Pd-Catalyzed Enyne Cycloisomerization
J. Am. Chem. Soc., Vol. 121, No. 26, 1999 6137
were washed with brine, dried (MgSO4), filtered, evaporated, and
chromatographed (SiO2; 10% Et2O in hexane) to give the title compound
(1R,3R,5S,8R,9S,11R)-9-(Bromomethyl)-3-[(tert-butyldimethylsilyl)-
oxy]-11-[[(tert-butyldimethylsilyl)oxy]methyl]-5,9-dimethyl-4-meth-
ylidine-10-oxotricyclo[6.2.1.01,5]undec-6-ene. To a dichloroethane
solution (175 mL, 0.075 M) of 10a (7.40 g, 13.26 mmol, 100 mol %)
at room temperature were added bis(dibenzophospholyl)propane (541.8
mg, 1.32 mmol, 10 mol %), o-(diphenylphosphino)benzoic acid (407.7
mg, 1.32 mmol, 10 mol %), and palladium acetate (297 mg, 1.32 mmol,
10 mol %). The solution was stirred at room temperature for 20 min
and was then gently refluxed for 21 h, at which point the solvent was
removed in vacuo and the residue chromatographed (SiO2; 1:4 CH2-
Cl2/hexane) to give the title compound in 70% yield (5.17 g, 9.28
mmol). Rf ) 0.45 (1:1, CH2Cl2/hexane). [R]D ) -71.5° (c ) 2.28,
8 (8.61 g, 20.77 mmol, 92%). Rf ) 0.35 (1:1 CHCl3/benzene). [R]D
)
1
1.38° (2.0% in CH2Cl2). IR (neat): 2250, 1650, 1470 cm-1. H NMR
(400 MHz, CDCl3): δ 5.48 (br s, 1H), 3.87 (dd, J ) 10.1, 4.9 Hz, 1H),
3.69 (dd, J1 ) J2 ) 9.5 Hz, 1H), 3.42 (d, J ) 10.1 Hz, 1H), 3.34 (d,
J ) 10.0 Hz, 1H), 2.87 (ddd, J1 ) 9.4, J2 ) J3 ) 4.6 Hz, 1H), 2.83 (d,
J ) 16.4 Hz, 1H), 2.74 (d, J ) 16.3 Hz, 1H), 2.44 (br d, J ) 19.0 Hz,
1H), 2.30 (br s, 1H), 2.10 (br d, J ) 18.1 Hz, 1H), 1.65 (s, 3H), 0.90
(s, 9H), 0.08 (s, 3H), 0.05 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
124.3, 117.4, 84.5, 80.4, 61.7, 46.6, 42.9, 37.2, 25.8, 27.7, 25.1, 18.5,
18.1, -5.6, -5.7. HRMS: calcd for C18H29Br81NO2Si [M+ - 15]
401.1130, found 401.1111.
CH2Cl2). IR (neat): 1472, 1362, 1256 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 5.82-5.87 (m, 2H), 4.96 (s, 1H), 4.46-4.54 (m, 1H), 3.56-
3.64 (m, 2H), 3.42-3.49 (dd, J ) 10.1, 6.26 Hz, 1H), 3.46-3.48 (d,
J ) 9.34 Hz, 1H), 2.40-2.52 (m, 2H), 2.13-2.21 (m, 2H), 1.46 (s,
3H), 1.18 (s, 3H), 0.87 (s, 9H), 0.85 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 159.5, 134.1, 124.1, 111.5, 108.5, 89.1,
85.5, 77.3, 77.2, 76.9, 76.8, 76.8, 71.4, 60.9, 52.7, 50.4, 45.2, 41.5,
39.0, 25.7, 25.5, 25.2, 23.5, 18.1, 17.6, -4.8, -4.9, -5.7. HRMS: calcd
for C26H46Br81O3Si2 [M+ - 15] 543.2148, found 543.2152.
