Reports: DNI151710-DNI1: Enantioselective Allylic Amination of Olefins
Uttam K. Tambar, PHD, University of Texas Southwestern Medical Center at Dallas
The selective functionalization of hydrocarbons
with metal catalysts is one approach to the conversion of abundant and
inexpensive components of petrochemical feedstock into chemical products of
greater value. Our lab has been particularly interested in the selective
functionalization of unsaturated hydrocarbons, such as unactivated olefins and
1,3-dienes. In our ACS-PRF grant application, we proposed the enantioselective
synthesis of chiral amines via metal-catalyzed allylic amination of unactivated
terminal olefins, which are attractive starting materials for the generation of
complex medicinally valuable molecules. During the grant funding period, we
have made significant progress towards achieving this goal.
Our strategy for
the conversion of unactivated olefins into chiral amines is based on a two-step
oxidative process (Scheme 1). An
olefin reacts with a sulfur-based oxidant to generate an ene adduct. This intermediate is converted in the
second step into a chiral amine through a metal-catalyzed enantioselective
[2,3] rearrangement. Our approach was inspired by the work of Sharpless,
Kresze, and Katz, who reported that olefins react with arylsulfonyl
sulfurdiimide reagents via a hetero-ene reaction to generate zwitterionic
species, which undergo spontaneous [2,3]-rearrangements.
Scheme 1
Our key insight into this chemistry was that the
[2,3]-rearrangement of the ene adduct between an olefin and a sulfur-based
oxidant can be controlled by a chiral palladium(II) catalyst, which accelerates
the enantioselective formation of an allylic amine derivative (Scheme 2). Prior
to our work, the most promising strategies for allylic amination of terminal
olefins were based on the metal-catalyzed activation of inert CÐH bonds via
organometallic intermediates. Despite some success, these approaches have not
produced general methods for the catalytic enantioselective intermolecular
allylic amination of unactivated terminal olefins. We have successfully
implemented a conceptually distinct allylic amination strategy that is based on
a metal-catalyzed enantioselective [2,3]-rearrangement of a reactive
zwitterion.
Scheme 2
As we described
in our original ACS-PRF grant, we have started to examine unsymmetrical
sulfur-based oxidants, which provide a unique opportunity to generate CÐN or
CÐO bonds (Scheme 3). Preliminary results suggest that we may be able to
develop highly enantioselective and chemoselective allylic aminations and
allylic hydroxylations from the same ene adduct. Thermal and basic conditions
for the rearrangement of this ene adduct result in the formation of divergent
products.
Scheme 3
Our discovery
that the ene adducts between olefins and sulfur-based oxidants are susceptible
to catalyst-controlled transformations is a general framework for the selective
functionalization of unsaturated hydrocarbons. This approach takes advantage of
the unique reactivity of arylsulfonyl sulfurimide reagents.
Although the
following new reactions were not included in our original ACS-PRF grant
application, we have recently extended our research program to develop other
selective transformations of unsaturated hydrocarbons. For example, we have
developed a copper-catalyzed allylic alkylation of terminal olefins (Scheme 4).
The allylic alkylation of unactivated olefins is a powerful chemical strategy,
but this type of reaction has been mainly limited to specific carbon
nucleophiles with limited substrate scope. We developed a one-pot, two-step
copper-catalyzed allylic alkylation of a diverse range of unactivated terminal
olefins with Grignard reagents. We utilized this reaction to synthesize skipped
dienes, which are difficult to synthesize by known allylic alkylation methods.
Scheme 4
We have also
developed a copper-catalyzed aminoarylation of 1,3-dienes (Scheme 5). The
difunctionalization of dienes is a useful strategy for incorporating molecular
complexity into a class of simple substrates. We developed an aminoarylation of
1,3-dienes via the sequential [4+2] cycloaddition with a sulfurdiimide reagent
and copper-catalyzed allylic substitution with Grignard reagents. The
regioselective and diastereoselective aminoarylation of unsymmetrical dienes
was successfully realized, which highlights the utility of this method for
generating products with multiple functional groups and stereocenters.
Scheme 5
In the future,
we will continue to explore the problem of converting inert CÐH bonds in
unsaturated hydrocarbons into any functionalized bond (CÐC, CÐO, and
CÐhalogen), with a broader goal of changing the ways in which pharmaceutical
drugs and other functional materials are produced.
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