Issue 2, 2023

Utilizing biocatalysis and a sulfolane-mediated reductive acetal opening to access nemtabrutinib from cyrene

Abstract

The chiral building block 5-amino-2-hydroxymethyltetrahydropyran 1a has been previously synthesized through a cumbersome 9-step synthesis from tri-O-acetyl-D-glucal, which renders access to nemtabrutinib (2), a BTK inhibitor currently being evaluated for the treatment of various hematologic malignancies, inefficient and wasteful. Herein, we describe the development of a protecting group-free, 2-step synthesis of 1a from Cyreneâ„¢, a biorenewable feedstock. The improved synthesis involves a biocatalytic transamination reaction of Cyreneâ„¢ to install the desired amine stereocenter in a single step with high diastereoselectivity. The enzymatic reaction is followed by a stereo-retentive reductive acetal opening reaction of the chiral cyrene amine intermediate 3a to furnish 1a. A mechanistic investigation of the acetal opening reaction is also described which uncovered reaction conditions for the sulfolane mediated in situ generation of diborane as the active reductant. The streamlined synthesis of 1a from Cyreneâ„¢ reduced the step count from 9 to 2 synthetic steps which resulted in a >27% yield improvement and a significant reduction in the environmental impact of the synthesis.

Graphical abstract: Utilizing biocatalysis and a sulfolane-mediated reductive acetal opening to access nemtabrutinib from cyrene

Supplementary files

Article information

Article type
Paper
Submitted
03 nov 2022
Accepted
06 dec 2022
First published
23 dec 2022

Green Chem., 2023,25, 606-613

Utilizing biocatalysis and a sulfolane-mediated reductive acetal opening to access nemtabrutinib from cyrene

N. Kuhl, B. W. H. Turnbull, Y. Ji, R. T. Larson, M. Shevlin, C. K. Prier, C. K. Chung, R. Desmond, E. Guetschow, C. Q. He, T. Itoh, J. T. Kuethe, J. A. Newman, M. Reibarkh, N. R. Rivera, G. Shang, Z. Wang, D. Zewge and D. A. Thaisrivongs, Green Chem., 2023, 25, 606 DOI: 10.1039/D2GC04117K

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