5-tert-Butylproline
J . Org. Chem., Vol. 61, No. 26, 1996 9453
(m, 1 H), 3.79 (s, 3 H), 4.51 (t, 1 H, J ) 7.5), 9.0 (br s, 2 H); 13
HCl, saturated with NaCl, and extracted with EtOAc (2 × 250
mL). The organic phases were combined, washed with brine,
dried, filtered, and evaporated to a minimum volume of EtOAc
from which 4 was allowed to crystallize, giving 1.37 g (75%)
of a white solid, mp 170 °C.
C
NMR (CD3OD) δ 26.5, 27, 29.9, 33.7, 54.1, 61.4, 71.9, 170.2;
HRMS calcd for C10H20NO2 [MH]+, 186.1494 found 186.1501.
A solution of 7 (100 mg, 0.45 mmol) in CH3CN (3 mL) was
then treated with solid K2CO3 (124 mg, 0.90 mmol, 200% mol),
stirred for 30 min, and treated with a solution of di-tert-butyl
dicarbonate (147 mg, 68 mmol, 150% mol) in CH3CN (1 mL).
After the solution was stirred for 24 h at rt, a second portion
of di-tert-butyl dicarbonate (147 mg, 68 mmol, 150% mol) in
CH3CN (1 mL) was added, and the resulting solution was
stirred 24 h, evaporated to a yellow solid, and chromato-
graphed on silica gel using a gradient of 0-7% Et2O in CHCl3
as eluant. (2S,5S)-N-(BOC)-5-tert-butylproline methyl ester
((2S,5S)-9, 99 mg, 77%) was first to elute: [R]20D -43.6° (c 0.94,
(2S,5R)-5-ter t-Bu tylp r olin e ((2S,5R)-6). A solution of
(2S,5R)-N-(BOC)-5-tert-butylproline ((2S,5R)-1, 90 mg, 0.33
mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid
(0.5 mL), stirred at room temperature for 12 h, and evaporated
to a clear oil. (2S,5R)-5-tert-Butylproline trifluoroacetate: 1H
NMR δ 1.08 (s, 9 H), 1.68 (m, 1 H), 2.06 (m, 1 H), 2.44 (m, 2
H), 3.55 (m, 1 H), 4.44 (m, 1 H), 6.51 (br m, 1 H), 10.07 (br m,
1 H), 11.77 (br s, 1 H); 13C NMR δ 25, 25.9, 29.1, 32, 58.9,
71.9, 172.7. The oil was dissolved in water and passed through
an ion-exchange column of Dowex 1-X8 (hydroxide form)
eluting with 0.01 M AcOH and provided 6 as a white solid:
1
CH3OH); H NMR δ 0.9 (s, 9 H), 1.51 (s, 9 H), 1.8-2.4 (m, 4
H), 3.74 (s, 3 H), 3.97 (d, 0.3 H, J ) 8.4), 4.06 (d, 0.7 H, J )
8.5), 4.4 (d, 1 H, J ) 9.5); 13C NMR δ 25.2 (26.1), (27.3) 27.4,
27.5, (29) 30, (36.3) 37, (52.2) 52.4, (61.3) 61.7, (67.5) 67.6,
mp 265 °C dec; [R]20 -29.7° (c 0.26, 1 N HCl).
D
Hydr ogen ation of δ-Oxo-r-[N-(P h F)Am in o]h eptan oates
4, 5a , a n d 5b. A 0.6 M solution of (2S)-6,6-dimethyl-5-oxo-
2-[N-(PhF)amino]heptanoates (4, 5a , and 5b (100 mol %) in
9:1 MeOH:AcOH was treated with palladium-on-carbon (10
wt %, 5 mol % of Pd) and stirred under 4 atm of hydrogen for
24 h. The mixture was filtered on Celite, the catalyst was
washed with MeOH, and the combined organic phase was
evaporated to a residue that was analyzed directly by 1H NMR
in order to determine the cis:trans ratios reported in Table 1.
(2S,5R)-5-ter t-Bu tylp r olin e Meth yl Ester Tr iflu or oa c-
eta te ((2S,5R)-7). A sample for comparison was obtained as
a low-melting solid from stirring a 0.1 M solution of (2S,5R)-
N-(BOC)-5-tert-butylproline methyl ester ((2S,5R)-9) in 4:1
CH2Cl2:CF3CO2H for 18 h at room temperature followed by
evaporation of the volatiles under vacuum; [R]20D -18.7° (c 0.4,
MeOH); 1H NMR δ 1.09 (s, 9 H), 1.67 (m, 1 H), 2.06 (m, 1 H),
2.3 (m, 1 H), 2.46 (m, 1 H), 3.64 (m, 1 H), 3.9 (s, 3 H), 4.58 (br
d, 1 H, J ) 9), 6.12 (br s, 1 H), 12 (br s, 1 H); 13C NMR δ 25.2,
26.1, 29, 32.1, 54.2, 58.7, 71.3, 170.9.
