aldols, anti-6 and syn-6 in 55% and 22% yield and in 95%
and 20% ee, respectively. Cyclohexanone gave aldol 7 as
an inseparable 7:1 mixture of anti and syn diastereomers in
41% yield. The major isomer, anti-7, was formed in 86%
ee and the minor isomer, syn-7, in 89% ee. The assignment
of the absolute configurations of aldols 6 and 7 is based on
the results obtained in the reaction of cyclohexanone with
benzaldehyde.11
deprotection gave (S)-ipsenol (10) in good overall yield
(Scheme 4).16
Scheme 4. Total Synthesis of (S)-Ipsenol.
As in the aldol reactions with acetone, we found that the
only significant side products with cyclic ketones were the
corresponding aldol condensation products, albeit in lower
yields. Independent experiments allowed us to establish that
the elimination products do not arise from the proline-
catalyzed dehydration of aldols 4.12 On the basis of these
results, we propose that the aldol condensation products are
formed in a Mannich-reaction-elimination sequence as
outlined in Scheme 3.
The procedure we describe extends the methodology of
proline-catalyzed direct asymmetric aldol reactions to include
reactions using R-unsubstituted aldehydes as acceptors.
Although the method is limited by modest yields and long
reaction times, we feel the accessibility of both enantiomeric
forms of proline, as well as the operational simplicity17 of
this process, make it compare favorably to other methods
for the direct catalytic asymmetric aldol reaction between
ketones and R-unsubstituted aldehydes.
Scheme 3. Enones 5 Are Formed via Mannich Condensation
Acknowledgment. We are most grateful to Richard A.
Lerner, The Scripps Research Institute, for his generous
support and encouragement.
OL006976Y
(12) Treating aldol 4e in acetone/CHCl3 with L-proline for 3 days did
not yield any significant amounts of enone 5e.
(13) Oertle, K.; Beyeler, H.; Duthaler, R. O.; Lottenbach, W.; Riediker,
M.; Steiner, E. HelV. Chim. Acta 1990, 72, 353-358.
Despite the rather modest yields typically obtained under
the new conditions, the reactions can easily be scaled up to
generate useful quantities for natural product synthesis. To
illustrate this point, we have developed a new asymmetric
synthesis of the bark beetle pheromone (S)- ipsenol (10),
which is used in insect traps and needed in kilogram
quantities.13 Aldol 4d was protected and converted to
enoltriflate 8.14 A highly efficient Stille coupling15 with
tributyl(vinyl)tin furnished known diene 9,13 which after
(14) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302.
(15) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-3040.
(16) For selected asymmetric syntheses of ipsenol, see: (a) Mori, K.
Tetrahedron Lett. 1975, 26, 2187-2190. (b) Ikeda, N.; Arai, I.; Yamamoto,
H. J. Am. Chem. Soc. 1986, 108, 483-486. (c) Brown, H. C.; Randad, R.
S. Tetrahedron Lett. 1990, 31, 455-458. (d) Trost, B. M.; Rodriguez, M.
S. Tetrahedron Lett. 1992, 33, 4675-4678. Also see ref 13.
(17) Hexanal (2.40 mL, 20 mmol) and L-proline (230 mg, 2 mmol, 10
mol %) were stirred in 100 mL of dry acetone for 168 h. Silica gel (ca. 5
g) was added, and the mixture was evaporated. The residue was pored on
a preloaded silica gel column and chromatographed with hexanes/ethyl
acetate (4:1) to give enone 5b (1.12 g, 40%) and aldol 4b (1.11 g, 35%) in
73% ee (AS, 2% 2-propanol/hexanes, 1 mL/min, tR ) 13.3 min, tS ) 15.7
min). Almost identical results were obtained using an aqueous workup
(phosphate-buffered saline/ethyl acetate). All new compounds described
herein gave satisfactory spectroscopic data.
(11) Unpublished results. The four stereoisomeric products of the proline-
catalyzed aldol reaction between cyclohexanone and benzaldehdye are
known and have been characterized by: Denmark, S. E.; Stavenger, R. A.;
Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982-4991.
Org. Lett., Vol. 3, No. 4, 2001
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