7362 J . Org. Chem., Vol. 66, No. 22, 2001
Vedejs and Kongkittingam
concentrated (aspirator). The residue was purified by prepara-
tive TLC on silica gel (20 × 20 × 0.1 cm, 4:1 hexane/EtOAc
eluent) to give the title compound (20 mg, 98%): analytical
TLC on silica gel, 1:1 hexane/ether, Rf ) 0.25; analytical HPLC,
CHIRALCEL AD (98.5:1.5:0.5 hex/IPA/HOAc, 1 mL/min, P )
232 psi), tR ) 19.59 min (minor diastereomer, tR ) 30.54 min)
>99.7:0.3 dr; IR (neat, cm-1) 3428, N-H; 1710, CdO; 1633,
CdC; 400 MHz NMR (CDCl3, ppm) δ 7.79-7.54 (2H, m), 7.53-
7.49 (1H, m), 7.46-7.42 (2H, m), 6.87 (1H, d, J ) 9.6 Hz), 6.66
(1H, dq, J ) 9.8, 1.6 Hz), 5.12 (1H, dd, J ) 9.8, 9.8 Hz), 5.09
(1H, d, J ) 9.6 Hz), 4.22 (2H, q, J ) 6.8 Hz), 3.05 (3H, s),
1.94-1.86 (1H, m), 1.93 (3H, d, J ) 1.6 Hz), 1.32 (3H, t, J )
6.8 Hz), 1.04 (9H, s), 0.88 (3H, d, J ) 6.6 Hz), 0.79 (3H, d, J
) 6.6 Hz). 13C NMR (100 MHz, CDCl3, ppm) δ 171.7, 167.7,
167.1, 138.2, 134.3, 132.7, 131.6, 128.6, 127.0, 60.9, 56.2, 55.1,
36.0, 31.1, 29.9, 26.6, 19.4, 18.7, 14.2, 13.8.
OJ (92% hex/IPA, 1 mL/min, P)290 psi) tR ) 17.33 min. Pure
material was obtained by crystallization from CH2Cl2/hexane,
mp 167-168 °C. Molecular ion (M + H) calcd for C22H28N3O2:
366.21815; found (CI, CH4) m/e ) 366.2184, error ) 1 ppm;
base peak ) 79 amu; [R]25 -91.0 (c 1.0, CHCl3); IR (neat,
D
cm-1) 3416, O-H; 3266, N-H; 1652, CdO; 400 MHz NMR
(CDCl3, ppm) δ 7.28-7.24 (2H, m), 7.18-7.10 (2H, m), 7.00-
6.97 (2H, m), 6.85-6.81 (2H, m), 6.73-6.71 (2H, m), 6.14 (1H,
br s), 5.52 (1H, br s), 3.75 (3H, s), 3.63-3.56 (2H, m), 3.53-
3.50 (1H, m), 3.50-3.44 (1H, m), 2.37 (1H, dd, J ) 6.0, 6.0
Hz), 2.14-2.06 (1H, br), 1.51 (3H, s), 1.49 (3H, s). 13C NMR
(100 MHz, CDCl3, ppm) δ 175.5, 139.2, 137.7, 128.2, 127.4,
127.2, 126.5, 125.5, 121.5, 120.9, 120.7, 119.0, 109.4, 67.2, 66.5,
63.3, 38.1, 32.7, 25.5, 24.6.
From a mixture of 26 and 27: The 6:1 mixture of 26 and
27 (0.125 g, 0.36 mmol) was stirred with K2CO3A1.5 H2O
(0.030 g, 0.18 mmol) in MeOH (1 mL). DMSO (0.1 mL, 1.44
mmol) and 30% aqueous H2O2 (0.17 mL, 1.44 mmol) as
described above, and the same workup was used to give the
crude product after solvent evaporation. The residue was
purified by column chromatography on silica gel (15 × 2 cm,
25:1 to 20:1 CH2Cl2/MeOH eluent) to furnish 28. Diastereomer
29 (0.0115 g) was eluted first, followed by the desired 28
(0.0689 g, 52%, 63% based on recovered starting material).
N-[(1′R)-2′-H yd r oxy-1′-p h en ylet h yl]-(2R)-2-a m in o-3-
m eth yl-3-(1-m eth ylin dol-3-yl)bu tyr am ide (29). To a stirred
suspension of 27 (0.0407 g, 0.11 mmol) and K2CO3A1.5 H2O
(0.011 g, 0.06 mmol) in DMSO (0.5 mL) cooled in water bath
(ca. 20 °C) was added dropwise 30% aqueous H2O2 (0.35 mL).