(84.6) 84.7, (146.8) 149.9, (172.5) 172.8; HRMS calcd for C18H11
-
NO3 [M - O-t-Bu]+, 212.1287 found 212.1275. Next to elute
was (2S,5R)-N-(BOC)-5-tert-butylproline methyl ester (2S,5R)-9
(11 mg, 9%).
Ep im er iza tion of (2S,5R)-N-(BOC)-5-ter t-bu tylp r olin e
Meth yl Ester ((2S,5R)-9). A solution of methyl ester (2S,5R)-9
(143 mg, 0.5 mmol) in 10 mL of THF at -78 °C was treated
with 1.2 mL of KN(SiMe3)2 (120 mol %, 0.5 M in toluene),
heated to 50 °C, and stirred for 16 h. Methanol (6 mL) was
added, and the mixture was partitioned between 1 M NaH2-
PO4 (15 mL) and EtOAc (15 mL). The aqueous phase was
extracted with EtOAc (3 × 15 mL), and the combined organic
phase was washed with brine, dried, evaporated and purified
by chromatography using 0-25% EtOAc in hexanes. First to
elute was (2S,5R)-9 (84 mg, 59%) followed by (2R,5R)-9 (54
mg, 38%): [R]20 21.6° (c 0.25, CH3OH). Last to elute was a
D
mix of acids 1 (4 mg, 3%).
(2S,5S)-5-ter t-Bu tyl-N-(BOC)p r olin e ((2S,5S)-1). A so-
lution of methyl ester (2S,5S)-9 (50 mg, 0.18 mmol) in 1 mL
of dioxane was treated with 1 mL of 1 N NaOH and stirred
for 48 h at room temperature. The reaction mixture was
extracted with water (5 × 1 mL), the aqueous phases were
combined, acidified with citric acid to pH 2, saturated with
NaCl, and extracted with EtOAc (3 × 2 mL). The organic
phases were combined, dried, filtered, and evaporated to give
39 mg (82%) of (2S,5S)-1: [R]20D -16.3° (c 0.7, MeOH); 1H NMR
δ 0.9 (s, 9 H), 1.41 (s, 5.4 H), [1.46 (s, 3.6 H)], 1.90 (m, 2 H),
2.05 (m, 1 H), 2.30 (m, 1 H), [3.85 (d, 0.4 H, J ) 8.5)] 3.98 (d,
0.6 H, J ) 8.5), 4.28 (d, 0.6 H, J ) 9.3) [4.34 (d, 0.4 H, J )
9.4)]; 13C NMR δ 25.0 (26.1), 27.5, 28.1 (28.3), 29.1, 36.5 (36.8),
61.0, 66.2, 80.2 (80.6), 155.3, 179.9.
(2S,5R)-5-ter t-Bu tylp r olin e ter t-bu tyl ester ((2S,5R)-
8): 1H NMR δ 0.95 (s, 9 H), 1.46 (s, 9 H), 1.47 (m, 1 H), 1.75
(m, 2 H), 2.04 (m, 1 H) 2.84 (dd, 1 H, J ) 6.2, 9.8), 3.65 (dd, 1
H, J ) 5.5, 9); 13C NMR δ 26.5, 26.6, 27.2, 27.9, 30.8, 60.4,
69.7, 81, 174.1.
