexadienol,177 In the last-mentioned study, independent confirmation is provided that the previously announced stereochemistry of anticapsin requires revision revision [i [itt has the (S)-conf (S)-configiguration at C-4; see Vo1.26, p.41. Construction of the side-chain of arogenic acid, (yS)-b-( 1-carboxy-4-hydroxy-2,5-cycloexadien- 1 yl)-L-alanine, is conveniently achieved through Michael addition of the anion of methyl 1,6dihydrobenzoate to methyl N-acetyldehydroalaninate. 178 Further exploration of routes to vancomycinic acid acid precursors (35)' (35)'79*'80 79*'80 nd polyoxamic acid (36; a synthesis involvi involving ng -

 

20

Amino Ac ids, Pepti Peptides des and Proteins

/CH2

H2T

i-iv

H02C

1

/CH-NBzl H02C

Reagents: i, -CH=CH

-

CH2-CH2-;

ii, BzlNH2; iii

NaBH,;

iv, NaIO,,

Scheme 17

OMe

'2

-

+ -02c 3N*0H

OH

RuCI,

 

I : Amino Acids

21

-C6H5 + -C02H)181 has been reporte reported. d. The same metho method d of generating a carboxy group appears in a synthesis from a-aryl-P-alanines, o off 2'-deoxymu 2'-deoxymugineic gineic acid and nicotianamine.Is2 Complex synthetic targets are also represented in cilastatin (37), constructed from L-cysteine, 7-bromo-2-oxoheptanoic acid, and ( + )-(S)-2,2-dimethylcyclopropanecarboxylic acid.Is3 The synthesis o off several otherr cyclo othe cycloprop propanes anes [trans-a-2-(carboxymethyl)cyclopropyl]glycine from Blighia unijugata, synthesized by dibromocyclopropanation of (38) prepared from Dserine;IX4 ll four f our stereoisomers of carnosadine carnos adine (39; (39; a set of constrained arginines, see Vo1.26 Vo1.26,, p. 19); 19);'85 '85 1 R,2S)- and (1 S,2S)-dehydrocoronamic acids from dimethyl 2-vinylcyclopropanedicarboxylic acid (selectively hydrolysed by successive treatment with two esterases with different regioselectivities) hen routine iintroducti ntroduction on of the amino group through the Curtius rearrangement'86] have been described. Full details (see Vo1.25, p.21) of a synthesis of (2S,4R)- and (2S,4S)-diastereoisomers of hypoglycin A have been described, incorporating a Sharpless epoxidation epoxidati on stage in aan n asymmetric methy methylenecyclopropan lenecyclopropanee synthesis.1 8 7 (2R,3S)-3-Hydroxylysine (2R,3S)-3-Hy droxylysinehas been synthesized through Hayashi's chiral ferroceno-gold catalysed ox oxazoline azoline formation formati on from 4-phthalimidobutan 4-phthalimidobutanal al and an d methyl isocyanoacetate, and the (2S,3R)-enantiomer through a route incorporating a Sharpless cis-hydroxylatio cis-hydroxylation.188 n.188 Total synthesis of the azctidinecarboxylic acid derivative, mugineic acid (40, = H; equally correctly described either as a P-hydroxyornithine derivative or an a-hydroxy-GABA derivative) (see Vo1.25, p.23)Is9 and its 3-epi-hydroxyderivative (40; X OH)'90 involve a common com mon intermediate (41) (41).. The lat latter ter report also describes the synthesis of distichonic acid A an and d 2'-hydroxynicotinamin 2'-hydroxynicotinamine. e. Naturally-occurring proline derivatives of continuing interest, the kainoids kainoids and bulgecinine, have been synthesized by new routes. Condensation of glyoxal with the (R)-phenylglycinol derivative (42) proceeds via a cyclic iminium ion that undergoes tandem aza-Cope-Michael reactions en route to (-)-a-allokainic acid.I9l A six-step route to DL-kainic acid (43 in Scheme 18) uses a similar reaction sequence to set up the ring system with the correct relative stereochemi ~ t r y . ' urther ~ ~ details have been published193of published193of a synthesis of (-)-a-kainic acid X

employing a ring construction step group based has on reported the Pauson-Khand Vo1.26, p.24) and the same research an effectivereaction synthesis(see of a-allokainic acid (Scheme 19).194 9).194A A short, efficient route to 4-arylkainoids starts with trans-4-hydro~y-L-proline.'~~ adical cyclization of a protected L-serinal 44) s at the heart of an elegant synthesis of (+)-b~lgecinine,'~~ lso reached through reduction of appropriately substituted 2-amino-4-oxoalkanoic acids (45; somewhat capricious stereoselectivity is involved in the reduction).'97 Clavalanine Clavalanine and erythro-4-hydroxyornithinewere also prep prepared ared from the same starting material in this study. A route to (S)-(-)-pipecolic acid (46 47) employing the chiral oxazolidine approach is also capable of extension to the synthesis of 2- and 6-alkyl analogues. g 8 'PCA', an unusual hydrazino acid that is a constituent of the Luzopeptins, has been synthesized by the condensation of di-t-butyl azodicarboxylate with the dianion of (Me0)2CHCH2CH(OH)CH2C02Etsee also Ref.79).'99 --+

 

Amino Acids, Peptides and Proteins

22

HO

APh (41)

MeOC ( C H 2 ) 2 0 B ~ ' C H ) 2 0 ut ___

RLo Ph

 

I

23

Amino Acids

O

N

R CO2Et

Z

Re ag ents ; i, Et3 N, Me CN , r.t., the n SnBu, SnBu,H/A H/AIB IBN, N, ZCI; ii, Me Li, TiC CI,I,; iii, BF 3.E t2 0; iv, oxid ative ring -op en ing (RuO, RuO,//NaI NaIO, O,)); v, CH2= pp h3 or CH212 CH212/Z /Zn; n; vi vi,, separate diastereoisomers then OH-, ion exchange exchange Scheme 18

CO2Et

Reagents: i, MeCOCH =CH,;

ii, CH2=PPh2 Scheme 19

44)

(+)-bulgecinine

 

24

A m n o Acid s, Pep ides and Proteins

4.4 Synthesis of a-Alkyl Analogues of Protein Amino Acids - The synthesis of hom ochiral examples of known abs olu te configuration of this clas classs of substi substituted tuted a-amino acid has been considered to be a difficult enterprise, but the extraordinary fact that a configurationally-stable anion can be generated from N-Boc-N-methyl-L-phenylalanine sing Li 2,2,6,6-tetramethylpiperidide opens the do or to a-alkyl analogues analogues.200 .200 Th e conventi conventional onal ap proa ch, a-m ethyla tion of a Schi Schiff ff bas basee of a protein am ino acid, is illustrated in a synthesis of a-methylhomocysteine (Scheme 20).201 a Allylation of pipecolic acid and ensuing steps yield the a-(2-alkoxycarbonyl)ethyl analogue.202The analogue.202 The hydantoin route is often inappropriate, because of the drastic conditions condit ions need needed ed to rele release ase the am ino acid, bu t 3-(toluene-p-sulfonyl)hydantoins carrying adenine and thymidine side-chains are easily hydrolysed to give the corresponding am ino acids, in dilu te alkali alkali a t sli slightly ghtly elevated elevated temperatures.203 Grignard addition to fluoroacetonitrile followed by routine stages gives a fluoromethylglutamic acid, whose cyclization leading to the glutamate racemase inhibitor, aziridinoglutamate, aziridinoglutamate, h as bee beenn worked The need fo r resol resolution ution is avoide avoidedd in the chiral oxazoli oxazolidinone dinone ap pro ach , use usedd for a synthesis of (S)-2-methylpr0line,~~~ lthough the oxazolidinone hydrolysis step th at com pletes the pro cedure ca n be simpli simplified. fied.206 206 (S)-a-2-Am inoethyl-

methionine has been obtain ed in 1 8 % yield from the 5-(methylthioethyl)oxazolid in in oonn ee,, t h rroo u g h e n ol o l a ttee a llkk yl y l aatt i oonn w it it h B rrC CH2C CN N a n d ro u ttii n e e l a b ~ r a t i o n . ~ ~ ’ Stereoselective alkylation of isobornyl 2-cyanopropanoate is exemplifi exemplified ed with syntheses of a-methyl-L- and D-tryptophan208and D-tryptophan208and a-methyl-D- and -L-phenylalanine.209 ap-Di-alkylaspartic acids are readily obtained via p-lactams prepared from Schif Sch ifff bas bases es A rN = C R C 02 M e and ke kete tene nes. s.*I *I00 4.5 Synthesis o f a-Amino Acids Carrying Alkyl Side-Chains, and Cyclic Analogues - W ith the proviso th at ‘us ‘usee of on e a-am ino aci acidd f or the synthesis of another’ is covered in the later Section 6 . 3 (Specific Reactions of Amino Acids) papers collected here deal with approaches to aliphatic synthetic targets from

other starting points. (S)-2-Aminosuberic acid has been prepared from (E)-CH2 = CH(CH2)5CH = C H C H 2 0 H through asymmet asymmetri ricc epoxidation, ring-op ring-openi ening ng wit withh benz benzhydr hydrylylamine, and oxidative cleavage.21 Other amination processes include Curtius rearrangemen t (diphenyl (diphenyl ph osp ho roa zid ate) of selectivel selectively-hydrol y-hydrolysed ysed 2,22,2-dial dialkylkylcyclopropane- 1, l dicarboxylic acid esters,212 esters,212 and ringring-clos closure ure of 2,5-dibromoadipic acid acid (R )-p ant ola cto ne esters using benzylamine to giv givee transtrans-pyrrolidinepyrrolidine2,5-di 2,5-dicar carboxyl boxylic ic acids. acids.213 213 1,2-t 1,2-transrans-Placi Placing ng of NH 2 and O H in a 172 -trans relati rel ationsh onship ip o n cycl cyclopent opentadi adiene ene (AcO OH th then en N H3 /M eO H) and Candida antarctica resolution starts a route to (2$,3R)-3-hydro~yproline.~l~ n unusual synthesis of 3-phenyl-3-hydroxyproline ro m a n N-benzoylethyl-N-toluene-ps u lfo lfonn yyll g ly ly ccii n aami midd e i n vvoo llvv eess p h ot ot o ch c h eemi mi ccaa l c y c l i z a t i ~ n . ~ ~ ~ Carboxylation of 4-(hydroxymethy1)pyridine through reaction of its 0-trimethylsilyl-N-oxide with Me3SiGN and saturation of the ring leads to the 4-substituted piperidine-2-ca piperidine-2-carboxyli rboxylicc acid.216 Hyd rogenation of dimethyl

 

1: Amino Acids

25

H0,SCH2CH2,

ii, iii

(MeS)2C=N

M ,e

H3ilC'CO2H 0

Br-

0

Reagents: i, base, MeI; ii, aq. HCI; iii, Br2, H 2 0

Scheme 20

CH2Br

CH,Br

I

e0 2C N= CC0, CC0,Et Et

I

Me02CNHCC02Et

I

C02Et -

OCH2CFCH

Reagents: i, HOC H2C E C H , (P (PPh Ph,) ,),,Pd/CuI Pd/CuI;;

ii, Bu3SnH/AIBN

Scheme 21

NHC02Me

 

26

3,5-pyridinedicarboxylate rovides a 1:

boxylic acids.217

Amino Acid s, Peptides and Proteins

cis-trans mixture of piperidine dicar-

4.6 Models for Prebiotic Synthesis of Amino Acids - Conventional studies under this heading con tinue muc h a s tthey hey have do ne fo r many year years, s, repr represe esente ntedd by C02/CO/N2/H20 mixtures subjected to electric discharge (giving 6 protein amino acids, glycine predominating, and 2 non-protein amino acids when CO is abu ndan t),218 nd by 6oCo y-irradia y-irradiated ted aque ous gly glycin cinee (Asp, Ser, Th r, an d G lu, and MeNH2 + EtNH2 formed from reaction of a glycine radical with glycine breakdown brea kdown pro ducts).219 Current speculation, that deep oceans were the sites of the origin of life, is helped by confirmation confirmation (hy dro the rm al synthesis synthesis;; Vol. 25, p.34) of the generation of am ino aci acids ds from C2H2/H20/02/H2/(NH4)2C03mixtures a t 200-275". 200-275".220 220

Synthesis of a-Alkoxy a-Amino Acids, and Analogous a-Heteroatomsubstituted a-Amino Acids - Asymmetric synthesis of (R)-a-sulfenylglycine has been achieved by the reaction of MeSSMe with 2-hydroxypinan-3-one Schiff bases.221 Fmoc-a-Methoxyglycine Fmoc-a-Methoxyglyci ne has bee beenn prepare preparedd by addition of Fmo c-carb am ate to

4.7

gl glyox yoxyl ylic ic acid, acid, then then 0-m ethyla tion by M eO H /H .222 Ano dic a-methoxylation of a-am ino aci acids ds has become a ro utine step iinn m any synthetic app lications (nota bly, substitution by alkyl groups), and illustrated with asparagine and serine derivat i v e ~n d~ p~r 0~1 i n e . ~ ~ ~ Independent studies were aimed at the provision of anomeric tetrahydrofuranosyl am ino acids an d pyranosyl analogues (Sch (Scheme eme 2 1)22 1)2255 (Sch (Scheme eme 22)226 within the context of analogues of the herbicide ( +)-hydantocidin, whose short synthesis synthe sis (see (see Vo1 Vo1..26, 26, p. p.24) 24) fro m P-D-ribofuranosy l amide results fro m fo rtui tou s a -b ro mo P-a P-a m mii d e fo rrma ma t iioo n a n d t re reaa t me nntt w it it h s il ilv er er ~ y a n a t e . ~ ~ ' Several exam ples of the uses in synthe synthesis sis,, of glycine derivatives co nfo rm ing to the title title of this section, ar e cit cited ed els elsewhere ewhere in this C ha pte r. -

Synthesis o f a-(a-Halogeno-alkyl) a-Amino Acids A review has appe ared descri describing bing Uk rainian work on th e synthes synthesis is of fluorine-containing am ino acids acids.228 .228 A wellwell-esta establis blished hed rou te t o PP-difluoroalanine from Z N H C H ( C H F 2 ) C H = C H 2 through oxidation to gener generat atee th thee carboxy group, has been rendered a practical proposition through an efficient synthesis229 of H 2 N C H (C H F2 )SE t . H B r. a-(Fluoromethyl)-P-fluoroalanine, an important intracel cell pH indica tor, can be prepare preparedd in 44% overal overalll yi yiel eldd from 1,3-difluoropropan2-01, through application of standard methods [ 1,3-difluoroacetone -, (FCH2)C (FCH2 )C NC HP hCH zOH (FCH2)CH (CN)NH 2 us usiing TMSCN]. TMSCN].230 230 a Trifluoromethyl-a-amino acids are readily obtainable from imidazolidin-2,5diones (48).231 P-Difluoromethyl-m-tyrosine has been prepared through an uneventful uneventf ul Ev ans oxazolidinone synthes synthesis. is.232 232 (2S,4S)-5-Fluoroleucine has been synthesized from L-pyroglutamic acid through diastereoselective methylation, followed by less stereochemically-demanding steps.233 4.8

 

27

1: Amino Acids

Reagents: i, TfOMe, then Na NaBH, BH, and HgCI2; ii, Ag20 Ag 20 then CH2N2; iii, H2-Pd/C H2-Pd/C

Scheme 22

0e0 x F3C CF3

(48) X = O o r S

(49)

Reagents: Reage nts: i, Sharpless dihydroxylat dihydr oxylation; ion; ii, SO SOCI,; iv, NaN3 and reduction

Scheme 23

iii, NaIO4/RuC NaI O4/RuCi3; i3;

 

A m n0 Acids, Pep ides ides and Proteins

28

trans-4-Fluoro-L-pipecolic acid and the 4,4-difluoro-analogue have been prepared from di(ethy1amin di(ethy1amino)sulfur o)sulfur tetrafluor tetrafluoride ide and the oxazolidinone (49)’ available from L-aspartic and (2R,5R)-5-chloropipecolic acid has been obtained by elaboration of the readily-available N-methoxycarbonyl S ) - 5 -

TBD M S oxy- 2- 0xo- p i p e r i d i n e . ~~~ Examples of side-chain halogenation of amino acid derivatives are to be found in the later Section 6.3, though it could be noted here, that 4-alkyl-5-ethoxyoxazoles azol es (easil (easily y pr prepared epared from N-acylamino acids) are useful substrates for perfluorination.236 Synthesis of a-(a-Hydroxyalkyl) a-Amino Acids - Hydroxylation of alkenes leading to hydroxyalkyl side-chains is represented in a number of different strategies. Where the a-amino acid moiety is in place, as with L-vinylglycine 1,2-dihydroxylation ation using Os04 yields [CH2= CHCH(NH2)C02H], then 1,2-dihydroxyl hydroxythreonine stereo~pecifically.~~~ n a similar approach, 1 aminocyclohexene- 1 -carboxylic acids, formed from 4-arylideneoxazolin-5-ones by Diels-Alder addition to dienes, give iodohydrins that yield y-hydroxy-a-amino acids through reductive dehalogenation and hydrolysis.238Protected hydrolysis.238Protected aspartic asp artic acid enolates provide (3R)- and (3S)-hydroxy-L-aspartates through treatment with

4.9

electrophilic hydroxylating agents.239 electrophilic Grafting the a-amino acid moiety on to a hydroxylated structure is illustrated new w synthesis of C-or-D-g C-or-D-glucosyl-a-a lucosyl-a-amino mino acids star starting ting with a protected 1in a ne allyl- 1 -deoxyglucos -deoxyglucose, e, then Sharpless epoxidation, selective mesylation, tritylation tritylation,, and azid azidolys olysis is and routine elaboration.240 elaboration.240A A similar approach leading to (2S, (2S,3S)3S)and (2R,3R)-3-hydroxyleucine (Scheme 23) also succeeds because of favourable regio~ electivity.~ercury(I1) ~~ oxide oxidation of D-glucosamine gives D-glucosaminic acid, and straightforw straightforward ard replacement of the 3-hydroxy grou gr oup p b by y H, giving (2S,4S,SR)-4,5,6-trihydro~ynorleucine.~~~ onosaccharide-derived azidolactones continue to serve (see Vol. 26, p.33) as starting materials for tetrahydroxy- 1-aminocyclop -aminocyclopentaneentane- an and d cyclohexaneca cyclohexanecarboxylic rboxylic acids with unambiguous control o off ste re o~ he mi st ry .~ hreo-3-Hydroxy-L-glutamic ~~ acid244and acid244 and (2S,3R)3 - h y d r o ~ y o r n i t h i n e ~ave ~ ~ been prepared through a high highly ly stereoselective iodocyclocarbamation of the chiral alkene (50) obtained from 0-benzyl-L-serine.

4.10

Synthesis of a-(a-Amino-alkyl) a-Amino Acids -- The synthesis of isoxazolidin-5-ones, and their use in the synthesis of fl-amino- and p-(Nhydroxy1amino)-alanines, has been described.246Substitution of aminating agent for hydroxylating agent in a process described in the preceding section239has section239has been bee n successful in lea leading ding to (3R)- and (3S)-amino-L-aspartates.