After stirring for 36 h, the mixture was worked up as described
for 28. Preparative TLC on silica gel (20 × 20 × 0.1 cm, 25:1
CH2Cl2/MeOH eluent) gave 29 (0.019 g, 48%): analytical TLC
on silica gel, 20:1 CH2Cl2/MeOH, Rf ) 0.26; analytical HPLC,
N-[(1′R)-2′-H yd r oxy-1′-p h en ylet h yl]-(2S)-2-a m in o-3-
m eth yl-3-(1-m eth ylin dol-3-yl)bu tyr on itr ile [(S, R)-26] an d
N-[(1′R)-2′-Hydr oxy-1′-ph en yleth yl]-(2R)-2-am in o-3-m eth -
yl-3-(1-m eth ylin d ol-3-yl)bu tyr on itr ile (27). To a stirred
room-temperature solution of aldehyde 258 (0.43 g, 2.13 mmol)
in dry CH2Cl2 (10 mL) were added (R)-2-phenylglycinol (0.44
g, 3.2 mmol) and Sc(OTf)3 (0.1 g, 0.2 mmol). After 1 h, the
reaction mixture was cooled to 0-5 °C, and tributyltin cyanide
(1.01 g, 3.2 mmol) was added. The mixture was allowed to
warm to room temperature over 20 h before being diluted with
saturated aqueous NaHCO3. The aqueous layer was separated
and was extracted with CH2Cl2. The combined CH2Cl2 extracts
were washed with H2O and brine, dried (Na2SO4), and
concentrated (aspirator). The residue was purified by column
chromatography on silica gel (15 × 2 cm, 2:1 hexane/EtOAc
eluent) to give product as a mixture of diastereomers. The
diastereomers were separated by preparative TLC on silica
gel (20 × 20 × 0.1 cm, 30:1 CH2Cl2/MeOH eluent, two elutions).
The lower Rf zone was 26 (0.6 g, 81%): analytical TLC on
silica gel, 20:1 CH2Cl2/MeOH, Rf ) 0.51; analytical HPLC,
CHIRALCEL OD (90% hex/IPA, 1 mL/min, P ) 290 psi)
tR ) 9.86 min. Molecular ion (M + H) calcd for C22H26N3O:
348.20759; found (CI, NH3) m/e ) 348.2074, error ) 1 ppm;
CHIRALCEL OJ (92% hex/IPA, 1 mL/min, P ) 290 psi) tR
)
25.00 min. Pure material was obtained by crystallization from
ether/CH2Cl2, mp 164-165 °C; [R]25 -71.3 (c 1.01, CHCl3);
D
IR (neat, cm-1) 3350, O-H; 400 MHz NMR (CDCl3, ppm) δ
7.85-7.83 (1H, m), 7.34-7.12 (8H, m), 6.92 (1H, s), 5.96 (1H,
br s), 5.02 (1H, br s), 3.79 (1H, d, J ) 4.0 Hz), 3.77 (3H, s),
3.51-3.36 (3H, m), 2.38 (1H, dd, J ) 7.2, 4.0 Hz), 1.57 (3H, s),
1.53 (3H, s), 1.14 (1H, dd, J ) 6.4, 6.4 Hz). 13C NMR (100 MHz,
CDCl3, ppm) δ 175.5, 141.0, 137.9, 128.4, 127.4, 127.3, 127.0,
125.2, 121.9, 120.8, 120.5, 119.1, 109.9, 67.1, 64.8, 63.9, 38.9,
32.8, 25.4, 24.6
base peak ) 172 amu; [R]25 -126.2 (c 1.31, CHCl3); IR (neat,
D
cm-1) 3455, O-H; 3343, N-H; 400 MHz NMR (CDCl3, ppm)
δ 7.36-7.34 (1H, m), 7.31-7.17 (5H, m), 7.08-7.06 (2H, m),
6.96-6.92 (1H, m), 6.95 (1H, s), 3.99 (1H, dd, J ) 8.8, 4.0 Hz),
3.76 (3H, s), 3.74 (1H, s), 3.68 (1H, ddd, J ) 10.8, 6.0, 4.0 Hz),
3.46 (1H, ddd, J ) 10.8, 8.8, 6.0 Hz), 2.11-2.04 (1H, br), 1.84
(1H, dd, J ) 6.0, 6.0 Hz), 1.61 (3H, s), 1.59 (3H, s). 13C NMR
(100 MHz, CDCl3, ppm) δ 138.2, 137.7, 128.7, 128.0, 127.5,
127.2, 125.6, 121.5, 120.8, 119.6, 118.9, 117.7, 109.6, 67.2, 63.0,
57.8, 38.5, 32.8, 25.6, 25.1. The higher Rf zone was 27 (0.085
g, 11%): analytical TLC on silica gel, 20:1 CH2Cl2/MeOH, Rf
) 0.61; analytical HPLC, CHIRALCEL OD (90% hex/IPA, 1
(2S)-2-Am in o-3-m et h yl-3-(1-m et h ylin d ol-3-yl)b u t yr -
a m id e (30). To a stoppered 10 mL round-bottomed flask,
