摘要：Jin-Teng Che1,2,Wei-Yi Ding1,2,Hong-Bo Zhang1,Yong-Bin Wang1,Shao-Hua Xiang1& Bin Tan1

转自：康龙化成

Enantioselective Synthesis of2-substituted Bicyclo[1.1.1]pentanes via Sequential Asymmetric Imine Addition of Bicyclo[1.1.0]butanesand Skeletal Editing

Jin-Teng Che1,2,Wei-Yi Ding1,2 ,Hong-Bo Zhang1,Yong-Bin Wang1,Shao-Hua Xiang1& Bin Tan1

1 ShenzhenGrubbs Institute, Department of Chemistry, Southern University of Science andTechnology, Shenzhen, China.

2 These authors contributed equally:Jin-Teng Che, Wei-Yi Ding

—Nature Chemistry, 2025 ,doi.org/10.1038/s41557-024-01710-x

Recommended by Feng Wang_SC

KEYWORDS: Enantioselectivity, nitrogen insertion and deletion, skeletal editing(反应类型), C(sp3)–C(sp3) (成键类型), Chiral Brønsted acid (催化剂), BCB, imines (原料), Chiral BCP (产物), bioisosteres (其他)

ABSTRACT: The substitution of an aromatic ring witha C(sp3)-richbicyclic hydrocarbon, known asbioisosteric replacement, plays a crucial role in modern drug discovery. Substituted bicyclo[1.1.1]pentanes(BCPs)areparticularly noteworthy owing to their uniquely three-dimensionalstereochemical complexity. 1,3-Difunctionalized BCPs have been widely used as bioisosteres forpara-substituted phenyl rings, and they have been incorporated into numerouslead pharmaceutical candidates. 2-Substituted BCPs (substituted at the bridgeposition) can function as alternatives to ortho or meta-substituted arenerings; however, the general and efficient construction of these scaffoldsremains challenging, particularly if performed in an enantioselective manner.Here Prof. Tanetal. present an approach for synthesizing enantioenriched 2-substituted BCPs by a nitrogen-atominsertion-and-deletionstrategy,involving a chiral Brønsted acid-catalytic enantioselective cycloaddition of bicyclo[1.1.0]butaneswithimines and nitrogendeletionofresulting aza-bicyclo[2.1.1]hexanes(aza-BCHs)with generally good enantiopurity retention. Mechanistic experiments verify theradical pathway. Chiral BCPs have been readily incorporated into medicinallyrelevant molecules, and a drug analogue has been successfully prepared enantioselectively.

Background: a, A representative application ofthe BCP skeleton for the substitution of para-oriented benzene in medicinalchemistry. b, 2-Substituted BCPs with 3D stereochemical complexityare promising candidates for ortho- or meta-substituted benzenes. c, Theresearch status of the bioisosteric replacement of benzene. d, Qin’s report on the construction ofenantioenriched 2-substituted BCPs with only one example. e,The work of Robertson and Wong with two examples

This work: enantioselective skeletal editingstrategy for the enantioselective synthesis of multisubstituted BCPs

The proposed reaction mechanism for thedeveloped N-atom insertion-and-deletion process

Summary and comments

Prof.Tan etal. have developed an innovativeasymmetric molecular skeletal editing strategy for the enantioselectivesynthesis of densely functionalized BCPs. By utilizing Brønstedacid-catalysed cycloaddition and nitrogendeletion reactions, Prof.Tan etal. achieve a concise and modularaccess to structurally diverse chiral BCPs as the 3D bioisosteres of benzene rings. Generally, theexcellent stereochemical integrities of aza-BCHs generated from the first stepare maintained during the nitrogen deletion process. In addition, theincorporation of medicinally relevant molecules into BCPs and the preparationof drug analogues have been realized to stimulate interest in the medicalchemistry community. Mechanistic studies offer effective supports for theformation of 1,4-biradical intermediates. This approach expands the potentialchemical space and molecular diversity of chiral BCPs accessible to medicinalchemists, providing new avenues for drug discovery and development.

来源：新浪财经