Chiral N-Acyl-tert-butanesulfinamides
J . Org. Chem., Vol. 64, No. 15, 1999 5477
in several portions with venting. To a second 250 mL round-
bottom flask were added the symmetrical anhydride (52 mmol)
and THF (100 mL). The contents of the flask were cannulated
to the sulfinamide-containing flask dropwise over the course
of 35 min. Aqueous K2CO3 (50 mL, 1 M) was then added
dropwise (carefully!) to quench the remaining KH and elec-
trophile. The contents of the flask were concentrated, acidified
with 1 M HCl, and extracted with CH2Cl2 (3 × 200 mL). The
organic layers were combined, washed with saturated NaHCO3
(3 × 300 mL), and dried (Na2SO4).
to come to room temperature over 4 h. A dilute solution of
AcOH in THF was added, and the mixture was concentrated,
diluted with CH2Cl2 (100 mL), washed with 0.1 M NaHSO4 (3
× 100 mL), saturated NaHCO3 (3 × 100 mL), and brine (3 ×
100 mL), dried (Na2SO4), and concentrated.
(R,R)-N-2-P h en ylm eth ylbu ta n oyl-ter t-bu ta n esu lfin a -
m id e (17a ). Alkylation of 0.93 g (3.7 mmol) of (R)-13 with
iodoethane (450 µL, 5.6 mmol) afforded 0.84 g (83%) of 17a as
a colorless solid after purification on silica gel (5 cm × 20 cm
eluting with 90:10 to 50:50 hexanes/EtOAc). The diastereo-
meric ratio was determined to be 90:10 by reverse phase HPLC
analysis (10:90-100% MeOH/H2O-1% TFA, 60 min, 1 mL/
min, 254 nm; 17a , tR ) 47.5 min; 17b, tR ) 44.6 min). The
material could be recrystallized from ethyl ether-hexane
mixtures: mp 105-107 °C. Spectral data matched those listed
previously.
(R)-N-Bu ta n oyl-ter t-bu ta n esu lfin a m id e (19). Acylation
of 6.0 g (49 mmol) of (R)-9 with butanoic anhydride (8.1 g, 52
mmol) afforded 7.9 g (84%) of (R)-19 as a colorless solid after
purification on silica gel (50:50 to 70:30 EtOAc/hexanes). The
enantiomeric purity was determined to be >99:1 by HPLC
analysis on a chiral phase (Diacel AS column, 90:10 hexane/
EtOH, 1 mL/min, 232 nm; (S)-19, tR ) 6.9 min; (R)-19, tR
)
(R,R)-N-2-P h en ylm eth yl-3-m eth ylbu tan oyl-ter t-bu tan e-
su lfin a m id e (20a ). Alkylation of 0.25 g (1.0 mmol) of (R)-13
with 2-iodopropane (150 µL, 1.5 mmol) afforded 0.24 g (82%)
of 20a as a colorless solid after purification on silica gel (2 ×
15 cm, 15:85 to 40:60 EtOAc/hexanes). The diastereomeric
ratio was determined to be 90:10 by reverse phase HPLC
analysis (10:90 to 35:65% MeOH/H2O-1% TFA, 254 nm, 60
min, 1 mL/min; 20a , tR ) 40.3 min; 20b, tR ) 41.9 min). The
material could be recrystallized from ethyl ether-hexane
9.2 min). The material could be recrystallized from ethyl
ether-hexane mixtures: mp 53-54 °C; [R]23 -24.2 (c 1.00,
D
CH2Cl2); IR 3169, 2964, 1701, 1676 cm-1; 1H NMR (300 MHz)
