C O M M U N I C A T I O N S
Table 3. Substrate Scopea
Upon oxidation and elimination under irreversible conditions, 2a
is isolated with only 40% ee. These facts raise the possibility that
elimination of Cys may be the irreversible and stereochemistry-
determining step. By analogy, we note that elimination of catalyst
through R-proton abstraction has also been shown to be rate-
1
0
determining in variants of the Morita-Baylis-Hillman reaction.
Thus, we have derived models 15 and 16 that may explain the
formation of the observed enantiomer, in light of reversible ring-
forming C-C bond formation. Each model benefits from stable
arrangements of the cyclohexanone-derived enolates that minimize
allylic strain. Furthermore, each maintains π-overlap of the enolate
with the σ*-C-S orbital of the bond that is to be cleaved. The
differential rates of elimination therefore may derive from the more
stable amide-chelated enolate 15 in comparison to the ester-chelated
a
Reactions were run at -40 °C (see Supporting Information for reaction
b
details). Yields refer to the mass isolated after silica gel chromatography.
All enantiomeric excesses were measured using chiral HPLC. The absolute
configuration of 2c was determined by X-ray crystallography of the
corresponding hydrazone. See Supporting Information for details. The other
products were assigned by analogy.
c
As shown in entries 5-7, optimized conditions were found such
that, within 24 h, product 2 is isolated in 70% yield with 95% ee
entry 7).
1
1
enolate 16 in plausible conformers of the Cys adducts.
(
As is inherent in Scheme 1, the reaction may be run with a
substoichiometric quantity of catalyst. Cyclization of 1a to give
a may be conducted with 20 mol % of 5, leading to 75% isolated
2
yield with 92% ee after 24 h (Table 3, entry 2). Further reduction
of catalyst loading (10 mol %) leads to 2a with nearly identical ee,
but with a reduced yield of 41% within this time frame (entry 3).
A modest rate reduction was also observed in the conversion of
Further studies of the scope and mechanism of this catalytic
reaction are in progress.
1b to 2b with 20 mol % of catalyst 5 (entry 4 versus 5). As a
Acknowledgment. This research is supported by the National
Science Foundation (CHE-0639069).
result, since such a simple and commercially available catalyst
mediates this transformation, we elected to perform a preliminary
study of reaction scope with a full equivalent of 5 to maintain
convenient reaction rates and useful yields for a range of substrates.
As shown in Table 3, the reaction of symmetrical bis(enones) is
relatively insensitive to electronic effects. For example, para-
methoxy substitution (1b) and para-bromo substitution (1c) lead
to similar results. Products 2b and 2c are isolated with 90 and 93%
Supporting Information Available: Experimental procedures and
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For example, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2
004, 43, 5138. (b) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481.
2
ee, respectively (entries 4 and 6). The para-NO -substituted
(
2) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904.
compound 1d delivers 2d within 4 h, but with a modest drop in
selectivity (84% ee, entry 7). Aliphatic compounds are also
substrates for the process. Bis(methylketone) 9 undergoes the
cyclization to give 10 in 90% ee, with an isolated yield of 55%
after 40 h (entry 8). Furan-substituted bis(enone) 11 also results in
a selective reaction (12, 92% ee, 54% yield, entry 9). Finally,
unsymmetrical keto ester 13 forms 14 in 66% yield, with a reduced
ee of 67% (entry 10).
The basis of the enantioselectivity induced by a single amino
acid warrants mechanistic speculation. Two experimental observa-
tions have guided our thinking. First, we note that conducting the
reaction in the presence of 18-crown-6 does not lead to 2a as the
major product, and instead deconjugated 17 dominates (26% yield,
(3) McMurry, J.; Begley, T. The Organic Chemistry of Biological Pathways;
Roberts and Co.: New York, 2005.
(
4) Rauhut, M. M.; Currier, H. U.S. Patent 307499919630122, American
Cyanamid Co., 1963.
(
5) (a) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J.
Am. Chem. Soc. 2002, 124, 2402. (b) Frank, S. A.; Mergott, D. J.; Roush,
W. R. J. Am. Chem. Soc. 2002, 124, 2404. (c) Mergott, D. J.; Frank, S.
A.; Roush, W. R. Org. Lett. 2002, 4, 3157. (d) Agapiou, K.; Krische, M.
J. Org. Lett. 2003, 5, 1737.
(
6) For some examples of variants with electrophilic olefins with other
activating groups, see: (a) Luis, A. L.; Krische, M. J. Synthesis 2004, 15,
2
1
579. (b) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127,
0168.
(7) For a review, see: Huddleston, R. R.; Krische, M. J. Synlett 2003, 12.
(
8) (a) Brown, P. M.; K a¨ ppel, N.; Murphy, P. J. Tetrahedron Lett. 2002, 43,
8
707. (b) Erg u¨ den, J.-K.; Moore, H. W. Org. Lett. 1999, 1, 375.
(9) For dramatic solvent effects in vinylogous Morita-Baylis-Hillman
reactions, see: Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5, 4223.
10) (a) Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org.
Chem. 2005, 70, 3980. (b) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones,
G. C. Angew. Chem., Int. Ed. 2005, 44, 1706. (c) Raheem, I. T.; Jacobsen,
E. N. AdV. Synth. Catal. 2005, 347, 1701.
(
8
4% ee, eq 1). Thus, we believe that K ion chelation is operative
in the selective reactions. Second, we have observed that, after only
h under normal conditions, in addition to 2a (29% yield, 95%
2
(11) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc. 2000,
22, 12868.
1
ee), the cyclized cysteine-substituted diketone derivative of 4 is
isolated, but it appears as a mixture of five diastereomers (eq 2).
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