SnCl4 (0.5 equiv)11 to afford the [3 + 2] adduct 3a (dr >
20:1) along with homoallylic alcohol 11 (dr 6:1) in a ratio
of 2.3:1. The stereochemistry of 3a is consistent with the
involvement of the syn-synclinal12 transition state A il-
lustrated in Scheme 2. The competition of an allylation
reaction pathway leading to 11 prompted an evaluation of
the effect that a different trialkylsilyl group would exert on
the partition between the two competing pathways. Encour-
aged by reports from Meyers13 and Woerpel14 detailing the
[3 + 2] annulation reactivity of allylic trityldimethyl- and
benzhydryldimethylsilanes, respectively, we sought to modify
our synthesis by substituting the benzhydryldimethylsilyl-
substituted allene 8b for 8a in the sequence outlined in
Scheme 2. Thus, hydroboration of 8b followed by addition
of 6 gave the desired â-hydroxysilane diastereomer (9b) as
the major product, in this case favored by a ratio of 1.6:1
over 10b. Although this reversal in diastereoselectivity from
the phenyldimethylsilyl series is fortuitous, its origins are
not yet clear.15 Silylation of 9b gave 5b, which was subjected
to the SnCl4-promoted reaction with 4 using the previously
described conditions to give 3b (dr 3.3:1) and 11 (dr 1:1) in
a much-improved ratio of 16:1. The reason for the diminished
[3 + 2] annulation diastereoselectivity (relative to 5a f 3a)
in this case is unclear; however, the desired diastereomer of
3b is obtained in 62% overall yield from 5b, with minimal
interference from the allylation pathway leading to 11.
Reports of efficient, stereoselective syntheses of 2,2,5-
trisubstituted tetrahydrofurans via [3 + 2] annulation reac-
tions of tertiary allylsilanes (e.g., 5 f 3) are scarce;9 this
synthesis of 3b from 5b thus represents a valuable extension
of this methodology.
Scheme 3. A-Ring Assembly via Intramolecular Aldol
Cyclization
as a TIPS ether, the TBS ethers were cleaved with p-TsOH‚
H2O in MeOH to provide diol 15 in 81% yield over two
steps. Swern oxidation19 of 15 gave the keto aldehyde 16
which, without purification, was treated with Na2CO3 in
MeOH-H2O20 to effect aldol cyclization. This provided the
desired aldol product 17 in 46% yield, along with 35% of
its C(10) epimer 18. Gratifyingly, these compounds were
separable by silica gel chromatography, and resubjection of
18 to the original aldol conditions (Na2CO3 in MeOH-H2O)
returned the identical 1.3:1 equilibrium ratio (1H NMR
analysis) of 17 and 18 in 99% yield. Consequently, aldol 17
was obtained in 71% overall yield from 15 after two recycles
of 18.
Installation of the B ring of 2 was initiated by the
homologation of the carbon chain at C(7) of 17. Accordingly,
treatment of 17 with TES-Cl and imidazole followed by
hydrogenolysis of the primary benzyl ether gave alcohol 19
in 96% yield (Scheme 4). Swern oxidation of 19 followed
by in situ treatment of the resulting aldehyde with (triph-
enylphosphoranylidene)acetaldehyde at room temperature
gave the expected (E)-enal, which was hydrogenated over
Pd/C to afford keto aldehyde 20 in 71% yield over three
steps. Initial attempts to achieve cyclization of 20 in the
We next turned our attention to the elaboration of 3b (an
inseparable 3.3:1 mixture of diastereomers) via the first of
two carbocyclizations required by our synthetic plan. Subjec-
tion of 3b to Woerpel’s modification (KH, t-BuOOH, TBAF
in N-methyl pyrrolidinone (NMP))16 of the Tamao-Fleming
oxidation17 proceeded via siloxane intermediate 1218 and gave
triol 13 in 68% yield along with 14% of its C(8) epimer
(Scheme 3). Regioselective silylation of 13 with TBS-Cl and
imidazole in DMF then provided the di-TBS ether 14 in 91%
yield. After masking the remaining C(12) hydroxyl group
(10) (a) Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945. (b)
Brown, H. C.; Joshi, N. N. J. Org. Chem. 1988, 53, 4059.
(11) Use of stoichiometric quantities of SnCl4 gave inferior ratios of 3:
11; for example, 21% 3a and 45% 11 were isolated from 5a using 1.1
equiv of SnCl4.
(12) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J.
Org. Chem. 1994, 59, 7889.
(13) (a) Brengel, G. P.; Rithner, C.; Meyers, A. I. J. Org. Chem. 1994,
59, 5144. (b) Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1996, 61, 3230.
(c) Groaning, M. D.; Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1998, 63,
5517.
(14) (a) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2000, 2, 1379. (b) Peng,
Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675.
(15) The allylborations of 6 with γ-silylallylboranes 7a and 7b are
stereochemically mismatched in the pathway leading to 9a and 9b.
(16) (a) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(b) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945.
(17) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694. (b) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29. (c) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599.
(19) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(20) For related intramolecular aldol cyclizations to form bicyclo[3.2.1]-
octanes, see: (a) Coates, R. M.; Shah, S. K.; Mason, R. W. J. Am. Chem.
Soc. 1979, 101, 6765. (b) Pak, H.; Canalda, I. I.; Fraser-Reid, B. J. Org.
Chem. 1990, 55, 3009.
(18) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley,
J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
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