(1R,5R,6S/R,8R)-6-(Bromomethyl)-1-[2R/S-[(tert-butyldimethyl-
silyl)oxy]but-3-ynyl]-8-[[(tert-butyldimethylsilyl)oxy]methyl]-2,6-
dimethyl-7-oxobicyclo[3.2.1]hept-2-ene (10). To a solution of 8 (5.2
g, 12.5 mmol, 100 mol %) in toluene (50 mL, 0.25 M) at -78 °C was
slowly added DIBAL (50 mL of a 0.25 M solution in toluene, 12.5
mmol, 100 mol %) dropwise via an addition funnel. The reaction
mixture was allowed to stir for 2 h, at which point the cooling bath
was removed and half-saturated NaHSO4(aq) was added dropwise via
an addition funnel. The temperature of the reaction mixture should not
be allowed to exceed 0 °C. Once the addition was complete, the reaction
mixture was transferred to a separatory funnel containing ice cold
diethyl ether and water. The reaction mixture was extracted twice with
diethyl ether, and the combined extracts were dried (Na2SO4). The
combined organic extracts containing the crude aldehyde were not
evaporated, but added directly to a solution of chloromagnesium
acetylide (50 mmol, 400 mol %) in THF (0.25 M with respect to the
Grignard reacgent, 200 mL) at -20 °C via cannula. After transfer of
the crude aldehyde was complete, the cooling bath was removed and
the reaction mixture was allowed to stir for 0.5 h. The reaction mixture
was partitioned between diethyl ether and half-saturated NH4Cl, and
the aqueous layer was extracted three times with diethyl ether. The
combined organic extracts were dried (MgSO4) and evaporated. The
crude residue was then dissolved in DMF (5 mL, 2.25 M with respect
to 8), and TBSCl (2.83 g, 18.7 mmol, 150 mol % with respect to 8)
and imidazole (2.12 g, 31.2 mmol, 250 mol % with respect to 8) were
added. The reaction mixture was heated to 60 °C and allowed to stir
for 4 h, at which point the reaction mixture was charged onto a
chromatographic column (SiO2; 1:3, CH2Cl2/hexane). The title com-
pounds 10a (2.86 g, 5.1 mmol, 41% yield) and 10b (1.40 g, 2.51 mmol,
20%) were obtained in a combined yield of 61% as a 2:1 mixture of
epimers at the propargylic center.
(1R,3R,5S,8R,9S,11R)-9-(Bromomethyl)-5,9-dimethyl-3-hydroxy-
11-(hydroxymethyl)-4-methylidine-10-oxotricyclo[6.2.1.01,5]undec-
6-ene (15). To a solution of the above bis(TBS) ether (989 mg, 1.77
mmol, 100 mol %) in THF (7 mL, 0.25 M) at room temperature was
added TBAF (5.3 mL of a 1 M solution in THF, 5.3 mmol, 300 mol
%). The reaction mixture was allowed to stir for 22 h, at which point
it was partitioned between water and dichloromethane. The aqueous
layer was extracted with dichloromethane, and the combined organic
layers were dried (MgSO4), evaporated, and chromatographed (SiO2;
70% ethyl acetate in hexane) to provide the title compound 15 (518
mg) in 89% yield. Rf ) 0.25 (70% ethyl acetate in hexane). Mp )
144-145 °C. [R]D ) -120.9° (c ) 2.1, CH2Cl2). IR (neat): 3500-
1
3250, 3100, 1450, 1260 cm-1. H NMR (400 MHz, CDCl3): δ 5.93-
5.85 (m, 1H), 5.15 (s, 1H), 5.01 (s, 1H), 4.61-4.57 (t, J ) 6.92 Hz,
1H), 3.71-3.66 (A part of ABX system, dd, J ) 8.34, 10.64, 1H),
3.59 (A part of AB system, d, J ) 9.73 Hz, 1H), 3.51-3.47 (B part of
ABX system, dd, J ) 5.73 Hz, 10.68, 1H), 3.35 (B part of AB system,
d, J ) 9.39 Hz, 1H), 2.60 (m, 1H), 2.51 (m, 1H), 2.31-2.26 (A part
of ABX system, dd, J ) 8.17, 13.74 Hz, 1H), 2.22-2.17 (B part of
ABX system, dd, J ) 7.02, 14.04 Hz, 1H), 1.49 (s, 3H), 1.21 (s, 3H).
13C NMR (50 MHz, CDCl3): δ 159.8, 133.9, 124.0, 109.4, 88.9, 85.9,
70.9, 59.9, 52.2, 50.3, 44.8, 40.1, 38.7, 25.2, 24.2. HRMS: calcd for
C15H21Br81O3 [M+ - 15] 315.0419, found 315.0398.
Data for the Lower Rf Isomer. Rf ) 0.45 (5% EtOAc in hexane).
[R]D ) -24.5° (c ) 4, CH2Cl2). IR (neat): 3300, 1470 cm-1. 1H NMR
(300 MHz, CDCl3): δ 5.41 (br s, 1H), 4.69-4.72 (br d, J ) 8.0 Hz,
1H), 3.72-3.77 (dd, J ) 5.0, 9.5 Hz, 1H), 3.48-3.51 (d, J ) 10.0 Hz,
1H), 3.45-3.51 (dd, J1 ) J2 ) 9.9 Hz, 1H), 2.85-2.90 (ddd, J1 ) J2
) 5.0, J ) 10, 1H), 2.39-2.40 (d, J ) 2.1, 1H), 2.29-2.37 (M, 2H),
2.14-2.20 (dd, J ) 2.7, 5.4 Hz,1H), 1.75-1.83 (dd, J ) 8.1, 15.0 Hz,
1H), 1.60 (s, 3H), 1.44 (s, 3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.21 (s, 3H),
0.17 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 138.8, 124.1, 86.7, 83.6, 80.8, 77.2, 77.1, 72.6, 60.4, 58.7, 45.3, 42.0,
41.2, 38.2, 26.0, 25.8, 25.7, 24.6, 18.7, 17.9, -4.3, -4.6, -5.6, -6.0.
