Issue 34, 2018

Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)

Abstract

Quantitative structure–activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.

Graphical abstract: Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)

Supplementary files

Article information

Article type
Edge Article
Submitted
10 May 2018
Accepted
17 Jul 2018
First published
18 Jul 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 6922-6927

Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)

T. T. Metsänen, K. W. Lexa, C. B. Santiago, C. K. Chung, Y. Xu, Z. Liu, G. R. Humphrey, R. T. Ruck, E. C. Sherer and M. S. Sigman, Chem. Sci., 2018, 9, 6922 DOI: 10.1039/C8SC02089B

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