Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp3 C-H Functionalization

alpha-Amino acids (alpha AA) are one of the most useful chiral building blocks for synthesis. There are numerous general strategies that have commonly been used for alpha AA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the C alpha center and others that consider conversion of existing alpha AA precursors carrying suitable functional groups on side chains (e.g, serine and aspartic acid). Despite significant advances in synthetic methodology, the efficient synthesis of enantiopure alpha AAs carrying complex side chains, as seen in numerous peptide natural products, remains challenging. Complementary to these conventional strategies, a strategy based on the selective functionalization of side chain C-H bonds, particularly sp(3) hybridized C-H bonds, of various readily available alpha AA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of alpha AAs. However, many hurdles related to the low reactivity of C(sp(3))-H bonds and the difficulty of controlling selectivity must be overcome to realize the potential of C-H functionalization chemistry in this synthetic application. Over the past few years, we have carried out a systematic investigation of palladium-catalyzed bidentate auxiliary-directed C-H functionalization reactions for alpha AA substrates. Our strategies utilize two different types of amide-linked auxiliary groups, attached at the N or C terminus of alpha AA substrates, to exert complementary regio- and stereocontrol on C-H functionalization reactions through palladacyde intermediates. A variety of alpha AA precursors can undergo multiple modes of C(sp(3))-H functionalization, including arylation, alkenylation, alkynylation, alkylation, alkoxylation, and intramolecular aminations, at the beta, gamma, and even delta positions to form new alpha AA products with diverse structures. In addition to transforming alpha AAs at previously unreachable positions, these palladium-catalyzed C-H functionalization strategies enable new retrosynthetic logic for the synthesis of many basic alpha AAs from a common alanine precursor. This approach reduces the synthetic difficulty for many alpha AAs by bypassing the requirement for stereocontrol at C alpha and relies on straightforward and convergent single-bond coupling transformations at the beta-methyl position of alanine to access a wide range of beta-monosubstituted alpha AAs. Moreover, these beta-monosubstituted alpha AAs can undergo further C-H functionalization at the beta-methylene position to generate various beta-branched alpha AAs in a stereoselective and programmable fashion. These new strategies offer readily applicable methods for synthesis of challenging alpha AAs and may facilitate the efficient total synthesis of complex peptide natural products.