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FACULTAD DE FARMACIA DEPARTAMENTO DE FARMACOLOGÍA Y QUÍMICA TERAPÉUTICA

SÍNTESIS ESTEREOSELECTIVA DE cis -DECAHIDROQUINOLINAS: -DECAHIDROQUINOLINAS: INTERMEDIOS AVANZADOS PARA EL ACCESO A LAS LEPADINAS LEPADINAS  

MARISA MENA CERVIGÓN 2006

 

 

7.

EXPERIMENTAL

281

 

 

 

 Experimental

Experimental General.. All reactions were carried out under an argon atmosphere with dry, freshly General distilled solvents under anhydrous conditions. Analytical TLC was performed on SiO 2  (silica gel 60 F254, Merck) or Al2O3  (ALOX N/UV254, Polygram), and the spots were located with iodoplatinate reagent. Chromatography refers to flash chromatography and was carried out on SiO 2  (silica gel 60, SDS, 230-240 mesh ASTM) or Al2O3  (aluminium oxide 90, Merck). Drying of organic extracts during workup of reactions was performed over anhydrous Na2SO4. Optical rotations were recorded with a Perkin-Elmer 241 polarimeter. 1H and

13

C NMR spectra were recorded with a Varian

Gemini 200 or 300 instrument. Chemical shifts are reported in ppm downfield (δ (δ) from 1

Me4Si. Si.   All new compounds were determined to be >95% pure by

H NMR

spectroscopy.

CHAPTER 2. (R  (R )-1-CHLORO-5-METHOXYMETHOXY-OCTANE )-1-CHLORO-5-METHOXYMETHOXY-OCTANE ((C) C)

O

1.4 eq. MCPBA

Cl

R -salen

Cl

CH2Cl2

43%

1.3 h from 5 ºC to rt

6-Chloro-hex-1-ene

1,2-epoxy-6-chlorohexane

83%

OH O

EtMgBr, CuI

Cl

82%

Cl B

(R )-O -methyl-mandelic acid DCC DMAP O

OMOM

O

MOMCl, DIPEA 98%

Ph OMe

Cl

Cl C

C3H7 D

  (1S  (1S )-1,2-epoxy-6-chlorohexane )-1,2-epoxy-6-chlorohexane To a solution of (+)-1,2-epoxy-6-chlorohexane (888 mg, 6.6 mmol), which was prepared from 6-Chloro-hex-1-ene (MCPBA, DCM) by the procedure previously 41

reported , the catalyst ((R  ((R ,R )- Salen, Salen, 20 mg, 0.005 eq.) and AcOH (36 µL, 0.025 eq.) at 0 ºC, H2O (66 µ (66 µL, L, 0.55 eq.) was added in one portion. After 16 h, (1S  (1S )-1,2-epoxy)-1,2-epoxy283

 

Capítulo 7

6-chlorohexane (382 mg, 2.83 mmol, 43%) was isolated by distillation under reduced pressure (67 ºC, 0.1 atm). The enantiomeric purity of the recovered epoxide was determined by optical rotation. Colourless oil. [[α α]25D  +8 +8   (c  1.0,   1.0, CHCl3); 1H NMR  NMR  (200 MHz, CDCl3): δ 1.40-1.70 (m, 4H), 1.70-1.95 (m, 2H), 2.50 (dd (dd,, J  =  = 4.9, 2.7 Hz, 1H), 2.76 (dd, J  =  = 5.0, 3.8 Hz, 1H), 13

2.86-2.98 (m, 1H), 3.56 (t, J  =   = 6.6 Hz, 2H); C NMR (50 MHz, CDCl3): δ 23.4 (CH2), 31.7 (CH2), 32.2 (CH2), 44.8 (CH2), 46.9 (CH2), 52.0 (CH).