δ 0.95 (t, 3, J ) 7.4), 1.25 (s, 9), 1.61-1.69 (m, 2), 2.31-2.40
(m, 2), 7.89 (bs, 1); 13C NMR (101 MHz) δ 13.7, 18.6, 22.1, 38.1,
57.1, 174.7. Anal. Calcd for C8H17NO2S: C, 50.23; H, 8.89; N,
7.34. Found: C, 50.30; H, 8.89; N, 7.34.
En ola te Alk yla tion Op tim iza tion . For alkylation experi-
ments (Table 2), the procedure to C-alkylate (r a c)-10-13 was
followed by employing the base (entries 1-4) or solvent (entries
6-7) listed. For entry 5, enolate formation and alkylation were
performed at 0 °C. For entries 8-9, 2.5 equiv of the additive
listed was introduced before enolate formation. For entries 10-
11, 2.5 equiv of the additive listed was introduced after enolate
formation and before enolate alkylation. The general alkylation
procedure employing KH/LTMP (entry 12) is given in the
following sections. For entries 13-14, NaH or KO-t-Bu (2.5
equiv LTMP) was substituted for KH. Diastereoselectivity was
determined employing an HPLC assay (10-100% MeOH/
H2O-0.1% TFA, 254 nm, 60 min, 1 mL/min: 17a , tR ) 47.5
min; 17b, tR ) 44.6 min). Yields were determined by HPLC
conversion of starting material to diastereomeric products or
by a mass balance recovery of the diastereomeric mixture after
column chromatography. (R,R)-N-2-P h en ylm eth ylbu ta n oyl-
ter t-bu ta n esu lfin a m id e (17a ). The diastereomerically pure
material obtained from purification on silica gel could be
recrystallized from ethyl ether-hexane mixtures: mp 106-
mixtures: mp 124-126 °C; [R]23 -32 (c 1.00, CH2Cl2); IR
D
3259, 1675, 1049 cm-1; 1H NMR (300 MHz) δ 0.90 (s, 9), 1.06
(d, 3, J ) 7.0), 1.08 (d, 3, J ) 7.0), 2.00-2.07 (m, 1), 2.27-
2.32 (m, 1), 2.77 (dd, 1, J ) 11.4, J ) 13.3), 2.92 (dd, 1, J )
4.0, J ) 13.3), 6.72 (bs, 1), 7.14-7.26 (m, 5); 13C NMR (101
MHz) δ 20.2, 21.1, 21.7, 31.2, 36.1, 56.5, 57.4, 126.4, 128.6,
129.2, 139.7, 175.7. Anal. Calcd for C16H25NO2S: C, 65.00; H,
8.53; N, 4.74. Found: C, 64.90; H, 8.45; N, 5.10.
(S,R)-N-2-P h en ylm et h ylb u t a n oyl-ter t-b u t a n esu lfin a -
m id e (17b). Alkylation of 0.88 g (4.6 mmol) of (R)-18 with
benzyl bromide (820 µL, 6.9 mmol) afforded 0.93 g (72%) of
17b as a colorless solid after MPLC purification on silica gel
(10:90 to 50:50 EtOAc/hexanes, linear gradient). The diaster-
eomeric ratio was determined to be 14:86 by reverse phase
HPLC analysis. The material could be recrystallized from ethyl
ether-hexane mixtures: mp 103-105 °C. Spectral data
matched those listed previously.
(S,R)-N-2-P h en ylm eth yl-3-m eth ylbu tan oyl-ter t-bu tan e-
su lfin a m id e (20b). Alkylation of 0.80 g (4.0 mmol) of (R)-19
with benzyl bromide (717 µL, 6.0 mmol) afforded 0.85 g (72%)
of 20b as a colorless solid after MPLC purification on silica
gel gel (10:90 to 40:60 EtOAc/hexanes, linear gradient). The
diastereomeric ratio was determined to be 17:83 by reverse
phase HPLC analysis. The material could be recrystallized
108 °C; [R]23D -14.0 (c 1.00, CH2Cl2); IR 3166, 1698, 1062 cm-1
;
1H NMR (400 MHz) δ 0.95-0.99 (m, 12), 1.55-1.61 (m, 1),
1.72-1.80 (m, 1), 2.55-2.60 (m, 1), 2.80 (d, 2, J ) 6.1), 7.15-
7.21 (m, 2), 7.23-7.27 (m, 3), 7.43 (s, 1); 13C NMR (101 MHz)