charged with noncrystallized 28 (0.163 g, 0.44 mmol) and
20%Pd(OH)2 on carbon (Pearlman’s catalyst) (0.20 g) was
added dry MeOH (4.0 mL). The reaction flask was stoppered
with a septum secured by wire. The reaction mixture was
successively degassed (aspirator) and backfilled with hydrogen
gas (balloon) (three times). The mixture was then stirred at
room temperature for 12 h under hydrogen (balloon). Cata-
lyst was removed by filtration through a Celite pad and
washed with 10:1 CH2Cl2/MeOH. Solvents were removed by
aspirator to provide crude material which was purified by
column chromatography on silica gel (15 × 1.5 cm, 20:1 to 10:1
CH2Cl2/MeOH eluent) to provide 30 (0.10 g, 95%): analytical
TLC on silica gel, 10:1 CH2Cl2/MeOH, Rf ) 0.32. Pure material
was obtained by crystallization from MeOH/CH2Cl2, mp 175-
176 °C. Molecular ion calcd for C14H19N3O: 245.15290; found
mL/min, P ) 290 psi) tR ) 19.24 min; [R]25 -25.2 (c 1.1,
D
CHCl3); IR (neat, cm-1) 3474, O-H; 3358, N-H; 400 MHz
NMR (CDCl3, ppm) δ 7.74-7.72 (1H, m), 7.33-7.22 (7H, m),
7.13-7.09 (1H, m), 6.98 (1H, s), 4.06 (1H, br s), 3.76 (3H, s),
3.67 (1H, dd, J ) 6.8, 4.4 Hz), 3.58 (1H, ddd, J ) 11.2, 5.6, 4.4
Hz), 3.50 (1H, ddd, J ) 11.2, 6.8, 6.8 Hz), 1.83-1.78 (1H, br),
1.67-1.63 (1H, br), 1.66 (3H, s), 1.64 (3H, s). 13C NMR (100
MHz, CDCl3, ppm) δ 139.7, 137.7, 128.6, 128.0, 127.33, 127.28,
125.6, 121.7, 120.5, 119.9, 119.1, 117.5, 109.8, 65.6, 63.8, 58.6,
39.2, 32.8, 25.8, 24.8.
N-[(1′R)-2′-H yd r oxy-1′-p h en ylet h yl]-(2S)-2-a m in o-3-
m eth yl-3-(1-m eth ylin d ol-3-yl)bu tyr a m id e (28). From puri-
fied 26: To a stirred suspension of 26 (0.053 g, 0.15 mmol)
and K2CO3A1.5 H2O (0.013 g, 0.075 mmol) in MeOH (0.5 mL)
were added DMSO (43 µL, 0.6 mmol) and 30% aqueous H2O2
(68 µL, 0.6 mmol), respectively. The reaction mixture was
brought to 45 °C for 6 h, and then water and EtOAc were
added. The aqueous layer was separated and was extracted
with EtOAc. The combined EtOAc extracts were washed
successively with H2O and brine, dried (Na2SO4), and concen-
trated (aspirator). The residue was purified by preparative
TLC on silica gel (20 × 20 × 0.1 cm, 20:1 CH2Cl2/MeOH eluent)
to furnish 28 (0.0392 g, 72%): analytical TLC on silica gel,
20:1 CH2Cl2/MeOH, Rf ) 0.22; analytical HPLC, CHIRALCEL
m/e ) 245.1520, error ) 4 ppm; base peak ) 172 amu; [R]25
D
+45.4 (c 1.19, CHCl3); IR (neat, cm-1) 3339, N-H; 3289, N-H;
1679, CdO; 400 MHz NMR (CDCl3, ppm) δ 7.87-7.85 (1H,
m), 7.33-7.31 (1H, m), 7.26-7.22 (1H, m), 7.13-7.09 (1H, m),
6.89 (1H, s), 6.56 (1H, br s), 5.56 (1H, br s), 4.06 (1H, s), 3.76
(3H, s), 1.60 (3H, s), 1.45 (3H, s), 1.30 (2H, s). 13C NMR (100
MHz, CDCl3, ppm) δ 176.3, 138.0, 126.8, 125.6, 121.7, 120.9,
118.9, 109.6, 61.8, 38.8, 32.7, 26.1, 23.2.
(2S)-2-[(Ben zot h ia zole-2-su lfon yl)a m in o]-3-m et h yl-3-
(1-m eth ylin d ol-3-yl)bu tyr a m id e (31). To a stirred 0-5 °C
solution of noncrystallized 30 (0.14 g, 0.58 mmol) and BtsCl
(0.15 g, 0.64 mmol) in CH2Cl2 (6 mL), was added a solution of
Na2CO3 (0.26 g, 2.5 mmol) in water (6 mL) at 0-5 °C. The
resulting suspension was allowed to warm to room tempera-