(4R  (4R )-8-Chloro-octan-4-ol )-8-Chloro-octan-4-ol (B) A mixture of CuI (11 mg, 0.06 mmol) in Et2O (8 mL) was cooled to -78 ºC and treated with EtMgBr (3.4 mL, 3.4 mmol) 1 M in THF. After 15 min, (1S  (1S )-1,2-epoxy-6)-1,2-epoxy-6chlorohexane (382 mg, 2.84 mmol) in Et2O (1 mL) was added, and the mixture was brought to r.t. overnight. The mixture was hydrolyzed with HCl (2 mL) and extracted with Et2O (3 x 50 mL). The resulting organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to an oil which was purified by chromatography (SiO2, 9:1 hexane/AcOEt) to give B  as a colourless oil (432 mg, 82%).  82%).  R f f   = 0.15 (SiO2, 9:1 hexane/AcOEt);   1H NMR  NMR  (200 MHz, CDCl3) δ 0.93 (t, J  =   = 7.1 Hz, 3H), 1.21.7 (m, 6H), 1.7-1.9 (m, 2H), 3.55 (t, J  =   = 6.6 Hz, 2H), 3.50-3.70 (masked, 1H);

13

C

NMR   (50 MHz, CDCl3): δ 14.1 (CH3), 18.8 (CH2), 23.0 (CH2), 32.2 (CH2), 32.6 (CH2), NMR 36.6 (CH2), 39.7 (CH2), 45.0 (CH2), 71.4 (CH).

(D) DMAP (2 mg, 0.013 mmol) was added all at once over a mixture of B (21 mg, 0.13 mmol), (R  (R )-O  )-O -methylmandelic -methylmandelic acid (22 mg, 0.13 mmol) and DCC (30 mg, 0.14 mmol) in CH2Cl2  (1 mL). The reaction mix mixture ture was stirred at rt overnigh overnight. t.

Then, the

dicyclohexylurea was removed by filtration and the filter cake was washed with hexane (3 x 10 mL) and the combined filtrates were washed with HCl (2 x 10 mL), Na2CO3 (2 x 10 mL) and brine (2 x 10 mL), dried over Na2SO4 and concentrated to an oil which was purified by chromatography (SiO2, 9:1 hexane/AcOEt) to give D as a single diastereoisomer (37 mg, 90%).  90%).  Colourless oil. R f f   = 0.26 (SiO2, 9:1 hexane/AcOEt); 1H NMR  NMR  (200 MHz, CDCl3) 0.72 (t, J  =   = 7.0 Hz, 3H), 1.2-1.6 (m, 6H), 1.75-1.85 (m, 2H), 3.42 (s, 3H, OMe), 3.46 (t, J  =   = 6.6 Hz, 2H), 4.75 (s, 1H, CHOMe), 4.86-4.99 (m, 1H).

284

 

 Experimental

(4R  (4R )-1-chloro-5-methoxymethoxy-octane )-1-chloro-5-methoxymethoxy-octane ((C) C) To a solution of B  (381 mg, 2.33 mmol) in CH 2Cl2  (8 mL) was added diisopropylamine (8.1 mL, 46.6 mmol) followed by MOMCl (1.8 mL, 23.3 mmol). The resulting mixture was stirred at rt overnight. The reaction was quenched with H 2O. The aqueous aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated to an oil which was purified by chromatography (SiO2, 9:1 hexane/AcOEt) to give C  as a colourless oil (474 mg, 98%).   R f f   = 0.46 (SiO2, 9:1 hexane/AcOEt);   1H NMR  98%). NMR  (200 MHz, CDCl3): δ 0.92 (t, J  =  = 7.0 Hz, 3H), 1.2-1.6 (m, 6H), 1.75-1.85 (m, 2H), 3,38 (s, 3H), 3.54 (t, J  =  = 6.6 Hz, 2H), 3.50-3.60 (masked, 1H), 4.65 (s, 2H);

13

C NMR  NMR  (50 MHz, CDCl3): δ 14.3 (CH3), 18.5

(CH2), 22.7 (CH2), 32.7 (CH2), 33.6 (CH2), 36.5 (CH2), 45.0 (CH2), 55.5 (CH3), 77.0 (CH), 95.4 (CH2).

