C O M M U N I C A T I O N S
Scheme 3
role in the reaction. We reasoned that a redesigned imine,
specifically with reduced steric hindrance as in 6, might accom-
modate isomerization of the imine from 1•6-trans to the cis-imine
form 1•6-cis, which would place the imine phenyl group in the
presumably favored pseudo-equatorial position, and give rise to the
anti-diastereomer. Indeed, we were delighted to discover that imine
6 performed superbly upon treatment with silane 1, giving anti-
diastereomer 7 in 91% yield, and with >20:1 dr and 97% ee. Thus,
either diastereomer of the product may be accessed from the same
cinnamylsilane 1 based solely upon the remarkably subtle difference
between imines 3 and 6. Assuming our mechanistic model is correct,
this constitutes the first demonstration of the ability to both induce
and control imine cis-trans isomerization in a reaction of this type.
An examination of the scope of these cinnamylation reactions
was carried out, and the results are compiled in Table 1. With only
a few exceptions, both the syn- and anti-selective reactions proceed
with good to excellent efficiency and diastereoselectivity, and with
very high levels of enantioselectivity (products 8-19). In the syn
series, we were further gratified to find that aliphatic aldehyde-
derived imines perform well in terms of diastereo- and enantiose-
lectivity (products 12 and 13), although the same does not hold for
the anti series (typically <40% ee). This caveat notwithstanding,
the results shown here represent the first general method for the
highly enantioselective cinnamylation of imines, with the added
and important benefit that either product diastereomer may be
accessed from a single readily available chiral cinnamylsilane (1).
Our use of the o-hydroxybenzyl group appears to be the first
such use in the context of imine addition reactions. We therefore
sought to establish a simple method for the cleavage/deprotection
of this group to reveal the free amine products. Hydrogenation was
a seemingly straightforward possibility, but initial attempts using
standard protocols were unsuccessful. Eventually, it was discovered
that Pd(OH)2/C-catalyzed transfer hydrogenation worked well,
providing amine 20 in 73% yield from 7 (Scheme 3). A second
example using o-methoxyphenyl substrate 18 proceeded smoothly
as well, giving 21 in 80% yield.
We have reported the first general and highly enantioselective
imine cinnamylation reaction, which provides experimentally simple
and inexpensive access to high value added products containing
vicinal carbinamine and benzylic stereocenters. Through the
introduction of a new imine directing/activating group, a diastere-
ochemical switch has been developed, wherein either product
diastereomer may be accessed based solely upon a simple structural
change to the imine. This latter discovery obviates a traditionally
requiredsand in the present case, a problematicssynthesis of the
cis reagent (2), and it may have implications for the further
development of imine allylation reactions as well as other asym-
metric imine addition reactions.
Acknowledgment. This work was supported by a grant from
the National Science Foundation (CHE-04-53853) and a focused
Funding Award from Johnson & Johnson. We thank Merck
Research Laboratories and Amgen for unrestricted support. J.D.H.
was the recipient of an NDSEG Fellowship from the DOD.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs. This material is
Table 1. Highly Enantioselective Imine Cinnamylation Reactions
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a This reaction was conducted at 60 °C. b This reaction was conducted
in CHCl3 at 50 °C. c This reaction was conducted in CH2Cl2 at reflux.
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