Catalytic Asymmetric Synthesis of 3‐Substituted Proline Derivatives by Using Phase‐Transfer‐Catalyzed Conjugate Addition

Abstract

The catalytic enantio‐ and diastereoselective synthesis of trans‐3‐substituted proline derivatives has been accomplished by chiral phase‐transfer‐catalyzed asymmetric conjugate addition of N‐(diphenylmethylene)glycine ester to α,β‐unsaturated aldehydes. Various 3‐substituted prolines that contain aromatic, heteroaromatic, and alkyl groups were synthesized efficiently with good to high enantioselectivity. This synthetic method can be applied to the efficient enantioselective synthesis of core structures of L‐pyrrolysine and telaprevir, which are important biologically active compounds. The practicability of the method was demonstrated by a gram‐scale synthesis of a core structure of telaprevir.

Synthesis of Proline Analogues via Rh-Catalyzed Asymmetric Conjugate Addition

“…Whereas racemic syntheses of trans -3-substituted proline have been demonstrated, only few enantioselective routes exist . Such methods can provide reliable stereocontrol; however, multiple functional group interconversions are required to isolate the desired deprotected amino acid from a more functionalized scaffold.…”

N-TFA-Gly-Bt-Based Stereoselective Synthesis of Substituted 3-Amino Tetrahydro-2H-pyran-2-ones via an Organocatalyzed Cascade Process

“…Asymmetric reactions between imino glycine derivatives and α,β-unsaturated aldehydes were first developed by Belokon et al, wherein a chiral glycinate Schiff base Ni­(II) complex reacted with substituted acroleins under basic conditions to yield Michael addition products in excellent chiral induction (Scheme A). , An organocatalyzed asymmetric version of this transformation with nonchiral Ni­(II) complexes afforded Michael adducts in up to 95% ee (Scheme B) . Other than the nickel complexes, free glycine ester Schiff bases are also good partners for Michael additions under chiral PTC conditions, and an optically pure bicyclic amino acid, which is the key intermediate for Telaprevir production, was prepared in up to 93% ee (Scheme C). − Asymmetric 1,3-dipolar cycloaddition of imino glycinates with methacrolein was discovered by Carretero et al, and chiral pyrrolidines were prepared in good enantioselectivity (69% ee) (Scheme D). , …”