285

 

Capítulo 7

CHAPTER 4. (2S  (2S ,,3S  3S )-3-AMINO-1-(4-METHOXYPHENYL)BUTAN-2-OL )-3-AMINO-1-(4-METHOXYPHENYL)BUTAN-2-OL (5a) (S ) CO2H

CO2H O

HO

(+)-DIPCl / Et3N THF 8.5 h  from -20 ºC to 25 ºC

5 eq. MeI / 4 eq. K2CO3 DMF 15 h 25 ºC

OH

HO I

92%

O

CO2Me  5 eq. NH(OMe)Me.HCl 10 eq. iPrMgCl 2 M THF OH THF

MeO

N OH

MeO

4.5 h  from -20 ºC to 25 ºC

II

O

II IIII

O

O N

TBSCl / Imidazole DMF 24 h 25 ºC

MeO

O MeMgBr 3 M THF

OTBS

THF 4h   from 0 ºC to 25 ºC

IV

67 % from I

(S )

4 eq. NaBH4 / 0.15 eq. CeCl3 MeOH 1.5 h -20 ºC

OH (R )

OTBS

MeO V

2 eq. MsCl / 2 eq.Et3N CH2Cl2

OTBS

MeO

VI

15 h 25 ºC

81 % from IV

 9  95 5%

e.d. 84 % N3 (S ) (S )

OMs (S ) (R )

H2 / Pd-C

3 eq. NaN3 MeO

OTBS VII

NH2 (S ) (S )

MeO

OTBS IX

DMF 72%

OTBS

MeO

 

90%

NH2 (S ) (S )

HCl 5% v/v MeOH 1h rt 80%

EtOH

VIII

MeO

 

OH 5a

  (S )- β  )- β  β  -  (4-hydroxyphenyl)lactic (  4-hydroxyphenyl)lactic acid [L-Hpla] (I) β  β-  A solution of  β -(4-hydroxyphenyl)pyruvic -(4-hydroxyphenyl)pyruvic acid (Aldrich, 901 mg, 5 mmol) in THF (18 mL) was treated with Et 3N (0.7 mL, 5 mmol) at -20 ºC. After 30 min at this temperature, a solution of (+)-DIPCl (1.9 g g,, 6 mmol) in THF (6 mL) was was added, and the resulting solution was stirred at rt for 8 h. The reaction mixture was quenched 286

 

 Experimental

with 2 N aqueous NaOH (10 mL) and H 2O (5 mL). The aqueous layer was washed with tert -butylmethylether -butylmethylether (2 x 20 mL) and the organic layer with H 2O (2 x 30 mL). The combined aqueous phases were acidified with HCl 2 N to pH 1 and extracted with AcOEt (4 x 50 mL), dried and concentrated to give L-Hpla I (846 mg, 92 %) as a white solid. The spectroscopic data were identical to its enantiomer previously 30

R f  =

25 10.7   (c  0.56,  0.56, [α] D  −10.7 [α

(SiO2,

reported . 0.40 1:1 AcOEt/MeOH); m.p. 162-164 ºC. 1 CHCl3); H NMR NMR   (200 MHz, CDCl3) δ 2.90 (dd, J  =   = 14.0, 8.0 Hz, 1H, H-3), 3.4 (br s,

1H, OH), 4.34 (dd, J  =  = 7.8, 4.4 Hz, 1H, H-2), 6.75 (d, J  =  = 8.4 Hz, 2H, H-6, H-8), 7.10 (d, J   = 8.8 Hz, 2H, H-5, H-9);

13

C NMR (50 MHz, CDCl3): δ 40.7 (C-3), 73.0 (C-2),

116.0 (C-6, C-8), 129.5 (C-4), 131.5 (C-5, C-9), 157.0 (C-7), 177.5 (C-1).

