2316 J . Org. Chem., Vol. 65, No. 8, 2000
Vedejs and Kongkittingam
(2H, m) 1.06-0.85 (12H, m); partial 13C NMR: (CDCl3, ppm;
minor rotamer signals marked *) δ 176.7* 176.1, 170.1, 169.4*,
82.1*, 81.2, 65.8*, 62.5, 58.6, 58.4*, 43.3*, 42.8.
g, 0.162 mmol) to produce Bts-(S)-Leu-(S)-MeLeu-(S)-MeVal-
O-tert-Bu (17) (observed 0.118 g, theoretical yield 0.101 g;
>98% conversion): analytical TLC on silica gel, 7:3 hexane/
EtOAc, Rf ) 0.32; >99.75:0.25 dr after N-methylation and
HPLC assay. Pure material was obtained by crystallization
Bts-(R)-Leu -(S)-MeVa l-O-ter t-Bu (14). Bts-(R)-Leu-(S)-
MeVal-O-tert-Bu (14) (observed 0.092 g, theoretical yield 0.085
g; >95% conversion) was prepared following procedure E from
Bts-(R)-leucine (ent-3b) (0.062 g, 0.187 mmol) and (S)-MeVal-
O-tert-Bu (5a ) (0.0324 g, 0.17 mmol); >99.75:0.25 dr after
N-methylation and HPLC assay; [R]25D -106 (c ) 1.05, CHCl3).
HRMS, M - 73, 424.1365, error ) 7 ppm; IR (neat, cm-1) 3251,
N-H; 1731, CdO; 1643, CdO; 300 MHz NMR (CDCl3, ppm) δ
8.19-8.14 (0.6H, m) 8.08-8.04 (0.4H, m) 7.96-7.89 (1H, m)
7.60-7.47 (2H, m) 6.30 (0.4H, br d, J ) 9.0 Hz) 6.20 (0.6H, br
d, J ) 9.0 Hz) 4.83 (0.6H, ddd, J ) 11.0, 8.0, 2.7 Hz) 4.58 (0.4H,
ddd, J ) 11.0, 8.0, 2.7 Hz) 4.41 (0.6H, d, J ) 10.2 Hz) 3.64
(0.4H, d, J ) 10.2 Hz) 3.16 (1.8H, s) 2.81 (1.2H, s) 2.22-1.97
(2H, m) 1.78-1.22 (2H, m) 1.48 (3.6H, s) 1.24 (5.4H, s) 1.08-
0.72 (12H, m).
from ether/hexane: mp 99-100 °C; [R]25 -58.8 (c ) 1.69,
D
CHCl3). HRMS, M - 73, 551.2465; base peak ) 100 amu; IR
(KBr, cm-1) 3178, N-H; 1732, CdO; 1635, CdO; 300 MHz
NMR (CDCl3, ppm) δ 8.17-8.08 (1H, m) 8.01-7.94 (1H, m)
7.66-7.52 (2H, m) 6.22 (0.9H, d, J ) 9.2 Hz) 6.19 (0.1H, d,
J ) 9.2 Hz) 5.25-5.15 (1H, m) 4.77-4.61 (1H, m) 4.66 (0.9H,
d, J ) 10.2 Hz) 3.80 (0.1H, d, J ) 9.6 Hz) 3.03 (2.7H, s)
3.00 (0.3H, s) 2.86 (2.7H, s) 2.75 (0.3H, s) 2.24-1.99 (2H, m)
1.62-1.37 (2H, m) 1.45 (0.9H, s) 1.40 (8.1H, s) 1.28-1.17
(1H, m) 1.11-0.91 (10H, m) 0.84-0.70 (4H, m) 0.59-0.41 (6H,
m).
