Stereodivergent synthesis of enantioenriched unnatural -amino acids enabled by synergistic dual metal catalysis

Enantioenriched unnatural alpha-amino acids are one of the most important organic compounds which play a central role in both synthetic chemistry and pharmaceutical science. The catalytic asymmetric construction of unnatural alpha-amino acids has been intensively investigated for decades with many efficient methodologies being established, such as asymmetric Strecker reaction, enantioselective hydrogenation of dehydroamino acids, and asymmetric Mannich or Mannich-type reactions of N-protected alpha-iminoesters. Despite a variety of powerful catalytic systems showing high levels of reactivity and stereocontrol ability for amino acids synthesis, most of those methods can prepare only one of all possible stereoisomers through a chiral catalyst-controlled, thermodynamically or kinetically favored transition state. Metallated azomethine ylides are well-known as 1,3-dipoles, which have been widely employed in catalytic asymmetric 1,3-dipolar cycloaddition reactions to prepare enantioenriched N-heterocycles since the 1990s. In 2011, our group demonstrated the first example by leveraging metallated azomethines as nucleophiles in asymmetric Michael reaction, affording alpha-amino acid derivatives in high yield and stereoselectivity. Since then, the catalytic asymmetric alpha-functionalization of metallated azomethine ylides attracted considerable attention and now is arguably one of the most straightforward and stereoselective methods for unnatural alpha-amino acids. In particular, chiral alpha-amino acid synthesis from azomethine ylides enabled by synergistic dual metal catalysis has met with tremendous success in the past few years. This strategy involves the concurrent activation of two or more reactants by distinct catalysts, leading to the generation of corresponding more reactive species simultaneously in the reaction system, therefore can often exhibit superior catalytic reactivity than traditional mono-catalysis. Significantly, a pairwise combination of two distinct chiral metal catalysts build-up the potential of stereodivergent synthesis of the target compounds, which will not only greatly enhance the synthetic utility, but also be beneficial to further structure-activity relationship study of biologically active chiral compounds. In this review, we present recent progress on the stereodivergent preparation of unnatural alpha-amino acids catalyzed by chiral metal/metal catalytic system. Specifically, synergistic Cu/Ir-catalyzed asymmetric allylic alkylation reactions of aldimine esters are discussed in the first part. By emerging chiral copper-coordinated azomethine ylide chemistry with chiral iridium-catalyzed allylation, stereodivergent synthesis of a series alpha-amino acid derivatives, including acyclic amino acids, cyclic amino acids, as well as alpha-amino gamma-butyrolactones were successfully developed. Subsequently, an overview of synergistic Cu/Pd catalysis for stereodivergent allylation of azomethine ylides is provided. The key chiral electrophilic pi-allylpalladium species could be generated in situ from either Pd-catalyzed decarboxylative/oxidative addition of substituted allyl carbonates or Pd-H insertion to 1,3-dienes/allenes, both of which are well compatible with stereochemically controllable nucleophilic Cu-azomethine ylides, giving the desired coupling products in a highly stereoselective manner. The Cu/Pd catalysis was proven to be compatible as well for stereodivergent allenylic alkylation reactions. Both 2,3- and 3,4-allenylic alcohol derivatives have been successfully employed as precursors of allenylic alpha-allypalladium species to react with Cu-azomethine ylides. In addition to asymmetric allylic and allenylic alkylation reactions, the recently disclosed synergistic Cu/Ni-catalyzed stereodivergent propargylation reactions of azomethine ylides are then introduced. In each section, mechanistic investigations on how synergistic catalysis can realize the desired transformation and independent computational studies on the stereochemistry outcome are discussed in detail. Applications of synergistic dual metal catalysis strategy in the synthesis of unnatural alpha-amino acid-based natural products as well as bioactive molecules are also described, which highlight the great potential of both stereodivergent synthesis and synergistic catalysis. Overall, this review summarizes the most prominent work on synergistic dual-metal-catalyzed stereodivergent construction of enantioenriched unnatural alpha-amino acid derivatives. These examples undoubtedly suggested that synergistic catalysisenabled stereodivergent synthesis has provided powerful methods to synthesize a series of useful unnatural alpha-amino acids in a stereo-chemically predictable and switchable way.