(2S  (2S )-2-Hydroxy-3-(4-methoxy-phenyl)-propionic )-2-Hydroxy-3-(4-methoxy-phenyl)-propionic acid methyl ester (II) K2CO3 (558 mg, 4 mmol) was added to a solution of hydroxy acid I (182 mg, 1 mmol) in DMF anh. (1 mL). After the mixture had been stirred for 15 min at rt, MeI (0.32 mL, 5 mmol) was added drowise and the mixture was stirred overnight. The mixture was quenched with H2O (20 mL) and extracted with AcOEt (3 x 20 mL). The dried organic extracts were concentrated to give II II (210  (210 mg) as a brown oil wich was used without further purification. The NMR data were identical to the racemic compound previously reported79. R f f   = 0.23 (SiO2, CH2Cl2); 1H NMR  NMR  (200 MHz, CDCl3) δ  2.40 (br s, 1H), 2.91 (dd, J  =   = 14.0, 6.6 Hz, 1H), 3.06 (dd, J  =   = 14.0, 4.4 Hz, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 4.42 (dd, J  =  = 6.6, 4.4 Hz, 1H), 6.83 (d, J  =  = 8.4 Hz, 2H), 7.13 (d, J  =  = 8.4 Hz, 2H); 13

C NMR (50 MHz, CDCl 3): δ 39.6 (CH2), 52.4 (CH3), 55.2 (CH3), 71.4 (CH), 113.9

(CH), 128.2 (C), 130.5 (CH), 158.6 (C), 174.5 (C). (C).  

(2S  (2S )-2-Hydroxy-N  )-2-Hydroxy-N -methoxy-3-(4-methoxy-phenyl)-N  -methoxy-3-(4-methoxy-phenyl)-N -methyl-propionamide -methyl-propionamide (III) To a solution of ester II II   (210 mg, 1 mmol) in THF (15 mL) cooled to -20 ºC under argon atmosphere Me(MeO)NH.HCl (542 mg, 5 mmol) was added and then over 30 min a solution of iPrMgCl 2.0 M in THF (5 mL, 10 mmol) was added dropwise maintaining maintai ning tthe he temper temperature ature a att -20 °C. The m mixture ixture was sti stirred rred 2 h at --20 20 °C and 2. 2.5 5 h from

-20 °C to rt. The mixture was quenched with saturated saturat ed aqueous NH4Cl

solution (50 mL). The organic layer was dried and concentrated to afford the corresponding Weinreb amide III III (240  (240 mg) as a yellow oil, which was used without fur 79

Rho, H; Ko, B. Synth. Commun.  Commun. 1999 1999,, 29 , 2875. 287

 

Capítulo 7

ther purification: R f f   = 0.29 (SiO2, CH2Cl2 /MeOH 99:1). 1H NMR  NMR  (200 MHz, CDCl3): δ  1.60 (br s, 1H), 2.81 (dd, J  =   = 13.8, 7.2 Hz, 1H), 3.01 (dd, J  =   = 13.9, 3.8 Hz, 1H), 3.72 (s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 4.55-4.65 (m, 1H), 6.83 (d, J  =   = 8.7 Hz, 2H), 7.14 (d, J  =  = 8.4 Hz, 2H);

