M. Kirihara et al. / Tetrahedron: Asymmetry 14 (2003) 1753–1761
1759
mmol) and diphenylphosphoryl azide (1.19 mL, 5.56
mmol) were added to the benzene solution of crude
(R)-9 and the resulting mixture was heated under reflux
for 30 min under a nitrogen atmosphere. Benzyl alcohol
(5.0 mL) was added to the solution and the reaction
mixture was heated under reflux for 24 h under a
nitrogen atmosphere. Then, 5% aqueous citric acid was
added and the resulting mixture was extracted with
benzene (30 mL×3). The extract was dried over anhy-
drous magnesium sulfate and evaporated to afford
crude (R)-10a. The crude product was purified by
recrystallization (n-hexane/ethyl acetate) to give pure
(R)-10a (642 mg, 50%) as colorless crystals.
Mp 68ꢀ71°C (n-hexane/ethyl acetate); [h]2D8 +33.7 (c
0.26, CHCl31); IR (neat) cm−1: 3323, 1695, 1526, 1476,
1282, 1253; H NMR (CDCl3) l: 1.62ꢀ1.82 (2H, br),
2.95 (1H, br), 3.82 (2H, br), 5.14 (2H, s), 5.43 (1H, br),
7.36 (5H, br); 19F NMR (CDCl3) l: −139.16 (2F, t,
J=10.0 Hz); MS (m/z) 257 (M+); HRMS calcd for
C12H13F2NO3 (M+), 257.0863; found 257.0818.
5.9. t-Butyl (R)-(+)-N-[2,2-difluoro-1-(hydroxymethyl)-
cyclopropyl]carbamate (R)-11b
To a stirred solution of 10b (300 mg, 1.13 mmol) in
methanol (5 mL) was added a 0.20 M aqueous solution
of potassium carbonate (5.65 mL, 1.13 mmol) and the
resulting mixture was stirred at room temperature for
30 min. The reaction mixture was extracted with chlo-
roform (30 mL×3) and the combined extract was dried
over anhydrous magnesium sulfate. The solvent then
was evaporated to afford crude (R)-11b. The crude
product was purified by recrystallization (n-hexane) to
afford pure (R)-11b (165 mg, 66%) as colorless crystals.
According to the GC analysis (CP Cyclodextrin-b-236-
M-19) of this compound, the enantiomeric excess was
over 99% ee. Mp 89ꢀ90°C (n-hexane); [h]2D9 +33.2 (c
0.83, CHCl3); IR (neat) cm−1: 3366, 1691, 1676, 1521,
Mp 90ꢀ93°C (n-hexane/ethyl acetate); [h]2D9 +30.8 (c
0.50, CHCl3); IR (neat) cm−1: 3332, 3019, 1741, 1706,
1
1529, 1457, 1367, 1250, 1041, 1028; H NMR (CDCl3)
l: 1.75 (2H, br), 2.07 (3H, s), 4.07 (1H, dd, J=12.4, 2.2
Hz), 4.54 (1H, d, J=10.3 Hz), 5.12 (2H, br), 5.28 (1H,
br), 7.36 (5H, br); 19F NMR (CDCl3) l: −139.85 (2F,
q-like); FAB-MS (m/z) 300 (M++H); FAB-HRMS
calcd for C14H16F2NO4 (M++H), 300.1047; found
300.1050.
5.7. (R)-(+)-{2,2-Difluoro-1-[(t-butoxy)carbonylamino]-
cyclopropyl}methyl acetate (R)-10b
1
1283, 1021; H NMR (CDCl3) l: 1.46 (9H, s), 1.70ꢀ
1.81 (2H, m), 3.35 (1H, br), 3.73ꢀ3.81 (2H, m), 5.21
(1H, br); 19F NMR (CDCl3) l: −138.99 (2F, t-like); MS
(m/z) 223 (M+), 123 (M++H−t-BuOCO); HRMS calcd
for C4H7F2NO (M++H−t-BuOCO): 123.0496; found
123.0461.