4.1 1 Synthesis of a-Amino Acids Carr Carrying ying U Unsatu nsaturate rated d Al Aliph iphati atic c Si de ch ai ains ns As usual, there is interest in each of the categories covered by the heading of this Section: the ap-unsaturated-a-amino acids, alias ‘dehydro-amino acids’, are constituents of natural peptides, while they and their homologues (vinyl- and allyl-glycine) allyl-gly cine) are ar e inc increasingly reasingly valuable in synthesis. Protected dehydroalanine is easily formed from serine derivatives, treatment of

 

I:

29

Amino Acids 0

Bz NHC02E

OR

RO

(51

(52)

 

30

Amino Ac ids, Peptides and Proteins

Z -Se r(0 r(0 T ss)O )O E t w iitt h B u 4 N I/ N a O H b ei ei n g c uurr rree nntt llyy re ~ o m m e n d e d . ~ ~ ’h e potassium salt of N-acetyl a-(diethylphosphony1)glycine condenses readily with aldehydes, aldehyde s, exemplif exemplified ied in th e synthesis synthesis of de hy dro -am ino acids car carrying rying lon g side chains, (E)- o r ( Z ) - E t 0 2 C C ( N H A c ) = CHCk2(CH2),C02Me.248 N-Acyl-2,3dehydro-2-amino acid esters result from perrhenate-catalysed decomposition of a-azido acid esters in solution in org an ic solvent solventss con tain ing an acyl chloride.249 A general synthesis of ap-dehydroamino acids from a glycine derivative is exemplified exemplif ied with the pre par atio n a nd hydrolysis of 4-alkylaminom ethylen e t h i a z o 1 -5 -0 n e s . ~ ~ he h~e reaction sequenc sequencee from th e aldehyde ((51) 51) form ed from D-arabinose and L-serine, to the highly functionalized dehydroamino acid (52) postulated to be a constituent of azinomycins, includes a Wittig condensation w i th a g l y c y l p h ~ s p h o n a t e . ~ ~ ~ An ap-dehydroamino acid with an extended side-chain, methyl (-)-(Z)-2-(Zamino)-4,5-cyclopropane-hex-2-enoate as been been prep prepare aredd through m anipulation of functional groups on 5-(t-butyldimethylsilyloxy)furan-2(5H)-one.252A more routine routi ne ap pro ach to suc h syste systems ms is Michael addition to a protec protected ted dehy droa lanine, nin e, which offe offers rs conve convenient nient acces accesss to (Z)-d ehy drotry ptop hans throu gh PdC1 PdC12/ 2/ NaO Ac-A cOH catalysed reaction with indoles (s (see ee al also so Refs. 177,l 78).253 Synthesis of a-Amino Acids with Aromatic or Heteroaromatic Groupings in Side Chains - Increa Increasing sing int interes erestt in th e therapeutic therapeutic use of com m on am ino acids

4.12

capable of neutron capture when carrying appropriate substituents has encouraged studies in the synthesis of organic boron derivatives (see also Refs.9, Refs .9,868) 868).. Sta nd ard m ethod s have been applied applied fo r the synthesis of 0 n d mborono-L-phenylalanines. Grignard reaction of 0 and m-bromotoluene with B(OMe)3 and functionalization so that alkylation of diethyl acetamidomalonate can be carried ou t, was foll followed owed by a-chym otrypsin resolution.254 resolution.254p-Borono-DLp-Borono-DLphenylalanine and -DL-phenylserine were prepared by aldolization of methylisocyanoacetate using the aldehyde (53). (53).255 255 A seri series es of pa pe rs h as appeared, describing the synthesis of phenylalanines substituted in the phenyl moiety by carboranyl groupings. One of these starts with methyl p(54), and react bromobenzoate p-(HC H4CO 2 M e+ phthalimidomalonate decaborane reaction = C )-C 6with 5 5 ) .ion 256 of the derived via benzyl bromide diethyl Other stan dar d m ethod s a re represented, represented, e.g. e.g.257 257 the elabo ration of an all ally1 chainn carryi chai carrying ng a carbo ranylp hen yl grouping, into the acyl gro up of a chiral N-acyloxazolidinone cf. Sectio n 4.2). 5-Fluoro-D - and L-DO PA s and ‘*F-anal ‘*F-analogues ogues hav havee bee beenn pre prepare paredd starting from 5-nit 5-nitrovanil rovanillin, lin, throu gh the ac etam idom alona te route an d Balz Balz-Sch -Schieman iemannn substitution of a diazonium group by fluorine, followed by chromatographic resolut res olution ion.25 .2588 6-F luoro -L-D OP A a nd its 3-0 -m ethyl derivat derivative ive have also been obtained obtai ned by sta nd ard synthetic synthetic methods. methods.259 259 Homochiral bis-amino acid diary1 ethers exist in natural products, and 0 arylation of tyrosine derivatives employing fluoroarenes has been established using suitably suitably mild reaction conditions.260 Simple heteroaromatic side-chains are represented in P-(2-pyridyl)-L-alanine, prepared from 3-(2-pyridyl)acrylic acid through catalysis by L-phenylalanine

 

1: Amino Acids

31

ammonialyase (present in Rhodotorula rubra mycelium);261 nd in the pyrimidine isostere (56) of the potent NMDA antagonist, SDZ EAB 515,262 ynthesized by alkylation of Ph2C = NCH2C02Me.~-Isoxazol-4-yl-L-alanines re potent potent NMDA agonists, and further synthetic studies (see Vo1.25, p.38) have been described of homologues (57 and 58),263 AMPA and 4-methylhomoibotenic acid have been prepared through cycloaddition of suitably substituted bromonitrile oxides to alkynes.264Resolution alkynes.264 Resolution using (-)-phenylethylamine and absolute configurational assignment by by X-ray crystal analysis is is included in one of these prepar preparations. ations.263 263 A related alanine derivative that carries a P-he P-heteroc terocyclic yclic moiety is the neurallyactive quisqualic acid. Conformationally-constrained analogues have been synthesized, using st stan andar dard d methods.26 methods.265 5 The homochiral aa-ami amino no acid (59) carrying a thiazoline side-chain was obtained by a novel manipulation of the penicillin nucleus.266 P-Substituted tryptophans (see also Refs.129-131, 144, in Section 4.2) have been obtained by Lewis-acid catalysed ring-opening by indoles, of the aziridine (60). Opposing regioselectivities are observed; the lactone 61, from 60, RR' = 0 leads to p-amino acids, and the acetsl (60, R = H, R' = OTBDMS) yields (62) from which P-substituted tryptophans were obtained.267 obtained .267 rythro-P-Alkylated tryptophans can be obtained by conjugate addition to (63) formed from the tryptophan derivative (64) that Crich's research group has been establishing as a valuable synthon in recent years.2683,4-Bridged years.2683,4-Bridged tryptophans (65) are, likewise, obtained starting from tryptophan itself, via 4-bromodehydrotryptophan and cyclization of the derived 4-brom0-a-propenyl-DL-tryptophan.~~~ ther 3,4cyclized tryptophan analogues formed with the a-amino group through an isoleucyl isole ucyl bridge2 bridge270 70 ar aree members of a famil family y of conformat conformationally ionally constra constrained ined amino acids that includes potential protein kinase C modulators. These analogues support a wide range of pharmacological studies that reflect the importance of derivatives of the parent amino acid, and the fact that N-ethylL-tryptophan benzyl ester is a weak antagonist at the Substance P(NK1) receptor has stimulated the synthesis of indole-substituted analogues [N-acetyl-L-(3',5'-ditrifluoromethy1)tryptophan was found to be particularly effective] by standard me meth thod ods. s.27 271 1 Anfrom effi effici cien entt ssyn ynth thes esis is of 5 - a ~ i d o t r y p t o p h a n ~mploys ~~ a standard route, starting 5-nitroindole. Synthesis of a-Amino Acids Carrying Sulfur- or Selenium-containing Side Chains - This class of amino acid is gaining further importance, since certain sulfur functional groups react with nitric oxide. L-Thiocitrulline (readily prepared from L-ornithine) and its S-methyl derivative, an and d Lhomothiocitrulline, homothiocitrullin e, ar aree potent inhibitors of nitric nitric oxide synthase, and an d presumab presumably ly owe this property t o their structur s tructural al similarity with arginine analogues.273 analogues.273 Conventional synthetic strategies are involved in the synthesis of S-alkyl-L~ y s t e i n e s *see ~ ~ also Ref.53) and of the conformationally conformationally-constrained -constrained L-methionine (66) obtained by elaboration of the Diels-Alder adduct of 5-norbornen-2-01 with a protected d e hy dr ~ a l a ni n e . ~~ ~ L-( + )-Selenomethionine has been prepared from L-homoserine lactone and MeSeLi.276

4.13

 

Amino Acids, P eptides and and Proteins

32

oCH2C02H

HO2C#:Y

PhtN

c02-

 

1: Amino Acids

33

4.14 Synthesis of a-Amino Acids Carrying Phosphorus Functional Groups in Side area s of interest in compo compounds unds of this clas class, s, as distant isosteres o off Chains - Main areas some common amino acids, are being sustained by current research (see also Refs.99,114), e.g. into the synthesis of (R)-4-oxo-5-phosphononorvaline, H203PCH2COCH2CH(N+H3)COi- (a selective NMDA glutamate site antagonist) in four steps from D-as D-aspart partic ic Stereosele Stereoselective ctive synthesis of L-phosphinothricin [MeP(0)(OH)CH2CH2CH(NH2)C02H], present in the herbicide ‘glufosinat ‘glufosinate-ammonium’, e-ammonium’, has be been en reviewed. reviewed.278 278 The mdifluoroalky1)phosphonate analogue of phosphoserine has been synthesized starting from O-benzyl-N-B~c-L-serine.~~~ -(Z-Amino)-5-(Boc-amino)pentylphosphinic acid, an isostere of lysine, has been synthesized from 3,4dihydr0-(2H)-pyran.~~O Phosphonate-bridged Phosphonate-bri dged phenylalanin phenylalanine e derivatives (67) that are capable of selective de-protection so that they can be incorporated into peptides have been synthesized from the corresponding p-iodo-L-phenylalanines (an improved synthesis of this amino acid has been worked out), through Pd-catalysed coupling.281 The phosphonotyrosine isostere N-Fmoc-4-phosphono(difluoromethyl)-L-phenylalanine, has been prepared from the organozinc reagent from P-iodoalanine together with the requisite iodoarene,282an iodoarene,282and d independently ffrom rom the methyl ester of its die thy lph osp h~n ate .~~ ~ -Boc-(4’-dimethylphosphonomethyl)-L-phenylalanine (68) has been obtained through a route that employs the iodarene-organozinc reagent C-C-bond-forming methodology.284

4.15 Synthesis of Isotopically Labelled Amino Acids

All the familiar isotopes featured under this heading over the years are represented in the current literature. 2H-Labelled protein amino acids, intended to assist biosynthetic studies, often call for the most ingenious synthetic strategies, as illustrated by (2S,4S)- and (2S,4R)-[5,5,5-2H3]1eucine. he route starts from (R)-pulegone -, [2-2H]citronellal -+ [5,5,5-2H3]i~~valeric cid (through de-carbonylation using Wilkinson’s catalyst followed by oxidation), then follows standard steps.285 Labelled aziridines (69; prepared from labelled malates, starting with fumaratesl -

fumarase or by enzymic amination) serve as starting materials for syntheses of stereospecifically-[2H]-labelled D-serine, D-cystine, and P-chloro-D-alanine, through nucleophilic ring-opening ring-opening.286 .286 Synthesis of labelled D-(prop-2yny1)glycine (70) fo foll llow owss an id iden enti tica call stra strate tegy gy us usin ing g a ca carb rban anio ion n as n ~ c l e o p h i l e . ~ ~ ~ Regiospecific labelling of the aromatic ring in phenylalanine is achieved by treating a protected tyrosine tetrazolyl ether ether o r its 0- r m-isomer m-isomer,, wit with h 2H2 2H20. 0.28 288 8 The development of established methods (see Vol. 26, p.38) allowing the preparation preparatio n of 2H-L-glutami 2H-L-glutamic c acid, an and d 2H-, I3C- and 15N-L-glutamicacids, 15N-L-glutamicacids, on a gram scale from 2-oxoglutaric 2-oxoglu taric acid, includes several points of interest; e.g e.g.. the involvement involveme nt of glutamate dehydrogen dehydrogenase ase wi with th 2 2H2 H2 0 as solvent, for C-3- and C-4labelling, an and d exch exchange ange a t CC-4 4 b by y equilibration in 20% 2HC1-2H20 2HC1-2H20.289 .289 related approach to 13 13CC- and 15N-L-alanineusing alanine dehydrogenase, and to other 15N-L-a-aminoacids, 15N-L-a-amino acids, includes full experimental C-Labelled amino acids are accessible only through super-rapid methods of synthesis (and equipment ensuring the safety of operators), due to the short

’

 

34

Amino Acid s, Peptides and and Proteins

half-life of the isotope, but this requirement has not only been met satisfactorily over recent years, but with sufficient leeway to permit purification to be included in the cycle. Thus, a 45-minute process (including HPLC purification) serves for the preparation of [P- 'C]-p-chloro-L-phenylalanine rom 4-Cl-C&4-* 'CH2Br and the Li enolate of a chiral imidazolinone (see Scheme 5 , Section 4.2) followed by hydrolysis.29 hy drolysis.291 1 The special reactivity of th the e L-tryptopha L-tryptophan-derived n-derived bis(Nmethoxycarbonyl)hexahydropyrrolo[2,3-b]indole (64, cf. Ref. 1 37) allows rapid alkylation by 11CH31en route to [a- CH3]-L-tryptophan CH3]-L-tryptophan and its NN-carboxylic carboxylic anhydride.292The anhydride.292 The use of the Anatech RB-86 robotic synthesizer permits rapid synthesis of [1-' 'C]-L -L-t -tyr yros osin ine e from the the ana nalo logo gou us i ~ o c y a n i d e see ~ ~ ~Vol. 19, p.20) and of [CH3-l C]-L-methion C]-L-methionine ine through robot-contr robot-controlled olled methylation of homocysteine l a ~ t o n e . ~ ~ ~ 14C]Methyl-L-tryptophan -tryptophan has bee been n prepared by methylation of the Li a-[14C]Methyl-L enolate of a Schiff Schiff base of an L-tryptop L-tryptophan, han, followed by enzymic resolution.2 resolution.295 95 and by similar processing of the L-tryptophan-derived bis(N-methoxycarbony1)hexahydropyrrolo[2,3-b]indole 64).296The ~t-[~H]methyl-analogueas also prepared in the latter study. The simplest simple st amino acid ssyntheses yntheses leading to labelled glycin glycines, es, amination of [13C]bromoacetica [13C]bromoacetic acid esters with B o c ~ ~ ~ N nd - carboxylation K ~ ~ ~ ~ of BocNMeCH2SnBu3 with 14C0 14C02 2after lithiation with MeLi,298are MeLi,298are typical of numerous syntheses of labelled protein amino acids over the years, a further example be being ing 15N-[2H3]acetyl-L-asparticcid as a standard for isotope dilution GC-MS analysis of N-acetyl-L-aspartic acid in urine.299The urine.299The glycine isotopomers were used for spectroscopic assignments.297 ['sF]-Labelled amino acids, e.g. P-[18F]fluoro-alanine300rovide useful substrates for in vivo drug delivery delivery and similar diagnostic studies studies,, a popular substrate being 6-['*F]fluoro-L-DOPA, whose 3-0-methyl derivative has been prepared by fluorodestannylation of the corresponding stannylated DOPA.301 synth esis of L-[35S]cystein L-[35S]cysteine e nd -methioSaccharomyes cerevisiae mediates the synthesis nine from Na235S04.302 Aromatic iodination iodin ation of tyrosine, b by y either the Chlorami Chloramine-T/12 ne-T/12 or analogo analogous us Iodogen methods, is a standard preparation of 2,5-di-iodotyrosine7and 2,5-di-iodotyrosine7and has been applied for [ 251]-labelling 251]-labellingof of ~ t - m e t h y l - l - t y r o s i n e . ~ ~ ~ 4.16 Synthesis of P-Amino Acids and Higher Homologous Amino Acids Extraordinary growth of interest in this topic is evident in the current literature. The driving force, apart from the usual mechanistic interest in novel bondforming processes, must be the importance of the isolated examples of natural amino acids, amides and peptides wit within hin this category; perhaps also the intuitive expectation tha t ha t many mo more re physiologica physiologically-active lly-active natu natural ral j3 j3-a -ami mino no acids are waiting to be discovered. A major proportion of these studies now concerns stereoselective synthesis, and an d recent work with p p-amino -amino acids has bee been n re revie viewe wed d from this po point int of vie view. w.304 304 Some general methods are extensions of those used for the stereoselective synt sy nthe hesi siss of a a-a -ami mino no aci acids ds,, ssuc uch h as th the e C -5-aldoli~ation~ nd ~ ~C-5-alkylati0n~~~ of six-membe six-membered red chiral perhydropyrimidino-4-ones (Sch (Scheme eme 24 24)) an and d alkylation at

 

1: Amino Acids

35

BzlOpC

-0pc

BocNH

2 H Wmc:

- O p C a \ pH NH3

;;xNbR H

Reagents: i

h Me)/NvNoz

C02Me

NH20H, then ZCVNaOH; ii, (CH20), , TsOH; iii, remove Z, then LiHDMS; NH20H,then iv, Amberlyst H-75; v, LiAIH4, then H30+

Scheme 2 4

 

36

Amino A cids, Peptides and Proteins

C-6 of unsaturated analogues (71),307 addition of chiral imines [ S ) PhCHMeN = CHR to (E)- or (2)-a-silyloxyketene acetals mediated by chiral boron reagents,308or reagents,308or -CH2C02Me o ( + )-(S)-p-tol )-(S)-p-tolylS(0)N ylS(0)N CHP h to gi give ve (R)addition tion of the highly syn-stereoselect syn-stereoselective ive 3-amino-3-phenylpropanoic cid,309 addi nitrogen nucleophile (R)-PhCHMeNLiCH2Ph to alkyl cinnamates (72 + 73)3 o and anti-addition to cr~tonates;~'he cr~tonates;~'he reasons ffor or high stereoselectivity in the latter approach have b bee een n discussed.312 h he e adducts can be further alkylated wi with th excellent stereoselec stereoselectivity, tivity, and an e example xample of this is included in the novel establishment of an asymmetric Michael addition of a homochiral magnesium amide (R)-PhCHMeN(MgBr)CH2Ph.313further example of a synthetic target that has been achieved through asymmetric Michael reactions is (2S,3R)-2methyl-3-aminopentanoic acid [(R)-PhCHMeNLiCH2Ph + t-butyl (E)-2-methylpenten-2-0ateI.~4 Amination of ethyl 2-methyl-4,4,4-trifluoroacetoacetatesing benzylamine and appropriate appropria te further steps (including peni penicill cillin in acylase resolution - he (R)-enantiomer is most readily hydrolysed) forms the basis of a synthesis of all four stereoisomers of a-methyl-~-trifluoromethyl-j3-alanine.315 he [ 1,3]-proton shift at the heart of this process can be biased by (-)-cinchonidine to give enantiomerically-enriched (R)-j3-fluoroalkyl-fI-amino acid derivatives (up to 36% e.e.).316A e.e.).316A similar approach is ssee similar een n in the addition of benzylam benzylamine ine to ethyl (R)-tran (R)-trans-4,5-0s-4,5-0isopropylidene-4,5-dihydrox isopropyliden e-4,5-dihydroxy-2-pentenoate y-2-pentenoateScheme 25),3 7 and in the addition of phthalimide salts to imides of chiral imidaz~lidinones.~'An imidaz~lidinones.~'An interesting alkylation process N02CH2CH2C02But + N02CH[CH(OH)CH2F]CH2C02But uses 2-fl~oroethanol/COCl2.~~~ -(0-Hydroxypheny1)-p-alanines are available through tth he addition o off (Me3Si)2N-Li to c o ~ m a r i n s . ~ omochiral ~~ N-diphenylamino-3-amino-1,2-diols nylamino-3-amino1,2-diols formed by aminolysis of epoxyalka epoxyalkanols nols ca can n be converted into j3-amino acids via ally la mine^.^^^ Reductive dimethylamination of ap-unsaturated ap-unsatu rated acids has be been en described.321P-Amination of 3-hydroxycyclobutanecarboxylate esters through treatment with carbonyldi-imidazole and sodium azide involves involves an acy acylnitrene lnitrene insertion step.322 Nucleophilic addition to imines (PhCH = NS02R + BrZnCH2C02But -+ H2NCHPhCH2C02H)323 H2NCHPhCH2C02H)3 23 and the related process with N-acyl-a-m N-acyl-a-methoxyethoxya r n i n e ~llustrate ~~~ one general approach to p-amino acid synthesis, while 1,2-~yanohydroxylationof alkenes by nitrile-imines [EtO,CC = N +N-CH2Ph 3-carboxypyrazolines RCH(CH2CN)NHCH2Ph]325 provides an alternative amination pathway. Hydrogenation of homochiral aziridine-2-carboxylates ver 3 days gives gives P-amino acid esters.326 Further syntheses of N-benzoyl-(2R,3S)-3-phenylisoserinemethyl ester, the derivatized side-chain moiety of taxol, have be been en described, employing conventional synthesis and resolution, while the other incorporates yeast-catalysed reduction to introduce a second chiral centre into (S)-phenylglycine-derived acyl cyanides PhCH(NH2)COCN.328Diastereoselective PhCH(NH2)COCN.328Diastereoselective reduction of N-protected P-amino-a-ketoacids has been achieved, by H2/RuCl/(R)-BINAP for the preparation of L-i~ oserine,' ~nd ~ employing microbial reduction for the preparation of lthough oxazolones offer standard routes to a (2R,3S)-(-)-phenyli~oserine.~~~ amino amin o acids, exploitation of their rreactivity eactivity at C-2 in a j3 j3-a -ami mino no acid synthesis has -

