5
To a suspension of SnCl (415 mg, 2.20 mmol, 0.50 equiv) in
distilled acetaldehyde (1.30 mL, 23.3 mmol, 4.50 equiv), a
2
anhydrous CH Cl (13 mL) was added tert-butyl diazoacetate 7d
solution of 8c (2.00 g, 5.20 mmol) in THF (25 mL), and pyridine
(1.46 mL, 18.1 mmol, 3.50 equiv). The reaction was allowed to
warm up to RT and stirred for 3 h. The mixture was then
2
2
(1.3 g, 8.8 mmol, 2.0 equiv) at 20 °C under argon atmosphere. A
solution of aldehyde 6 (1.0 g, 4.4 mmol) in anhydrous CH Cl2
2
(4.4 mL) was then added dropwise via cannula. After 4 h of
quenched by a slow addition of water and extracted with Et O (3
2
stirring, the reaction was not over and a further of SnCl (208 mg,
x 10 mL). The organic extracts were dried over MgSO , filtered
2
4
1
.10 mmol, 0.25 equiv) followed by tert-butyl diazoacetate 7d
and concentrated under vacuum. The crude material was then
purified by flash chromatography (95:5 PE/EtOAc) to furnish the
product 9c as a colorless oil (2.05 g, 96%) as an inseparable 1:1
mixture of diastereomers; R (95:5 PE/EtOAc) 0.43; n (liquid
(1.3 g, 8.8 mmol, 2.0 equiv) were added. After another 2 h, no
significant evolution of the reaction was observed by TLC. The
solvent was then removed in vacuo and the crude material was
f
max
purified by flash chromatography on silica gel (98:2 PE/Et O) to
film) 2955 2857, 1764 1726, 1697, 1449, 1387, 1274, 1248,
−1
2
yield pure product 8d as a yellow oil (1.35 g, 88%); (β-keto ester
1131, 1057 cm ; diastereomer A: δ (400 MHz CDC1 ) 7.02
H 3
2
5
form) R (95:5 PE/Et O) 0.5; [a] -67.0 (c 1.00, CHCl ); n
(
(1H, q, J 7.3 Hz, CH CHC), 5.82 (1H, ddd, J 17.2, 10.4, 6.8 Hz,
f
2
D
3
max
3
−1
liquid film) 2932, 1728, 1680, 1255, 1151, 1084, 1002 cm ; δ
CH CH(CHOSi)), 5.21–5.04 (2H, m, CH CH(CHOSi)), 4.36–
H
2
2
(
400 MHz, CDCl ) 5.74 (1H, ddd, J 17.2, 10.4, 6.4 Hz,
4.22 (3H, m, CH CH(CHOSi) and CH O), 3.11 (1H, quint, J 7.0
3
2
2
CH CHCH), 5.18 (1H, dt, J 17.2, 1.6 Hz, CH2transCHCH), 5.12
Hz, CH CHCHO), 1.87 (3H, d, J 7.3 Hz, CH ), 1.15 (3H, d, J 7.0
3 3
2
(1H, dt, J 10.0, 1.2 Hz, CH2cisCHCH), 4.27-4.24 (1H, m,
Hz, CH ), 1.10–1.00 (2H, m, CH Si), 0.88 (9H, s, SiC(CH ) ),
3 2 3 3
CH CHCHOSi), 3.50 (1H, d, J 16.0 Hz, OCCH CO), 3.41 (1H,
0.06 (9H, s, Si(CH ) ), 0.04 (3H, s, SiCH ), 0.02 (3H, s, SiCH ),
2
2
3 3
3
3
d, J 16.0 Hz, OCCH CO), 2.86 (1H, dq, J 6.8, 5.6 Hz,
diastereomer B: δH (400 MHz CDC1 ) 6.86 (1H, q, J 7.3 Hz,
2
3
CH CH(COCHOSi), 1.46 (9H, s, (CH ) )C), 1.09 (3H, d, J 6.8
CH CHC), 5.75 (1H, ddd, J 17.2, 10.4, 6.8 Hz, CH CH(CHOSi)),
3
3 3
3
2
Hz, CH CH(COCHOSi)), 0.90 (9H, s, SiC(CH ) ), 0.07 (3H, s,
5.21–5.04 (2H, m, CH CH(CHOSi)), 4.36–4.22 (3H, m,
3
3 3
2
SiCH ), 0.03 (3H, s, SiCH ); δ (100.6 MHz, CDCl ) 205.5,
CH CH(CHOSi) and CH O), 3.11 (1H, quint, J 7.0 Hz,
3
3
C
3
2
2
1
66.6, 138.0, 116.1, 81.6, 75.6, 52.6, 51.4, 27.9, 25.8, 18.1, 12.2,
CH CHCHO), 1.98 (3H, d, J 7.3 Hz, CH ), 1.14 (3H, d, J 7.0 Hz,
CH ), 1.10–1.00 (2H, m, CH Si), 0.88 (9H, s, SiC(CH ) ), 0.05
3 2 3 3
3
3
+
-4.4, -5.0; HRMS (CI): M+H , found 343.5555. C H O Si
18
35
4
requires 343.5554.
