3730
P. Chabaud et al. / Tetrahedron 61 (2005) 3725–3731
w
14.65 (C ). R : 0.31 (cyclohexane/EtOAc: 70/30). HPLC
assay: 85% by area %.
through a Celite pad, and solvent evaporated under
reduced pressure. The crude product was purified by flash
column chromatography (cyclohexane/EtOAc: 95/5 to 60/
40) to give the title compounds 9 (7 mg, 18% yield from 7C
8, colorless oil, less polar product), 2 (28 mg, 68% yield
from 7C8, colorless oil, most polar product) and 1 (5 mg,
12% yield from 7C8, colorless oil).
7
f
4
.1.6. (2S, 4S)-tert-butyl-N-tert-butyloxycarbonyl-3-
ethylidene-4-hydroxyprolinate 8.
.1.6.1. Procedure C: reduction with Superhydride .
w
4
To a solution of (2S) tert-butyl-N-tert-butyloxycarbonyl-3-
ethylidene-4-oxoprolinate 6 (1.5 g, 4.82 mmol, 1 equiv) in
freshly distilled THF (60 mL) under argon, was added at
1
.1.8. Compound 9. H NMR (CDCl ) (400 MHz) d 4.19
and 4.12 (1H, 2!d, JZ8.2 Hz, H ); 3.63 (1H, m, H ); 3.30
4
3
w
K78 8C Superhydride (LiBHEt , 1 M in THF) (9.64 mL,
3
2 4
9
1
.64 mmol, 2 equiv). The mixture was stirred at K78 8C for
5 min and quenched with 10% aqueous citric acid (60 mL).
(1H, m, H ); 2.23 (1H, m, H ); 1.98 (1H, m, H ); 1.71 (1H,
m, H ); 1.56 (1H, m, H ); 1.48 (18H, m, BocCtBu); 1.29
4 3 4
4
6
1
3
It was then diluted and extracted with EtOAc (200 mL). The
combined organic layers were dried on anhydrous MgSO4,
(
1H, m, H ); 1.00 (3H, t, JZ7.4 Hz, H ) C NMR (CDCl3)
6 7
d 171.22 (C]O ester); 155.00 (C]O Boc); 81.19 and 79.73
(Cq Boc and tBu); 63.13 (C ); 45.81 and 45.16; 44.15 (C );
and concentrated under reduced pressure. The crude product
2
3
was purified by flash column chromatography (cyclohex-
ane/EtOAc: 80/20) and the title compound 8 was obtained
as a colorless oil (1.32 g, 88% yield from 6).
2
HRMS (FAB ) calculated for C H NO (MCH)
3
Rf: 0.60 (cyclohexane/EtOAc: 70/30).
8.55 (C ); 28.35 (Boc and tBu); 23.41 (C ); 12.97 (C ).
4 6 7
C
C
1
6
30
4
2
00.2175, found 300.2167. [a]D K3.2 (c 0.63; CHCl3).
3
1
H NMR (CDCl ) d 5.90 (1H, 2!q, JZ7.0 Hz, H ); 4.76
3
6
and 4.70 (1H, 2!s, H ); 4.37 (1H, m, H ); 3.65–3.76 (1H,
dd, JZ11.9, 16.0 Hz, H ); 3.40–3.53 (1H, 2!dd, JZ11.9,
1
.1.9. Compound 2. H NMR (CDCl ) (500 MHz) d 4.28
2
4
4
3
5
and 4.22 (1H, 2!d, JZ8.4 Hz, H ); 4.14 (1H, q, JZ7.2 Hz,
2
1
6.0 Hz, H ); 3.30 (1H, ls, KOH); 1.79 (3H, d, JZ7.0 Hz,
5
13
7
H
); 3.84 (1H, 2!dd, JZ10.6, 7.5 Hz, H
); 3.10 (1H, 2!
4
5
H ); 1.49 and 1.46 (18H, 2!s, Boc and tBu) C NMR
dd, JZ10.6, 7.0 Hz, H ); 2.06 (1H, m, H ); 1.61 (1H, m,
5
3
(
Boc); 138.43 and 137.71 (C ); 125.77 (C ); 82.65 and 80.47
CDCl ) d 171.89 (C]O ester); 154.43 and 153.87 (C]O
3
H ); 1.43, 1.42, 1.41 and 1.39 (18H, m, BocCtBu); 1.26
6
3
6
13
(
1H, m, H ); 1.02 (3H, t, JZ7.4 Hz, H ) C NMR (CDCl3)
6 7
(
Cq Boc, tBu); 74.51 and 73.63 (C ); 60.74 (C ); 55.17 and
4 2
d 170.86 (C]O ester); 154.53 and 153.92 (C]O Boc);
81.65 and 80.23 (Cq Boc and tBu); 72.60 and 72.42 (C );
62.53 and 62.33 (C ); 52.45 and 52.41 (C ); 51.11 and 51.21
C ); 28.47 and 28.27 (Boc and tBu); 21.10 (C ); 12.74 (C ).
5
HRMS (FAB ) calculated for C H NO (MCH)
3
Rf: 0.31 (cyclohexane/EtOAc: 70/30). HPLC assay: 96% by
area %.
