Catalytic Asymmetric Amine Synthesis using Ni/Photoredox Decarboxylations

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PROJECT SUMMARY/ABSTRACT The asymmetric synthesis of amines is of critical importance in organic chemistry. Amines are common motifs in pharmaceutical molecules and impart useful properties on bioactive molecules (e.g., solubility, hydrogen bonding). General catalytic methods for the asymmetric synthesis of amines are highly desirable, particularly when they make use of widely available starting materials. The proposed research seeks to synthesize amines from widely available carboxylic acids and alcohols by employing a dual catalytic Ni/photoredox strategy and using hydroxylamine ester reagents as amine sources and oxidants. Photoredox catalysis provides access to organic radicals via decarboxylation under mild reaction conditions, while the Ni catalyst serves as a catalytic aminating reagent. The first reaction in Aim 1 seeks to convert carboxylic acids into chiral amines using the strategy described above. A second reaction will target an alcohol-to-amine conversion by using oxalyl chloride to generate alkyl oxalates that undergo decarboxylation to furnish an organic radical under photocatalytic conditions. This transformation will complement classical methods for alcohol-to-amine conversion (e.g., SN2, reductive amination, Mitsunobu reactions), but will exhibit advantages of increased selectivity and scope, reduced stoichiometric waste, along with a fundamentally distinct mechanism whereby enantioselectivity will be achieved. The final point is especially appealing because achiral alcohol starting materials may be transformed into enantioenriched amines through the stereoconvergent reaction of a prochiral radical with a chiral Ni catalyst. Aim 2 seeks to generalize the reaction conditions to replace pre-generated hydroxylamine esters with amine coupling partners and exogenous oxidants. This modification will allow for all of the reagents to be purchased from commercial vendors, which should expedite the incorporation of the method into organic synthesis. With the adaptation that utilizes commercial reagents, it is hoped that the proposed research will impact pharmaceutical synthesis, including medicinal chemistry efforts wherein commercial availability of coupling partners should enable rapid drug library diversification, and process chemistry applications in which the ability to purchase large amounts of inexpensive commercial reagents will facilitate adoption in large-scale applications.