-

 

1 : Amino Acids

37

also been realized (Scheme 26).331This amounts to one-carbon homologation of an aldehyde, also achieved using nitromethane; the ensuing conversion (-CH2N02 + -C -C02 02H) H) involves drastic conditions (12M HC1 HC1,1 ,10O 0O0, 0,46 46 h) but is neverthelesss appropria nevertheles appropriate te for an erythro-phenylnorstatine synthesis.332 Examples of the extension of standard practice in the a-amino acid field are: alkylation of p-alanine carrying two chiral auxiliary groups, viz. N-(hydroxypinany1idene)-P-alanine ny1idene)-Palanine (-)-menthy1 (-)-menthy1 ester;333hydrogenation ester;333hydrogenation (H2/Pd) of 3-aryl-2-aminomethacrylic esters BocNiPrCH2C(= CHA CHAr) r)C02 C02Me Me give givess racemic p-amino acid esters.334An esters.334 An asymmetric Diels-Alder approach gives the fused-ring didemnin analogues (74).335 reland enolate-Claisen enolate-Clai sen rearrangement rearrangemen t of p-alanine ally ally1 1 esters, (E)- and (Z)-RCH = CHCH202C CHCH202CCH2CHzN CH2CHzNR' R' R2, leads tto o a-alkyl-&am a-alkyl-&amino ino acids (75 and 76). 76).336 336Alkylation Alkylation a- to the carboxy group of a @-aminoacid @-aminoacid derivative through the aldol route allows versatile chain extension.337 Amidiniomycin (77) has been synthesized from norbornylene via meso cisdicarbomethoxycyclopentane; the route depends on enzymic discrimination between enantiotopic ester groups for its success.338A success.338A synthesis of (2S,3R)-3amino-2-hydroxyalkanoic acids by amination of (78) may require a broader study if, as claimed, it is to t o be accepted as a 'general' 'general' synthetic route.339 Syntheses star starting ting with an a-amin a- amino o acid include Wo Wolf lfff rearr rearrangement angement of the diazomethyl ketone derived from an N-protected a-am diazomethylketone a-amino ino acid340 followed b by y diazo-transfer diazo-transf er and oxidation (dimethyl dioxirane) to give N-protected p-amino a keto-esters without racemization. Homologation, through the Wolff procedure, of protected L-arginine gives dipeptides when irradiation is performed in the presence of an amino acid ester.341One-carbon ester.341One-carbon homologation of a-amino acids, by their conversion in into to 2-(2-aminoalkyl)thiaoles followed by hydrolytic thiazole cleavage and further elaboration cf Scheme 22, Ref. 226) has been demonstrated to give give a-hydroxy-&amino a-hydroxy-&amino aldehydes and an d Schmidt rearrangement r earrangement of cis cis-- 1-carboxy-2-carbomethoxy-bicyclo[2.2.1heptene gives gi ves the corresponding corres ponding p-amino acid ester.343 ester.343 Unprecedented Unprecedente d syntheses of mechanistic interest have been describ described, ed, by which unique p-amino acid targets have been attained (e.g. 79), by ring-contraction of tetra etrahy hyd dro rois isoq oqu uinol inolin ine lk lkaadirect loi oid ds aft aamination fter er l i t h and i a t ialkylation ~ n , ~nd~ (80) from by thehydro2-(pnaphthy1)oxazoline (8e1) aby followed lysis. 45 Ozonolysis of N-ethoxycarbonyl-2,3-dihydropyrroles n methanol gives the corresponding N-formyl-N-ethoxycarbonyl+amino acid methyl esters; the we well ll-known oxidative ring-opening of of 1,2,3,4-tetrahydropyridines o give 5-aminoalkanalss is also ex anal explored plored furt further her in this thi s study study.'.'& & An extension of the amination approach leading to p-amino acids has been established.. A tandem conjugate addition-hydroxylatio established addition-hy droxylation n using S ) PhCHMeNLiCHzPh and [( + )-camphorsulfonylJoxaziridineeads to homochiral 3-amino-2-hydroxyalkanoic cids (82; R = Ph, alias allophenylnorstatine, a component of the HIV-protease inhibitor kyno~tatin);~~~ nd to (83; R = hexyl, alias m i ~ r o g i n i n ) . ~oth ~ ~ (2R73R)- and (2S,3R)-diastereoisomersof the lastmentioned example were prepared, establishing the latter to be the absolute configuration of the natural ACE inhibitor. (3S,4S)-Statine and its isomers are

 

Amino Acids, Peptides and P roteins

38

Reagents: i, BzlNH2; ii,

HP

Pd/C, EtOH Scheme 25

.NHBz

R

OAc for the S,S-isomer)

Reagents: i, Boc-phenylglycinal; ii, Et3N; iii, 6M-HCI, 11 0 C , 1 2 h ; it.,. S 0 C l 2 ; v , BzCI; vi, Pseudornonas fhorescens, vinyl acetate Scheme 26

 

39

I : Amino Acids

0

OMe

H

NH

-

O K N H

(79)

/N

 

40

Amino Acids, Peptides and Proteins Proteins

Ph P

h ZN

4

R d

p

Ph\ Ph N

d R

OAc

ii

P

N h

zp/-o.. F

R d

(+ epimer as minor product) Reagents: i, DIBALH; ii, AqO; iii, ii i, C CH H, =C(OM =C(OMe)O e)OTBD TBDMS, MS, ZnBr ZnBr,, Scheme 27

 

I

Amino Acids

41

easily prepared by aldol reactions of a protected L-leucinal, and a highly diastereoselective diastereosel ective rout route e has bee been n established employing diethylalumin diethylaluminium ium enolates derived from [q-C5H5]Fe(CO)(PPh3)(COMe), o give the intermediate (84).350 Simple alternative routes, addition of lithi lithiated ated me methoxyallene thoxyallene to an N-Boc-aminoalkanal followed by ozonolysis [BocN(CH2Ph)CHiPrCH0 -+ (2S,3S)-nor~tatine],~~~ miBocN(CH2Ph)CHiPrCH(OH)C(OMe) C = CH2 nation of aldols ~-Boc-aminoalkanal/PhCH2C02Hdianion] with Ph3P(0)N3 and an d ring-opening o off the resulting di diastereoisome astereoisomeric ric 4, 4,5-disubstitu 5-disubstituted ted oxazolidin2-0nes,~~ nd~ azide ring-opening of the appropriate homochiral 2,3-epoxyalkanol an ol,, giving statine and its 3 - e ~ i m e r , ~ re~typical ~ of routes established over recent years. A further fur ther statine sy synthesis nthesis involves the use of a homochiral oxazinone (Scheme 27) that is alkylated in an unusual way.354Similar way.354Similar alkylation of N-p N-protected rotected N-a N-a-amino acid carboxylic anhydrides (NCAs) uses Meldrum’s acid (Scheme 28); reduction of the resulting resultin g tetramic acids g giv ives es statine analo analogues.355 gues.355 Synthesis of y- and higher homologous amino acids is studied for much the same reasons that motivate efforts in the a nd p-amino acid area: the provision of authentic samples of biologically-important amino acids and their analogues, and also the growing interest in dipeptide and oligopeptide isosteres th that at 6-amino -

acids and higher homologues represent. ‘Conformationally-constrained y-aminobutyric acid’ (GABA) is one way of describing the spirobicyclic condensation product (85) of 2-(N-benzylimino)cyclopentanecarboxylic acid with dibrom ~ e t h a n e . -erythro-a ~~~ P-dihydroxyG P-dihydroxyGABA ABA an and d y-erythroni y-erythronine ne have been prepared through oxidative degradation of 4-aminopent- 1-ene-2,3-diols formed fr from om pe pent ntaa-1, 1,44-di dien en-3 -3-0 -01 1 by Sha Sharpl rpless ess epo epoxid xidati ation on foll follow owed ed by a m i n a t i ~ n . ~ ~ ’ Since dolaisoleu dolaisoleucine cine t-butyl ester formed from the a aldol ldol adduct from 2-N-methy 2-N-methyllL-isoleucinal L-isoleucin al and t-b t-butyl utyl glyoxylate is identical with the nat natural ural y-amino acid acid,, the assigned.358Dolaproine, Dolaproine, a y-amino acid from 3R,4S,SS)-stereochernistry can be assigned.358 (-)-dolastatin 10, has been assigned the (2S,2‘R,3’R)-stereochemistry hrough examination of the product from a corresponding route from the Boc-L-prolinal/ (S)-HOCPh (S)HOCPh2CHP 2CHPh02C h02CEt Et aldol adduct, ver verifi ified ed by X-ray crystal analysis.359An alternative route to natural dolaproine reli relies es on preferential antianti-addition addition of (Z)crotylboron reagents (86) to homochiral N-Boc-aminoalkanals (Scheme 29).360A simplified route to E/Z-y-amino acid esters Me02CNHCHRCH = CHCO,Et, through a one-pot partial reduction (DIBALH) to the aldehyde and homologation wi with th (EtO)2P(O (EtO)2P(O)CHLiCO )CHLiCO2Et, 2Et, has been described.3 described.361 61Both enantiomers of 4aminohex-5-enoic acid (vigabatrin) have been prepared in this way, starting with N-Z-L- or -D-methionine methyl ester and concluding with reduction of the double bond and introduction of the terminal alkene group through oxidative elimination of methanesulf methanesulfinic inic Wittig reactions of MeC( = PPh3)C02Me (or the corresponding phosphonate) with a-Boc-alaninal gives a 2: 1 anti anti/syn /syn-mixture of 2-methyl-4-aminopentanoiccid derivatives after catalytic hydrogenat i ~ n . ~ ~ ~ A variety of routes exist, to lactams of various ring sizes, although their cleavage to give a-amino acids can be problematical. A study of N-acylated lactams from this point of view has established the use of toluene-p-sulfonic acid

 

Amino Acids, Peptides and Proteins

42

Reagents: i, Meldrum Meldrum's 's acid, acid, NEt3; ii, A , AcOEt; iii, NaBH,;

iv, NaOH, aq. acetone

Scheme 28

t

,OH

Reagents: i, THF, r.t.

Scheme 29

N Ts (87)

CO,Me NHTs

 

I : Amino Acids

43

in methanol for the purpose.364 Oxidation of N-Tro N-Troc-piperidine c-piperidiness with Ru RuC1 C13/ 3/ N a I 0 4 an and d hydrolysis under unsp unspecif ecified ied conditions gives 5-aminoalka 5-aminoalkanoic noic acids.365Pyrrolidin Pyrrolidin-2-one -2-one ring opening is the final stage in a synthesis of 4-amino2,2-dimethylbutanoic 2,2-dimethyl butanoic Diastereosele Diastereoselective ctive alkylation of S-lactams carrying a chiral N-substituent has been established.367 A rout route e to &-amino acids has be been en establishe established, d, exemplified by regioselective addition of alkylcopper reagents to each of the four stereoisomers of the Ntoluene-p-sulfonylaziridine 87).368Analogues [(2R,4S)-5-amino-4-hydroxypentanoic acids] of a particular natural example of this family o f amin amino o acid have bee been n synthesized from L-glutamic acid via the silylated a-hydroxymethyl-lactone (88).369 a-N-Boc-Aminoald a-N-Boc-Aminoaldehydes ehydes yi yiel eld d &-amino y-hydroxy y-hydroxyacid acid de derivatives rivatives through condensation wit with h ally allylic lic bromides,3 bromides,370 70 as do corresponding met methyl hyl ketones through reaction with a-brom~alkanoates.~~~ itsunobu amination of an allylic alcohol with phthalimide is a step in a route to a 6-aminoalkenoic acid.372

4.17 Resolution o f DL-Amino Acids - Active development of existing methodology, especially in topic areas under the heading of chromatographic resolution, would be an accurate description of current research. Analytical aspects (determination of enantiomer ratios by chromatographic and related means) are mostly covered in Section 7, and configurational assignments achieved achi eved through synthesis strategies are covered in earlier Sections. Classical laboratory procedures for the resolution of amino acids are represented in diastereois diastereoisomeric omeric salt formation with homochiral sulfonic The procedure is usefully complemented by salicylaldehyde-mediated racemization, illustrated by a preparation of D - p - h y d r ~ x y p h e n y l g l y c i n e . ~-Salicylide -Salicylidene~~ ne- and pyridoxylidene-DL-amino acids have been resolved analogously, through chromato ma togr grap aphy hy o off d de eriv ived ed dias diaste tere reoi oiso some meri ric c co copp pper er ~ h e l a t e s . ~arfey’s ~~ reagent can be used bo both th to generate diastereois diastereoisomeric omeric derivatives an and d to assign absolute configuration to individual enantiomers, for example to micri~ystins.~~~ se has been made of the different rates of condensation of ( + )-2-hydroxypinan-3-one with Schiff bases of DL-amino acids, to enrich samples with a particular enantiomer, to the extent of complete resolution in certain cases.377Examples cases.377Examples of the resolution of higher homologous amino acids in this way are relatively rare, but vigabatrin enantiomers (see preceding Section, Ref.362) have been secured through acylation of 5-vinylpyrrolidin-2-one wit with h (R) (R)-P -PhCH hCHMeC MeC 02H and subsequent crystallizat crystallization.378 ion.378 Resolution of DL-amino acids through preferential crystallization of one enantiomer i s underpinned by idiosyncratic physical solid state behaviour; thus, L-phenylalanine L-phenylalani ne crysta crystals ls added to a DL-glutami DL-glutamic c acid sample favour tthe he crystallization of the L-enantiomer L-enantiomer,, but all attempts failed to achieve the corresponding result using D- ~h en yl al an in e. ~~ -Hydroxyproline -Hydroxyprol ~ ine assi assisted sted the resolution of DL DL-allothreonine in analogous fashion.380Spontaneous resolution under racemizing conditions in prebiotic times was probably not of major importance, either for the origin of enantiomeric imbalance or for the amplification of an any y microsc microscopic opic imbalance.38

 

44

Amino Acids , Peptides and Proteins Proteins

A widening widening range of bo both th enzymes and an d non-protein DL-amino acids is being represented in resolution studies. The possibilities have been explored for the use of pronase with non-protein amino acid methyl esters,382Asperg illus niger lipase for kinetic resolution of pipecolic acid methyl ester,383Candida cyli cylindracea ndracea lipase ~ with a z i r i di ne c a r bo ~ y l a t e s, ~ipases for a-vinylglycine a-vinylglycine after reduction,385 hiol 2 an amino proteases with Z-amino acid methyl esters,386 ubtilisin Carl~berg,~~.’ acid amidase from Mycobacterium neoaurum with a,u-disubstituted a-amino acid a m i d e ~ ,ecanoyl-a-chymotrypsin ~~~ with N-dodecanoylamino acid p-nitrophenyl esters388mmobilized esters388 mmobilized Aspergill Aspergillus us ory zae aminoacylase with N-acetyl-p-chlorophen ~ l a l a n i n e ~nd~ ~for continuous column resolution of N-acetyl-DL-methionine,3w and an aminoacylase from Streptovercillium olivoreticuli or penicillin acylase from E.coli for preparative-scale resolution of 0 nd p-fluorophenyl p-fluorophenylglyglycines.391Novel procedures procedure s have ha ve bee been n studied; one on e feat featuring uring a D-a D-amino mino acid oxidase/aminotransferase/L-glutamiccid system that converts racemic mixtures of common and non-protein amino acids into the L-enanti~mers;~’~ nother using immobilized immobilized enzymes enzymes in a tea-bag method, meth od, with NN-acetylamino acetylamino acid methyl esters in reverse micellar med media;393 ia;393and and another establishing the resolution of Nacylamino acids using alcalase in supercritical supercritical C02.394 Aldolase from Streptomyces amakusaensis catalyses the reverse aldol reaction with (2S,3R)-P-hydroxya-amino acids, and therefore provides enantiomers when applied to the racemates.395 Most of the current research studies of resolution are based on physical principles, particularly involving chromatographic separation over chiral stationary phases (CSP’s). The technique continues to develop rapidly, and reviews have appeared of of Pi Pirkle C S P ’ S ~ nd ~ ~ preparative-scale resolution by this approach.397 approach. 397 Long-estab Long-established lished examples of CSP’S CSP’S are represented in recent papers, including cellulose thin-layer chromatography with a cyclodextrin-containing mobile phase, showing additive contributions to discrimination discrimination leading to large separation factors for trypt~phans.~~~ ovine serum albumin (BSA) achieves the resolution of N-alkanoyl DL-[3H]leucines the D-enantiomer is more strongly retained and separation factors are strongly dependen dependentt upon the solutes 7.0,form in the stationary phase.39 phase.399 9For Fo rbound the free acidsitin at a t pH pin Hthe the L-enantiomer is more strongly to amino BSA when is solutions immobilized of a membrane. membrane.400 400Cyclodextrin Cyclodextrinss can accomplish accompli sh the resolution of DL-ala DL-alanine nine p-naphthylamide.401 p-naphthy lamide.401 New examples exampl es include p-cyclodextrins p-cyclodextrins to wh whic ich h D- o r L-phenylalanine cyanomethyl esters are linked,402 6’-(3-aminopropylamino)-6’deoxycyclomaltaheptaose (which binds L-tryptophan more strongly than p-cyclod e ~ t r i n ) , r~chiral ch ~ iral alcohols immobilized within a po poly( ly(et ethy1 hy1ene ene)) film film (en (enantioantioselective tran transpor sportt of amin amino o acids)404 and an d 4-vinylpyr 4-vinylpyridine-1 idine-1 -vinylimi -vinylimidazole dazole copolyme copo lymers rs impr imprinte inted d wit with h N-Z-L-a N-Z -L-aspar spartic tic acid (see Vo Vo1. 1.26 26,, p. p.49 49). ).405 405 Crys Crystals tals of imprinted D-phenylglycyl-D-phenylglycine ormed from solutions containing N-acetyl-L- or D-leucine ethyl ester are capable of enantioselective binding of these solutes. solutes.406 406 Capillary GLC GL C of N-trifluoroacetyl-DL-amino acid n-butyl esters over L-Phe-tetra-amide CSPs has proved effective in enantiomer ratio determination^.^^ Chromatogra Chromatographic phic resolution on the ligand-exchan ligand-exchange ge principle is represented in the use of copper(II)-6-deoxy-6-(N-histamino)-~-cyclodextrin

