Mechanism, origin of diastereoselectivity and factors affecting reaction efficiency of serine/threonine ligation: A computational study. Issue 18 (1st May 2020)

• Record Type: Journal Article
• Authors: Xu, Yanyan; Qi, Chenze; Wang, Chen
• Is Part Of: Tetrahedron. Volume 76:Issue 18(2020)
• Publication Date: 2020-05-01
• Subjects: Serine/threonine ligation -- Mechanism -- Theoretical calculations -- Diastereoselectivity -- Structure-activity relationship; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2020.131143
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: The mechanism of serine/threonine ligation was investigated by density functional theory. The reaction sequentially proceeds through imine capture, 5-endo-trig cyclization and [1, 5] O -to- N acyl transfer steps, all of which occur with the assistance of pyridinium. The imine capture and 5-endo-trig cyclization steps are reversible whereas the [1, 5] O -to- N acyl transfer step is irreversible. The [1, 5] O -to- N acyl transfer step proceeds through a stepwise addition-elimination mechanism with the C–O bond cleavage as the rate-determining step of the overall reaction. The diastereoselectivity for the exclusive formation of the S -configured N, O-benzylidene acetal-linked peptide originates from the disfavored steric repulsion between the leaving phenolic oxygen and the side chain of the C-terminal peptide in the R -configured C–O bond cleavage transition state in the acyl transfer step. A suitable ring size as well as a good leaving group in acyl transfer are responsible for the high efficiency of the serine/threonine ligation reaction. Graphical abstract: Image 1 Highlights: Mechanism of serine/threonine ligation was computationally studied. All steps occur with the assistance of pyridinium. C–O bond cleavage in acyl transfer step is rate-determining. Steric repulsion between side chain and leaving group causes diastereoselectivity. Suitable ring size and good leaving group facilitates the reaction.