B. Vivet, F. Cavelier, J. Martinez
FULL PAPER
11.93 Hz, 1 H, SiCHHCH), 1.00 [d, J ϭ 6.86 Hz, 3 H, CH(CH
3
)
2
], was dissolved in CH
2
Cl
2
/Et
2
O (4:6, 10 mL) and DIEA (0.9 mL,
1
.30–1.35 (dd, J ϭ 4.52 Hz, 14.56 Hz, 1 H, SiCHHCH), 2.10 (s, 2 5.2 mmol) was added. After stirring for 4 h, Boc
I), 2.10–2.15 [m, 1 H, CH(CH ], 3.55 (s, 3 H, OCH ), 5.12 mmol) was added and the solution was stirred overnight at
.60 (s, 3 H, OCH ), 3.80–3.90 (m, 1 H, CHα Val), 3.95–4.00 (m, room temperature. The mixture was evaporated in vacuo and the
H, CHCH Si). – MS (FABϩ); m/z (%): 397 (100) [M ϩ H]. – residue diluted with EtOAc (40 mL). The organic phase was
ϭ 19.32 min (from 70% to 100% C in a 30 min run). washed with 1 KHSO (3 ϫ 15 mL), H O (15 mL), dried with
MgSO , and then concentrated in vacuo. The product was purified
2
O (113 mg,
H, SiCH
3
1
2
3
)
2
3
3
2
HPLC: t
R
4
2
4
(R)-N-(9-Fluorenylmethoxycarbonyl)silaproline Methyl Ester (R-9)
by chromatography on silica gel in EtOAc/hexane (10:90) to give
and (S)-N-(9-fluorenylmethoxycarbonyl)valyl-(R)-silaproline Methyl
Ester (10): The (R,R)-isomer 3 (960 mg, 2.42 mmol), freshly puri-
2
5
4
0
65 mg of 12 (70%), oil. [α]
D
ϭ –36.2 (c ϭ 1.0, CH
2
Cl
, 400 MHz), (two
], 1.00–1.05 (dd, 1 H, J ϭ 3.31 Hz,
5.14 Hz, SiCHHCH), 1.10–1.20 (dd, 1 H, J ϭ 10.15 Hz, 15.14 Hz,
SiCHHCH), 1.30 and 1.40 (2s, 9 H, Boc), 2.70–2.90 (m, 2 H,
SiCH N), 3.60 (s, 3 H, OCH ), 4.55 and 4.70 (2dd, J ϭ 3.31 Hz,
0.15 Hz, 1 H, CHα); C NMR (CDCl , 100 MHz), (two conf.):
δ ϭ –2.27 and –1.96 [2s, Si(CH ], 16.58 and 17.53 (2s, SiCH CH),
8.72 and 28.80 [2s, C(CH ], 34.60 and 34.89 (2s, SiCH N), 52.22
and 52.36 (2s, OCH ), 59.64 and 60.03 (2s, CHα), 80.02 and 80.27
2s, C(CH ], 156.23 and 157.09 (2s, CϭO urethane), 175.14 and
75.33 (2s, CϭO ester). – MS (ESIϩ); m/z (%): 274 (50) [M ϩ H],
96 (25) [M ϩ Na], 312 (8) [M ϩ K], 174 (40) [M ϩ H – Boc], 218
ϭCMe ], 547 (20) [2 M ϩ H], 569 (50) [2 M
ϩ Na], 842 (4) [3 M ϩ Na]. – HRMS (FABϩ): calcd. for
Si [M ϩ H]: 274.1475; found 274.1478.
2 f
). – R ϭ
1
.24 (EtOAc/hexane 1:9) – H NMR (CDCl
3
fied by chromatography was stirred overnight at 25 °C, in CH
O/HCO H (49:49:2, 10 mL). After evaporation, the residue was
distributed between CH Cl and 2 Na CO solution. The organic
3
CN/
3 2
conf.): δ ϭ 0.20 [s, 6 H, Si(CH )
H
2
2
1
2
2
2
3
layer was carefully concentrated on a rotary evaporator at room
temperature and purified by chromatography on silica gel with
MeOH/EtOAc (10:90) as eluent. The mixture of 5 and 8 (441 mg),
eluted after 6, was dissolved in THF (15 mL). DIEA (394 µL,
2
3
1
3
1
3
3
)
2
2
2
3
)
3
2
2
.26 mmol) and FmocOSu (76 mg, 2.26 mmol) were added. After
3
stirring overnight at room temperature, THF was evaporated in
vacuo and the residue was diluted with EtOAc (30 mL). The or-
[
1
2
3 3
)
ganic phase was washed with 1 KHCO
MgSO ), and evaporated. The residue was purified by chromato-
graphy on silica gel with EtOAc/hexane (20:80) to give 280 mg of
(30% from compound 3) and 420 mg of 10 (35% from com-
pound 3).
