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

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 mali...

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Published inGreen chemistry : an international journal and green chemistry resource : GC Vol. 25; no. 2; pp. 66 - 613
Main Authors Kuhl, Nadine, Turnbull, Ben W. H, Ji, Yining, Larson, Reed T, Shevlin, Michael, Prier, Christopher K, Chung, Cheol K, Desmond, Richard, Guetschow, Erik, He, Cyndi Qixin, Itoh, Tetsuji, Kuethe, Jeffrey T, Newman, Justin A, Reibarkh, Mikhail, Rivera, Nelo R, Shang, Gao, Wang, Zhixun, Zewge, Daniel, Thaisrivongs, David A
Format Journal Article
LanguageEnglish
Published Cambridge Royal Society of Chemistry 23.01.2023
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Summary: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 Cyrene™, a biorenewable feedstock. The improved synthesis involves a biocatalytic transamination reaction of Cyrene™ 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 Cyrene™ 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. The development of a protecting group-free, 2-step synthesis of 5-amino-2-hydroxymethyltetrahydropyran 1a from biorenewable Cyrene™ is described which renders access to BTK-inhibitor nemtabrutinib ( 2 ) more efficient and sustainable.
Bibliography:For ESI and crystallographic data in CIF or other electronic format see DOI
https://doi.org/10.1039/d2gc04117k
2215968
Electronic supplementary information (ESI) available: For experimental procedures, compound characterization and crystallography data. CCDC
2215969
and
ISSN:1463-9262
1463-9270
DOI:10.1039/d2gc04117k