δ 11.8, 21.5, 25.6, 38.6, 51.0, 57.2, 126.3, 128.4, 129.0, 139.1,
175.8. Anal. Calcd for C15H23NO2S: C, 64.00; H, 8.20; N, 4.98.
Found: C, 64.10; H, 8.21; N, 5.01. (S,R)-N-2-P h en ylm eth -
ylbu ta n oyl-ter t-bu ta n esu lfin a m id e (17b). The diastereo-
merically pure material obtained from purification on silica
gel could be recrystallized from ethyl ether-hexane mix-
tures: mp 103-105 °C; [R]23D +28.1 (c 1.00, CH2Cl2); IR 3176,
1706, 1059 cm-1; 1H NMR (400 MHz) δ 0.94 (bt, 3), 1.12 (s, 9),
1.55-1.61 (m, 1), 1.71-1.78 (m, 1), 2.50-2.60 (m, 1), 2.80 (dd,
1, J ) 6.3, J ) 13.6), 2.94 (dd, 1, J ) 8.4, J ) 13.6), 7.15-7.26
(m, 6); 13C NMR (101 MHz) δ 11.8, 22.0, 25.1, 38.0, 50.7, 57.5,
126.5, 128.6, 129.2, 139.2, 176.4. Anal. Calcd for C15H23NO2S:
C, 64.00; H, 8.20; N, 4.98. Found: C, 64.08; H, 8.15; N, 5.20.
Gen er a l Con d ition s for En ola te Alk yla tion . To a 25 mL
round-bottom were added an N-acylsulfinamide (3.95 mmol)
and THF (4 mL). The flask was cooled to 0 °C with an ice bath,
and 35% KH in oil (677 mL, 5.95 mmol) was added slowly.
After stirring for 1 h, the mixture was cooled to -78 °C with
a dry ice/acetone bath. To a second flask were added TMP (1.1
mL, 6.5 mmol) and THF (3 mL). The flask was cooled to -78
°C, and 2.1 M n-BuLi (2.8 mL, 5.95 mmol) was added dropwise.
The mixture was warmed to 0 °C for 1 h and cooled to -78 °C
whereupon the contents were transferred via cannula to the
first flask. After stirring for 30 min, the mixture was warmed
to 0 °C for 1 h and again cooled to -78 °C whereupon
alkylating agent (5.95 mmol) was added. After 1 h, the dry
ice/acetone bath was removed and the mixture was allowed
from ethyl ether-hexane mixtures: mp 119-122 °C; [R]23
D
+21 (c 1.00, CH2Cl2); IR 3152, 2955, 1695 1060 cm-1; 1H NMR
(300 MHz) δ 1.05-1.24 (m, 15), 1.95-2.01 (m, 1), 2.30-2.45
(m, 1), 2.89-2.91(m, 2), 7.18-7.26 (m, 6); 13C NMR (101 MHz)
δ 20.4, 22.0, 24.1, 30.8, 35.4, 56.0, 57.3, 126.5, 128.7, 129.1,
139.6, 175.5. Anal. Calcd for C16H25NO2S: C, 65.00; H, 8.53;
N, 4.74. Found: C, 65.09; H, 8.48; N, 4.69.
(R)-N,N-Meth yl-2-p h en ylm eth ylbu ta n oyl-ter t-bu ta n e-
su lfon a m id e (21). To a 25 mL round-bottom flask were added
17a (1.85 g, 6.58 mmol), DMF (6.6 mL), and TMG (1.07 mL,
8.55 mmol). The mixture was cooled to 0 °C with an ice bath
whereupon MeI (615 µL, 9.87 mmol) was added. After stirring
30 min, the reaction mixture was diluted with EtOAc (50 mL)
and washed with 0.1 M NaHSO4 (3 × 50 mL) and brine (3 ×
50 mL). The organic layer was added to a 100 mL round-
bottom flask and concentrated. To the flask were added CH3-
CN (20 mL), CH2Cl2 (20 mL), H2O (30 mL), and NaIO4 (2.26
g, 9.90 mmol). The reaction mixture was cooled to 0 °C with
an ice bath, and a catalytic amount of RuCl3 (10 mg) was
added. After stirring for 1 h, CH2Cl2 (20 mL) was added, and
the mixture was washed with brine (3 × 50 mL), dried (Na2-
SO4), and concentrated. Purification on silica gel (5 × 15 cm,
20:80 EtOAc/hexane) provided 1.72 g (85%) of 21 as a colorless
oil. The enantiomeric purity was determined to be >99:1 by
HPLC analysis on a chiral phase (Diacel OJ column, 97:3
hexane/IPA, 1 mL/min, 254 nm; (S)-21, tR ) 9.6 min; (R)-21,