To a solution of (R)-6 (1.00 g, 5.56 mmol) in acetone
(7.0 mL) was added Jones reagent (2.8 mL) at room
temperature and the mixture was stirred for 2 h. i-
Propanol (2 mL) was added and the solution was
diluted with ether (60 mL). The resulting mixture was
filtered through Celite®. The filtrate was dried over
anhydrous magnesium sulfate and evaporated to afford
the crude carboxylic acid [(R)-9] which was dissolved in
t-butanol (15.0 mL). Triethylamine (0.390 mL, 2.80
mmol) and diphenylphosphoryl azide (765 mg, 2.80
mmol) were added to the solution of crude (R)-9 and
the resulting mixture was heated under reflux for 24 h
under a nitrogen atmosphere. The solvent was evapo-
rated and the crude product was purified by recrystal-
lization (n-hexane) to give pure (R)-10b (375 mg, 51%)
as colorless crystals. Mp 67°C (n-hexane); [h]2D7 +29.75°
(c 0.97, CHCl3); IR (neat) cm−1: 3336, 1741, 1690, 1513,
5.10. (+)-{2,2-Difluoro-1-(R)-[(2-phenylacetyloxy)amino]-
cyclopropyl}methyl-2-(S)-acetyloxy-2-phenylacetate 12
To a stirred solution of (R)-11a (20.0 mg, 0.08 mmol)
in dichloromethane (2 mL) were added dicyclohexylcar-
bodiimide (19.0 mg), N,N-dimethylaminopyridine (1.0
mg. 0.01 mmol), and (S)-O-acetylmandelic acid (18.0
mg, 0.093 mmol). The resulting mixture was stirred at
room temperature for 1 h, and then diluted with ethyl
acetate (10 mL). The mixture was filtered through
Celite® and the filtrate was washed with water. The
organic layer was dried over anhydrous magnesium
sulfate, the solvent was evaporated, and the crude
product was purified by recrystallization (n-hexane/
ethyl acetate) to afford pure 12 (30 mg, 89%) as color-
less crystals. Mp 99ꢀ101°C (n-hexane/ethyl acetate);
[h]2D8 +81.7 (c 0.09, CHCl3); IR (neat) cm−1: 3332, 3019,
1741, 1706, 1529, 1457, 1367, 1250, 1041, 1028; 1H
NMR (CDCl3) l: 1.68–1.71 (2H, m), 2.14 (3H, s), 4.09
(1H, d, J=12.0 Hz), 4.75 (1H, d, J=12.0 Hz), 5.05ꢀ
5.17 (2H, dd-like), 5.26 (1H, br), 5.86 (1H, s), 7.31ꢀ
7.48 (10H, m); 19F NMR (CDCl3) l: −138.41ꢀ−141.15
(2F, q-like); MS (m/z) 434 (M++H), 433 (M+); HRMS
calcd for C22H21F2NO6 (M+), 433.1337; found
433.1303.
1
1457, 1254, 1219, 1040; H NMR (CDCl3) l: 1.46 (9H,
s), 1.68–1.69 (2H, m), 2.10 (3H, s), 4.60 (2H, br) 5.40
(1H, br); 19F NMR (CDCl3) l: −138.82ꢀ−140.90 (2F,
m); MS (m/z) 266 (M++H); HRMS calcd for
C11H18F2NO4 (M++H), 266.1240; found 266.1163.
5.8. Benzyl (R)-(+)-N-[2,2-difluoro-1-(hydroxymethyl)-
cyclopropyl]carbamate (R)-11a
To a stirred solution of 10a (299 mg, 1.00 mmol) in
methanol (5 mL) was added 0.20 M aqueous solution
of potassium carbonate (5.0 mL, 1.0 mmol) and the
resulting mixture was stirred at room temperature for
30 min. The reaction mixture was extracted with chlo-
roform (30 mL×3) and the combined extract was dried
over anhydrous magnesium sulfate. The solvent was
evaporated and the crude product was purified by
recrystallization (n-hexane/ethyl acetate) to afford pure
(R)-11a (149 mg, 66%) as colorless crystals.
6. X-Ray crystallographic data for 12
A colorless prismatic crystal of 12 was mounted on a
glass fiber. All measurements were made on a Rigaku