HRMS: calcd for C18H29Br81NO2Si [M+ - 57] 501.1679, found
501.1695.
Data for the Higher Rf Isomer. Rf ) 0.55 (5% EtOAc in hexane).
[R]D ) -24.0° (c ) 2, CH2 Cl2). IR (neat): 3310, 1470 cm-1. 1H NMR
(300 MHz, CDCl3): δ 5.40 (br s, 1H), 4.59-4.62 (br d, J ) 8.9 Hz,
1H), 3.81-3.85 (dd, J ) 4.9, 9.7 Hz, 1H), 3.42-3.51 (d, J ) 9.89 Hz,
1H), 3.44-3.50 (dd, J1 ) J2 ) 2.0 Hz, 1H), 3.32-3.36 (d, J ) 9.9 Hz,
1H), 2.81-2.89 (ddd, J1 ) J2 ) 5.1, J ) 10.1 Hz, 1H), 2.44 (s, 1H),
2.30-2.41 (m, 3H), 1.92-2.09 (m, 2H), 1.59 (s, 3H), 1.43 (s, 3H),
0.92 (s, 9H), 0.87 (s,9H), 0.35 (s,3H), 0.12 (s, 3H) (s, 6H). 13C NMR
(75 MHz, CDCl3): δ 138.8, 124.1, 86.7, 83.5, 80.4, 72.6, 60.3, 58.6,
45.5, 42.0, 41.4, 38.2, 25.8, 25.7, 25.6, 24.8, 18.6, 18.1, 18.0, -4.9,
-5.2, -5.6, -5.7. Anal. Calcd for C27H49Si2O3Br: C, 58.14; H, 8.85.
Found: C, 58.04; H, 8.79.
(1R,5S,8R,9S,11R)-9-(Bromomethyl)-4-(chloromethyl)-5,9-dimethyl-
11-(hydroxymethyl)-10-oxotricyclo[6.2.1.01,5]undec-3,6-diene (16).
To a -78 °C solution of the allyl alcohol 15 (670 mg, 2.03 mmol, 100
mol %) in ether (40 mL, 0.05 M) was added pyridine (413 mL, 5.08
mmol, 250 mol %) followed by thionyl chloride (593 mL, 8.14 mmol,
400 mol %). The cooling bath was removed, and the reaction mixture
was allowed to stir for 1.5 h. The reaction mixture was diluted with
ether (40 mL), and water (40 mL) was added. The aqueous layer was
extracted with ether, and the combined organic layers were dried
(MgSO4) and evaporated. The crude allyl chloride was chromatographed
(SiO2; 30% ethyl acetate in hexane) to provide the title compound 16
in 66% yield. Rf ) 0.2 (30% ethyl acetate in hexane). [R]D ) -21.3°
(c ) 3.5, CH2Cl2). IR (neat): 3500-3200, 1450, 1262 cm-1. 1H NMR
(400 MHz, CDCl3): δ 5.92 (d, J ) 3.0 Hz, 2H), 5.63 (br s, 1H), 4.05
(s, 2H), 3.63-3.52 (m, 3H), 3.40-3.37 (d, J ) 9.43 Hz, 1H), 2.75-
2.71 (d, J ) 16.41 Hz, 1H), 2.60-2.56 (m, 2H), 2.27-2.22 (d, J )
16.24 Hz, 1H), 1.52 (s, 3H), 1.12 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 144.8, 132.7, 125.9, 125.5, 91.6, 86.3, 60.8, 52.5, 52.1, 43.5,
40.1, 38.9, 36.4, 25.2, 20.3. HRMS: calcd for C15O20ClBr81O2 [M+
128] 220.1226, found 220.1241.
-
(1R,5S,8R,9S,11R)-9-(Bromomethyl)-4-(acetoxymethyl)-5,9-di-
methyl-11-(hydroxymethyl)-2-oxotricyclo[6.2.1.01,5]undec-3,6-diene.
To a solution of the allyl chloride 16 (47.5 mg, 0.136 mmol, 100 mol
%) in DMF (1.3 mL, 0.1 M) was added cesium acetate (52 mg, 0.272
mmol, 200 mol %). The reaction vessel was placed in a 60 °C oil bath
and was allowed to stir for 16 h, at which point the reaction mixture
was charged directly onto a chromatographic column (SiO2; 30% ethyl
b. Compounds en Route from Enyne Cyclization Product
Precursor 10a to Common Intermediate Bislactone Triol 38.