 

I : Amino Acids

45

(binding of D-amino D-a mino acids is favoured),M8 he use of copper(I1)- o r nick nickel(I1 el(I1)-N)-Nsubstituted-L-prol substit uted-L-proline-modif ine-modified ied silica gel, gel,40 409 9 an and d a similar use of (R)-2-a (R)-2-aminominoalkanol for chiral modification of stationary sta tionary phases.410 Results obtained obtai ned in ligand-exchangee resolutions using a range of metal salts have been compared,41 ligand-exchang and the routine method employing a chiral mobile phase additive has been studied for the resolution of fluorine-substituted phenylalanines and phenylglycines.41 Permeable membranes have been mentioned in the preceding paragraph, in their role as enantioselective barriers that can form the basis of preparative resolution technology. Membranes to whic which h L-phenylgly L-phenylglycine cine is bonded ar aree more permeable to the D-enantiomer of this amino acid,413and acid,413and hollow-fibre membranes carrying N-( 1-naphthyl)-L-leucine have shown promising enantioselect i ~ i t y . ~ ’iquid ~ membranes are particularly promising in this respect, 5cholesteryl-L-glutamate forming the basis of mixed micelles that preferentially bind the D-enantiomer from solutions of DL-phenylalanine in the presence of copper(I1) ions.415 1,2,4-Triazole-containing holesteryl esters offering preferential transport to D-phenylalanine primary alkylammonium salts.416Chiral salts.416Chiral discrimination is also revealed for Langmuir-Blodgett monolayers containing Npalmitoyl-DL-valine and DL-alanine and N-stearoyl-DL-valine, compared with L - a n a l o g ~ e s , ~y~ ~(cholesteryloxycarbony1)benzo- 8-crown-6 mono layer^,^^^ and by a variety of emulsion liquid membranes;419and membranes;419and several other papers in this Symposium Volume, Ref.419). A promising development is the demonstration of enantiomeric enrichment of derivatized and free amino acids by foamforming ‘chiral collectors’.420 A 44-mer RNA that binds L-citrulline and D- or L-arginine has been reported .42 Speculation surrounding the methods by which DL-amino acid mixtures, generated in prebiotic times, were supplanted by L-enantiomers has shifted towards the consequences of parity-violating phase transition phenomena (BoseEinstein condensation activation),422a activation),422a theory advanced by Salam (see Vol. 24, p.40) that he has recently reviewed.423Many reviewed.423Many of the main protagonists protagoni sts in this field field have theirbetween ideas in Lthisand publication; favouring energypresented differences D-enantiomers o f either a n amparity-violating i no a ~ i d , ~ ~ ~ through chiral interactions a t the ocean-air interface (see Vo Vo1. 1.25 25,, or through ssp pontaneous a m p l i f i c a t i ~ n . ~he ~ ~emergence * ~ ~ ~ of L-amino acids, as a consequence of parity-violating energy diffe difference rencess leading to electroweak neutr neutral al currents, has been reviewed more recently429by recently429by an advocate of an alternative theory (see Vo1.26, p.51). The origin of chirality in amino acids and carbohydrates is suggested to lie in sonically-induced phase transitions; a D- or L,-amino acid will eventually accumulate through sonication of a racemic amino acid.430A acid.430A much earlier idea, encapsulated in the Vester-Ulbricht theory, asserts that enantioselective destruction of the D-amino acids occurs more rapidly, relative to their L-enantiomers, under the influence of inherently asymmetric radiation. This has been reinvestigated to show that tha t DL-leucine bathed in radiat radiation ion from fr om a 22Na weak positron source suffers more rapid destruction of its D-enanti0mer.4~~9~~~ SR

 

46

Amino Acids, Peptides and Proteins

study of D- and L - a l a ~ ~ i nnd e ~of~ D~ and L - l e ~ c i n eegraded ~ ~ ~ with 90Sr-90Y P-radiation P-radiati on shows that irradiati irradiation on generates more radicals in the D-enantiomer, and the Vester-Ulbricht theory is therefore claimed to be given further support. Reviews of origins of chirality and life, giving explanations that make lesser demands o n the reader, have a p ~ e a r e d . ~ ~ ~ ? ~ ~ ~

5

Physico-Chemical Studies of Amino Acids

5.1 X-Ray Crystal Structure Analysis of Amino A cids and Their Derivatives - A pattern that has emerged i n recent years, the revision of earlier data and determination of structures of ne new w compounds compounds,, continue continuess to be represented in the current literature. The fact that X-ray crystallographic instrumentation has become bec ome more sophis sophisticated, ticated, so that th at rresults esults are more reliable reliable,, but also lless ess tedious to obtain, is mainly responsible for the increased activity in this area. Crystal structures for free amino acids have been reported for DL-ala~~ine:~~ LLar argi gini nine ne (as (as its its di dihy hydr drat ate, e, fo form rmat ate, e, an and d form format ate e d i h ~ d r a t e ) , ~-arginine ~~ fluor~borate, ~~ -arginine maleate dihydrate,M L-histidine monoaCetate, -arginine monoaCetate,44' 44' L-histidinium phosphite and a re-investigation of monoclinic L-histidine,a2 and

N-methylglycine mo mono nohy hydr drog oge en p h o ~ p h i t e . ~ ~ Crystal structures of amino acids hav have e bee been n surveyed with particular reference to their propensity towards polymorphis polymorphism.444 m.444 Derivatives that have been subjected to study are benzyl 2(S)-Boc-amino-4ox0-6-pheny1-5(E)-hexenoate,~~ L-valine N-carboxyanhydride,46 N-monochlora~etyl-D-a-rnethylchlora~etyl -D-a-rnethyl-leucine,~~ leucine,~~ -acetyl-L-proline methyl ester, -(4S)-acetyl-L-proline hydroxy-L-proline hydroxy-L -proline me methyl thyl ester, a nd -(4S)-fluoro-L -(4S)-fluoro-L-proline -proline methyl ester,448 N-chlorosulfonyl-L-proline benzyl ester,49 Z-[(E)-5-(p-nitrobenzyloxycarbonylmethinyl)]-L-prol methinyl) ]-L-proline ine t-butyl N-[N-benzyloxycarbonyl-L-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl]-L-phenylalanine methyl ester,451 and Boc Boc-L-Ltryptophan (2-thymin-1-y1)ethyl (2-thymin-1-y1)ethyl ester.452While ester.452While crystalline N-acetyl L-proline methyl ester is characterized b by y a cis-pept cis-peptide ide bond, th the e ring ring-substituted -substituted analog analogues ues adopt the trans-configuration trans-configuration.448 .448 5.2 Nuclear Magnetic Resonance Spectrometry - An NMR study qualifies for inclusion inclusio n in this section only iiff th the e object of th the e study involves more tthan han routine support of synthetic studies. Conformational studies are included within this policy, and a familiar example, interpretation of 'H-NMR (as well as IR data) of C2HC C2 HC13 13 solutions of N-acetyl-L N-acetyl-L-proline -proline N-methylam N-methylamide, ide, provid provides es more reliable conformer ratios based on improved understanding of spectral parameters.453 Rela Re late ted d sstu tudi dies es inv nvol olvi vin ng ch chlo loro ro-s -sub ubst stit itut uted ed t r y p t o p h a n ~ ~nd ~ ~ bacoflen analogue anal oguess [3[3-(th (thien ien-2-2-y1)y1)- and 3-(furan-2-yl)-y-aminobutyric adopt the common approach of calling for data from both H- nd 13C-NMR measurements. Establishment of absolute conf configuration iguration of a-amino aci acid d enantiomers, and of other a-chiral amines, through through interpret interpretation ation of 'H-NMR data of amides formed with (S)-0-methyl (S)-0-methylmandelic mandelic an and d enantiomeri enantiomeric c purity determinat determination ion of

 

1: Amino Acids

47

deuteriated esters of amino acids through 2H-NM 2H -NMR R measuremen measurements ts using pol poly(yy(ybenzyl-L-ghtamate) benzyl-Lghtamate) in CH& as a chiral lyotropic liquid crystal solvent,457 re studies that illustrate familiar stereochemical applications of 'H- and 2H-NMR Another analytical application is represented in the estimation of carbamate formation in aqueous solutions of amino amin o while the extraordin extraordinary ary sensitivity of current NMR instrumentation is further illustrated (see Vo1.23, p.46) in the detection of glutamic acid, glutamine, and N-acetylaspartic acid in brain tissue.459NMR tissue.459NMR parameters for glycine in frozen aqueous solutions have been collected;460valu collected;460values es of of 'H-NMR 'H- NMR spin-lattice an and d spin-spin relaxation times increase for aqueous solutions of glycine and proline with increases in temperat ur e and c~ ncent r at i on. ~ ~'magic ~ angle spinning' study by 'H-NMR of Lalanine has been directed at the assessment of molecular dynamics in the solid st ate 462 13C-NMR studies with similar objectives have been reported; reporte d; one br broad oad study relates chemical shifts for each carbon atom to torsion angles for N-formyl-Lalanine- and -~aline-amides~~~ nd L-threonine and L-tyrosine?@ while another study illustrates illu strates the usefulness of 13C-NMR 13 C-NMRmeasurement measurementss for asse assessin ssing g protonation equilibria for ornithine, lysine, and hydroxylysine in aqueous dimethyl ~ulfoxide.~~' pectra of N-alkyl- or aryl-N-carbamyl and their N-nitroso derivatives, have been correlated with structure.466 structu re.466 Forr 17 Fo 170-N 0-NMR, MR, the frontiers continue continue to be pushed back but bu t gaining re results sults with little general applicability to revealing subtle details of amino acid structures in solutions; for example, further further cross-polarized cross-polarized dynamic angle spi spinning nning dat dataa on 70-labelled amino acids have been been collected.467 collected.467Specialized applications continue, however, however, for 'P-NMR, 'P- NMR, with accurate enantiomeric analysis using amides formed from amino acids and the chiral phosphorinane HP(O)(OCHMeCH2NEt2)2,"68 MeCH2N Et2)2,"6877Se-NMR data da ta can be used for absolute configuratio configurational nal assignments to amino acids converted into imidaz01-2-selenones.~~~ Optical Rotat Optical Rotatory ory Dispersion an and d Circular Dichroism - Reports over the years have described the use of these techniques to determine subtle structural 5.3

details forofamino acids, though empirical rules sometimes fail.toThus, the CD spectrum Nu-acetyl-L-ornithine and homologues is found be what the simple rules predict for the D-config~ration,~~~ nd anomalous optical rotation data have been found for NE-acetyl-L-lysine nd Na-acetyl-L-lysine.471and Na-acetyl-L-lysine.471and Naa~ et yl - l - ar gi ni ne. ~eliable ~ ~ correlation, correlation, of CD C D with absolute configuration configuration,, h has as been established (L-derivatives (L-derivatives show posi positive tive CD C D near 31 310 0 nm an and d negative CD a t 28 2800-29 290 0 n nm) m) for Eu(fod)3 complexes of amino and an d of amin amino o acid esters.474The CD features of trinuclear trin uclear complexes between amino acids a cids aand nd [M30(02CCH3)6L3In+ L = water or pyridine, n = 0 or 1) are suitable for the assignment of absolute configuration through the application of a semi-empirical helicity C D in the Soret wavelength region for solutions of homochiral amino acid derivatives and achiral porphyrins has been ascribed to hydrogen bonding association.476 Raman optical activity of amino acids (usually measured as CD) has been

 

48

Amino Acids, Peptides and Proteins

reviewe revie wed.4 d.477 77This is a topic area th that at has developed slowly, and its fund fundamen amental tal basiss is st basi still ill bei being ng worked ou out, t, assisted b by y studies such as comparis comparisons ons of meas asur ured ed and ca calc lcul ulat ated ed R Raman aman CD fo forr LL-al alan anin ine ea and nd iits ts i s o t ~ p o m e r s . ~ ~ ~

5.4 Mass Spectrometry - Increased activity associated with the newer instrumental techniques would be an appropriate inference based on the current literature covering mass spectrometric studies of amino acids and derivatives, There is also an awareness th that at some lon long-known g-known variants of M S techniques have been bee n under-used under-used,, such a ass negative ion measurement measurement,, which giv gives es ‘clea ‘cleaner’ ner’ spectra for N-(2,4-dinitrophenyl)amino intense inte nse [[M M-11- peak peakss for N-ph N-phos ospho pho-amino and can allo allow w discrimina discrimination tion betw between een the four fo ur yhydroxyornithine hydroxyornithi ne diastereoisom diastereoisomers ers after bis(N-benzyloxycarbonylation).481Both positive posi tive-- and negative-ion modes have been applied to generate spectra fr from om free amino acids (glycine, methionine, histidine, and cysteine), the spectra showing prominen prom inentt [M [M--11- a and nd [M*-l]- peaks peaks.482 .482 New techniques providing spectra of amino acids themselves include time-offlight M S of phenylalanine bombarded with 2.5 MeV carbon ions,483and ions,483and pulsed laser-initiated ionization4esorption of tryptophan embedded in rhodamine B and and of crosslinking amino acids pyridinoline an and d its deoxy- an and d glucosylgalactosyl-derivatives.48s luster ion formation from a mixture of two differen diff erentt amino acids in a Na Na+-c +-con onta taini ining ng matrix has bee been n studied, leading to a an n Na+ ion affinity scale for amino acids (a Li+ affinity scale was constructed similarly).4861H-2H-Excha similarly).486 1H-2H-Exchange nge invo involvin lving g amino acids and CH CH30 302H 2H,4 ,487 87 nd gasphase proton affinity studies for amino acids, have been the subject of study over several ye year ars, s, ap appl pliied to gl gly ycine an and d it itss i ~ o t o p o m e r s . ~ orresponding ~~ FT-ion cyclotron resonance studies of phenylalanine and its N-methyl- and NNdimethyl-analogues dimethyl-ana logues have been described.489 described.489Theoretical aspects have been pre pre-sented, of kinetics of protonati proto nation on leading tto o cluster ions [( [(amino amino acid) acid)22-H] H] + in the gas phase.490 Gas-phase basicities, a subtly-diff subtly-different erent para paramete meter, r, have bee been n determined for amino acids49’ acids49’with with particular attention to lysine an and d histidine, by the kinetic method. Other Spectroscopic Studies o f Amino Acids - Several projects cited in 5.5 preceding sections have relied on more than one spectroscopic technique, commonly including I R and other vibrational spectroscopic methods. A remarkably simple positive answer to the question: do diastereoisomeric interactions exist between enantiomers in the solid state? has emerged from IR spectra of L-proline, L-proline, DL-prol DL-proline, ine, and of a an n equimolar mixture of th the e two, which is not simply the weighted average of the preceding two spectra.492The spectra.492The result does not, of course, clarify clarify th the en nat atur ure e of th these ese inter interactions, actions, but much more detail is available through IR studies of glycine in neon, argon, and krypton matrices (three different conformers are ar e established for th the e first an and d a similar result for proline a an nd * *H H-labelled p r ~ l i n e .R-Raman ~~~ spectroscopy of solid Laspartic acid and 2H4- an and d ~SN-isotopo ~SN-isotopomers495 mers495nd nd of solid L-glutamic acid and 2H4- and SN-isotopom SN-isotopomers496 ers496 ield fundament fundamental al vibrat vibration ion modes for these amino acids.

 

I : Amino A c i h

49

Another familiar interest is revealed in the establishment of intramolecular hydrogen-bonding patterns for derivatives of p - and y-amino acids through I R study of CH2C1 CH2C12 2 olut olutions.4 ions.497 97 The rotationa rot ationall spectrum of p-alanine determined in a free-ex free-expansio pansion n jet spectrometer provides evidence evidence for the existence of the same types of intramolecular interactions inte ractions within two conformers, as already found in gaseous gl glyc ycin ine e and alanine.498 Photoelectron spectra have been determined for phenylalanine and its Nmethylmethy l- and N N - d i m e t h y l - a n a l o g ~ e s . ~ ~ ~ 5.6 Physico-Chemical Studies of Amino Acids - This section covers useful interpretations, in terms of the behaviour of amino acids, of some simple laboratory measurements. Thus, the solub solubility ility behaviour of fourteen amino acids in water as a function of pH and temperature has been considered on tthe he basis o off fundamental structural and thermodynamic parameter^;^^ solubilities of Lisoleucine, L-leucine, and L-valine in aqueous NaOH increase as the NaOH concentrati conce ntration on is increased, then decrease sharply after a fter the 1:1-rati 1-ratio o has been passed.500The passed.500 The solubility o off the di dipeptid peptide e deriv derivative ative Z-L-A Z-L-Asp-Lsp-L-Phe-O Phe-OMe Me (i. (i.e., e., Zaspartame) in water containing L-phenylalanine methyl ester shows complex

dependence upon concentration, pH and on other parameters, showing that the solutes interact in more ways than simply through ionic attractions and repulsions.501Concentrated proli proline ne solutions show non-ideal behaviour (freezi (freezing ng point depression and isopiestic data), and this explains the protective effect of proline on enzyme activity (due to the fact that it exerts a role as inert spacefilling so solu lute te to he help lp ma main inta tain in a nat natiive po poly lype pept ptid ide ec o n f ~ r m a t i o n ) . ~ ~ ~ The variou variouss lipophilicity scal scales es for amino acids have bee been n rev review iewed, ed,503 503and and a new ne w h hydrophi ydrophilicit licity y scale has been proposed based on ca calcula lculations tions o off solvat solvation ion parameter^.^^ A multi-channel sensor system has been trained to correlate the 'taste' characteristics of amino acids.5 acids.505 05 Guest-host studie studiess contin continue ue (s (see ee also Section 4.1 4.17), 7), with wat water-so er-soluble luble calix[nlarenes (89; n = 4, 6, 8) that strongly bind amino acid meth methyl yl esters into their cavity.506The related cyc cyclic lic tetra tetramer mer forms 1 1 complexes with aroma aromatic tic amino acids, and the chiral porphyrin (9 1) shows enantiodiscrimination towards amino acid esters.508The C2-symmetricchiral C2-symmetricchiral porphyrin analogue [92; R = (R)CH2CHMeOH CH2C HMeOH]] is an effe effecti ctive ve trans transporte porterr of lith lithium ium salts of amino acids through CH2C12 mem membra branes nes,509 ,509 an and d a phenanthroline-copper(1) template supports a bis(2-aminoacylpyridine) receptor that binds Z-L-glutamic acid and other dicarboxylic acids. acids.510 510A similar mechanis mechanism m accounts for the binding of Z-aspartic acid to an 2-acylaminopyridine-substituted eterocyclic template, to which a broaderr range of Z broade Z-amino -amino acid acidss sho shows ws modest binding.51 Cyclo-oligomers of cylindrical shapes have been synthesized that present amide groups to guest molecules, and show high selectivity towards N-acetylamino acid N-methylar n i d e ~ . ~he ' ~ crown ether (93) has been shown to use its carboxy-group as well as the macrocycle ato atoms ms to com comple plex x with amino acids.513 The enantiomeric discrimination factors that are sought in such studies are bein be ing g put on a firmer numeri numerical cal basi basis, s, as illustrated for st standar andard d molar enthalpies

