mixture in 75% yield over two steps.9,10 Finally, exposure
of 8 to a first-generation Grubbs olefin metathesis catalyst11
in dilute CH2Cl2 followed by ParikhꢀDoering oxidation12
of the resulting diastereomeric cyclohexenols produced 5
in 82% yield over two steps. Over 30 g of 5 were prepared
through this method.
Scheme 3. Lewis Acid Catalyzed Contrasteric DielsꢀAlder
Reactiona
Following our synthesis of 5, we next attempted the key
Lewis acid catalyzed contrasteric DielsꢀAlder reaction
depicted in eq 1 of Scheme 3. Danishefsky et al. had
previously demonstrated that 2-cyclohexenone 9, bearing
a γ-OTBS group, participates in a contrasteric intermole-
cular DielsꢀAlder reaction with 1,3-butadiene when ca-
talyzed by AlCl3 to provide cis-decalin 10 in 76% yield (eq 1,
Scheme 3).13 In this transformation, the β-CꢀC bond is
formed syn relative to the γ-OTBS group in high diaste-
reoselectivity (>10:1 syn/anti). We anticipated similar
stereoselectivity in our proposed DielsꢀAlder reaction,
despite the additional Lewis basic groups in our substrate.
Gratifyingly, treatment of 5 with 1,3-butadiene in the pre-
sence of TiCl4 at 5 °C for 3.5 h afforded a >10:1 mixture
of adducts, favoring the desired syn diastereomer 11. This
reaction, which can be performed on a multigram scale
with high diastereoselectivity, is to our knowledge the
most complex example of a contrasteric DielsꢀAlder yet
reported.
a Reagents and condtions: (a) 1,3-butadiene (20 equiv), AlCl3
(0.9 equiv), PhMe, 23 °C, 1 h, 76% (>10:1 syn/anti). (b) 1,3-butadiene
(8.0 equiv), TiCl4 (1.0 equiv), PhMe, ꢀ78 to 5 °C, 3.5 h, 76% (>10:1 syn/
anti). Abbreviations: TS = transition state.
The stereoselectivity ofthisreactionis likely governedby
subtle steric and stereoelectronic effects. Approach of 1,3-
butadiene to 5 syn to the γ-OTBS substituent is sterically
occluded by both the γ-OTBS and R-OPiv groups and thus
counterintuitive (transition state 1, Scheme 3). However,
stereoelectronic considerations suggest that pseudoaxial
approach of 1,3-butadiene to the β-carbon of the chairlike
ground state conformation of 9 is kinetically favored.14
Additionally, the Cieplak model has been invoked to
rationalize the stereochemical outcome for the aforemen-
tioned DielsꢀAlder reaction.15 In accordance with this line
of reasoning, formation of the β-CꢀC bond syn with
the electron-withdrawing γ-OTBS group stabilizes the
forming σ*-CꢀC orbital through hyperconjugation with
the electron-donating σ-CꢀH bond (transition state 2,
Scheme 3). It is plausible that a synergism of individually
small stereoelectronic effects bias the reaction pathway
toward the observed product diastereomer 11.
of the ketone at C6 rather than at C2 to generate enol
silane 12 as a single regioisomer.16 This regioselection is
particularly noteworthy since C2ꢀH is presumably more
acidic than C6ꢀH. Chemoselective oxidation of 12 was
accomplished upon treatment of 12 with DDQ to afford
dienone 4 in 78% overall yield, again as a single regio-
isomer.17 The mild nature of this procedure prevented
overoxidation of the dienone moiety. Next, regio- and
diastereoselective addition of dimethylphenylsilyl zincate
tothe δ-position of 4 generatedextendedzincenolate inter-
mediate 13.18 In situ R-oxidation of 13 with MoO5•pyr•
HMPA (MoOPH) delivered cis-decalin 3 as a single regio-
and diastereoisomer in 82% yield. The one-pot 1,6-con-
jugate addition/enolate oxidation sequence was amenable
to a variety of oxidants including Davis oxaziridine and
DMDO; however, MoOPH proved to be the most efficient
oxidant on a large scale.19 Overall, the tandem reaction
sequence generated the sterically congested C6-tertiary
carbinol and an allylic silane, which was planned to serve
as a latent enone surrogate.
The synthesis of 2 continued with a series of carefully
controlled oxidations of the cis-decalin carbon skeleton of
11 (Scheme 4). Exposure of 11 to TMSI, generated in situ
from TMSCl and NaI, promoted thermodynamic enolization
Exposure of 3 to excess organocerium reagent derived
from n-propylmagnesium chloride led to carbonyl addi-
tion exclusively from the convex face of the molecule and
(12) Parikh, J. P.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(13) Jeroncic, L. O.; Cabal, M. P.; Danishefsky, S. J.; Shulte, G. M.
J. Org. Chem. 1991, 56, 387–395.
(14) Angell, E. C.; Fringuelli, F.; Pizzo, F.; Porter, B.; Taticchi, A.;
(17) (a) Ryu, I.; Murai, S.; Hatayama, Y.; Sonoda, N. Tetrahedron
Lett. 1978, 19, 3455–3458. (b) Corey, E. J.; GuzmanꢀPerez, A.; Loh,
T.-P. J. Am. Chem. Soc. 1994, 116, 3611–3612.
Wenkert, E. J. Org. Chem. 1986, 51, 2642–2649.
(15) (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540–4552.
(b) Ohkata, K.; Tamura, Y.; Shetuni, B. B.; Takagi, R.; Miyanaga, W.;
Kojima, S.; Paquette, L. A. J. Am. Chem. Soc. 2004, 126, 16783–16792.
(c) Carreno, M. C.; Gonzalez, M. P.; Houk, K. N. J. Org. Chem. 1997,
62, 9128–9137.
(16) (a) Miller, R. D.; McKean, D. R. Synthesis 1979, 9, 730–732.
(b) Moher, E. D.; Collins, J. L.; Grieco, P. A. J. Am. Chem. Soc. 1992,
114, 2764–2765. (c) Krafft, P. A.; Holton, R. A. Tetrahedron Lett. 1983,
24, 1345–1348.
(18) (a) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning, J. R.;
Overman, L. E. Org. Lett. 2009, 11, 5658–5661. (b) Vaughan, A.; Singer,
R. D. Tetrahedron Lett. 1995, 36, 5683–5686. (c) Lipshutz, B. H.;
Sclafani, J. A.; Takanami, T. J. Am. Chem. Soc. 1998, 120, 4021–4022.
(d) Crump, R. A. N. C.; Fleming, I.; Urch, C. J. J. Chem. Soc., Perkin
Trans. 1 1994, 701–706. (e) Tckmantel, W.; Oshima, K.; Nozaki, H.
Chem. Ber. 1986, 119, 1581–1593.
~
ꢀ
(19) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944–5946. (b) Vedejs,
E.; Larsen, S. Org. Synth. 1986, 64, 127–132 and references therein.
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