3
(2 ϫ 15 mL), dried
(
4
(
100) [M ϩ H – CH
2
2
9
12 4
C H24NO
(
S)-N-(tert-Butoxycarbonyl)silaproline Methyl Ester (S-12): Same
Compound 9: Oil. – [α]2
(
5
ϭ –34.7 (c ϭ 0.98, CH
Cl
, 400 MHz), (two conf.):
], 1.20–1.40 (m, 2 H,
N), 3.70 and 3.75 (2s, 3 H,
2
CH fluorene), 4.80 and 4.90 (2dd,
D
2
2 f
). – R ϭ 0.5
procedure as for R-12, but with the (R,S)-isomer 4. The product
was obtained as an oil. – [α] ϭ ϩ36.1 (c ϭ 0.98, CH Cl ). All the
D 2 2
other spectral data are identical to those obtained for compound
R-12.
1
EtOAc/hexane 1:9). – H NMR (CDCl
δ ϭ 0.20 and 0.30 [2s, 6 H, Si(CH
SiCH CH), 2.80–3.10 (m, 2 H, SiCH
OCH ), 4.20–4.50 (m, 3 H, CH
3
2
5
3 2
)
2
2
3
J ϭ 3.08 Hz, 10.40 Hz, 1 H, CHα), 7.20–7.80 (m, 8 H, aromatic (R)-N-(Benzyloxycarbonyl)valyl-(R)-silaproline Methyl Ester (13a):
H). – 13C NMR (CDCl
, 100 MHz), (two conf.): δ ϭ –2.09 and – A solution of R-12 (50 mg, 183 µmol) in CH Cl (2 mL) was stirred
.92 [2s, Si(CH ], 16.57 and 17.72 (2s, SiCH
2s, SiCH N), 47.69 and 47.77 (2s, CHCH
), 59.62 and 60.19 (2s, CHα), 68.04 (s, CHCH
3
2
2
1
(
3
)
2
2
CH), 34.63 and 35.14
fluorene), 52.58 (s, evaporated in vacuo and the residue was coevaporated three times
fluorene), with hexane/Et O (4:2, 10 mL) to remove TFA. The trifluoroacet-
for 1 h at room temperature with TFA (2 mL). The mixture was
2
2
OCH
3
2
2
1
20.37, 125.41, 125.62, 127.44, 128.06, 141.72, 144.47, 144.64 (8s, ate salt (53 mg, 183 µmol) was dissolved in CH Cl (8 mL). HBTU
2 2
aromatic C), 157.46 (s, CϭO urethane), 174.61 and 174.79 (2s, Cϭ
O ester). – MS (ESIϩ); m/z (%): 396 (60) [M ϩ H], 418 (100) [M
(69 mg, 183 µmol), (Z)--Val–OH (46 mg, 183 µmol) and DIEA
(73 µL, 421 µmol) were added. After stirring for 3 h at room tem-
ϩ Na], 813 (45) [2 M ϩ Na]. – HRMS (FABϩ): calcd. for perature, the reaction mixture was evaporated in vacuo and the
C
22
4
H26NO Si [M ϩ H]: 396.1631; found 396.1631. – HPLC: t
R
ϭ
resulting residue dissolved in EtOAc (25 mL). The organic phase
15.88 min (from 50 to 80% B in a 30 min run).