(2S)-5-ter t-Bu tyl-∆5-d eh yd r op r olin e Tr iflu or oa ceta te
(11). A solution of acid 4 (320 mg, 0.74 mmol) in CH2Cl2 (15
mL) was treated with TFA (0.76 mL) and anisole (0.38 mL),
heated at reflux for 48 h, cooled to room temperature, and
evaporated to a solid that was dissolved in a minimum volume
of CHCl3 and precipitated with excess hexane. The precipitate
was recovered with the aid of a centrifuge, redissolved, and
retreated in the same way two additional times to provide pure
11 (201 mg, 96%): [R]20D 81° (c 0.1, CHCl3);26 1H NMR (CD3OD)
En a n tiom er ic P u r ity of (2S,5R)-N-(BOC)-5-ter t-bu tyl-
p r olin e ((2S,5R)-1). A room-temperature solution of (2S,5R)-
N-(BOC)-5-tert-butylproline ((2S,5R)-1, 20 mg, 0.07 mmol) and
either (R)- or (S)-R-methylbenzylamine (24 µL, 0.19 mmol) in
1 mL of acetonitrile was treated with benzotriazol-1-yl-1,1,3,3-
tetramethyluronium tetrafluoroborate (26 mg, 0.08 mmol) and
stirred for 2 h when TLC showed complete disappearance of
the starting acid. Brine (2 mL) was added to the reaction
mixture that was then extracted with EtOAc (2 × 3 mL). The
combined organic phase was extracted with 2 N HCl (2 × 2
mL) and NaHCO3 (2 × 2 mL), washed with H2O (2 × 2 mL)
and brine, dried, filtered, and evaporated to a residue that was
directly examined by 1H NMR. When (S)-R-methylbenzyl-
amine of 99% diastereomeric purity was used, examination of
δ 1.39 (s, 9 H), 2.37 (m, 2 H), 2.65 (m, 2 H), 5.05 (m, 1 H); 13
C
NMR (CD3OD) δ 25.6, 25.7, 27.6, 35.9, 38.7, 171.5, 208.1;
HRMS calcd for C9H16NO2 (M+) 170.1181, found 170.1178.
Hyd r id e Red u ction of (2S)-10. A solution of (2S)-5-tert-
butyl-∆5-dehydroproline (10, 141 mg, 0.5 mmol) in THF (30
mL) was heated to reflux, treated with solid (H3C)4NHB(OAc)3
(197 mg, 0.75 mmol, 150 mol %), and stirred for 6 h. The
solution was cooled to room temperature, treated with 1 N HCl
(10 mL), and evaporated to a residue. The proton NMR
spectrum of the residue exhibited a 85:15 trans:cis ratio of
diastereomers. The residue was dissolved in water and
purified on 11 g of Dowex 1-X8 ion-exchange resin (hydroxide
form, 20-50 mesh) using a gradient of 0-10% acetic acid in
water as eluant. Evaporation of the collected ninhydrin
positive fractions gave 76 mg (96%) of solid (2S,5RS)-5-tert-
butylprolines (6) possessing an 87:13 ratio of diastereomers.
(2S,5S)-N-(BOC)-5-ter t-b u t ylp r olin e Met h yl E st er
((2S,5S)-9). A 0 °C solution of gaseous HCl (1g, 27 mmol) in
161 mL of MeOH was treated with a solution of 5-tert-
butylproline (490 mg, 3.1 mmol, 5R:5S ) 8.6:1) in MeOH (25
mL). The mixture was allowed to warm to rt, stirred for 16
h, and evaporated to a yellow solid containing an 8.6:1 mixture
of (2S,5R)- and (2S,5S)-7 (522 mg, 76%). The spectral char-
acteristics of (2S,5S)-5-tert-butylproline methyl ester hydro-
chloride ((2S,5S)-7) are as follows: 1H NMR (CHCl3 acidified
with TFA) δ 1.07 (s, 9 H), 1.9-2.2 (m, 3 H), 2.5 (m, 1 H), 3.65
1
the tert-butyl singlets in the H NMR in CDCl3 demonstrated
(S)-10 to be of 99% diastereomeric purity. Hence, cis-1 is
presumed to be of >99% enantiomeric purity.
(1′S,2S,5R)-N-(BOC)-5-ter t-bu tylp r olin e N′-r-m eth yl-
ben zyla m id e ((S)-10): 1H NMR δ 0.93 (s, 9 H), 1.34 (s, 9 H),
1.47 (d, 3 H, J ) 6.9), 1.78 (m, 2 H), 2.2 (m, 2 H), 3.9 (dd, 1 H,
J ) 3, 7.7), 4.3 (t, 1 H, J ) 8.8), 5.1 (quintet, 1 H, J ) 6.9), 7.3
(m, 5 H).
(1′R,2S,5R)-N-(BOC)-5-ter t-bu tylp r olin e N′-r-m eth yl-
ben zyla m id e ((R)-10): 1H NMR δ 0.74 (s, 9 H), 1.47 (s, 9 H),
1.51 (d, 3 H, J ) 7), 1.84 (m, 2 H), 2.1 (m, 1 H), 2.25 (m, 1 H),
3.83 (m, 1 H), 4.34 (t, 1 H, J ) 8.7), 5.1 (quintet, 1 H, J ) 7),
7.3 (m, 5 H).