Stereodivergent Synthesis of Carbocyclic Quaternary α‐Amino Acid Derivatives Containing Two Contiguous Stereocenters

Abstract

Comprehensive Summary A novel approach to stereodivergent synthesis of carbocyclic α‐quaternary amino acid derivatives, bearing two contiguous stereocenters, is proposed through sequential dual Cu/Ir‐catalyzed asymmetric allylation and ring‐closing metathesis. A variety of five and six‐membered carbocyclic α‐quaternary amino acid derivatives could be readily achieved in good to high yields with exclusive regioselectivities, excellent diastereoselectivities (13: 1‐ > 20: 1 dr) and enantioselectivities (generally >99% ee). Of particular note is that the current protocol is also a versatile synthetic tool for the stereodivergent construction of the challenging seven and eight‐membered carbocyclic α‐amino acid derivatives. All four stereoisomers of these important molecules could be precisely synthesized through the permutation of chiral Cu/Ir catalytic system. The power of this strategy has been demonstrated for the facile access to some biologically active chiral molecules, such as spiro‐hydantoins.

Synergistic Dual Catalysis in Stereodivergent Synthesis

“…In Wang's following study, using α-terminal alkene substituted azomethine ylides as nucleophiles, one pot Cu/Ir enabled stereodivergent allylation and subsequent Ru-catalyzed ring-closing metathesis to construct five-to eight-membered cyclic amino acids in a stereodivergent manner were established (not shown). 57 Comprehensive computational studies were carried out by Houk and co-workers 58 to explore the origin of regio-and stereoselectivities of Wang's synergistic Cu/Ir catalysis and their previous Cu/Pd catalysis. 59 Computational models and distortion/interaction analyses has identified versatile modes of stereoinduction wherein the copper azomethine ylide species can face-selectively intercept metal-π-allyl intermediates utilizing attractive dispersion interactions and/or sterically caused (Scheme 24).…”

“… Notably, inexpensive D 2 O was used as the deuterium source. In Wang’s following study, using α-terminal alkene substituted azomethine ylides as nucleophiles, one pot Cu/Ir enabled stereodivergent allylation and subsequent Ru-catalyzed ring-closing metathesis to construct five- to eight-membered cyclic amino acids in a stereodivergent manner were established (not shown) …”

Stereodivergent synthesis of α-fluoro α-azaaryl γ-butyrolactones via cooperative copper and iridium catalysis

“…In continuation of our interest in synergistic catalysis [ [95] , [96] , [103] , [104] , [105] , [106] , [107] , [108] ], we sought to overcome these challenges through the employment of the dual Cu/Ir catalytic system. Thus, the chiral Cu(I) complex could bind α-fluoro azaaryl acetates via the C = N moiety in azaaryl rings and the nearby carbonyl groups of acetates to form bidentate coordination of Cu(I) salt [67] , [68] , [69] .…”