13

C NMR (50 MHz, CDCl3): δ 29.7 (CH3), 40.1 (CH2), 55.2 (CH3),

61.4 (CH3), 69.8 (CH), 113.8 (CH), 129.2 (C), 130.4 (CH), 158.4 (C), 168.6 (C). (2S  (2S )-2-(tert  )-2-(tert -Butyl-dimethyl-silanyloxy)-N  -Butyl-dimethyl-silanyloxy)-N -methoxy-3-(4-methoxy-phenyl)-N  -methoxy-3-(4-methoxy-phenyl)-N methyl-propionamide (IV) To a solution of Weinreb amide III III (231  (231 mg, 0.97 mmol) in DMF (3 mL) at rt under argon atmosphere imidazol (344 mg, 4.8 mmol) was added and then over the resulting mixture a solution of TBSCl (330 mg, 2.1 mmol) in DMF (2 mL) was added. The mixture was stirred for 18 h and then diluted with Et 2O (20 mL). The organic layer was washed with H2O (10 mL), HCl 1 N (10 mL), NaHCO 3 (10 mL) and brine (10 mL), dried and concentrated to an oil which was purified by chromatography (SiO2, CH2Cl2) to afford the corresponding Weinreb amide IV (229 mg, 67% from I) as a yellow oil. R  oil. R f f   = 0.23 (SiO2, CH2Cl2). 1H NMR  NMR  (200 MHz, CDCl3): δ  −0.14 (s, 3H), −0.10 (s, 3H), 0.81 (s, 9H), 2.76 (dd, J  =  = 13.5, 8.7 Hz, 1H), 2.98 (dd, J  =  = 13.4, 4.4 Hz, 1H), 3.19 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H), 4.58-4.63 (m, 1H), 6.82 (d, J  =   = 8.4 Hz, 2H), 7.14 (d, J  =   = 9.0 Hz, 2H);

13

C NMR (50 MHz, CDCl3): δ −5.3 −5.3 (CH3), −5.2 (CH3),

18.3 (C), 25.7 (CH3), 29.7 (CH3), 40.3 (CH2), 55.3 (CH3), 61.5 (CH3), 71.9 (CH), 113.6 (CH), 130.1 (C), 130.7 (CH), 158.3 (C), 168.5 (C).

(3S  (3S )-3-(tert  )-3-(tert -Butyl-dimethyl-silanyloxy)-4-(4-methoxy-phenyl)-butan-2-one -Butyl-dimethyl-silanyloxy)-4-(4-methoxy-phenyl)-butan-2-one (V) To a solution of Weinreb amide V (222 mg, 0.63 mmol) in THF (8 mL) cooled to 0 ºC under argon atmosphere MeMgBr 3 M in Et 2O (1 mL, 3.1 mmol) was added dropwise. The reaction mixture was stirred for 4 h at 0 ºC and then it was quenched with saturated aqueous NH4Cl solution (5 mL). The organic layer was dried and concentrated to an oil which was purified by chromatography (SiO 2, CH2Cl2) to afford the corresponding ketone V (194 mg) which was used without further purification. The crude product was cromatographed (SiO 2, CH 2Cl2) to provide the pure ketone V  to measure the optical rotation.  rotation.  R f f   = 0.5 (SiO2, CH2Cl2); [α]25D  −39.5 39.5   (c  1.2,   1.2, CHCl3); NMR  (200 MHz, CDCl3): δ  −0.25 (s, 3H), −0.09 (s, 3H), 0.86 (s, 9H), 2.10 (s, 3H),    1H NMR  2.74 (dd, J  =  = 13.6, 8.0 Hz, 1H), 2.86 (dd, J  =  = 13.6, 4.4 Hz, 1H), 3.79 (s, 3H), 4.12 (dd, 288

 

Capítulo 7

−4.66 (CH3), 15.0 (CH3), 17.9 (C), 25.8 (CH3), 36.6 (CH3), 38.7 (CH2), 55.3 (CH3), 74.8 (CH), 79.7 (CH), 113.6 (CH), 130.2 (C), 130.7 (CH), 158.2 (C). Anal. Calcd for C18H32O5SSi: C 55.63, H 8.30, S 8.25. Found: C 55.93, H 8.60, S 7.95.

