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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 an efficient strategy for converting 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 C–H 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

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. After several years of effort, we have finally realized the key results that were outlined in our original ACS-PRF grant. We have started to examine unsymmetrical sulfur-based oxidants, which provide a unique opportunity to generate C–N or C–O bonds. We were interested in developing an enantioselective, regioselective, and E/Z selective allylic oxidation of internal olefins (Scheme 3). Instead of catalyzing an enantioselective [2,3]-rearrangement of chiral racemic ene adducts that were generated from internal olefins and unsymmetrical sulfur-based oxidants, we pursued an enantioselective ene reaction of these two substrates as a more general approach for oxidizing internal olefins. We have developed a highly enantioselective and regioselective ene reaction of the unsymmetrical sulfur-based oxidant depicted in Scheme 3 and internal cis olefins. The resulting enantioenriched ene adducts can undergo selecitve allylic sulfurations, allylic hydroxylations, allylic alkylations, and allylic aminations.

Scheme 3

Although the following 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