 

50

Amino Acids, Peptides

and Proteins

of binding by cyclodextrins of L- or D-phenylalanine and L-phenylalaninamide. Values have been determined by microcalorimetry, and are independent of c ~ n f i g u r a t i o n . ~ 'icroc icrocalori ~ alorimetric metric d ata also show tha t the chir chiral al discri discrimination mination of L-ascor L-ascorbic bic acid-Fe3 acid-Fe3 tow ard s enantiomeric a-helical peptides is no t exert exerted ed to towar wards ds cy cyst stei eine ne en an tio ~ ne rs .~ Heterogeneo us liqui liquidd systems are of growing interest, from the po int of vi view ew of amino acid transport; systems studied recently (see also Refs.413-419) are basic amino acids/water/CHC13 + sodium di(2-ethylhe~yl)sulfosuccinate~*~ r ganic rganic solvent/water/arylboronic acids + crown ethers,517and ethers,517 and organic solvent/water/ 18-crown-6 + picri picricc acid.518 Reverse micellar micellar extraction of a m ino acids fro m aque ous media by di-octyldimethylammonium chloride is sensi sensitive tive t o co-solutes and physical parameter^.^'^ In the glycine glycine o r L-lysi L-lysine/oct ne/octyl yl P-D-glucos P-D-glucoside/ ide/water water syste sys tems, ms, fr from om 3 to 7 amino acid molecules can be bound by each molecule of the gl gluc ucos osee deriv derivat ativ ive, e, re resu sult ltiing in a lowe loweri ring ng of its cri criti tica call mic micel ella larr c o n c e n t r a t i ~ n . ~ ~ ~ Equilibria involving transfer of arginine, from solutions containing HC1 a n d N a C l t o a cati on exchange mem brane, hav e been evaluated.521Sorption evaluated.521Sorption of amino acids aci ds on to ion exc exchan hange ge m emb ranes has bee beenn D ip ip ooll e m o m e n t d a t a h aavv e b ee ee n ccoo llll e c te d f o r LL - c y st st e in e a n d L - c y ~ t i n e . ~ ~ ~ A review review ha s app ear ed covering ssolute olute-sol -solute ute and solut solute-sol e-solvent vent interactions tha t occur in solut solutions ions of am ino Th e vis viscos cosit ityy of a solut solution ion of an am ino acidd has been rel aci relat ated ed to the effect effectss of the solute solute on water and da ta have been collected for viscosities of aliphatic a-amino acids in 0.5 a n d 2 M urea.s26 urea. s26 Ap paren t m olar volumes volumes of aliphati aliphaticc a-am ino acids in 0.5 a n d 2 M ur urea ea,5 ,527 27 and of aqueous LL-va vali line ne,, L-iso L-isole leuc uciine, ne, and L - l e ~ c i n e ~ ~ave * been calculated from from densiti densities es and volum etric hea t capacit capacityy da ta. Thermodynamic parameters, enthalpies of dilution of L-threonine and La ~ p a r a g i n e , nthal nthalpies ~ ~ ~pies of interact interaction ion of a m ino acids and pepti peptides des with with crown ethers in water,530 water,530 ap pa re nt molal hea t capacities an d volumes of aliphatic aam ino acids at 288288-328K, 328K,531 531 and simila similarr thermal propert properties ies of am inopolyc inopolycararboxylic acid solutions532 have b een collected. M icroca lorim etric stud ies provide enthalpy of dilution data for ternary aqueous solutions that contain glycine, an alkanol alkanol, , and another a-amino Electrical measurements for the effects of weak static and alternating lowfrequenc fre quencyy magnetic fi fiel elds ds on curren t fl flow ow throu gh aqu eous am ino and potentiometri potent iometricc titrations lleading eading to proto nation cons tants for glyc glycine ine in aqu eous NaC1535aa nd NaC1535 n d t h e p ro ro t o n - b iinn d i n g i s o t h e r m f oorr g l y ~ i n eave ~ ~ been ~ presented, as have corresponding dissociation constants for L-proline, L-histidine and L tryptophan.537The tryptophan.537 The protonation rates for L-tryptophan in acidic media decrease with increasing increasing pH .538 5.7 Molecular Orbital Calculations for Amino Acids - Development of familiar themes un der this heading is cont inu ing with calculations of solvation energies of zwittenonic forms of glycine, alanine and serine in different conformations in water,539hyd water,539 hyd ration parameters a nd conf orm ations ooff N-acetylamino N-acetylamino acid met methyl hyl esters,540aa n d 2-(N-acetylamino)isobutyric a c id N - m e t h ~ l a m i d e ~ nd esters,540 ~ l of twenty com m on am ino acids subst substitut ituted ed in the same way.542 way.542

 

I

Amino Acids

51

S03Na

I

S 03N a (89)

Ar

 

Amino A cids, Peptides and and Proteins

52

Quantum mechanical force fields generated by [glycine.nH20] supermolecules in basic glycine solutions,543 solutions,543electrostatic properti properties es of am amin ino o acids modelled using atomic multiple moments,544and moments,544and molecular connectivity models leading to structure-property relationships for amino illust illustrate rate anothe ano therr area of computational interest (see also Ref.546). Spectroscopic data generated through molecular orbital calculations concern vibrational frequencies of three non-ionized conformations of cysteine and ~ e r i n e , hemical ~ ~ ~ shift changes related to dihedral angles for glycine and g l y ~ i n a m i d e , ~nd ~ ~gas-phase proton transfer energy values for eight of the protein amino acids.549An acids.549An erratum has been published550concerning published550concerning Ref.461 in Chapter 1 of Vol.26 (p.55). (p.55). 6

Chem ical Studies of Amino Acids

Preparative applications of racemization are covered elsewhere in this Chapter (Section 4; e.g., Ref.l67), and the content of papers eligible eligi ble for discussion in this section is usually limited to t o a narrow topic, e.g. that the rate r ate of racemization of L-aspartic acid in water a t 100 100"" is increased w whe hen n 6.1

Racemization

-

dimethyl sulfoxide is added.551 It has become clear that the dating of fossils based on the presumed constancy of racemization rates of their indigenous amino acids is liable to considerable error because of unspecifiable catalysis, though the basis of a claim, that the kinetics of amino acid racemization are non-linear, is obscure.552Application obscure.552Application of the method to amber-entombed insects using samples ranging in age from 100 y to 130 x lo6 y can only provide results matching those of other dating methods if it is assumed that the amber environment retards racemization rates by a factor of greater than 104.553This, indeed, represents slow racemization and is about the same rate as DNA degradation by de-p~rination.~~~ he dating method applied to Homo tirolensis (i.e. the male corpse found in 19 199 91 a t a high altitude in the Austrian Tyrol) and also to a specimen of ginger from Egypt, (5200 both of the same agebut in fact gaverate considerably different age values, and not only that, the y), racemization in the colder specimen was faster 555Since 555Since 0 - and di-tyrosine were detected in H o m o tirolensis, and these are markers for free radical attack on proteins, the authors suggest that the hydroxyl radical formed by sunlight at high altitudes may accelerate amino acid racemization.

This Section covers reactions at the amino and carboxy groups (and reactions at both) as well as reactions at the acarbon atom of or-amino acids + H3NCH H3NCHRC02 RC02-; -; the following following Secti Section on cov covers ers reactions of ami a mino no aci acid d side-chain side-chainss R. Thermolysis of butyrine, 3-amino- and 4-aminobutanoic acids gives many reaction products,556 products,556wh whil ilee decarboxylation of L-threonine L-t hreonine an and d L-hydroxyproline occurs at 170 in cycl cycloh ohex ex-2 -2-e -eno none ne,, giv ivin ing g opt optic ical ally ly-a -act ctiv ivee P - a m i n o - a l k a n ~ l s . ~ ~ ~ Irradiation of DL-lysine with soft X-rays causes the change of zwitterion to free 6.2

General Reactions of Amino Acids

 

I : Amino Acidr

53

base,, and decar base decarbox boxyla ylati tion on le lead adin ing g tto o 1, 5- di am in 0p en ta ne .~~adicals ~ formed by y - i r r a d i a t i o n o f DL- t h r e ~ n i n end ~ ~by ~ pyrolysis of DL-serine, DL-threonine and an d D DL-ty L-tyrosi rosine ne at 200 200-6 -600 00 for 2-180 min560 have bee been n sstudi tudied ed by by ESR. yy-Ra Radi diol olys ysis is of aq aque ueou ouss phe pheny nyla lala lani nine ne le lead adss to t y r ~ s i n e . ~ ~ ' Studies of these types, that often provide essential warnings of sample breakdown to those preparing samples of amino acids for analysis, are few and far between. However, in-depth study of the N-halogenation of amino acids and decomposition of the reaction products, continues to expand (see Vo1.26, p.56), with decomposition kinetics being determined for N-~hloro-valine,~~~ nd compared with da data ta for N-chloro-sar N-chloro-sarcosine, cosine, -N-methylala -N-methylalanine, nine, -N-methylval -N-methylvaline, ine, and - p r ~ l i n e . -Bromo-am -Bromo-amino ~~~ ino acids hav have e been studied.5 studied.564 64The Grob fragmentation pathway that is followed by these these derivatives in aqu aqueous eous solutions5 solutions565 65can can be promoted by metal a l k ~ x i d e s . ~ -Nitrosation ~~ (N204/CH2C12) f a-(acetylamino)acids gives gives more stable produ products cts tha than n hitherto bel belie ieve ved, d, but they fragment in alkaline media to give a-hydro~yacids.~~~ eaction within a Co(II1) complex [formed with K3(Co(C0 K3(Co(C03) 3)3}] 3}] at a pyridoxylid pyridoxylidene-amino ene-amino acid acid ligand generate generatess an a-hydroxy-a-amino a-hydroxy -a-amino A kinetic study of the nitrosation of imino acids has revealed intramolecular migration of the nitroso group from an intermediate nitrosylcarboxylate nitrosylcarbo xylate formed at high high pH.5 pH.569 69 Conversion Conversio n of a-amin a-amino o acids into a a-nitr -nitro o acids emp employing loying the powerful o oxyg xygen en transfer agent HOF.MeCN (formed in aqueous MeCN with F2) involves racemization. 70 N-Acylation N-Acylatio n reactions include formylation of amino aci acid d esters w wit ith h tri-et tri-ethyl hyl ~ r t h o f o r m a t e ~ nd ~ ' conversion of N-formyl-a-trifluoromethyl-a-aminocids into i s ~ c y a n i d e s . he ~ ~analogous analogo ~ us iisocya socyanate natess OC OCNC NCR(C R(CF3) F3)C02 C02 Me nd hydr hydraazi zides des are startin starting g materials for the synthesis of a ~ a p e p t i d e s , nd ~ ~N-acryloylN-acryloyl-L~ Lprolinamides have been prepared for the first time, for use in copolymer preparations.574 preparations .574 N-Acylatio N-Acylation n of amino acids using vi vinyl nyl esters has been been advocated575 advocated 575 the method is well-known well-known iin n the literature). N-(L-Maley1)ati N-(L-Maley1)ation on of amino acids (with glycine and proline as exceptions) can be accomplished with the aid of aminopeptidase A.576Solid-state A.576Solid-state N-phthaloylation of amino and 3-carboxybenzoylation of DL-alanine using isophthalic acid578has acid578has been asses ass esse sed d using differential scanning calorimetry. An analogous product (94), previously undetected, emerges from Maillard reactions involving y-aminobu y-aminobutyric tyric acid ac id,, 6-am 6-amin inoc ocap apro roic ic ac acid id,, Na Na--acet ety yl-LL-llys ysiine ne,, an and d p e n t o ~ e s . ~madori ~~ compounds formed at an early stage of the Maillard process, have been generated from D-glucose and a-amino acids, and subjected to FAB-MS and NMR

N-[2-(4-Nitrophenyl)sulfonylethoxy)carbonyl]ation of amino acids gives Nprotection that can be reversed by bases in aprotic solvents.581 Novel N-alkylation of amino acid esters by tricarbonyl(cyclohexadieny1)iron cations,582an cations,582 and d tthr hrou ough gh high-pressure rea eact ctiion with ~ x i r a n e s ,ogether ~ ~ ~ with more traditional reductive alkylation methods using aldehydes (preparation of N-all N-a lly1 y1 and -propargyl- derivatives,5 derivatives,584 84 se of Ph PhCHO CHO/NaT /NaTeH eH fo forr preparatio preparation n of N-benzylamino N-benzylam ino acids585)have bee been n described. The preparation of pure Nmethylamino methylamin o acids b by y c conversion onversion of Z Z-amino -amino acids into oxazolidino oxazolidinones nes using

 

54

Amino Aciak, Peptides and Proteins

formaldehyd e followed by Et,SiH/T formaldehyde Et,SiH/TFA FA reduction (NaBH4 is somewhat le less ss effec effecti tive) ve)586 586or by tthe he correspond corresponding ing reaction of N-benzy N-benzylamino lamino acids with the reduction step accomplished by hydr~genation),~~~ ollows established methodology. Direct methylation of N-Boc-0-TBDMS-D-tyrosine with MeI/BuLi/-78 seems, however, to proceed uneventfully.588Coupling uneventfully.588Coupling (R)- or (S)-homophenylalanine ethyl ester with lactates gives (R,S)- and (S,R)-N-[(1-ethoxycarbonyl-3rocedures have been described for the preparation of phenyl)pr~pyl]alanine.~~~ N-(9-phenylfluoren-9-yl)-L-alanine nd -L-aspartic acid dimethyl ester.590Bis-Nester.590Bis-Nalkylation through throug h reductive aminocyclizat aminocyclization ion of L-valine methyl ester with ketoaldehydes is accomplished with hi high gh diastereosel diastereoselectivity ectivity (Scheme 30), but with little stereochemical stereochemical bias for simpler ketones.591N-Alkylation of sodium salts of secondary amino acids uses 4-chloro-N-benzylpyridin-2(H)-one (DMSO, 160180°).592 Following recent results (see Vo1.26, p.62) that have established the condensation of amino acids to form peptides in aqueous NaCl by copper salts,593 nother non-enzymic reaction with the same outcome under putative prebiotic conditions has been established. This is based on cyanamide driving the reaction: FeS + H2S -+ FeS2 (Pyrite) which then brings about the condensation of thioglycollic acid HSCH2C02H so as to activate the amino acid carboxy group for peptide bond formation. formation.594 594 A quite diff differen erentt discovery, but connected in its prebiotic relevance, concerns the finding that mixtures of amino acids can exert the cata ca taly lyti tic c ac acti tivi viti ties es sh show own nb by y PP-ga gala lact ctos osid idas ase, e, car carbon bonic ic an anhy hydr dras ase, e, and c a t a l a ~ e . ~ ~ ~ Carbamylation of L-aspartic acid596 nd N-(9-acridinylthiocarbamoyl)ation f amino acids597have acids597have been described, the first of these studies being aimed at establishing the finer details of the biogenesis of dihydro-orotic acid, and the second providing a derivatization protocol that is some 6-22 times faster than and d givi giving ng a fluorescent product. phenylthiocarbamoylation, an y-Irradiation y-Irradiati on of amino acid solutions in the pre presenc sence e of the spin-trap 2-methyl2-nitrosopropane7 2-nitrosopropa ne7 gi give vess isolatable t-butylamin t-butylaminoxyl oxyl acids Bu ButN( tN(0. 0.)CH )CHRC0 RC02H 2H 5 9 8 The solid-stat solid-state e reaction of p-benzoquinone with with amino acids that is accompli accomplished shed by grinding the mixture, gives a purple solid A,.,ax 562 nm) that contains free radicals different from those generated when the reactants meet in aqueous solution. 599 Selective removal of the t-butoxycarbonyl group from N-Boc-amino acid tbutyl esters occurs on treatment with dry HC1 in EtOAc; t-butyl ethers also survive the process.60 process.600 0 Oxidation of amino acids by peroxomonosulfate in aqueous alkali starts with electrophilic electrophil ic attack at nitrogen to gi give ve an imino acid through involvement of the a-CH proton.601There proton.601There are, ar e, as usual, numerous papers covering routine oxidation studies of amino acids in the current literature, representative examples dealing with kinetics of chromium(VI)/HC104 oxidation of alanine, valine, and phenylalanine,602and alanine,602 and electrolyti electrolytic c oxidat oxidation ion of methionine tto o iitts s ~ l f o x i d e ~this * ~ study employs carb carbon, on, platinum o r gold electrodes modified with Langmuir-Blodgett films of stearic acid or N-stearoyl-L-valine, N-stearoyl-L-valine, and in the latter case, faster oxidation of the D-enantiomer was observed). Enhanced colour for the ninhydrin reaction has b bee een n reported for 5-arylninhy-

 

I : Amino

Acids

55

d r i n ~ .hat ~ ~the enolate ion of Ruhemann's Purple within two five-membered rings of partial anti-aroma anti-aromatic tic character (as seen in the cyclopentadienyl anion) is the chromophore responsible for the long-wavelength absorption feature is backed up u p by molecular orbital calculations.605 Esterification studies that carry special interest include benzyl ester formation accompanying N-benzyloxycarbonylation, resulting from reaction of excess 2-C1 with a-isopropyl- and a-vinyl-a-am a-vinyl-a-amino ino acids.m6 acids.m6Also, Also, the formation of aryl esters from N-phenylace N-phenylacetylglycine tylglycinein the standard fashion (a phenol + dicyclohexylcarbodi-imide + py/TsOH) involves low yields,607which can be overcome through an indirect route via N-Boc-N-phenylacetylglycine,hrough esterification followed by Boc removal. N-Boc-Amino acid chloromethyl esters have been prepared using chlorosulfo chlorosulfonylmethyl nylmethyl chloride C1 C1S0 S020C 20CH2 H2C1 C1.6 .608 08 The BOP reagent, although little used now in peptide synthesis after its replacement with safer alternatives, is advocated for mild esterification of N- and side-chain protected amino acidsm9 Dicyclohexylcarbodi-imide esterification (catalysed by DMAP DM AP)) to couple syn-pheny syn-phenylisoserine lisoserine to b baccatin accatin 111 to form ta taxol xol can be effected starting with the derivatized anti-compound.610Lipase-catalysed anti-compound.610Lipase-catalysed regiospecific esterification of the primary hydroxy group of butyl a-D-glucopyranoside to 2,2,2-trichloroethyl N-Boc-4-aminobutyrate has been reported;61 lack of space precludes mention of further routine papers covering enz enzymic ymic esterifica esterification tion of amino acids that are in the current literature. Ester cleavage from N-acylated amino acid benzyl esters can be achieved using N-bromosuccinimide,612 N-bromosuc cinimide,612 or lithium iodide in aprotic non-polar solvents.613 Lithium iodide also cleaves methyl and tert-butyl esters. Studies of enantioselective hydrolysis of N-protected DL-amino acid esters show no signs of slackening. Remarkably large rate enhancements for the hydrolysis of L-isomers are achiev achieved ed with careful optimization of salt concentration {[KCl] = 0.03M for the N-

dodecanoyl-DL-phenylalanine p-nitrophenyl ester/Z-L-Phe ester/Z-L-Phe-L-His-L-Leu -L-His-L-Leu-OH/di-OH/ditetradecyldimethylammonium bromide chiral micelle system} 614 Similar studies exploring other chiral species have involved (2S)-N-benzyl-N-(long-chain lky1)P-aminoalkanob/Cu(II), P-aminoalkan ob/Cu(II), Zn(II), or Co(I1) salts615 salts615and and N-dodecyl-NN-dimethyl 1 -octadecylammonium bromide vesicles carrying chiral amine groupings and metal salts.616 A more conventional appro approach ach is represented in subtilisinmediated transesterification of Z-DL-Ala-ONP with 1- b ~ t a n o l . ~ l ~ Reduction of the carboxy group of an N-protect N-protected ed a-amino acid to the primary alcohol function ((-C0 C02H 2H -CH,OH -CH,OH)) is occasionally acco accompli mplished shed in a roundabout way, e.g. Boc-L-Val-OMe + RMgBr followed followed by by 1 % HF in MeCN,618 but BH3.SMe BH3.SMe2619*620 2619*620 r Li LiA1 A1H4 H4 is stra straight ightforw forward. ard. These last two papers describe the application application of Swern oxidation to the alkanols, to give the corresponding aldehydes (see also Ref.624; for the use of py.S03, see Ref.619), while the conversion of the primary alkanol into iodomethyl (PPh3/12) permits cyclization cyclization an and d further functional group tr transformatio ansformations ns to be performed leading to 3-carboxycyclopentylamines;625he homochiral a-aminoalkanals are increasingly increasingl y valuable in broad areas of organic synthesis, and may be secured in high yie yield ld by LiA1(OBu LiA1(OBuf)3H f)3H reduction of either Boc-L-amino acid phenyl esters626 or the methyl ester of a protected argini~~e),~*~ r Boc-L-amino acid

