C O M M U N I C A T I O N S
Table 2. Scope of the Organocatalytic Enone Hydrogenation
operationally simple reaction that allows the rapid and chemose-
lective access to â-substituted cycloalkenones. Full details of this
survey will be disclosed shortly.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen, Merck,
and the Astellas Foundation. S.G.O. is grateful for an NSERC
fellowship.
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds are provided.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Akabori, S.; Sakurai, S.; Izumi, Y.; Fujii, Y. Nature 1956, 178, 323.
(b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (c)
Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1999. (d) Noyori, R.
Angew. Chem., Int. Ed. 2002, 41, 2008.
(2) For recent asymmetric metal-catalyzed reductions, see: (a) Moritani, Y.;
Appella, D. H.; Jurkauskas, V.; Buchwald, S, L. J. Am. Chem. Soc. 2000,
122, 6797. (b) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett.
2003, 5, 2417. (c) Lipshutz, B, H.; Servesko, J. M.; Petersen, T. B.; Papa,
P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273.
(3) Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K. I.; Watson, J. D.
Molecular Biology of the Cell, 3rd ed.; Garland: New York & London,
2002.
a Enantiomeric excess determined by chiral GLC analysis. b Yield
determined by NMR. c Performed with 1.3 equiv of Hantzsch ester.
d Performed with 1.1 equiv of ethyl Hantzsch ester 1.
unsaturated systems that provide stable iminium intermediates (entry
5, R ) Ph, 73% yield, 91% ee). Interestingly, the 3-benzyloxy-2-
cyclopentenyl system is a suitable substrate for this reduction
protocol, a surprising result given the anticipated stability of the
corresponding iminium adduct and the capacity of the subsequent
enamine intermediate to undergo â-benzyloxy elimination (entry
4, 89% yield, 91% ee). Importantly, this enantioselective transfer
hydrogenation appears to be suitable for a diverse range of ring
sizes, including cyclopentenyl, cyclohexenyl, and cycloheptenyl
architecture (cf. entries 1, 9, and 12, 70-82% yield, 90-95% ee).
This protocol has also been validated with enones that incorporate
alkyl substituents at other ring positions, an important consideration
with respect to natural product synthesis (e.g., entry 10, gem-
dimethyl, 66% yield, 98% ee).
(4) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 32. (b) Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola,
N.; List, B. Angew. Chem., Int Ed. 2005, 44, 108. (c) Mayer, S.; List, B.
Angew. Chem., Int. Ed. 2006, 45, 4193.
(5) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(6) Furyl imidazolidinone 4 is now commercially available from Aldrich
Chemical Co., Milwaukee, WI.
(7) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894.
(8) Three recent examples of iminium activation catalysis from our laboratory
include: (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1172. (b) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 9328. (c) Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. For a recent
review on iminium catalysis see: (d) Lelais, G.; MacMillan, D. W. C.
Aldrichimica Acta 2006, 39, 79.
(9) For an interesting analysis of the proposed transition state structures for
the hydride transfer step with NADH-type compounds, see: (a) Wu, Y.;
Houk, K. N. J. Am. Chem. Soc. 1987, 109, 2226. (b) Donkersloot, M. C.
A.; Buck, H. M. J. Am. Chem. Soc. 1981, 103, 6554. (c) Young, I.; Post,
C. B. J. Am. Chem. Soc. 1993, 115, 1964. (d) Wu, Y.; Lai, D. K. W.;
Houk, K. N. J. Am. Chem. Soc. 1995, 117, 4100.
(10) Representative procedure: To a flask containing the R,â-unsaturated ketone
(1 equiv) in Et2O (0.5 M) at 0 °C was added catalyst 3 (20 mol %),
followed by tert-butyl Hantzsch ester (1.1 equiv), then trichloroacetic acid
(20 mol %). The resulting mixture was stirred at 0 °C until complete
consumption of the unsaturated ketone was determined by TLC analysis.
The reaction mixture was then passed through a plug of silica gel with
the aid of Et2O and then purified by silica gel chromatography.
The sense of asymmetric induction observed in all cases is
consistent with selective engagement of the Hantzsch ester reductant
with the Si face of the cis-iminium isomer 5 (MM3-5). This result
is in complete accord with our previous Diels-Alder studies
involving cyclic enones and furanyl imidazolidinone 4.
In summary, we have developed the first enantioselective
organocatalytic transfer hydrogenation involving cyclic enones, an
JA0653066
9
J. AM. CHEM. SOC. VOL. 128, NO. 39, 2006 12663