Bts-(S)-MeLeu -(S)-MeLeu -(S)-MeVa l-O-ter t-Bu (18). Ac-
cording to procedure A, noncrystallized Bts-(S)-Leu-(S)-MeLeu-
(S)-MeVal-O-tert-Bu (17) (0.098 g, 0.16 mmol) was employed
to produce Bts-(S)-MeLeu-(S)-MeLeu-(S)-MeVal-O-tert-Bu (18)
(observed 0.117 g, theoretical yield 0.101 g, >99% conver-
sion): analytical TLC on silica gel, 7:3 hexane/EtOAc, Rf )
0.37; analytical HPLC, CHIRALCEL AD (96 hex/IPA, 1 mL/
Bts-(S)-Leu -(R)-MeVa l-O-ter t-Bu (en t-14). Following pro-
cedure E, Bts-(S)-leucine (2b) (0.065 g, 0.198 mmol) was
coupled with (R)-MeVal-O-tert-Bu (ent-5a ) (0.035 g, 0.18 mmol)
to produce Bts-(S)-Leu-(R)-MeVal-O-tert-Bu (ent-14) (0.077 g,
89%): analytical TLC on silica gel, 7:3 hexane/EtOAc, Rf )
0.28; >99.75:0.25 er, >99.5% ee after N-methylation and
min, P ) 203.1 psi) TR ) 28.08 min; >99.75:0.25 dr, [R]25
D
HPLC assay; [R]25 +105.7 (c ) 1.25, CHCl3).
-111.1 (c ) 1.01, CHCl3). HRMS, M - 73, 565.2557, error )
7 ppm; base peak ) 297 amu; IR (neat, cm-1) 1733, CdO; 1652,
CdO; 300 MHz NMR (CDCl3, ppm) δ 8.21-8.14 (1H, m) 8.00-
7.94 (1H, m) 7.65-7.52 (2H, m) 5.38 (1H, br t, J ) 7.3 Hz)
5.11 (1H, br t, J ) 7.1 Hz) 4.71 (0.8H, d, J ) 10.2 Hz) 3.86
(0.2H, d, J ) 10.2 Hz) 3.18 (2.4H, s) 3.15 (2.4H, s) 3.11 (0.6H,
s) 3.09 (0.6H, s) 2.91 (2.4H, s) 2.80 (0.6H, s) 2.23-2.08 (1H,
m) 1.78-1.18 (6H, m) 1.46 (1.8H, s) 1.42 (7.2H, s) 1.04-0.68
(18H, m).
D
Bts-(R)-MeLeu -(S)-MeVa l-O-ter t-Bu (15). Bts-(R)-MeLeu-
(S)-MeVal-O-tert-Bu (15) (observed 0.097 g, theoretical yield
0.083 g, >99% conversion) was prepared using procedure A
from Bts-(R)-Leu-(S)-MeVal-O-tert-Bu (14) (0.081 g, 0.162
mmol): analytical HPLC, CHIRALCEL AD (98 hex/IPA, 1 mL/
min, P ) 203.1 psi) TR ) 14.95 min; >99.75:0.25 dr, [R]25
D
-33.4 (c ) 1.1, CHCl3). HRMS, M + 1, 512.2267, error ) 3
ppm; IR (neat, cm-1) 1731, CdO; 1653, CdO; 300 MHz NMR
(CDCl3, ppm) δ 8.21-8.14 (1H, m) 8.00-7.94 (1H, m) 7.64-
7.51 (2H, m) 5.17-5.06 (1H, m) 4.67 (0.6H, d, J ) 10.5 Hz)
4.33 (0.4H, d, J ) 10.5 Hz) 3.17 (1.8H, s) 3.12 (1.8H, s) 3.08
(1.2H, s) 2.88 (1.2H, s) 2.38-2.14 (1H, m) 2.02-1.90 (0.4H,
m) 1.88-1.77 (0.6H, m) 1.52-1.35 (1H, m) 1.49 (3.6H, s) 1.44
(5.4H, s) 1.31-0.99 (5H, m) 0.91-0.79 (8H, m).