(9H, s, Si(CH ) ), 0.04 (3H, s, SiCH ), 0.01 (3H, s, SiCH );
3 3 3 3
diasteromer A: δC (100.6 MHz, CDCl ) 206.2, 166.6, 146.6,
3
4
4
.6. Methyl (4R,5S)-5-((tert-butyldimethylsilyl)oxy)-2-ethylidene-
-methyl-3-oxohept-6-enoate (9b)
1
0
1
1
4
40.7, 140.0, 117.1, 76.9, 65.0, 53.8, 27.4, 19.8, 19.0, 17.2, 15.2,
.00, -2.7, -3.4 , diasteromer B: δC (100.6 MHz, CDCl ) 201.,
3
68.1 145.0, 140.8, 138.3, 117.2, 76.9, 64.9, 50.5, 27.4 , 19.7,
To a vigorously stirred solution of titanium (IV) chloride (1.39
+
9.0, 17.3, 14.5, 0.00, -2.7, -3.4; HRMS (ESI): M+Na , found
mL, 12.7 mmol, 1.80 equiv) in THF (25 mL) under nitrogen
atmosphere at 0 °C were successively added freshly distilled
acetaldehyde (1.80 mL, 31.7 mmol, 4.50 equiv), a solution of β-
keto ester 8b (2.12 g, 7.05 mmol) in THF (10 mL), and pyridine
35.2373. C H O Si Na requires 435.2365.
21 40
4
2
4
.8. tert-Butyl (4R,5S)-5-((tert-butyldimethylsilyl)oxy)-2-
ethylidene-4-methyl-3-oxohept-6-enoate (9d)
(1.98 mL, 24.6 mmol, 3.50 equiv). The reaction mixture was
allowed to reach 20 °C and stirred for 2 h. It was then quenched
To a vigorously stirred solution of titanium (IV) chloride (0.75
mL, 6.8 mmol, 1.80 equiv) in THF (25 mL) under nitrogen
atmosphere at 0 °C were successively added freshly distilled
acetaldehyde (0.98 mL, 17.2 mmol, 4.50), a solution of β-keto
ester 8d (1.3 g, 3.8 mmol) in THF (5.8 mL), and pyridine (1.1
mL, 13 mmol, 3.4 equiv). The reaction mixture was allowed to
reach 20 °C and stirred for 2 h. It was then quenched with a slow
with a slow addition of water, extracted with Et O, dried under
2
MgSO , filtered and concentrated in vacuo. The crude material
4
was then purified by flash chromatography on silica gel (95:5
PE/Et
:1 mixture of diastereomers; R (95:5 PE/ Et O) 0.25; n
max
2
O) to yield the product 9b (2.13 g, 92%) as an inseparable
1
f
2
(
1
liquid film) 2966, 2935, 2858, 1725, 1702, 1464, 1381, 1252,
−1
193, 1134, 1068, 1029 cm ; diastereomer A: δ (400 MHz
addition of water and extracted with Et O. The combined organic
H
2
CDC1 ) 7.05 (1H, q, J 7.6 Hz, CH CHC), 5.82 (1H, ddd, J 17.3,
layers were dried over MgSO , filtered and the solvents were
3
3
4
1
0.4, 6.8 Hz, CH CHCH), 5.19 (1H, dd, J 17.2, 1.2 Hz,
removed in vacuo. The crude material was then purified by flash
2
CH2transCHCH), 5.08 (1H, dd, J 10.4, 1.6 Hz, CH2cisCHCH),
.34-4.31 (1H, m, CH CHCHOSi), 3.82 (3H, s, OCH ), 3.14-3.06
