.
Angewandte
Communications
DOI: 10.1002/anie.201303202
Asymmetric Catalysis
Formation of Quaternary Centers by Copper-Catalyzed Asymmetric
Conjugate Addition of Alkylzirconium Reagents**
Mireia Sidera, Philippe M. C. Roth, Rebecca M. Maksymowicz, and Stephen P. Fletcher*
Alkenes are among the most readily available organic
molecules, and are feedstocks for the preparation of many
commodity chemicals.[1] Using alkenes as starting materials in
synthesis is practical because they are inexpensive and easy to
handle. We recently reported[2] that alkenes can be used as the
equivalents to premade alkyl metal species in copper-
catalyzed asymmetric conjugate additions (ACA).[3] In these
reactions hydrometalation (HM) of terminal alkenes with the
Schwartz reagent[4] generates alkylzirconocenes,[5] which
undergo asymmetric 1,4-additions catalyzed by complex A
(Scheme 1). These processes are currently limited to the
formation of tertiary centers from ACA to unsubstituted
cyclic enones.[2] Herein we report that this approach can be
used to form quaternary centers.
alkyl nucleophiles, copper catalysis allows enantioselective
addition of dialkylzincs,[8] trialkylaluminums,[9] and Grignard
reagents[10] to trisubstituted enones.
The development of new synthetic methodology capable
of coupling unactivated partners is a significant goal of
contemporary chemistry. The premade alkyl metal nucleo-
philes which are currently used to form quaternary centers are
not ideal and only a few are readily available. They are highly
reactive and can present practical (and safety) issues,[11] and
their use typically requires cryogenic reaction temperatur-
es.[3b,7,12] These factors limit the options that are available in
reaction design and present significant challenges to the
incorporation of these procedures into large-scale or indus-
trial processes.[11] Additionally, the sophistication of the alkyl
groups which can be added in these procedures is quite
restricted.[7] While simple groups can be used, nucleophiles
containing stereogenic centers and even protected functional
groups are essentially unknown. Below, we describe the
development and use of a system which allows alkenes to be
used as alkyl metal equivalents in highly enantioselective
copper-catalyzed ACAs to trisubstituted cyclic enones. A
wide variety of simple and functionalized alkenes are readily
available, and allows easy variation in the alkyl groups which
can be added. It is noteworthy that these reactions operate at
room temperature, tolerate a wide range of reaction con-
ditions, and use a new, readily available phosphoramidite[13]
ligand. These results suggest that this new approach may be
more general and practical than those requiring preformed
organometallics.
Scheme 1. Hydrometalation/asymmetric conjugate addition of alkenes.
Cp=cyclopentadienyl, Tf=trifluoromethanesulfonyl, TMS=trimethyl-
silyl.
Our studies began with evaluating the coupling of
4-phenyl-1-butene (1) and 3-methyl-2-cyclohexen-1-one (2)
under reaction conditions that we had previously applied in
1,4- and 1,6-conjugate addition reactions.[2] Hydrometalation
of 1 and subsequent asymmetric conjugate addition to 2 in the
presence of the phosphoramidite (S,S,S)-C, (CuOTf)2.PhH,
and TMSCl (Table 1, entry 1) gave (S)-3 in 45% yield and
60% ee. The use of the diastereomeric (R,S,S)-D gave (R)-3
and improved the ee value to 70% (Table 1, entry 2) while
isomeric (R)-E gave (R)-3 with 61% ee. The use of
(CuOTf)2·PhH without TMSCl gave very low (< 20%)
conversion. Using (R,S,S)-D in combination with different
copper sources (Table 1, entries 4, 5, 7, and 8) showed that the
reaction was highly sensitive to the copper counterion and
that triflimidate provided high levels of enantioselectivity. In
the case of CuNTf2 the enantioselectivity could be improved
(to 88% ee) by omitting TMSCl from the procedure (entries 5
and 6), without affecting the conversion. We found that
filtering off the AgCl byproduct from copper sources
generated by silver exchange gave slightly higher (ca. 5–
10% ee) enantioselectivity. Using ligand (R)-E with copper
The ability to construct all-carbon quaternary centers with
high levels of enantioselectivity is widely regarded as one of
the most significant and challenging goals in asymmetric
catalysis.[6] An important approach to this problem, pioneered
and developed by the groups of Hoveyda and Alexakis,
involves transition metal catalyzed ACA reactions of organo-
metallics to trisubstituted Michael acceptors.[7] In the case of
[*] Dr. M. Sidera,[+] P. M. C. Roth,[+] R. M. Maksymowicz,
Dr. S. P. Fletcher
Department of Chemistry, Chemistry Research Laboratory
University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: stephen.fletcher@chem.ox.ac.uk
[+] These authors contributed equally to this work.
[**] The authors thank the EPSRC for generous support of this research
in the form of a Career Acceleration Fellowship to S.F. (EP/
H003711/1). We are grateful to Prof. A. Alexakis for GC analysis of
3b and Dr. B. Odell for assistance with the NMR experiments.
Supporting information for this article is available on the WWW
2
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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