was successively washed with aqueous 0.1 KHSO (3 ϫ 10 mL)
4
and saturated NaHCO
3
(3 ϫ 10 mL). Evaporation of the dried
) organic phase gave 70 mg of 13a (90%), oil. – R ϭ 0.23
, 400 MHz): δ ϭ 0.30 [s, 6
], 0.90 [d, J ϭ 6.77 Hz, 3 H, CH(CH ], 1.05 [d, J ϭ
.77 Hz, 3 H, CH(CH ], 1.10–1.20 (dd, J ϭ 4.33 Hz, 15.10 Hz, 1
H, SiCHHCH), 1.20–1.35 (dd, J ϭ 10.08 Hz, 15.10 Hz, 1 H,
SiCHHCH), 2.10 [m, 1 H, CH(CH ], 2.90–2.95 (d, J ϭ 13.37 Hz,
H, SiCHHN), 3.15–3.20 (d, J ϭ 13.37 Hz, 1 H, SiCHHN), 3.70
s, 3 H, OCH ), 4.60–4.70 (dd, J ϭ 5.63 Hz, 9.29 Hz, 1 H, CHα,
val), 5.00–5.05 (dd, J ϭ 4.33 Hz, 10.08 Hz, 1 H, CHα, Sip), 5.10
s, 2 H, CH O), 5.60 (d, J ϭ 9.25 Hz, 1 H, NH), 7.30–7.45 (m, 5
1
Compound 10: Oil. – R
f
ϭ 0.35 (EtOAc/hexane 2:8). – H NMR
], 0.78 [d, J ϭ
], 0.85 [d, J ϭ 6.88 Hz, 3 H, CH(CH ],
CH), 2.10 [m, 1 H, CH(CH ], 2.55–2.65
(
(
MgSO
EtOAc/hexane 3:7). – H NMR (CDCl
4
f
(
6
0
CDCl
3
, 250 MHz): δ ϭ 0.20–0.30 [2s, 6 H, Si(CH
.85 Hz, 3 H, CH(CH
.85–1.00 (m, 2 H, SiCH
3 2
)
1
3
3
)
2
3 2
)
H, Si(CH
3
)
2
3 2
)
2
3 2
)
6
3 2
)
(
d, J ϭ 14.24 Hz, 1 H, SiCHHN), 2.95–3.05 (d, J ϭ 14.24 Hz, 1
H, SiCHHN), 3.55 (s, 3 H, OCH ), 4.10–4.40 (m, 4 H, CHα val
and CH CH fluorene), 4.85–4.95 (m, 1 H, CHα, Sip), 6.80 (d, J ϭ
.64 Hz, 1 H, NH), 7.20–7.70 (m, 8 H, aromatic H). – MS (ESIϩ);
m/z (%): 495 (100) [M ϩ H], 517 (30) [M ϩ Na], 989 (15) [2 M ϩ
H], 1011 (20) [2 M ϩ Na]. – HPLC: t ϭ 20.45 min (from 10 to
00% B in a 30 min run).
3
3 2
)
2
1
7
(
3
R
(
2
1
H, aromatic H). – MS (ESIϩ); m/z (%): 407 (100) [M ϩ H], 429
(50) [M ϩ Na], 445 (8) [M ϩ K], 813 (10) [2 M ϩ H], 835 (15)
(
S)-N-(9-Fluorenylmethoxycarbonyl)silaproline Methyl Ester (S-9):
R
Same procedure as for R-9, but with the (R,S)-isomer 4.The prod- [2 M ϩ Na]. – HPLC: t ϭ 26.31 min (from 10 to 100% B in a
uct was obtained as an oil. – [α]2
5
ϭ ϩ34.9 (c ϭ 0.98, CH
). All
2
Cl
2
30 min run).
D
the other spectral data are identical to those obtained for com-
pound R-9.
(
(
R,S)-N-(Benzyloxycarbonyl)valyl-(R)-silaproline Methyl Ester
13a, b): Same procedure as for 13a, but with the (Z)-(,)-Val–
(
R)-N-(tert-Butoxycarbonyl)silaproline Methyl Ester (R-12): The
OH. The product was obtained as an oil, 70 mg (90%). – R
(EtOAc/hexane 3:7). – H NMR (CDCl
3
f
ϭ 0.23
, 400 MHz), (two di-
]}, 0.80 and 0.85 [2d, J ϭ
], 0.9 and 0.95 [2d, J ϭ 6.77 Hz, 6 H,
], 1.00–1.25 [m, 4 H, 2 ϫ (SiCH CH)], 1.8–1.95 [m, 1
1
(R,R)-isomer 3 (930 mg, 2.35 mmol), freshly purified by chromato-
graphy was stirred for 2 h at 25 °C, in MeOH/10% HCl (3:1, 7 mL). ast.): δ ϭ 0.20 {m, 12 H, 2 ϫ [Si(CH
After evaporation, the residue was coevaporated three times with 6.77 Hz, 6 H, CH(CH
MeOH (10 mL). The mixture of 6 and 7 (710 mg) thus obtained CH(CH
3 2
)
3 2
)
3
)
2
2
810
Eur. J. Org. Chem. 2000, 807Ϫ811