chromatography on silica gel (98:2 PE/Et O) to yield the product
9d (900 mg, 63%) as an inseparable 1.6:1 mixture of
2
4
2
3
(
1H, m, CH CHCO), 1.97 (3H, d, J 7.6 Hz, CH CHCO), 1.14
diastereomers, only one diastereomer is described; R (95:5
3
3
f
25
(3H, d, J 7.2 Hz, CH CHC), 0.87 (9H, s, SiC(CH ) ), 0.05 (3H, s,
PE/Et O) 0.30; [a] -44 (c 1.00, CHCl ); n (liquid film) 2955,
3
3 3
2 D 3 max
SiCH ), 0.03 (3H, s, SiCH ), diastereomer B: δH (400 MHz
2930, 2858, 1722, 1697, 1643, 1462, 1392, 1367, 1249, 1151,
−1
3
3
CDC13) 6.89 (1H, q, J 7.2 Hz, CH CHC), 5.84-5.69 (1H, m,
1070, 1026, 1005 cm ; δ (400 MHz CDCl ) 6.94 (1H, q, J 7.6
H 3
3
CH CHCH), 5.15 (1H, dd, J 17.6, 1.2 Hz, CH2transCHCH), 5.10
Hz, CH CHC), 5.86-5.69 (1H, m, CH CHCH), 5.16 (1H, d, J
2
3
2
(
1H, m, CH2cisCHCH), 4.27-4.24 (1H, m, CH CHCHOSi), 3.76
17.2 Hz, CH2transCHCH), 5.09 (1H, d, J 9.2 Hz, CH2cisCHCH),
2
(
3H, s, OCH ), 3.14-3.06 (1H, m, CH CHCO), 1.88 (3H, d, J 7.6
4.35-4.31 (1H, m, (CH CH)CHOSi), 3.14-3.07 (1H, m,
3
3
2
Hz, CH CHCO), 1.14 (3H, d, J 6.8 Hz, CH CHC), 0.87 (9H, s,
CH CHCO), 1.85 (3H, d, J 7.2 Hz, CH CHCO), 1.46 (9H, s,
3
3
3
3
SiC(CH ) ), 0.01 (3H, s, SiCH ), -0.00 (3H, s, SiCH ); mixture of
OC(CH ) ), 1.14 (3H, d, J 6.8 Hz, CH CHC), 0.88 (9H, s,
3
3
3
3
3
3
3
diasteromers δ (100.6 MHz, CDCl ) 205.2, 200.2, 166.5, 164.9,
SiC(CH ) ), 0.06 (3H, s, SiCH ), 0.02 (3H, s, SiCH ); δ (100.6
3 3 3 3 C
C
3
1
5
-
45.5, 143.9, 139.4, 139.2, 138.5, 136.8, 115.8, 115.8, 75.6, 75.5,
3.0, 52.9, 52.5, 49.2, 26.0, 18.4, 18.3, 16.0, 15.8, 13.7, 13.2, -4.1,
MHz CDCl ) δ 205.4, 164.1, 144.3, 138.8, 138.1, 115.7, 81.7,
3
75.5, 52.1, 28.0, 25.2, 18.2, 15.6, 12.9, −4.3, −4.9; HRMS (ESI):
+
+
5.0; HRMS (EI): M , found 326.1920. C H O Si requires
M+Na , found 391.2271. C H O SiNa requires 391.2275.
17
30
4
20 36
4
3
26.1913.
4
.9. Methyl (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-5-
4
.7. 2-(Trimethylsilyl)ethyl (4R,5S)-5-((tert-
oxocyclopent-1-enecarboxylate (5b)
butyldimethylsilyl)oxy)-2-ethylidene-4-methyl-3-oxohept-6-
enoate (9c)
Compound 9b (2.10 g, 6.40 mmol) was dissolved in dry and
degassed CH Cl (128 mL), then Grubbs 2 catalyst was added
2
2
To a stirred solution of titanium (IV) chloride (1.02 mL, 9.30
mmol, 1.80 equiv) in THF (25 mL) at 0 °C was added freshly
(272 mg, 0.05 equiv). The solution was refluxed for 24 h. The
mixture was then concentrated in vacuo. Purification by flash