Mehta and Shinde reported an asymmetric total synthesis
that featured a lipase-mediated enzymatic desymmetrization
and ring-closing metathesis (RCM) along the C8-C9 bond.4
Watanabe’s synthesis was based on a highly functionalized
enantiopure cyclohexanone derivative obtained through an
enzymatic reduction.5 More recently, Snider and Zhou
proposed that Sch 642305 could be formed from an isomer
of the related macrolactone nigrosporolide (2) through a
transannular Michael reaction. This proposal was supported
through a biomimetic total synthesis.6
Scheme 2. Heathcock’s and Danishefsky’s Precedence for
Syn-Selective Conjugate Addition to 4-Substituted
Cyclohexenones
We reasoned that Sch 642305 (1) could be retrosyntheti-
cally traced back to simple building blocks in the highly
convergent manner shown in Scheme 1. Disconnection of
Scheme 1. Retrosynthetic Analysis
that this selectivity was due to a Cieplak effect of the
4-alkoxy group.9
Our synthesis of Sch 642305 started with the preparation
of the known cyclohexenone 4, which is most conveniently
available from quinic acid (Scheme 3).10 In parallel, the
Scheme 3. Synthesis of Silyl Enol Ether Key Intermediate 12
the 10-membered lactone through retro RCM along the C8-
C9 bond and functional group manipulations could afford
3. This compound, in turn, could be retrosynthetically
disassembled to afford silyloxy cyclohexenone 4, allyl halide
5, and enol ether (or enolate) 6. These three components are
readily available from commercial material.
In the forward direction, the conjugate addition of 6 would
have to proceed with syn selectivity. This seemingly counter-
intuitive proposal is based on literature precedent. In 1983,
Heathcock reported that Sakurai reactions of 4-methyl
cyclohexenone (7) preferentially afford the syn diastereomer
(Scheme 2a).7 This result was attributed to a lower-energy
chairlike transition state leading to the syn product. Subse-
quently, in a system more relevant to our synthetic plan,
Danishefsky reported that 4-silyloxy cyclohexenones such
as 4 undergo highly diastereoselective Lewis acid catalyzed
Mukaiyama-Michael and Sakurai reactions to form prima-
rily the syn isomer (Scheme 2b).8 Danishefsky postulated
known acetate11 of commercially available (S)-4-penten-2-
ol (10) was converted into silyl ketene acetal 11. In the
presence of a catalytic amount of TBSOTf, 11 underwent a
Mukaiyama-Michael addition to enone 4 with concomitant
silyl transfer.12 This afforded an inseparable 3.7:1 mixture
of syn-silyl enol ether 12 with its anti isomer (not shown).
Interestingly, preliminary results established that the same
reaction conditions using the TBS enol ether of isopropyl
acetate yield a 5:1 mixture of syn/anti isomers. These results
in combination with Danishefsky’s data suggest that there
is a trend for decreasing selectivity of the reaction with
increasing steric bulk of the silyl ketene acetal. In our case,
the use of TBSOTf as a catalyst was found to provide
(4) (a) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2005, 46, 6633-
6636. (b) Mehta, G.; Shinde, H. M. Chem. Comm. 2005, 3703-3705.
(5) Ishigami, K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 62, 2224-
2230.
(6) Snider, B.; Zhou, J. Org. Lett. 2006, 8, 1283-1286.
(7) Blumenkopf, T. A.; Heathcock, C. H. J. Am. Chem. Soc. 1983, 105,
2354-2358.
(8) (a) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111,
2599-2604. (b) Jeroncic, L. O.; Cabal, M.; Danishefsky, S. J. J. Org. Chem.
1991, 56, 387-395.
(9) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540-4552.
(10) (a) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51, 2332-
2342. (b) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3788-3740.
(11) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005,
127, 13796-13797.
(12) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1986, 1805-1808.
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