A Computational Study on the Reaction Mechanism of Stereocontrolled Synthesis of β-Lactam within [2]Rotaxane

Rong Liang; Qinghai Zhou; Xin Li; Ming Wah Wong; Lung Wa Chung

doi:10.1021/acs.joc.3c00330

A Computational Study on the Reaction Mechanism of Stereocontrolled Synthesis of β-Lactam within [2]Rotaxane

J Org Chem. 2023 Aug 4;88(15):10460-10469. doi: 10.1021/acs.joc.3c00330. Epub 2023 May 31.

Authors

Rong Liang^{1

2}, Qinghai Zhou^{1

3}, Xin Li¹, Ming Wah Wong², Lung Wa Chung¹

Affiliations

¹ Shenzhen Grubbs Institute, Department of Chemistry and Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen 518055, China.
² Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore.
³ The Education Ministry Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Frontiers Science Center of Biomimetic Catalysis, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China.

PMID: 37257155
DOI: 10.1021/acs.joc.3c00330

Abstract

The macrocycle effect of [2]rotaxane on the highly trans-stereoselective cyclization reaction of N-benzylfumaramide was extensively investigated by various computational methods, including DFT and high-level DLPNO-CCSD(T) methods. Our computational results suggest that the most favorable mechanism of the CsOH-promoted cyclization of the fumaramide into trans-β-lactam within [2]rotaxane initiates with deprotonation of a N-benzyl group of the interlocked fumaramide substrate by CsOH, followed by the trans-selective C-C bond formation and protonation by one amide functional group of the macrocycle. Our distortion/interaction analysis further shows that the uncommon trans-stereoselective cyclization forming β-lactam within the rotaxane may be attributed to a higher distortion energy (mainly from the distortion of the twisted cis-fumaramide conformation enforced by the rotaxane). Our systematic study should give deeper mechanistic insight into the reaction mechanism influenced by a supramolecular host.