to copper in a γ-selective manner and with anti stereochem-
istry, giving σ-allyl complex 2 (Scheme 2).7,8 A fast reductive
elimination from intermediate 2 would lead to product 3.
However, if conversion of 2 to 4 is faster than reductive
Scheme 1. Enantioselective Synthesis of R-Methyl Carboxylic
Acids via Metal and Enzyme Catalysis
Figure 1. Substrates investigated in the copper-catalyzed allylic
substitution.
enantiomers of the final product can be prepared with high
optical purity.
There are several examples of copper(I)-mediated substitu-
tions of enantiomerically pure allylic substrates that occur
with high 1,3-chirality transfer in an anti-SN2′manner (γ-
elimination of 2 to 3, selective formation of product 5 is
expected, provided that the equilibration between rotamers
2 and 2′ is slow.
If substituents A and B are identical, intermediates 4 and
6 will be enantiomers. Thus, fast equilibration of these
reaction intermediates (via 2 and 2′) prior to product
formation would lead to formation of a racemic R-product,
(i.e., 5 + 7).9 If substituents A and B are different,
intermediates 4 and 6 are diastereoisomers and under full
equilibration between 4 and 6 (via 2 and 2′) a Curtin-Hammet
situation would be at hand. The reactivity of these diaste-
reoisomers as well as their stability would determine the ratio
between 5 and 7.
Scheme 2. Isomerization of the Allyl Intermediates, Leading
to Different Products
The substrates investigated for allylic substitution are
depicted in Figure 1. Substrates 8 and 8′ have identical
substituents in the γ-position and for this reason loss of chiral
information according to Scheme 2 may occur. In a previous
study we found that loss of chiral information indeed takes
place in the copper-catalyzed cross-coupling of 8 with alkyl
Grignard reagents at low temperature.9 However, with aryl
Grignard reagents high conservation of chiral information
was obtained. Since the efficiency of the reaction of 8 with
aliphatic Grignard reagents was moderate, we also investi-
gated 9 and 10 as possible substrates for a selective
R-substitution with retained chiral information in the copper-
catalyzed allylic substitution reaction.
DKR of alcohol 11 was carried out using ruthenium
complex 1 and CALB to afford (R)-8. An elevated temper-
ature was required to obtain an acceptable rate of product
formation, and at 80 °C product (R)-8 was obtained in 97%
yield and >99% ee (Scheme 3).3b Isomerization of similar
allylic alcohols in the presence of ruthenium complexes such
as 1 is known to occur;10 however, the formation of a ketone
from the isomerization of 11 was not observed. The ester
with the opposite configuration at carbon, (S)-8′, was
obtained in 83% yield and 95% ee in an (S)-selective
DKR3a,11 of 11 using the protease Subtilisin Carlsberg and
selective).4 On the other hand, the formation of R-product
(anti-SN2 reaction) with conserved chiral information is less
studied. To the best of our knowledge, only cyclic allylic
substrates have been employed,4c except for one case5 where
the R-substitution of an acyclic substrate proceeded with 88%
conservation of chiral information. However, no further
studies or synthetic applications of this reaction have been
reported.
Oxidative addition of allylic esters to copper(I) is assumed
to occur with high stereoselectivity.5-8 The substrate adds
(4) (a) Trost, B. M.; Klun, T. P. J. Org. Chem. 1980, 45, 4256. (b) Ibuka,
T.; Akimoto, N.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Org. Chem. 1989,
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(5) Goering, L. H.; Tseng, C. C. J. Org. Chem. 1983, 48, 3986.
(6) (a) Goering, L. H.; Singleton, V. D., Jr. J. Org. Chem. 1983, 48,
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Goering, L. H.; Kantner, S. S. J. Org. Chem. 1981, 46, 2144. (d) Goering,
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J.-E.; Persson, E. S. M.; Bombrun, A. J. Org. Chem. 1994, 59, 4126.
(7) (a) Ba¨ckvall, J.-E.; Selle´n, M.; Grant, B. J. Am. Chem. Soc. 1990,
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1987, 827.
(8) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
(9) Norinder, J.; Ba¨ckvall, J.-E. Chem. Eur. J. 2007, 13, 4094.
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Org. Lett., Vol. 9, No. 24, 2007