Reports: DNI151710-DNI1: Enantioselective Allylic Amination of Olefins
Uttam K. Tambar, PHD, University of Texas Southwestern Medical Center at Dallas
Our strategy for
the conversion of unactivated olefins into chiral amines is based on a two-step
oxidative process (Scheme 1).
Scheme 1
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.