Asymmetric addition of alkylzinc reagents to cyclic α,β-unsaturated ketones and a tandem enantioselective addition/diastereoselective epoxidation with dioxygen

Article abstract of DOI:10.1021/ja036302t

Although over 100 catalysts have been reported to catalyze the asymmetric addition of alkyl groups to aldehydes, these catalysts fail to promote additions to ketones with >90% enantioselectivity. This paper describes the asymmetric 1,2-addition of alkyl g

Full text of DOI:10.1021/ja036302t

Published on Web 07/22/2003
Asymmetric Addition of Alkylzinc Reagents to Cyclic r,â-Unsaturated
Ketones and a Tandem Enantioselective Addition/Diastereoselective
Epoxidation with Dioxygen
Sang-Jin Jeon and Patrick J. Walsh*
P. Roy and Diane T. Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received May 23, 2003; E-mail: pwalsh@sas.upenn.edu
Table 1. Asymmetric Addition of Alkyl Groups to Cyclic Enones
We recently reported the asymmetric addition of alkylzinc
reagents to ketones using an easily prepared constrained-geometry
catalyst.1 A noteworthy aspect of this study is that it offers a solution
to a long-standing problem in synthetic organic chemistry: the
catalytic synthesis of tertiary alcohols from acetophenone derivatives
with high enantioselectivity. In contrast to related addition reactions
with aldehyde substrates, which are promoted by hundreds of
catalysts,2,3 only a handful of systems will promote additions to
ketones,1,4-7 and most of these require high catalyst loadings and
long reaction times.5-7 Despite significant effort in this area, we
are not aware of successful reports of the enantioselective addition
of alkyl groups to conjugated cyclic enones. In this Communication,
we report the results of an investigation into the efficient and highly
enantioselective 1,2-addition reactions of cyclic R,â-unsaturated
ketones. The resulting tertiary allylic alcohols are valuable inter-
mediates that can be further elaborated via directed epoxidation
reactions with excellent diastereoselectivities. The resulting epoxy
alcohols undergo Lewis acid promoted semipinacol rearrangement
to give â-hydroxy-R,R-disubstituted ketones. Furthermore, we have
developed a tandem, one-pot protocol for the enantioselective
addition/diastereoselective epoxidation simply by capping the
reaction with a balloon of dioxygen when the asymmetric addition
is complete.
a See Supporting Information for ee determination protocol.
asymmetric addition of alkylzinc reagents to aldehydes, it has
recently been definitively demonstrated that the alkyl group is
transferred from titanium, and not zinc.9 Thus, the oxophilic Ti-
alkyl adds in a 1,2-fashion, and the soft Cu-alkyl adds in a 1,4-
fashion.
The scope of the asymmetric ketone alkylation is illustrated in
Table 1. Addition of ZnMe2 and ZnEt2 to 2-methyl cyclopentenone
exhibits 98% and 96% enantioselectivity in 55% and 65% yield,
respectively. Increasing the length of the 2-substituent to pentyl
led to an increase in the enantioselectivities to 99% for both ZnMe2
and ZnEt2. Aryl-substituted substrates also underwent alkylation
with high enantioselectivity, but with diminished yields due to aldol/
dehydration side reactions.
Reactions of 2-phenyl cyclohexenone with ZnMe2 and ZnEt2 both
generated allylic alcohol products with 95% enantioselectivity, albeit
in 54% and 40% yield. Decreased yields were observed with the
exocyclic enone 6, which gave 20% and 32% yield with 99%
enantioselectivity in each case. Enones devoid of alkyl substituents
R to the carbonyl group are not particularly good substrates, giving
52% and 61% enantioselectivity (entries 11 and 12). Because of
Initial evaluation of ligand 1 in the asymmetric addition reaction
(eq 1) with ZnMe2 and ZnEt2 indicated that 2-substituted enones
are excellent substrates. Thus, as shown in Table 1, treatment of
enone 2 with 10 mol % ligand 1, 3 equiv of ZnMe2, and 1.2 equiv
of Ti(OiPr)4 at room temperature leads to the tertiary allylic alcohol
in 84% yield and 99% enantioselectivity after chromatography on
silica gel. Likewise, use of ZnEt2 under identical conditions
provided the allylic alcohol in 76% yield and 98% enantioselectivity
(entry 2). It is significant that the titanium catalyst is chemoselective,
giving only carbonyl addition and no conjugate addition. In contrast,
copper-catalyzed additions of dialkylzinc reagents to enones give
conjugate addition products.8 In a related titanium-BINOL-catalyzed
9
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J. AM. CHEM. SOC. 2003, 125, 9544-9545
10.1021/ja036302t CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 3. One-Pot Synthesis of Epoxy Alcohol Products with
Oxygen
Table 2. Semipinacol Rearrangement Products
a For reactions with ZnMe2, 1.5-2 equiv of ZnEt2 was added after
the similar steric environments of the oxygen lone pairs, discrimina-
tion of the enantiotopic carbonyl faces of these substrates is quite
challenging.
complete ketone consumption.
can be coupled with a diastereoselective epoxidation in which the
ultimate oxidant is generated from dioxygen. Rearrangement of the
resulting epoxy alcohols provides highly functionalized aldol type
products with excellent ee that are not accessible through traditional
aldol chemistry. We are currently investigating the mechanism of
the asymmetric addition and the epoxidation reaction.
The allylic alcohols in eq 1 are valuable chiral building blocks
that contain chiral quaternary centers. Such centers are difficult to
access, and, therefore, methods to synthesize them have attracted
considerable attention.10,11 The Lewis acid-promoted semipinacol
rearrangement of R-hydroxy epoxides is another useful method to
establish chiral quaternary centers.12,13 Thus, diastereoselective
epoxidation of selected allylic alcohols was examined using
m-CPBA. The desired syn-epoxy alcohols were obtained in >90%
yield. Treatment of the epoxy alcohols with BF3‚OEt2, as shown
in eq 2, resulted in semipinacol rearrangement cleanly providing
new â-hydroxy-R,R-disubstituted ketones in good yields (Table 2).
The ketone products are formed as single diastereomers with no
loss of ee in the epoxidation/rearrangement sequence. These densely
functionalized products contain chiral all-carbon stereocenters
(entries 1, 2, and 4).
We next investigated the possibility of performing a tandem one-
pot enantioselective ketone alkylation/diastereoselective epoxidation
sequence. Dialkylzinc reagents readily react with dioxygen to
provide metal peroxides.14,15 In the presence of titanium tetraiso-
propoxide, hydroperoxides are known to catalyze olefin epoxidation
with high diastereoselectivity.16 Performing the addition reaction
with ZnEt2 followed by exposure of the reaction mixture to
dioxygen (1 atm) resulted in complete conversion to the syn-epoxy
alcohol in under 4 h. Epoxidations in the presence of ZnMe2 were
very slow. In these reactions, 2 equiv of ZnEt2 was added before
exposure to dioxygen. The yields and enantioselectivities of the
epoxy alcohols (Table 3) are essentially identical to those of the
addition reactions reported in Table 1. Interestingly, the epoxidation
reaction outlined here is very different than the Sharpless asym-
metric epoxidation in that our reaction is conducted under basic,
aprotic conditions.17
Acknowledgment. This work was supported by the NIH
(GM58101).
Supporting Information Available: Procedures and full charac-
terization of new compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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An effective protocol for the enantioselective addition of alkyl
groups to cyclic conjugated enones is disclosed. This transformation
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