Issue 16, 2019

Investigations of the key macrolactamisation step in the synthesis of cyclic tetrapeptide pseudoxylallemycin A

Abstract

The total synthesis and structural confirmation of naturally occurring all L-cyclic tetrapeptide pseudoxylallemycin A is reported. X-ray crystallography revealed that the linear precursor adopted an all-trans (ttt) extended linear conformation, while its cyclic derivative adopts a trans,cis,trans,cis (tctc) conformation. Two kinetically favoured cyclic conformers prone to hydrolysis initially formed rapidly during cyclisation, with subsequent conversion to the thermodynamically stable tctc macrocycle taking place slowly. We postulate the initial unstable cyclic product undergoes an unprecedented nucleophilic ring opening with either the T3P or PyAOP by-products to give the linear ttt structure as a reactivated species and through a series of equilibria is slowly consumed by cyclisation to the thermodynamic product pseudoxylallemycin A. Consumption of the reactivated species by formation of pseudoxylallemycin A requires a transcis isomerism to occur and necessitates moderately increased reaction temperatures. Cyclisation with T3P was found to provide the greatest stereoretention. Synthesis and X-ray crystallography of the C-terminal epimer demonstrated its cyclisation to be kinetically favoured and to proceed without epimerisation despite also bearing an all-trans backbone.

Graphical abstract: Investigations of the key macrolactamisation step in the synthesis of cyclic tetrapeptide pseudoxylallemycin A

Supplementary files

Article information

Article type
Paper
Submitted
29 Jan 2019
Accepted
25 Mar 2019
First published
26 Mar 2019

Org. Biomol. Chem., 2019,17, 3902-3913

Investigations of the key macrolactamisation step in the synthesis of cyclic tetrapeptide pseudoxylallemycin A

A. J. Cameron, C. J. Squire, A. Gérenton, L. A. Stubbing, P. W. R. Harris and M. A. Brimble, Org. Biomol. Chem., 2019, 17, 3902 DOI: 10.1039/C9OB00227H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements