J. Am. Chem. Soc. 1998, 120, 445-446
445
Table 1. Enantioselective Addition of ZnPh2 to Ketones Catalyzed
by (+)-DAIB (eq 1)
Catalytic Asymmetric Addition of ZnPh2 to Ketones:
Enantioselective Formation of Quaternary
Stereocenters
Peter I. Dosa and Gregory C. Fu*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed September 10, 1997
A wide array of highly effective catalysts have been developed
for the enantioselective addition of organometallic reagents to
aldehydes.1,2 However, to the best of our knowledge there have
been no reports of efficient catalytic asymmetric addition of
organometallic reagents to ketones.3 In this communication, we
provide an example of such a process, establishing that 3-exo-
(dimethylamino)isoborneol (DAIB)1b serves as an effective
catalyst for the enantioselective addition of ZnPh2 to a range of
aryl-alkyl and dialkyl ketones, thereby producing a quaternary
stereocenter with good to excellent stereocontrol (eq 1).
In pioneering studies, Noyori has demonstrated that DAIB is
a remarkably efficient catalyst for the asymmetric addition of
ZnEt2 to aldehydes.1b,d We sought to expand the scope of DAIB-
catalyzed processes to include reactions of ketones, and we
a The sign of rotation of the predominant enantiomer is indicated in
parentheses. For entries 1, 4, and 7, the R isomer is formed
preferentially.
4
focused our initial efforts on the addition of ZnPh2 to 2-aceto-
naphthone. Although we observed a promising level of enantio-
meric excess in the desired tertiary alcohol (64% ee), the yield
was disappointing (26% yield; eq 2). The predominant reaction
product was ketone A, which is formed via an aldol-dehydration-
conjugate addition sequence.5
With the expectation that an additive would alter the nature of
the zinc species in solution, we introduced MeOH to the reaction
mixture.6 We were pleased to discover that the addition of 1.5
equiv of MeOH results in enhanced enantioselectivity and in an
improved yield of the desired tertiary alcohol (eq 3).7
(1) For reactions of organozinc reagents, see: (a) Oguni, N.; Omi, T.
Tetrahedron Lett. 1984, 25, 2823-2824. (b) Kitamura, M.; Suga, S.; Kawai,
K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-6072. (c) Soai, K.; Niwa,
S. Chem. ReV. (Washington, D.C.) 1992, 92, 833-856. (d) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994; Chapter
5.
(2) StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer,
J., Schaumann, E., Eds.; Thieme: New York, 1996; Part D, Section 1.3.
(3) For examples of efficient asymmetric additions of organometallic
reagents to ketones in the presence of a stoichiometric quantity of an
enantiopure magnesium alkoxide, see: Weber, B.; Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 84-86.
(4) We are aware of only one report of catalytic asymmetric addition of
ZnPh2 to a carbonyl group: Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem.
1997, 62, 444-445 (addition of ZnPh2 to 4-chlorobenzaldehyde in 57% ee).
We have explored the scope of DAIB-catalyzed reactions of
ZnPh2 with ketones, and we have established that for an array of
substrates the additions proceed with good to excellent enantio-
(5) For precedent, see: (a) Aldol-dehydration: Henrich, F.; Wirth, A.
Monatsh. Chem. 1904, 25, 423-442. (b) Conjugate addition: Soai, K.; Okudo,
M.; Okamoto, M. Tetrahedron Lett. 1991, 32, 95-96.
(6) MeOH reacts rapidly with ZnPh2 to form benzene and a zinc alkoxide.
(7) In these DAIB-catalyzed addition processes, enolization of the ketone
is a key side reaction that is detrimental from the standpoints of yield and
enantioselectivity. Thus, whereas ZnPh2 reacts with 2-acetonaphthone to
produce the tertiary alcohol in 58% yield and 72% ee (eq 3), it reacts with
2-acetonaphthone-d3 to afford the tertiary alcohol in 87% yield and 86% ee.
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