One‐Step Catalytic Enantioselective α‐Quaternary 5‐Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized α‐Quaternary Proline Derivatives

Abstract

The highly enantioselective cascade reaction between N‐protected α‐cyanoglycine esters and α,β‐unsaturated aldehydes is disclosed. The reaction represents a one‐step entry to polysubstituted 5‐hydroxyproline derivatives having a quaternary α‐stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two‐step entry to functionalized α‐quaternary proline derivatives.

α,β‐Unsaturated Aldehydes in the Synthesis of Five‐Membered Heterocyclic Compounds with One Heteroatom: Recent Advances from Developments in Metal‐ and Organocatalysis

“…In a modification of their original protocol, Cordova et al. have employed N ‐acyl‐protected α‐cyanoglycine esters 59 bearing two different electron‐withdrawing groups to prepare α‐quaternary proline derivatives 61 , bearing four contiguous stereocenters (Scheme ) . The use of an organic acid as the co‐catalyst increases the rate of the reaction by accelerating the iminium activation of enal 60 .…”

Asymmetric Synthesis of Quaternary α‐Amino Acids and Their Phosphonate Analogues

“…The Cordova group have reported a direct approach to the enantioselective synthesis of 5-hydroxy N-protected prolines with adjacent quaternary and tertiary chiral centers (84), by a cascade Michael addition-hemiaminal formation of N-protected a-cyanoglycine esters 83 with a,b-unsaturated aldehydes 36 (Scheme 23), mediated by diphenyl prolinol-TMS C23. [39] Various aryl-and alkyl-substituted prolines 84 were obtained in moderate to good yields and diastereoselectivities, with excellent enantioselectivities. Furthermore, Lewis-acid-mediated reduction of 84 provided 85 in moderate to good yields with retention of stereochemistry.…”

Direct Catalytic Asymmetric Synthesis of Pyrazolidine Derivatives

“…Moreover, all 3-hydroxypyrazolidines were formed exclusively as their α-anomers as determined by 1 H NMR analysis of the crude reaction mixture. In comparison, the α-anomer is also the most stable conformer in the formation of other hydroxy-substituted, heterocyclic five-membered hemiaminals and hemiacetals, such as 5-hydroxypyrrolidines and 5-hydroxyoxazolidines, respectively 17a–e. We next decided to investigate the effect of the N-protective group.…”

“…In comparison, the α-anomer is also the most stable conformer in the formation of other hydroxy-substituted, heterocyclic five-membered hemiaminals and hemiacetals, such as 5-hydroxypyrrolidines and 5-hydroxyoxazolidines, respectively. 17a – e We next decided to investigate the effect of the N-protective group. This was accomplished by selecting di-1- N -Boc-2- N -benzyloxycarbonyl (Cbz)-protected hydrazine 2 b as the dinitrogen source for the reaction with cinnamic aldehyde 1 a (Scheme 3 ).…”