 

56

Amino Ac ids, Peptides and and Proteins

mixed anhydrides. anhydrides.628 628 D IB A LH Reduction of diethyl L-aspa L-asparti rticc and gluta glutamic mic acids to aldehydes is a-selective, and if conducted in the presence of a lithium trialkylphosphonoacetate, leads to N-pro tected y-amino-@-unsat y-amino-@-unsaturate uratedd dicar dicar-boxylic boxyl ic acid este esters. rs.629 629 Reduction of benzyl benzyl aspar tates a nd elabo ration of the alkanols to enantiomerically-pure 3-amino and 3,4-diaminoalkanols has been described;630conversion described;630 conversion of a-(N,N-dibenzy1amino)aldehydes nto nitriles nitriles (-CHO -+ -CH 2CN ) and en ensu suin ingg alk a lkyl ylat atio ionn an d re reduc ducti tion on gi give vess 1, 3 -d i- a m in e ~ .~ ~h e' reduction reduct ion of the equivalent equivalent N-u rethan e-pro tected carboxyanhydr carboxyanhydrides ides by DIBALH or lithium tris[(3-ethyl-3-pentyl)oxy]aluminium hydride gives high y ie l d s w i t h o u t r a ~ e m i z a t i o n sodium ~~~ borohydride reduction gives the prot e c t e d P - a m i n ~ a l k a n o l s ~ ~ ~eduction ). of the Weinreb amide with lithium aluminium hydride gives the aldehyde [-C02H -+ -C O N M e (O M e ) -+ -CHO], and ensuing reductive amination with an amino acid ester has been described (-, -CH 2N HC H2 C0 2M e),634 though others have foun d this this las lastt st step ep problemati~al.~~~ Dissolving Dissol ving m etal reduction (Na/refluxing p rop an -1 01) of @,a-disubstituted a m in in o a c i d aam m id id eess iiss a nnee w m e tthh o d o f o b ta ta iinn iinn g P - a m i n ~ a l k a n o l s . onversion ~~~ of the carboxy gro up in to the acid fluoride is straightforw ard with NNbis(alkoxycarbony1)-L-a-amino acids, without racemization, using cyanuric fluoride; the same starting materials give Boc-N-carboxyanhydrides with the Vilsmeier reagent (SO C12/DM F)637.638 m oc- am ino acid chlorides ar e reduced Vilsmeier [ B u ~ S ~ H / P ~ ( P oP corresponding ~~)~] aldehydes in ra the r lo low w yields yields.63s .63sConverConversion of the carboxy carboxy g roup of L-tryptophan into ketone ketoness via the Weinreb amide [-+ -C O N M e (O M e ) -+ -C O C H 2 P(0 )(O M e )2 -+ -C H = C H A r e t ~ ] ,r the ~ ~one~ step Weinreb-amide-to-vinyl-ketone route using ally1 magnesium bromide,640 conversion of a methyl ketone, formed from a protected phenylalanine in this way, into a n is isopropyl opropyl g roup ,@ ' an d clean decarbo nylatio n of an a-alkylpi a-alkylpipecoli pecolicc acid using diphenylphosphoroazidate,@2 ill illustr ustrate ate furt further her fu nction al grou p manipulations. Cyclizati Cycliz ation on of P-am inoalkanols w ith Ph2POC1 giv gives es N-diphen ylphosphinoyl a ~ i r i d i n e s . eduction ~~ an d cyclizati cyclization on o f vi vinylgl nylglycine ycine to th e oxazolidinone, then N-allylation, can beofaccomplis accomplished hed in a onproducts e-p ot proce process. ss.644 644 The generation heterocyclization from N-acylated amino acids continues to attract mechanistic and synthetic interest, focussing on 2-alkoxyoxazol-5(4H)-ones formed from N-alkoxycarbonyl-L-amino acid mixed anhydrides a n d i s o p r o p e n y l c h l ~ r o f o r m a t e nd ~ ~ from analogous symmetrical anhydrides on treatment with NN'-di-isopropylcarbodi-imide.646 Ureas, e.g. Boc-L-Ala-LN(Boc)CHMeCON('Pr)CONH'Pr, are also formed in this process by rearrangement of the symm etri etricc anhy dride to the N (Boc)-di (Boc)-dipepti peptide de followed followed by add ition to the carbodi-imide. The generation of a mixture of N-acylisourea, symmetrical anhy dride and oxazolone throu gh reaction reaction of an N-protected N-protected am ino aci acidd wit withh a carbodi-imide does not involve significant racernization, which becomes more pronounced when an amine is introduced (as in the normal course of peptide synthesis). As this process continues, it is aminolysis of the anhydride initially, and of the oxazolone at later stages, that introduces racemized products.647 N-M ethyla m ino acid ester esterss react react via an oxazolone and/or symmetrical anhydride

 

I

Amino Acids

57

Reagents: i, Na BH 3C N or NaBH(OA NaBH(OAc) c),; ,;

ii, BU'OK, and Curtius rearrangem ent

Scheme 30

PhCONR2CHR'C02H

-+

R'COCH(OH)CF3 + PhCONR2COCH(OH)CF3

Reagents: i, TFAA, Py, 100 C

Scheme 31

Reagents: i, CH2=C(OMe)C =CH2, etc.

Scheme 3 2

 

58

Amino Acids, Peptides and Proteins

in giving acyloxyphosphonium salts with the currently popular phosphonium peptide-bond-f pepti de-bond-forming orming reagent reagentss P yB rOP an d PyClOP (PyBOP reacts slugg sluggis ishly hly in this process).Hs N-Acyl-N-benzylamino acids yield 5-trifluoromethyloxazoles when treated with TFAA/py in benzene (Scheme 3 1), 19 while N-2-hydroxybenzyl analogues y i e l d t r i c y c l i c b e n z o x a ~ o l i n e s . ~quilibrium ~~ mixtures of thiazolinones, phenylthiocarbamoylamino aci acids ds an d N-phe nylthiohydantoins (PTH s) fformed ormed in the Edman peptide sequencing process can be converted into thiazolinones that are amenable t o ring-opening ring-opening with a fl fluore uoresce scent nt am ine. ine.651 651Oth Oth er inter interesti esting ng five-membered heterocycles include (99, formed from an amino acid and [Cp.Ir [Cp. IrC1(pC1(p-C1)2] C1)2],, an d cap abl e of highl highlyy dias diastere tereosele oselecti ctive ve ligand com plexat i o d S 2and 2 and (96) formed from amino acids and diphenylborinic acid cf- Vo1.26, ~ . 6 2 ) . ~ ~ ~ 1,3-Dipolar cycloadditions of am ino acid-deri acid-derived ved imines illust illustrated rated in previous Volumes of this series (see e.g., Vo1.23, p.55) continue to provide highlysubstituted five-membered five-membered hete heterocycl rocycles. es. Th us , decarboxylation of imines formed from amino acids and alloxan or 1-phenyl-3-methylpyrazolin-4,5-dioneives a z o m eett h i n e yyll id e s t hhaa t a dddd t o m a l e i r n i d e ~ . ~ighly-substituted ~~ homochiral pyrrolidines are formed between N-acryloyl-L-proline benzyl ester and R’CH = N + L i ))R R 2 C -C 0 2 M e . 65 6 5 5 o rma t i o n o f 3-(3,6-dioxopiperazin-2-yl)propanoic acid fro m y-methyl glu tam ate an d glycine glycine ethyl este ester656 r656 exemplif exemplifies ies a familiar six-membered heterocyclic amino acid condensation product, while a more unusual ring-enlargement process (s (see ee Vo1 Vo1..25, 25, p. p.69) 69) accom panies photolysis of N- ph tha loy l-L -D O PA methyl ester protected in its side-chain side-chain by 3’,4’-methyl 3’,4’-methyleenation nati on (corr (corresponding esponding treatm ent o f N-ph thaloy lthreo nine an d seri serine ne methyl e st ste rrss g iv eess p ht h t ha ha lloo yyll ggll y ccii nnee t h rroo u g h P - f r a g m e n t a t i ~ n ) . ~ ~ ~ Specific Reactions of Amino Acids The conventional use of this section over the the year yearss continues in this Volume, covering papers th at concen trate mainly on reactions at the side-chain of a-amino acids. By their nature, these processes often amount to the use o f one amino acid to synthesize another, and some

6.3

papers that could have been located here can be found in the earlier synthesis Sections 4.1-4.1 5. Side-chain Side-cha in halogenation of alip ha tic L-amino acid este esters rs (as their N-ph thaloyl derivatives) is is stereoselective (particu larly so with t-butyl esters), giving (2S,3R)P-hydroxyphenylalanine after substitution of the bromo-substituent that was introduced using NB S,658 and 4-brom o-L-glutamates (stereos (stereoselect electivit ivityy not investigated, but the diastereoisomer mixture was easily separated).659Fluorinaseparated).659Fluorination of a-fluoromethyltyrosine with acetyl hypofluorite gives the P-fluoroanalogue.6m o-Iodoalkenylglycines o-Iodoal kenylglycines CH2 = CICH,CH(NHAc)CO,Et undergo Michae Mich aell-ty type pe chain ext extensi ension on wit withh C H 2 CH C02E t/Pd(OA c)2 to gi give ve E t 0 2 C C H = C H C H = CHCH2CH(NHAc)C02Et.661 he corresponding reaction occurs with electrophiles, e.g. (E)-ICH ==CHCO2Et with C H 2 = C ( S ~ B U ~ ) C H ~ C H ( N H A C ) C Ohe~ E orga organozi ~ . nozinc ~ ~ ~nc synthon for formed med from L-glutamic acid (side-chain -C02H -, -2 n I) undergoes Pd-cata Pd-catalys lysed ed condensat i o n w i t h a n a ry l i o d i d e t o g i v e e n a n t i o me ri c a l l y -p u re h ~ mo p h e n y l a l a n i n e s , ~ ~ ~

 

1 : Amino Acidr

59

an d tthe and he equivalent serine-der serine-derived ived ssyn ynth th01 01-P -P~ ~ reacts with acryloyl chloride, followed either by cyclization to give 4-oxopipecolic acid, or by addition of benzylamine to give 4-0xolysine.~~~ hoto-activatable moieties have been added to the isopropenyl and carboxy side-chains of (-)-kainic acid.666 Diels-Alder Diels-Ald er additions o off buta- 1 3-diene667and of Danishefsky's diene [or (E)PhCH = C(CN C(CN)C02 )C02Me Me or 2-me 2-methox thoxybuta ybuta-- 1 3-diene]668o the 2-phenylox 2-phenyloxazolone azolone derived from ap-dehydrophenylalanine (Scheme 32) gives 1-aminocyclohexenecarboxylic acids which can be categorized as conformationally-constrained analogues of common or-amino acids. A heterocyclic version (97) aris arises es by 1,3dipolar addition of 2,6-dichlorobenzonitrile oxide to 4-methyleneoxazolidin-5Methylenation of the D-glyceraldehyde-derived 2-oxazolone gives a mixture of five five cyclop cyclopropanes, ropanes, with the (1S,2R)-derivat S,2R)-derivative ive as predominant Conventional modifications modification s to the alicyclic moiety of alicyclic a-am a-amino ino acids include ethylene biosynthesis from 1-aminocyclopropanecarboxylic acid671 acid671and and hydrogenolytic hydrogenolyti c ring-opening of aziridinecar aziridinecarboxylates boxylates (98).672Studies of ssaturated aturated heterocyclic imino acids include stereoselective additions of alkylcopper reagents to cyclic acylimini acyliminium um ions formed from pipecolic and a remarkable ringexpansion (Scheme 33) of 5- and 6-membered members of this class to 8- and 9 membered homologues through the reaction with acetylenic dipolarophiles of azomethine ylides ylides formed with formaldehyde. formaldehyde.674 674 Oxidation of urethane-protected L-proline methyl ester to L-pyroglutamic acid with iodosylbenzene/trimethylsilylazide/CH2C12lso causes 5-substituti 5-substitution on (insertion of N 3 C1, or OH; other substituents and reaction conditions can alter the pattern patt ern of reactions).6 reactions).675 75 Electroche Electrochemical mical oxidation of L-proline followed by methylcopper addition to give trans-5-methyl-L-pr0line.~~~ ,4-Dehydro-Lproline (from hydroxy-L-proline) serves as starting material in a route to (2S,3R74S)-epoxyprolin (2S,3R74S)-e poxyproline e m-chloroperb m-chloroperbenzoic enzoic acid) accompanied by its diaste diasterre ~ i s o m e r . ~he~ ~ epoxides give an 8.3: 1 mixture of 3-methyl-4-hydroxy- and egio- and 4-methyl-3-hydroxyprolines hrough LiCuMe2 ring-~pening.~~~ stereoselective hydroxylation of the enolate of 4-oxoproline is a stage in a route to swainsonine [(2R,3S,4R)-3,4-dihydroxy-2-hydroxymethylpyrr0lidine].~~~ Hydroxy-L-proline Hydroxy-L-pr oline is also the starting point (conversion into its cis-isom cis-isomer) er) in a synthesis of 'de(hydroxymethy1)desulfo-analogues' of the 0-sulfonated glycopeptides, bulgecins A, B , and C . 6 8 0 Aromatic side-chain modifications that have been accomplished include the preparation of Boc-L-(4-~arboxy)phenylalaninerom the corresponding tyrosine O-triflate,681preparation O-triflate,681 preparation of 0-glycosylated Fmoc-L-tyrosine pentafluorophenyl esters,682 anodic oxidation of 3,5-dibromotyrosine methyl ester to generate caremicolin models (99),683 anodic oxidation or thallium(II1) nitrate oxidation and zinc reduction to give isodityrosine and dityrosine derivatives.684Electroderivatives.684Electrooxidation685and oxidation685 and cyc cycli lic c voltammetric monitoring of the oxidation686o f L-DOPA, elaboration of the phenolic side-chain and transesteri transesterification fication of tyrosine, giving L-DOPA esters by combine combined d tyrosinase tyro sinase a and nd cl-chymotr cl-chymotrypsin ypsin treatment,68 treatment,687 7 are also reported. 5-S-Cystei 5-S-CysteinylDOPA nylDOPA undergoes oxidation under physiologica physiologicall conditions to give pheomelanins via 1,4-benzothia~ ines.~i~d~e an anio ion n ra radi dica call

 

Amino Acids, Peptides and Proteins

60

Reagents: i, HCHO; i i

RCfCC02Me

Scheme 33

C02Me Br

ci

TFAN

Br

H

(99)

H

 

I

61

Amino Acids

attack on tyrosine generates the oxygen-centred phenoxide radical, and the e v eenn tu tu aall r e aacc t i o n p ro r o dduu cctt is d i - m - t ~ r o s i n e . ~ ~ ~ G ene ratio n of a fluore fluorescent scent species species (hexcit 20 nm, hem 392nm) by treatm ent of tryptophan with nitrous acid has been reported, without speculation or evidence for its structure.690 structure.690X-R X-R ay analys analysis is691 691 up ports the stru cture (10 (100) 0) aass ssign igned ed to an Nim -trifl -trifluoroacetylated uoroacetylated reaction pro du ct from the react reaction ion of N-methox ycarbonyl-L-tryptophan bonyl-L-t ryptophan methy methyll ester ester wit withh T F A and pyri pyridin dine; e; the m inor reacti reaction on product (6 )692 is the all-cis isomer (101; R = H) accompanying 84% of the isomer with inverted inverted ring junction pro ton s, which iiss the prod uc t eexpecte xpectedd on the basis of existing knowledge of tryptophan cyclic tautomers. Thus, the wellestablis esta blished hed Nim -toluene-p-sulfonyl analogue, which undergoes a highly diastereoselecti eosel ective ve aldol add ition t o benzaldehyde benzaldehyde after d epr oto nat ion with LDA,693has appeared in several papers recently (see also Ref.268). The diastereoselectivity of Pictet-Spengler processing of tryptophan esters (RCHO + H 2 N imine -+ (2-Hydroxyethylthio)-substitucarbolines) depends on the ester alkyl tion a t posi positi tions ons 2 and 7 of the indole moiety of tryptophan by treatment with H ~ ( O A C )ollowed ~ by mercaptoethanol explai explains ns a si side-rea de-reacti ction on observe observedd d urin g peptide synthesis.695 Histidine chemistry described in the current literature covers a 1: 1: 1-adduct -

involving the imidazole moiety of th e Na-acetylamino acid, with involving with m alondialdehyde an d an alkan al (but no reaction reaction in the absenc absencee of the alkana alkana1), 1),696 696 orm ation of a Michael-type adduct N-Z- 1 3)-( 1'-formylmethy1)hexyl-L-histidine as a model for atta ck o n proteins by lipid breakdown products,697 and P-att P-attack ack by hydroqu inone on a prote pro tect cted ed hist histiidi dine ne to gi g ive th thee p-(2 p-(2,, 33-di dihy hydr drox oxyp yphe heny nyl) l) h o m ~ l o g u e . ~ ~ * S-[2-Carboxy- 1-(1H-imidazol-4-yl)ethyl]-3-thiolacticcid is a new histidine histidine m etabolite isolated from urine; it has been synthesized from the cysteine adduct th ro u g h H N 0 2 d e - a m i n a t i ~ n . ~ ~ ~ Arn dt-Eiste rt homologation of (2S,3S)-3-methylaspartic acid giving (2S,3R)-3methylglutamic acid competes favourably with a bis(1actim ether) synthesis.' l 7 Ra po po rt-ty pe alkylation of asp artic acid-deri acid-derived ved enolates gives gives syn- or anti anti-2,3-2,3pyrrolidinedicarboxylic acids,700 acids,700 also independently prepared in essential essentially ly the same been w ay;7o1 the samefrom con formationally-constrained aspartic (1 acid an alogues have synthesized the glutamic acid-derived synthon 02).702a-tert02).702 a-tertButyl-y-methyl N-Z-glutamate gives the y-anion with lithium hexamethyldisilazide, which is a convenient source of y-substituted glutamic acids through r e a c t i o n w i t h e l e c t r ~ p h i l e s . ~he ~ ~ protected N-hydroxyornithine analogue FmocNHCH(C02H)CH2CH2CHRNHOCH2CH2SiMe3merges from a synthesis starting with L-glutamic acid (side-chain -C02H - C H = N O T B D M S) a n d cyclized via the N-hydroxysuccinimide ester to give NaNs-protected Ns-hydrox y c y c lo - o r n ith i n e a n d i t s h o m ~ l o g u e . ~-Indolylmethyl ~ ketone formation through the side-chain carboxy group of aspartic acid provides the novel sweet compound monatin after stereospecific conversion of the side-chain carbonyl group into -C(OH)(C02H )-. )-.705 705 Protected L-pyroglutam ic acid acid continues to be on e of the mo st freque frequentlyntly-used used chiral synthons in general organic chemistry, and no less so as starting materia materiall for the prep aration of oth er am ino aci acids. ds. 4,4-Di4,4-Di-subst substitut itution ion can be acc accompli omplished shed -