(S)-MeLeu -(S)-MeLeu -(S)-MeVa l-O-ter t-Bu (19). Accord-
ing to procedure B, Bts-(S)-MeLeu-(S)-MeLeu-(S)-MeVal-O-
tert-Bu (18) (0.100 g, 0.156 mmol) and PhSH (33 µL, 0.326
mmol) were employed, and the reaction was performed for 4
h to produce (S)-MeLeu-(S)-MeLeu-(S)-MeVal-O-tert-Bu (19)
(0.069 g, 96% based on 13): analytical TLC on silica gel, 4.5:
1:0.5 n-BuOH/H2O/HOAc, Rf ) 0.49; >99.75:0.25 dr after
N-benzoylation and HPLC assay; [R]25D -181.1 (c ) 1.0, CHCl3)
Bts-(S)-MeLeu -(R)-MeVa l-O-ter t-Bu (en t-15). According
to procedure A, Bts-(S)-Leu-(R)-MeVal-O-tert-Bu (ent-14) (0.077
g, 0.155 mmol) was employed to produce Bts-(S)-MeLeu-(R)-
MeVal-O-tert-Bu (ent-15) (observed 0.080 g, theoretical yield
0.079 g, >99% conversion): analytical TLC on silica gel, 4:1
hexane/EtOAc, Rf ) 0.28; analytical HPLC, CHIRALCEL AD
(98 hex/IPA, 1 mL/min, P ) 203.1 psi) TR ) 16.71 min; >99.75:
[lit. [R]25 -183 (c ) 1.0, CHCl3)].3a HRMS, M + 1, 442.3666,
D
error ) 5 ppm; base peak ) 100 amu; IR (neat, cm-1) 3322,
N-H; 1732, CdO 1645; 300 MHz NMR (CDCl3, ppm) δ 5.70-
5.60 (1H, m) 4.74 (0.9H, d, J ) 10.2 Hz) 4.28 (0.1H, d, J ) 9.6
Hz) 3.45-3.33 (1H, m) 3.02 (2.7H, s) 3.00 (2.7H, s) 2.97 (0.3H,
s) 2.78 (0.3H, s) 2.30-2.11 (1H, m) 2.28 (2.7H, s) 2.27 (0.3H,
s) 1.94-1.60 (4H, m) 1.58-1.15 (3H, m) 1.46 (0.9H, s) 1.45
(8.1H, s) 1.10-0.75 (18H, m); partial 13C NMR: (CDCl3, ppm;
minor rotamer signals marked *) δ 175.8, 175.1*, 171.7, 171.4*,
170.0, 169.0*, 82.0*, 81.3, 65.6*, 62.5, 58.8, 58.7*, 51.2*, 50.8,
42.9, 41.8*, 38.8*, 37.9, 35.1, 34.9*.
0.25 dr, [R]25 +34.6 (c ) 1.12, CHCl3) (CDCl3, ppm; minor
D
rotamer signals marked *)
(R)-MeLeu -(S)-MeVa l-O-ter t-Bu (16). (R)-MeLeu-(S)-Me-
Val-O-tert-Bu (16) (0.050 g, 93% based on 5a ), the enantiomer
of ent-16, was prepared using procedure B from Bts-(R)-
MeLeu-(S)-MeVal-O-tert-Bu (15) (0.083 g, 0.162 mmol) and
PhSH (35 µL, 0.34 mmol); >99.75:0.25 dr after N-benzoylation
Bts-(R)-Leu -(S)-MeLeu -(S)-MeVa l-O-ter t-Bu (20). Fol-
lowing procedure E, Bts-(R)-leucine (ent-2b) (0.062 g, 0.185
mmol) was coupled with (S)-MeLeu-(S)-MeVal-O-tert-Bu (13)
(0.053 g, 0.168 mmol) to produce Bts-(R)-Leu-(S)-MeLeu-(S)-
MeVal-O-tert-Bu (20) (observed 0.110 g, theoretical yield 0.105
g; >95% conversion): analytical TLC on silica gel, 7:3 hexane/
EtOAc, Rf ) 0.32; >99.75:0.25 dr after N-methylation and
HPLC assay. Pure material was obtained by crystallization
and HPLC assay: [R]25 -101 (c ) 1.09, CHCl3). Molecular
D
ion calcd for C17H34N2O3: 314.2570; found m/e ) 314.2560,
error ) 3 ppm; base peak ) 100 amu; IR (neat, cm-1) 3322,
N-H; 1733, CdO; 1652, CdO; 300 MHz NMR (CDCl3, ppm) δ
4.84 (0.6H, d, J ) 10.5 Hz) 3.85 (0.4H, d, J ) 10.5 Hz) 3.48-
3.38 (1H, m) 2.99 (1.8H, s) 2.91 (1.2H, s) 2.36-2.13 (1H, m)
2.30 (1.8H, s) 2.26 (1.2H, s) 2.04-1.80 (1H, m) 1.73 (1H, br s)
1.52-1.20 (2H, m) 1.48 (3.6H,s) 1.46 (5.4H, s) 1.05-0.80 (12H,
m); partial 13C NMR: (CDCl3, ppm; minor rotamer signals
marked *) δ 176.8, 176.2*, 170.2, 169.0*, 82.3*, 81.2, 65.7*,
62.6, 58.7*, 58.5, 43.0, 42.2*.