(1S  (1S ,2S  ,2S ))-[ -[2-Azido-1-(4-methoxy-benzyl)-propoxy]2-Azido-1-(4-methoxy-benzyl)-propoxy]-tert  tert -butyl-dimethyl-silane -butyl-dimethyl-silane (VIII) To a solution of VII VII (70  (70 mg, 0.18 mmol) in DMF (1.5 mL) under argon atmosphere Na N3 (40 mg, 0.54 mmol) was added. The mixture was heated at 60 ºC for 6 h. Then, 3 equivalents more of NaN3  (40 mg, 0.54 mmol) were added and the mixture was stirred for 24 h. After cooling, the mixture was poured in water (5 mL) and extracted with Et2O (3 x 15 mL). The resulting organic layer was dried and concentrated to an oil which was purified by chromatography (SiO2, CH2Cl2) to give VIII VIII (43  (43 mg, 72%) as a colourless oil. R f f   = 0.86 (SiO2, CH2Cl2); [α]25D  −18.6 18.6   (c  1.0,   1.0, CHCl3);      1H NMR  NMR  (300 MHz, CDCl3): δ −0.13 (s, 3H), 0.09 (s, 3H), 0.93 (s, ( s, 9H), 1.29 (d, J  =  = 6.9 Hz, 3H), 2.70 (dd, J  =  = 13.6, 6.8 Hz, 1H), 2.80 (dd, J  =  = 13.6, 6.8 Hz, 1H), 3.80 (s, 3H), 3.44 (qd, J  =  = 6.9, 4.4 Hz, 1H), 3.95 (td, J  =  = 6.8, 4.4 Hz, 1H), 6.88 (d, J  =  = 8.8 Hz, 2H), 7.14 (d, J  =  = 8.4 Hz, 2H);

13

C NMR (75 MHz, CDCl 3): δ −4.9 −4.9 (CH3), −4.7 (CH3), 13.7 (CH3), 18.1

(C), 25.9 (CH3), 39.0 (CH2), 55.3 (CH3), 60.4 (CH), 76.3 (CH), 113.7 (CH), 130.0 (C), 130.5 (CH), 158.2 (C).

(2S  (2S ,3S  ,3S )-3-(tert  )-3-(tert -Butyl-dimethyl-silanyloxy)-4-(4-methoxyphenyl)-2-butanamine -Butyl-dimethyl-silanyloxy)-4-(4-methoxyphenyl)-2-butanamine (IX) A suspension of VIII (43 mg, 0.13 0.13 mmol) and Pd/C (23 mg mg)) in MeOH (1 mL) was stirred at room temperature under hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite and the filtrate was concentrated to give an oil which was purified by chromatography (Al2O3, CH2Cl2 saturated with NH3) to give  give  IX (36 mg, 90%) as a colourless oil. R f f   = 0.45 (Al2O3, CH2Cl2 saturated with NH3); [α [ α]25D  18.6   (c  1.2,  1.2, CHCl3);   1H NMR  NMR  (300 MHz, CDCl3): δ  −0.30 (s, 3H), −0.06 (s, 3H), 0.84 −18.6 (s, 9H), 1.11 (d, J  =   = 6.6 Hz, 3H), 2.20-2.40 (br s, 2H), 2.65 (d, J  =   = 6.6 Hz, 2H), 2.903.00 (m, 1H), 3.70-3.80 (m, 1H), 3.79 (s, 3H), 6.81 (d, J  =   = 8.4 Hz, 2H), 7.08 (d, J  =  = 8.4 Hz, 2H);

13

C NMR (75 MHz, CDCl3): δ −4.9 −4.9 (CH3), −4.65 (CH3), 17.9 (CH3), 18.1

(C), 25.9 (CH3), 37.5 (CH2), 50.7 (CH), 55.3 (CH3), 77.9 (CH), 113.6 (CH), 130.5 (CH), 131.0 (C), 158.0 (C). Anal. Calcd for C17H31NO2Si: C 65.97, H 10.10, N 4.53. Found: C 65.78, H 10.21, N 4.26.

290

 