 

62

Amino

Acids, Peptides and Proteins

a f te r L i H D DM M A d e - p r o t ~ n a t i o n , -Methylenation ~~~ and -cyclopropanation have been described, either via the 4-(dimethylaminomethyl)pyroglutamate formed from the lithium lithium enola te of a pyrog lutam ate an d Eschen Eschenmoser moser's 's salt, o r throug h an imidazolidinone synthesis (see Section 4.2; introduction of a B u 0 2 C C ( = CH2)CHZIndependen tly, the same rou te ha s been followed by oth er wo rkers, bu t with som e different different mi no r deta details ils.708 .708 Re du ctio n of the lactam carbonyl group of pyroglutamates to -CH2-, leaving other reducible functions functi ons intact, proceeds via the hemiam inal (success (successivel ively, y, LiEt3BH a n d S iEt,H/ BF 3.Et2 0).709 he hemiaminal w as reacted reacted with sta stabil biliz ized ed p hosp hon ates to give products of Wittig synthesis that were isolated as 5-substituted prolines (103 104; trans:& = 5:l) thro ug h cyclizat cyclization ion of the interm ediate alkene.710 LPyroglutaminol methoxymethyl ether has been used to synthesize ( + -1,8-di-epiand (-)-1-episwainsonine through construction of a piperidine ring on NH and ether functions, functions, and m anipu lation of the pyrrolidine pyrrolidine functi functional onal Pyroglutamic acid-derived synthons used in large-scale synthetic enterprises include (105; manzamine A);712and A);712and (106 and its epoxide; natural polyhydroxyl a t e d p y r r o l i d i n e ~ ) . ~he~ ~L-pyroglutamate-derived synthon (1 0 6 can be subjected ject ed to stereosel stereoselecti ective ve epoxidation to give (2S,3S)-3-hydroxyprolinerom which (-CO;?H + -C H 20 H ) castanodiol can be obtained,714 nd (2 (2S, S,3S) 3S)-3-3-met methyl hylpr prooline an d (2S,3R)-3-pheny lproline were p rep ared similarly.715 Pyroglutam inyl c h l o r i d e ( f r o m ooxx a l y l c h l o r i d e a nndd T M S - p y r ~ G l u ) nd ~ ~it its ~s N -Fm oc deri derivat vative ive (from Fmoc-L-glutamic acid via the dichloride formed using SOC13 have been obtained.717 NP-Glycosylated asparagines may be prepared by reaction of Fmoc-L-aaspartic esters with a glycosyl azide under the influence of Et3P/CH2C12.718NPAralkyl-protected asparagines and glutamines can be cleaved by boron tris(trif l u oorr o aacc e t a t e ) i n T F A / A c O H . ~ ' ~rou ~ rou te t o asp artic aci acidd P-semi-a P-semi-aldehyde, ldehyde, based on ozonolys ozonolysis is of a protected all allylgl ylglycine, ycine, avoids less satisfact satisfactory ory steps in routes from aspartic acid itself.720Low itself.720 Low yields when reducing the acid chloride (30 ) were encountered, however, in a route (-C02H + -COC COC11 -CH O) from amethyl Z-L-asp artate, bu t could be improved when the reduction reduction was perf performed ormed in presence of palladium.721Development palladium.721 Development of 6-oxodecahydroisoquinoline-3the N-acryloyl compound into thethe conformationally-constrained a-amino acid, carboxylic carboxyl ic acid, is descr described ibed in this T h e aldehyde was isolated as the dimethyl acetal, a device also used in a related study using glutamic acid y~ e m i a l d e h y d e , ~ ~hich , also features in a synthesis of differentially protected meso-2,6-diaminopi meso-2,6diaminopimelic melic Ap pro pria te protection was invol involved ved in all these studies, and in the latter route, manipulation of the side chain carboxy grou p (Witti (Wittigg hom ologation etc) of the oxazo lidinone w as us used. ed. F o rm r m a t iioo n ooff m eett h yl y l e tthh e rs rs f ro ro m pr p r o ttee ct ct e d s er er in eess a n d t h r e o n i n e ~ ~n d~ ~ benzyl benz yl et ethers, hers,726 726 ncludi ncluding ng benzylat benzylation ion providi providing ng precursors precursors to pho toactiva table ~ i d e - c h a i n s ,ol ollo ~low ~w ~ stand ard phase transfer alkylation proc procedur edures. es. Routes t o 2acetamido-2-deoxy-~-D-glycosides,728 corresponding 2-acetamido-galactog a l a c t o ~ i d e s , n~ d~ ~g l y c o t e t r a ~ s e s ~ave ~ ~ been explored. A cumbersome rou te from &-hydroxy-L-norl &-hydroxy-L-norleucine eucinegives gives homochiral3-amino-7-substituted a z e p i n o n e ~ . ~ ~2R,3S,4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine ~ and

 

63

1: Amino A cids

n

H02C

 

64

Amino Acid s, Peptides and Proteins

(2S,3R,4S,5S)-3,4-dihydroxy-2 (2S,3R,4S,5S)3,4-dihydroxy-2,5-dihydroxyme ,5-dihydroxymethylpyrrolidine thylpyrrolidine ave been prepared

from D-seri D-serine ne a nd D- ribon olacto ne, res respect pective ively. ly.733 733 A number of synthetic opportunities follow from the juxtaposition of amino, carboxy and primary alcohol functions in seiine, e.g. a lengthy synthesis of Fmoc-yy-di-t-butyl-y-carboxy-L-glutamicc i d f r o m D - ~ e r i n e . ~ ere, ~ ~ the carboxy group of the starting material becomes the extended side-chain of the product via an aldehyde, and the -CH20H side-chain becomes the eventual carboxy group, accounting for the 'L-from-D' nature of the process. The synthetic uses of L-serinal derivatives are proliferating, and two papers report improved syntheses syntheses of a protected protected form , the G arn er aldehyde (107; R = H), one route735 avoidi avoiding ng the need fo r methy methyll iodide and benz benzene ene and the other , als alsoo explored for the threonine homologue (107; R Me) using an LiBH4 and CO C1 2/D M S0 se sequenc quencee for the ini initi tial al st stages ages.7 .736 36 D-T hreo nine giv gives es the corresponding syn thon throu gh standa rd st steps eps.7 .737 37 P-Bra P-Branche nchedd a-a m ino acids have been obtained through the sequence -CHO -+ - C H ( O H ) C = C H -, bromoall e n e ~ . ~new ~ ~electrophilic L-alaninol synthon (1 08), prepared from L-serine, undergoes nucleophilic substitution by Gilman cuprates or Grignard reagent/ CuX complexes.739The complexes.739 The related N-acylated synthon derived from L-serine (109; R 1 = But, R 2 = H) gives bicyclic Dieckmann products leading to useful homochiral tetramic acids.740N-Z-L-Serine acids.740 N-Z-L-Serine p-lactone reacts with trimethylsilylamines M e3 SiN R2 primarily by alkyl oxygen cle cleavage, avage, to give optical optically-pure ly-pure p-aminoalanines (certain reaction conditions cause acyl-oxygen cleavage leading t o ~ e r i n a m i d e s ) . ~he~ chiral ~ oxazolidinone ((11 lo ), formed fro m serine, threonine or cysteine (S in place of ring 0 using bis(trichloroethy1) carbonate742gives carbonate742 gives N-ally1 N-all y1 derivatives tha t und erg o intramolecular oxime-alkene cycloaddition, t o g iv e p ~ r r o l i d i n e s . ~ther ~ ~ ring-closure reactions involving serine include samariu m m(( I 1 ) i o ddii d ee-- m mee ddii a ttee d c y ccll iz a t io n o f N - a l l ~ l - n~ d~ p r ~ p a r g y l - s e r i n a l s ~o ~ ~ givee 2,3,4-trisubsti giv 2,3,4-trisubstituted tuted pyrrolidines (1 1 1). Acces Accesss to homochiral Sa lky lpip era zine-2-carboxylic acids (1 12) is initiated by condensation of L-serine with an a-amino (o-Aminoalky1)-a-amino acids, notably lysine, are also represented in broader organic synthesi s, an d the side side-chai -chainn function ha s hat beenhave devel developed oped added into d iazoacetamides synthesis, L-N2CHCONH(CH2)4CH(NH2)C02Et been to C6*fullerenes full erenes to give a [60]ful [60]fullere lerene-fus ne-fused ed cyclopropane carrying an am ino acid structure.747 structure. 747 Simpler side-chai side-chainn m odifi odificati cations ons are illust illustrated rated by th e pre pa ratio n o f NE-(carboxymethy1)-L-lysine and NS-(carboxymethy1)-L-ornithine through N'-(carboxyethy1)-L-ornithine synthase-mediated reductive condensation with g l y ~ x y l a t e , nd ~ ~conventional conventiona ~ l p repara tions of N"N"-Fmoc-LFmoc-L-lys lysine ine an d NS -Fm ocL-ornithine fro m copper( copper(I1) I1) complexes of the am ino acids. acids.749 749 A m ore invol involved ved sequence (successi (successively, vely, sodium nitroprusside, CBr4/P Ph3, p-brom oaniline) leads t o NQ-Z-N -(p-bromopheny1) -(p-bromopheny1)-L-lysine -L-lysine similarly, to N'-(p-bromopheny1)L-histidine from Z-hi~tidine).~ he~ ~&-amino &-amino group of N*-Z-L-lysine methyl esterr has been converted (d imethyldioxirane in acetone) in to the nitr on e [ - N H 2 -, este - N + 0 - ) CMe21 from which (H then Ac20) Na-Z-NE-acetoxy-L-lysine methyl ester was secured.75' Th ere may be useful analytical applications associated associ ated w ith the finding th at the ninhydrin-Fe(II ninhydrin-Fe(II1) 1) syst system em reacts specifi specificall callyy

 

I

Amino Acids

65

R2g>C0,Me R

N

OACHRR

OSiMe2Bu'

H2

R

H

Oq~NYcH*)3cH

NHAc /

\ C02H

Me

C 02Me Me0

C 02Me

 

66

Amino Acid r, Peptides and Proteins Proteins

with lys with lysine ine at pH 1 (but n not ot with ornithine, arginine, histidin histidine, e, proline or gly~ine.~~~ Reactions of the side-chain amino group of lysine, some of them modelling in vivo protein behaviour, have been studied. A useful synthon (113) for the synthesis of substituted piperidines, piperidines , has been prepared in fiv five e steps from LL-lys lysine ine using conventional precedents.753With precedents.753With 4,5-epoxy-Z(E)-heptenal (a lipid peroxidation product), lysine gives the pyrroles [114; R' = CH(C02H CH(C02H)(CH2)4NH )(CH2)4NH2 2o orr (CH2)&H(NH2)C02H; R2 = H, CH(OH)Et)] together with the isomeric compounds formed through the a-amino With methylglyoxa methylglyoxal, l, reve reversib rsible le glycosylation occurs through conversion of the initially-formed imine into unknown 01igomers.~~~ he process is irreversible with arginine, giving 43dihydroxy-5-methylimidazolines 1 1 5), the imidazolin-4(5)-ones derived from these showing fluorescence (hexcit320 nm, hem 398 nm). L-Lysine has been converted into a protected L-a-amino-6-mercaptohexanoiccid via a pyridinium analogue.756Anodic oxidation of di-N-methoxycarbonyl-L-lysine ethyl ester in di-N-methoxycarbonyl-L-lysineethyl methanol gave the a-methoxyo a-methoxyoxazolidinon xazolidinone e (1 16) whose stere stereoselective oselective azidolysis and reduction have provided the first example of an optically-pure a-aminoamine.7s7 Efficient access has been worked out, to NG-methyl-D- and -L-arginine from the ornithines and MeNHC(SMe) = NH2+ I-,758 and further study of preparations of side-chain sid e-chain protected arginine, either the long w way ay rou round nd [synthesis of w,w'-bis(urethane)s w,w'-bis(uretha ne)s by Ns-guanylation of ornithine with bis(urethane)prot bis(urethane)protected ected 1 guanylpyrazole~ ],~r ~directly ~ by o - a r e n e s u l f ~ n y l a t i o n .n~ the ~ ~ latter study, no improvement on a currently-used protecting group of this family, the Mtrgroup, was achieved by the introduction of electron-donating alkyl groups into the aryl moiety. Electro-oxidation Electro-oxidation of arginine at Pt electrodes liberates nitrate ion through an electron transfer mechanism.761This is an interesting result, because it shows that inorganic nitrogen oxides can be released from arginine without the presence of nitric oxide synthase; the bustling activity in the nitric oxide area is illustrated by a synthesis synthe sis of the NO synthase inhibitor N -hydroxy-N -methyl-Larginine in 8 steps from NG-Z-L-argi NG-Z-L-arginine.762 nine.762 Tetrahydropyrimidines formed fromtetrahydropy reaction of rimidin-4( 2,4-diaminobutyric acid wit with h other amino have beenand related tetrahydropyrimidin-4( 1H)-ones have bee been n identified as self-degrada self-degradation tion products of bel bellenamine lenamine ((R)R)H2N(CH2)3CH(NH2)CH2CONHCH2NH2, P-lysinamide from Streptococcus nashvillensis that shows useful immuno-enhancing HIV protease inhibitory action. The formaldehyde need needed ed to t o generate the reaction products is supplied by hydrolytic cleavage of the -NHCH2NH2 moi moiety ety of the natural Methyl 4,5-diaminopentanoate cyclizes to 5-aminomethylpyrrolidinone and 5-aminopiperidinone in dilute aqueous alkali.765 The thiol function of cysteine shows important oxidation reactions, illustrated with a kinetic study of photo-oxidation H 2 0 2 ) of N -a~ etylcysteine~ ensitized ~~ by N-(9-methylpurin-6-yl)pyridinium alts,767 alts,767and and one-electron oxidation by the azide radical anion at pH 10.5 leading to intramolecular proton abstraction and subsequentt processes. subsequen processes.768 768 S-Arenesulfe S-Arenesulfenylation nylation of cysteine derivatives, with the objective of placing a photoactivatable group at sulfur, has been achieved using

 

I

Amino Acids

67

the ap app prop ropriat riate e pyrid-2-yl d i s ~ l f i d e . ~hiolysis ~~ of S-(SCM)cysteine hydrochIoride in water gives S-(alkanesulfenyl)~ysteines.~~~ -Trifluoromethylation -Trifluorom ethylation of N,C-protected cysteines has been accomplished,771 nd other S-protection strategies are featured in the current literature: (novel) S-(allyloxycarbonylaminom e t h y l ) a t i ~ n , ~nd ~ ~ (traditional) benzylation with improved methods for introduction through benzyl cations or ArCHO/Et$3H.773 Cyclic ketimine formation from (2-aminoethyl)-L-cysteine mediated by snake venom L-amino acid o x i d a ~ earallels ~ ~ ~ the process observed with the cystath cystathionine ionine de-amination product, S-(2-oxo-2-carboxyethyl)-L-homocysteine.775he ketimine readily undergoes autoxidation tto o the s ~ l f o x i d e . ~ itric ~ ~oxide is released from S-nitrosocysteine under physiological conditions, and there have been several recent studies of the consequences of this, one being the destruction of zinc-sulfur clusters in proteins.777 Studies of methionine and other S-alkyl cysteines reflect similar themes. Slow oxidation of S-(2-prope S-(2-propenyl)cystein nyl)cysteine e and its sulfoxide b by y aqueous nitric one- and two-electron oxidation of methionine by peroxynitrite HOONO via the radical HOONO. lead leading ing firs firstt to the sulfoxide an and d ultimately to the liberation of ethylene),779 ethylene),77 9 and 2,2'-bipyr 2,2'-bipyridinium idinium chlor chlorochromate ochromate oxidation of methion methionine, ine, established by a kinetic study tto o involve a sulfura sulfurane ne tran transition sition state.780 NPhthaloyl-L-methionine ethyl ester undergoes the expected reaction with S02C12 to give a a-chlorosulfide mixture that yields the aldehyde-containing side-chain on hydrolysis (-CHClSM (-CHClSMe e + -CHO).781 -CHO).781S-Phenyl-L-cysteine S-Phenyl-L-cysteine is best oxidized to the sulfone s ulfone with magnes magnesium ium monoperoxy monoperoxyphthalate, phthalate, giving a versatil versatile e synthon fo forr preparations of S ) - or (R)-cycloalkylglycines and prolines and analogues.782 Facile alkylation a to the sulfone function with stereocontrol is also the basis of the use of the same synthon for syntheses of (2S,3S)- and (2R,3R)-pyrrolidine2,3-dicarboxylic 6.4 Effects of Electromagnetic Radiation on Am ino Acids - The topics covered in this section over the years continue to surface in the literature, which has provided a aco coun unts ts of yy-rradiolysis of a aqu que eou ouss t y r ~ s i n e ~nd ~ ~ 3,5-di-

ithan o d ~320 tyro sin e . ~hoto-oxidation ~benzothiazines, ~ of whereas 5-S-cysteinylDOPA at wavelengths longer nm gives cleavage of the aliphatic moiety to yield yie ld DOPA is the consequ consequence ence of irradi irradiatio ation n a att 28 2800-32 320 0 nm.786 nm.786Time-resolved Time-resolved fluorescence of the protein cross-linking amino acid, dityrosine, has been evaluated.787 As usual, most of the papers concern tryptophan and its analogues, with investigations of products of photolysis o f tryptophan in aqueous solutions,788 and of quenching of singlet oxygen by aqueous tryptophan (comparisons with tyrosine, histidine, methionine and cysteine were also included in this Fluorescence decay studies focus on constrained tryptophan analogues, e.g. 3amino-l,2,3,4-tetrahydrocarbazole-3-carboxyliccid,790 amino-l,2,3,4-tetrahydrocarbazole-3-carboxylic cid,790and and on a new reference compound with an ultra-short fluorescence lifetime.791Supersonic lifetime.791Supersonic gas expansion studies of tryptophan and substituted analogues permit the allocation of fluorescence lifetime lifetimess t o indiv individual idual conformers.792Phosphorescence decay of tryptophan involves energy transfer between individual molecules in the triplet excited

 