from ether/hexane, mp 143-144 °C; [R]25 -122 (c ) 1.17,
D
CHCl3). HRMS, M - 73, 551.2363, error ) 0 ppm; base peak
) 100 amu; IR (KBr, cm-1) 3165, N-H; 1726, CdO; 1639, Cd
O; 300 MHz NMR (CDCl3, ppm) δ 8.25-8.15 (1H, m) 7.97-
7.90 (1H, m) 7.65-7.48 (2H, m) 6.34 (0.9H, d, J ) 8.1 Hz) 6.26
(0.1H, d, J ) 7.8 Hz) 5.47 (0.1H, dd, J ) 10.2, 7.6 Hz) 5.29
(0.9H, t, J ) 7.2 Hz) 4.75 (1H, ddd, J ) 11.0, 8.1, 2.7 Hz) 4.49
(0.9H, d, J ) 10.2 Hz) 3.91 (0.1H, d, J ) 10.2 Hz) 3.13 (0.3H,
s) 3.09 (2.7H, s) 2.68 (0.3H, s) 2.58 (2.7H, s) 2.08-1.95 (1H,
m) 1.89-1.75 (1H, m) 1.74-1.24 (5H, m) 1.41 (8.1H, s) 1.26
(0.9H, s) 1.04-0.81 (15.3H, m) 0.32 (2.7H, d, J ) 6.9 Hz);
partial 13C NMR: (CDCl3, ppm; minor rotamer signals marked
*) δ 175.9, 174.7, 171.7, 170.9*, 169.9, 168.8*, 82.0*, 81.3,
65.5*, 62.4, 58.7, 51.9*, 50.8, 42.8, 42.5*, 38.7*, 38.0, 35.1*,
35.1.
(S)-MeLeu -(R)-MeVa l-O-ter t-Bu (en t-16). According to
procedure B, Bts-(S)-MeLeu-(R)-MeVal-O-tert-Bu (ent-15) (0.078
g, 0.153 mmol) and PhSH (32 µL, 0.32 mmol) were employed,
and the reaction was performed for 3 h to produce (S)-MeLeu-
(R)-MeVal-O-tert-Bu (ent-16) (0.045 g, 77% based on ent-5a ):
analytical TLC on silica gel, 4.5:1:0.5 n-BuOH/H2O/HOAc, Rf
) 0.53; >99.75:0.25 dr after N-benzoylation and HPLC assay;
[R]25 +98.5 (c ) 1.13, CHCl3).
D
Bts-(S)-Leu -(S)-MeLeu -(S)-MeVa l-O-ter t-Bu (17). Fol-
lowing procedure E, Bts-(S)-leucine (2b) (0.059 g, 0.179 mmol)
was coupled with (S)-MeLeu-(S)-MeVal-O-tert-Bu (13) (0.051