5.07 (C ); 28.34 and 27.86 (Boc and tBu); 14.75 (C ).
5 7
C
C
4
1
6
27
5
2
14.1967, found 314.1964. [a]D C85.5 (c 1.18; CHCl3).
4
2
5
(
3
6
7
C
C
HRMS (FAB ) calculated for C H NO (MCH)
5
16.2124, found 316.2134. MS (FAB , NBA): 316 (MC
1H) , 631 (2MC1H) . [a]
.26 (cyclohexane/EtOAc: 70/30). HPLC assay: 97% by
area %.
1
6
C
30
3
C
C
26
w
.1.6.2. Procedure D: reduction with Superhydride ,
C20.74 (c 1.65; CHCl ). R :
D 3 f
4
CeCl . CeCl $7H O (216 mg, 0.55 mmol, 3.2 equiv) was
0
3
3
2
dried for 2 h under vacuum at 110 8C then THF (2 mL) was
added under argon at rt. The mixture was stirred overnight
and a solution of (2S) tert-butyl-N-tert-butyloxycarbonyl-3-
ethylidene-4-oxoprolinate 6 (55 mg, 0.18 mmol, 1 equiv) in
THF (2 mL) added dropwise at rt. The resulting mixture
1
4
.1.10. Compound 1. H NMR (CDCl ) d 4.06–4.16 (2H,
3
m, H and H ); 3.65 (1H, 2!d, JZ12.1 Hz, H ); 3.35–3.50
2
4
5
(
1H, m, H ); 2.10 (1H, m, H ); 1.43 and 1.38 (18H, 2!s,
5 3
w
Boc and tBu); 1.37 (1H, m, H ); 0.96 (3H, t, JZ7.3 Hz, H )
was cooled to K78 8C and Superhydride (1 M in THF)
(
6
7
1
3
C NMR (CDCl ) d 174.13 (C]O ester); 153.82 (C]O
Boc); 83.04 and 80.23 (Cq Boc and tBu); 72.48 and 71.59
0.36 mL, 0.36 mmol, 2 equiv) added. The solution was left
3
to stir for 30 min, then 10% aqueous citric acid (5 mL) was
added. The mixture was allowed to warm to rt and then
extracted with EtOAc. The combined organic layers were
(
(
C ); 62.44 (C ); 56.30 and 55.86 (C ); 49.29 and 48.21
4 2 5
C ); 28.40 and 27.91 (Boc and tBu); 18.11 and 17.94 (C );
3 6
2
6
1
hexane/EtOAc: 70/30). Mp: 99 8C (EtOAc). Elemental
2.37 (C ). [a] C19.77 (c 1.2; CHCl ). R : 0.40 (cyclo-
7 D 3 f
washed with brine, dried on anhydrous MgSO , filtered and
4
concentrated under reduced pressure. The crude product
was purified by flash column chromatography (cyclohex-
ane/EtOAc: 80/20) and the title compound 8 was obtained
as a colorless oil (40 mg, 71% yield from 6).
analysis calculated for C H NO : C, 60.93; H, 9.27; N,
16 29
5
4
.44, found: C, 61.34; H, 9.24; N, 4.16.
4
.1.11. (2S, 3R, 4S)-tert-butyl-N-tert-butyloxycarbonyl-3-
4
.1.7. (2S, 3R)-tert-butyl-N-tert-butyloxycarbonyl-3-
ethyl-4-hydroxyprolinate 1 via hydrogenation of 8 with
the use of Wilkinson’s catalyst). To a solution of (2S, 4S)-
tert-butyl-N-tert-butyloxycarbonyl-3-ethylidene-4-hydroxy-
prolinate 8 (200 mg, 0.64 mmol, 1 equiv) in anhydrous
toluene (7 mL) was added Wilkinson’s catalyst (118 mg,
0.13 mmol, 20 mol %). The resulting mixture was stirred at
ethylprolinate 9, (2S, 3R, 4R)-tert-butyl-N-tert-butyloxy-
carbonyl-3-ethyl-4-hydroxyprolinate 2, (2S, 3R, 4S)-tert-
butyl-N-tert-butyloxycarbonyl-3-ethyl-4-hydroxyproli-
nate 1 via hydrogenation on Pd/C of a mixture of 7 and 8.
To a solution of (2S, 4S)-tert-butyl-N-tert-butyloxycarbo-
nyl-3-ethylidene-4-hydroxyprolinate 8 and (2S, 4R)-tert-
butyl-N-tert-butyloxycarbonyl-3-ethylidene-4-hydroxypro-
linate 7 (83/17 obtained from Luche reduction, procedure B)
rt under H pressure (1 bar) for 3 days. The solution was
2
w
filtered on a Celite pad and the toluene evaporated under
reduced pressure. The crude product was purified by flash
column chromatography (cyclohexane/EtOAc: 90/10 to
80/20) to give the title compound 1 (102 mg, 51% yield
from 8, brown solid) which was recrystallised from EtOAc.
(
(
40 mg, 0.13 mmol) in EtOAc (4.5 mL) was added Pd/C
5%) (15 mg). The resulting mixture was left to stir for 36 h
at rt under H pressure (1 bar), then the Pd was filtered off
2