 Experimental

(2S  (2S ,3S  ,3S )-3-Amino-1-(4-methoxyphenyl)butan-2-ol )-3-Amino-1-(4-methoxyphenyl)butan-2-ol (5a) To a solution of IX IX (30  (30 mg, 0.1 mmol) in MeOH (1 mL) was added concentrated HCl (0.05 mL, resulting in a 5% v/v solution in MeOH). The resulting solution was stirred for 1 h at rt and then saturated aqueous NaHCO 3 (10 mL) was added. The product was extracted with Et2O (3 x 15 mL), dried and concentrated to an oil which was purified by chromatography (Al2O3, CH2Cl2 saturated with NH3 /MeOH 9:1) to give 5a 5a   (15 mg, 80%) as a colourless oil. R f f   = 0.3 (Al2O3, CH2Cl2 saturated with NH3 /MeOH 9:1);  [α]25D  −15.0 15.0   (c  1.0,   1.0, CHCl3); 1H NMR  NMR  (300 MHz, CDCl3): δ     1.12 1.12 (d, J  =   = 6.6 Hz, 3H), 2.56 (dd, J   = 14.0, 8.6 Hz, 1H), 2.74-2.86 (m, 2H), 3.40-3.46 (m, 1H), 3.78 (s, 3H), 6.84 (d, J  =   = 8.7 Hz, 2H), 7.14 (d, J  =   = 8.7 Hz, 2H);

13

C NMR  NMR  (75 MHz, CDCl3): δ 

20.5 (CH3), 39.6 (CH2), 50.3 (CH), 54.7 (CH2), 55.2 (CH3), 76.4 (CH), 113.7 (CH), 130.1 (C), 130.2 (CH), 158.0 (C).

291

 

Capítulo 7

CHAPTER 4. (2R  (2R ,,3S  3S )-3-AMINO-1-(4-METHOXYPHENYL)BUTAN-2-OL )-3-AMINO-1-(4-METHOXYPHENYL)BUTAN-2-OL (epi -5a)  -5a) 

(S )

OH

BocHN

SF3 N

O

(S )

O

PrNEt, 0 ºC CH2Cl2

(S )

N

2) 2 eq. O

O

80%

iPrMgCl 2 M THF

1) 1.05 eq

BocHN

HN(OMe)Me

BocHN

i

O

F

MgCl MeO

NHBoc (S )

0.25 0.25 M THF

O

  THF  5 h from -15 ºC to rt

A

76%

O

MeO B

NH2

NHBoc (R )

NaBH4 MeOH 76%

(S )

OH

MeO

(R )

TFA CH2Cl2 79%

MeO

C

(S )

OH epi --5 5a

  (3S  (3S )-3-(α )-3-(α-Boc)-amino-1-(4-methoxyphenyl)butan-2-one -Boc)-amino-1-(4-methoxyphenyl)butan-2-one  (B) (B)   A solution of N --Boc-L-alanine Boc-L-alanine Weinreb amide (176 mg, 0.8 mmol), which was prepared from N -Boc-L-alanine -Boc-L-alanine ([bis(2-methoxyethyl)amino]sulfur trifluoride, DIPEA, HN(OMe)Me, DCM) by the procedure previously reported 72, in dry THF (5 mL) under argon atmosphere was cooled to -15 ºC and iPrMgCl 2 M in THF (0.4 mL, 0.8 mmol) was added dropwise to afford a clear solution. Then 2-methoxybenzylmagnesium chloride 0.25 M in THF (6 mL, 1.5 mmol) was added dropwise. The reaction mixture was allowed to warm to rt over 30 min. After 5 h aged at rt, the reaction was complete. The mixture was cooled over an ice bath and aqueous HCl 1 N (5 mL) was added slowly, followed by AcOEt (5 mL). The aqueous layer was cut and the organic layer washed with H2O (5 mL), dried and concentrated to an oil, which was purified by chromatography (SiO2, CH2Cl2) to give B  as a colourless oil (170 mg, 76%).   R f f   = 0.16 (SiO2, CH2Cl2);      [α]25D  +21.4 76%). 21.4   (c   1.1, CHCl3); 1H NMR  NMR  (200 MHz, CDCl3): δ 1.31 ( d, J  =   = 7.4 Hz, 3H), 1.44 (s, 9H), 3.77 (d, J  =   = 10.2 Hz, 2H), 3.79 (s, 3H), 4.4 (m, 1H), 5.2 (br s, 1H), 6.86 (d, J  =  = 8.4 Hz, 2H), 7.12 (d, J  =  = 8.4 Hz, 2H); 292

13

C

 

 Experimental

NMR   (50 MHz, CDCl3): δ 17.9 (CH3), 28.4 (CH3), 45.4 (CH2), 54.5 (CH), 55.3 (CH3), NMR 79.2 (C), 114.1 (CH), 125.2 (C), 130.4 (CH), ( CH), 155.5 (C), 158.3 (C).

