Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction

Abstract

A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process.

Recent Advances in Asymmetric Isocyanide‐Based Multicomponent Reactions

“…[76] Cyclic imines could be obtained from meso-erythritol in good yields by a seven-step reaction sequence. [76] Cyclic imines could be obtained from meso-erythritol in good yields by a seven-step reaction sequence.…”

“…Yet another strategy for the construction of chiral cyclic imines for use in diastereoselective Ugi-Joullié reactions was recently presented by Riva and co-workers. [76] Cyclic imines could be obtained from meso-erythritol in good yields by a seven-step reaction sequence. Subsequent Ugi-Joullié reactions were performed with a variety of enantiomerically pure isocyanides to yield diastereomerically pure products (dr Ͼ 95 %) with the general structure of compound 75 or its epimer form.…”

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

“…The chiral isocyanides were prepared following an organocatalytic phase-transfer Mannich-type reaction [59], whereas the chiral imines 52a , b were obtained from a bio-catalytic protocol [60]. In particular, the rigid bicyclic imines are powerful starting points and they provide the Ugi-products 53a , b in high yields and mainly as trans- isomers (de >88%), without racemization.…”

“…In particular, the rigid bicyclic imines are powerful starting points and they provide the Ugi-products 53a , b in high yields and mainly as trans- isomers (de >88%), without racemization. As an extension, two other enantiopure isocyanides were combined with a variety of carboxylic acids furnishing a small library of bicyclic dipeptide mimics ( 55a – d, Scheme 17) in good yields and in high diastereomeric excess (de 70–96%) [60]. It is worth noting that deprotection of the acetal-group allows modulation of rigidity and polarity of the final molecules.…”

A Convenient Synthesis of 1,2‐Disubstituted‐cis‐3,4‐Dihydroxypyrrolidines via an Ugi‐Four‐Component‐Reaction/Cycloisomerization/Dihydroxylation Protocol

“…[13] On the other hand, Murruzzu and coworkers reported the synthesis of compound 10 by an OsO 4 -catalyzed dihydroxylation of 3-pyrrolines. [13] On the other hand, Murruzzu and coworkers reported the synthesis of compound 10 by an OsO 4 -catalyzed dihydroxylation of 3-pyrrolines.…”