Amino Acid s, Peptides and Proteins

68

state.793Low-temperature UV photolysis of tryptopha try ptophan n yiel yields ds stable products via anion and cation radicals, the products surviving warming to room temperature; th they ey sho show w tthe hems msel elv ves to be e effficient lu lumi mine nesc scen ence ceq ~ e n c h e r s . ~ ~ ~

7

Analytical Methods

7.1 Introduction - Several useful reviews of methods of amino acid analysis have appeared, e.g. e.g. analysis of dansylamino acids.795 7.2 Gas-Liquid Chromatography - The importance of sample clean-up prior to derivatization and GLC analysis of amino acids has been stressed.796 Derivatization incorporating an extractive alkylation of amino acids with pentafluorobenzyl bromide follo followed wed by N-heptafluorobutyroylation illustrates the greater attention being paid to sample authenticity, prior to GLC analysis incorporating negative ion CI-MS.797Similar CI-MS.797Similar derivatization approaches employ N(S)-isopropoxycarbonyl methyl esters (sulfur-containing amino acids),798and acids),798and N(0)-isobutoxycarbonyl t-butyldimethylsilyl esters. esters.799 799Alkyl Alkyl chloroformates can provide a one-step derivatization procedure for amino acids in aqueous solution,

to give N-alkoxycarbonylamino acid alkyl esters (the alkyl ester group derives from the breakdown of the chloroformate, but an alc alcohol ohol is usuall usually y added in tthe he reagent cocktail, to ensure complete reaction).800Use reaction).800Use of a different alcohol, of course, give givess more flexib flexibility ility but also more complications, since ethyl esters a are re also formed when when the EtOCOC1/CF3CH20H/pyridine eagent is used.s used.s0' 0' The stable isotope dilution technique has been employed in the otherwise standard GC-MS analysis of cysteic and homoc homocysteic ysteic acids, and cysteinesulf cysteinesulfinic inic and homocysteinesulfinicacids acids.802 .802 Enantiomer separation by GLC has been reviewed.*03 Chiral GLC analysis of N-trifluoroacetylamino acid methyl esters on a 2,6-di-O-butyl-3-O-trifluoroacetyl-y-cycl acetyl -y-cyclodext odextrin rin capillary column,804and of N-trifluoroacetylamino acid isopropyl esters with Chirasil-L-Val Chiras il-L-Val as stat stationary ionary phaseso phaseso5 5 has be been en accomplished. 7.3 Thin-Layer Chromatography - Routine they may be, but several projects have been reported recently that are useful; comparisons of cellulose with silica gel for their performance in quantitative TLC,806a TLC,806a study of resolution of DLamino acids on borat borate-gelle e-gelled d guara guaran-impregnated n-impregnated silica g gel elso so7 7and on copper(I1)L-proline-im L-prol ine-impregna pregnated ted silica gel gelso8 so8 from the point of vi view ew of the analy analytical tical resolution of DL-amino acids. Careful attention to detail is rewarded by reproducible quantitative TLC TL C of lysine lysine,, threonine and homoserine. homoserine.809 809 The preceding studies base their results on conventional ninhydrin colourformation, though other spray reagents (p-dichlorodicyanobenzoquinone, (p-dichlorodicyanobenzoquinone,pplicpplicable down to 0.1 0.1 pg,slo and 4-dimethylaminobenzaldehyde for quantitative quantitative TLC of tryptophan)811continue tryptophan)811continue to be advocated. New sol solven ventt system systemss pypy-C6H C6H6 6 = 2520, MeOH-CC4 = 1220, and acetoneCH2C12 = 0.3:8, have been been sugges suggested ted for the TL TLC C of PTHs.812

 

1 : Amino Acidr

69

7.4

High Performance Liquid Chromatography - Not all the papers cited here deal simply with analytical studies; the chemistry of stationary phases and of derivatizat deriva tization ion protoc protocols ols is frequently inv involv olved ed in the rreports eports.. Revi Re view ewss have appeared of amino ac acid id de ri ~a ti za ti on ,~ fluoro fluorogenic genic labelling,814 nd derivatization for enantiomeric analysi analysis.815 s.815 Nearly all HPLC analysis protocols for amino acids call for pre-column derivatization, usually usually the formation of a N-substituted N -substituted amino acid mixture from the sample, prior to chromatographic separation and quantitation of the individual components. One commo commonly-u nly-used sed derivatization protocol is N-phenylthiocarbamoylation (PTC; for a review, see Ref.816), for amino acids in genera1817 and arogenic acid (the biogenetic precursor in plants of phenylalanine and ty tyro rosi sine ne)) in pa part rtic icul ular ar,8 ,818 18 or as aspa part rtic ic an and d glu gluta tami mic c ac aciids and a ~ p a r a g i n e ,nd ~~~ hydrolysates hydroly sates o off pr proteina oteinaceous ceous material in pollen820 pollen820and and in old paintings.821Use paintings.821Use of the analogous N-butylthiocarbamoylamino acids seems to have no extra justification, though they show excellent chemical stability.8224-(3-Pyridinylstability.8224-(3-Pyridinylmethylaminocarboxypropyl)phenylthiohydantoins, the cyclization-rearrangement products of the correspondingly-substituted PTC-amino acids, have been studied by HPLC-electrospray MS.823 Conditions for HPLC analysis of PTH mixtures, mixtu res, avoiding reagent-related background peaks, have be been en established.824 N-(Fluoren-9-ylmethoxycarbonyl)amino cids (Fmoc-amino acids) are gradual ally ly gaini gaining ng acc acceptance eptance for HPLC analys analysis,825 is,825 eactions follo following wing derivatization being avoided avoi ded by the use of heptylamine tto o re remove move e exce xcess ss reagent.826 A specialized interest is represented in HPLC of Fmoc-(S)-alk(en)yl-L-cysteine sulfoxides sulfox ides in Analysi Analysiss of imino acids as Fmoc derivatives after removal of primary primar y ami amines nes from samples by conversion into isoind isoindoles oles (OPA(OPA-amino amino acids) using o-phthaldialdehyde and mercaptoethanol has been represented in analysis of glyphosate (N-phosphonomethylglycine),828 and in mainstream studies of protein amino acids,8 acids,829 29 inclu including ding special ref reference erence to automa automated ted analysis.830The OPA-amino O PA-amino acid pre-treatment procedure also al allows lows th the ee estimastimation tion of 4-h 4-hyd ydro roxy xypr prol olin ine e in bio biolo logi gica call flu fluid idss as it itss P T C - d e r i ~ a t i v e . ~ ~ ~ OPA-Derivatization and quantitation of the derivatives continues tto o be confidently used, and a total time of 17 minutes has been claimed for analysis of an amino acid mixture.832 It has been used for L-lysine in wheat gliadin proteins,833 or primary amino acids in rat plasma,834and plasma,834and in a rare example of post-column OPA-derivatization of amino acids separated by ion-exchange c h r o m a t ~ g r a p h y . ~s ~has ~ been mentioned frequently in the recent literature (see Vo1.25, p.75) there is some uncertainty about the reliability of OPAderivatization because of limited stability of the derivatives, and a study has shown that OPA-amino acid derivatives decompose to the extent of about 6 % over 15 h (though their t heir methyl esters reach this point of decay after 8 h).836 h).836The The structurally-related, highl highly y fluor fluorescent, escent, derivativesformed using naphthalene-2,3dialdehyde continue tto o be explored.837 Comparison of HPLC analyses of D- and L-threo-P-methylphenylalanine L-threo-P-methylphenylalanineby the o-phthaldia o-phthaldialdehyde-merc ldehyde-mercaptopropioni aptopropionic c cid method, use of Marfey’s reagent (1 -fluoro-2,4-dinitrophenyl-5-L-alaninamide), -fluoro-2,4-dinitrophenyl-5-L-alaninamide),nd nd alkaline acetic anhydride procedures,, as we cedures well ll as the us use e of GL GLC C (N-trifluoroacetyl isobutyl ester) leads to n o

 

70

Amino Acids, Peptides and Proteins

particular re c~ mm en da ti on .~-Acetylamino ~~ acids in urine have been estimated by HPLC HPL C with M S detection,839whereas derivatization a t the carboxy group with 9-anthryldiazomethane has been advocated for the determination of N-acetylamino acids released from proteins using pro tease^.^^^ Benz Benzoyl oyl chloride chloride has also been revisited for derivatization, and converts amino acids into 2-phenyl-5benzoyloxyoxazoles, benzoyloxy oxazoles, permitting analysis at the 1 pmol level with the assistance of electrospray M S monitoring.841 monitoring.841Analysis Analysis of kainic acid as either N-(4-azidobenzoy1)- or N-(4-azidoPTC)-derivatives, has been described.842 D a n s y l a t i ~ n nd ~ ~dabsylation844provide dabsylation844 ~ provide stable derivatives and good HPLC separation separat ion can be achieved. One of these was aimed a t verifyin verifying g the stability of common amino acids in 6 M HCl. Analysis by electrospray M S of underivatized basic amino acids and N-hydroxylamino acids is moderately successful, but dansylation gives improved reliability.845Dansyl-L-phenylalanine reliability.845Dansyl-L-phenylalanine can be detected down to approximately 5 x mol levels.846 -Hydroxyproline assay through dabsylation followed by OPA-derivatization OPA-derivatization provides reproducible reproducible results fo for lo low levels of a n a l ~ t e . ~ ~ ' In a comparison with PTC-derivatization, 6-aminoquinolinyl-N-hydroxysuccinimide treatment of amino acids (giving AQCamino acids; L a x48 nm)848is clearly superior unless there is a minimal time delay between derivatization and HPLC.849Highly fluorescent asymmetric ureas are formed between amino acids HPLC.849Highly and the carbamate of the AQC reagent, and HPLC analysis with their help gives results tha t hatt compare we well ll with classical ion-exchange ion-exchange analysis.850 Use of a polymeric reagent carrying this ca carbamate rbamate has been explored.s5' Post-column derivatization with 1,2-naphthoquinone-4-sulfonate h a ,05 nm)) has nm has be been en appl applie ied d to sam sampl ples es sepa separa rate ted d by by ion-pa ion-pair ir lliq iqui uid d chromat~graphy.~~~ Particular structural characteristics that allow specific analytical targetting are shown by some common amino acids. This is illustrated for cysteine and homocysteine analysis, conversion into the N-acetyl S-pyridinium derivative,853 or in into to deriv erivat ativ ives es fo form rmed ed with with r n o n ~ b r o m o b i n a n e , nd ~ ~derivatization ~ using 7 fluorobenzo-2-oxa-l,3-diazole-4-sulfonate.855on-derivatized samples (electrochemical detection of cysteine, using a glassy carbon electrode),ss6 and of SU Vfor adenosyl-L-ho adenosyl-L-homocysteine mocysteine and S-adenosyl-L-methionine S-adenosyl-L-m ethionine detection,857 proved to be suitable for analysis. An interesting development developby ment the HP HPLC LChave ionexchange analysis of underivatized amino acids exploits the chemiluminescence formed between amino acids and in situ-generated Ru(bipy)3.8s8Protocols Ru(bipy)3.8s8Protocols for HPLC of related amino acids (excitatory amino acids carrying sulfonic and sulfinic acid side-chain~),~~~ nd selenium analogues of sulfur-containing amino acids,860 ave been worked out. Tryptophan and its 5-hydroxy-derivative in cerebral fluid have been estimated by HPLC HP LC with electrochemical detection,861an and d thro th rough ugh fluoresence detection hexcit 302 nm, hern 340 nm).862 Increasing numbers of HPLC studies of crosslinking amino acids reflect the importance of some of them as markers for metabolic disorders. Pyridinoline and its deoxy-analog deoxy-analogue ue have domina dominated ted these reports,863 which which describe minor differences in protocol, one of which (use of acetylated pyridinoline as internal standard)8H needs care so as to minimize its decompo~ition.~~~ stimation of

 

1: Amino Acids

71

aldosine as its oxidative oxidative decarboxylati decarboxylation on product (Fe3 ), 6-(3-pyridyl)piperidine2-carboxylic 2-carboxyli c acid,866 acid,866and and of desmosine and isodesmosine isodesmosine as dansyl derivatives.867 Analysis of p-boronophenylalanine in tissue is an essential adjunct to studies of the uses uses of this amino acid in neutron c capture apture therapy.868 Estimation of enantiomer ratios for amino acids is most commonly achieved now by modifications of the derivatization methods outlined above. Thus, the use of a homochiral thiol ( N - a c e t y l - L - c y ~ t e i n e ~ r~ ~N-isobutyroyl-L?~~~ or D~ y s t e i n e ~ ~n' .the ~ ~OPA ~ ) procedure permits the complete separation of 18 DLamino acids. One of these papersp70describes papersp70describes a dating study concentrating on aspartic acid extracted from dentin, and applicable down to 1 pmol levels. ( + -I(9-Fluoreny1)ethyl (9-Fluoreny 1)ethyl chloroforma chloroformate te similarly y yiel ields ds diastereoisomer diaste reoisomer mixt mixtures ures allowing the estimation of D/L-ratios of amino acids in crustacean nerve A new fluorophore, N-[4-(6-methoxy-2-benzoxazolyl)benzoyl]-L-proline,as been bee n introduced for the same purp purpose.873 ose.873 Protected amin amino o acids for us use e in peptide synthesis have been derivatized with Marfey's reagent for enantiomeric purity estimations.874 The other main approach to HPLC determinations of enantiomer ratios involves the incorp incorporation oration of chiral species into a silica ge gell stationar stati onary y phase (a crown ether, applied to tyrosine and DOPA and analogues),8753-aminopropyanalogues),8753-aminopropylated silica gel acylated by 2,4-dinitrobenzoyl-(R)-( -naphthyl)glycine for the analysis of tryptopha tryptophan n and aspartic tetra-este tetra-esters rs of cali calix[4] x[4]aren arenes es bonded to silica gel for the estimation of DL-amino acid esters877)and esters877)and bovine serum al albu bumi min n b bon onde ded d to si sillica gel ffor or tthe he reso resolu luti tion on o off D L - t r y p t ~ p h a n . ~irkle~~ type columns have been used for enantiomeric analysis of amino acids derivatized with 4-fluoro-7-nitro- or 4-dansyl-7-fluoro-2,1,3-benzoxadiazole, he former reagent giving superior results.87 results.879 9 'Chiralcel-OD' [cellulose tris(3,5dimethylphenyl carbamate)] gives good results for a series of 17 Fmoc-amino acids.880

7.5

Fluorimetric Analysis - This section collects miscellaneous exploratory studies that have not been covered elsewhere in this Chapter, such as separation

of derivatized amino acids using the fast centrifugal centrifu gal analyserS8' analyserS 8' and enhancement of the fluorescence of naphthalene- 1,2-dialdehyde-derivatized mino acids by cyclodextrins as mobile phase constituents in HPLC.882

7.6

Other Analytical Methods - Clearly, the applications of capillary zone electrophoresis (CZE) and related methods are developing rapidly, as demonstrated by the dedication of a CR C volume to it.883There are seve several ral applicationss in the amino acids application One of these concentrat concentrates es on CZE of cysteine and cystine employing electrochemical detection, as does anothe?86 that also covers a broader range of analytes. Separation of a mixture of 24 dansylamino acids is sharpened by Tween micelles in the liquid phase,887 and separation of PTHs with good distinction of artefactual peaks has been accomplished.888 accomplishe d.888 hese stu studies dies u use se sample preparatio preparation n protocols that are familiar from the HPLC field, and this is also seen in use of Fmoc-derivatization for estimation of hydroxyprolin hydroxyproline e in serum after OPA-treat OPA-treatment,889 ment,889 enantiomeri enantiomeric c

 

72

Amino Acids, Peptides and Proteins

separations of PTHs using N-dodecanoyl-L-serine, -glutamic acid, or -valine micelles,ggOand micelles,ggO and of dansylamino acids891 usin using g cyclodextrins as buffer additives,892also additives,892 also used for dansyl- and OPA-amino acids.893The power of modern methodology is revealed in the estimation, at 140 ppm levels, of the enantiomeric purity of phenylalanine derivatized by 4-fluoro-7-nitrobenz-2,1,3oxadiazole and separated by CZE with cyclodextrin-containing buffers and using laser-induced (488 nm) fluorescen fluorescence ce detection.8 detection.894 94 Chiral stationary phases are also compatible with CZE enantiomeric purity determination, and mechanistic aspects have been explored.895The explored.895The practice of CZE resolution has been reviewed.896 Immunoassay techniques have not been surveyed thoroughly in this Chapter over the years, though attention is drawn to unusual relevant studies such as the estimation of desmosine d esmosine in biological

Assays for Specific Amino Acids - Most of the papers under this heading revolve around enzymatic methods, both in the biosensor category and in flow injection analysis techniques. However, the latter approach can also accommodate standard chemical methods of analysis, such as Chloramine-T oxidation of hydroxyproline to generate a stable colour with Ehrlich's reagent.898

7.7

Photometric estimation of tryptophan depends on the formation of a coloured complex by Fe3 t- /AcOH/glycollic acid oxidation.899 Simultaneous estimation of L-lysine and L-tyrosine based on enzyme-supported flow injection analysis uses two enzyme reactors and a single oxygen electrode.g00A electrode.g00 A similar approach accommodates L-alanine and L-phenylalanine, with a ffllow iinje njecti ction on fibr fibre e op optic tic bio biosen sensor sor pro provid viding ing the mea means ns o off q u a n t i t a t i ~ n , ~ ~ ' also for chemilumines chemiluminescence cence generated spe speci cific fical ally ly wh when en L-lysine is present, associated with a lysine oxidase/microbial oxidase/microb ial peroxidase membrane membrane.902 .902 Measurement of oxygen generated in the latter system defines the L-lysine content of a sample.g03 More conventional biosensor biosensor studies also appear in the current literature literature,, often leapfrogging existing technology, but usually adding further illustration of established methods. 'micro-enzyme sensor', based on immobilized acid oxidase, has beenA proposed for the qu quantitation antitation of L-amino acids in L-amino urine,904 and a combined L- and D-amino acid oxidase version assays total D- and Lamino acids.g05The acids.g05The immobilization of of a peroxidase with a D-ami D-amino no acid oxidase on an electrode measures D-amino acid concentrations in proportion to H202 liberated.906A liberated.906 A process for the electrodeposition of poly(tyramine) on to electrodes provides amino groups through which an L-amino acid oxidase can be immobilized to give satisfactory sensors.9o7An sensors.9o7An estimation of D-amino acids is based on the formation of D-norleucine by bacterial D-amino acid transaminase coupled with 2-oxohexanoic 2-ox ohexanoic acid.g08 The majority of curr current ent ami amino no ac acid-biosensor id-biosensor reports concern L-glutamic acid and its relatives, with immobiliz immobilized ed gluta glutamic mic acid oxidaseW9 linked through glutaraldehyde to an aminopropyl-platinized platinum wire, for amperometric r n e a s u r e m e n t ~ . ~ ~similar ~ glutarate-immobilized glutamic acid oxidase + glutaminase sensor permits amperometry of glutamic acid and glutamine, which

 

73

1 : Amino Acids

together with lactic acid can be estimated as a total entity using rhodinized carbon electrode^.^^' The list is completed by an L-glutamic acid + NADH sensor,9* a glutamic gluta mic acid decarboxy decarboxylase-coated lase-coatedelectrode?' electrode?' and an L-glutami L-glutamine ne sensor comprising kidney sl slic ices es and an ammonia-se ammonia-sensing nsingelectrode.914 electrode.914

References 1

2 3

4 5 6 7

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

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