(2R  (2R ,3S  ,3S )-3-(α )-3-(α-Boc)-amino-1-(4-methoxyphenyl)butan-2-ol -Boc)-amino-1-(4-methoxyphenyl)butan-2-ol  (C) (C)   To a solution of ketone B  (130 mg, 0.4 mmol) in MeOH (4 mL) cooled to -50 ºC NaBH4 (30 mg, 0.74 mmol) was added added and the reaction mixture was stirred for 1 h at -50 ºC. After that it was quenched with brine (4 mL) and extracted with CH2Cl2 (3 x 10 mL). The resulting organic layer was dried and concentrated  to give an oil which was purified by chromatography (SiO2, CH 2Cl2) to give C (100 mg, 76%) as a white solid. mp = 88-92 ºC. R f f   = 0.02 (SiO2, CH2Cl2);      [α]25D  −19.8 19.8   (c  1.0,   1.0, CHCl3);      1H NMR  NMR  (300 MHz, CDCl3): δ 1.16 ( d, J  =   = 6.9 Hz, 3H), 1.43 (s, 9H), 2.4 (br s, 1H), 2.50-2.75 (m, 2H), 3.60-3.80 (masked, 1H), 3.79 (s, 3H), 4.9 (br s, 1H), 6.84 (d, J  =   = 9.0 Hz, 2H), 7.13 (d, J  =   = 8.4 Hz, 2H);

13

C NMR  NMR  (50 MHz, CDCl3): δ 14.5 (CH3), 28.4 (CH3), 39.3

(CH2), 50.2 (CH), 55.2 (CH3), 75.3 (CH), 79.3 (C), 114.0 (CH), 130.1 (CH), 130.2 (C), 155.6 (C), 158.2 (C). Anal. Calcd for C 16H25NO4: C 65.06, H 8.53, N 4.74. Found: C 65.26, H 8.46, N 4.66.

(2R  (2R ,3S  ,3S )-3-Amino-1-(4-methoxyphenyl)butan-2-ol )-3-Amino-1-(4-methoxyphenyl)butan-2-ol (epi -5a) -5a) To a solution of C (95 mg, 0.32 mmol) in CH 2Cl2 (3 mL) cooled to 0 ºC under argon atmosphere trifluoroacetic acid (Aldrich, 1.2 mL, 16 mmol) was added and the mixture was stirred for 45 min at 0 ºC. The mixture was diluted with CH 2Cl2 (10 mL) and the organic layer was washed with NaHCO 3  (10 mL). The aqueous layer was extracted with CHCl3 /MeOH 8:2 (2 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated to an oil which was purified by chromatography (Al2O3, CH2Cl2 saturated with NH3 /MeOH 9:1) to give epi -5a as -5a as a colourless oil (50 mg, 79%). R f f   = 0.25 (Al2O3, CH2Cl2  saturated with NH3 /MeOH 9:1);     [α]25D  +15.7 15.7   (c   0.5, CHCl3); 1H NMR  NMR  (300 MHz, CDCl3) δ 1.07 (d, J  =   = 6.6 Hz, 3H), 1.97 (br s, 3H), 2.50-2.80 (m, 2H), 2.82-3.00 (m, 1H), 3.55-3.65 (m, 1H), 3.77 (s, 3H), 6.83 (d, J  =  = 8.8 Hz, 2H), 7.13 (d, J   = 8.8 Hz, 2H);

13

C NMR  NMR  (75 MHz, CDCl3): δ  17.4 (CH3), 38.3

(CH2), 50.1 (CH), 55.3 (CH3), 76.1 (CH), 114.0 (CH), 130.2 (CH), 130.3 (C), 158.1 (C).

293

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