Asymmetric Hydroboration Approach to the Scalable Synthesis of ((1R,3S)‑1-Amino-3-((R)‑6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)­cyclopentyl)­methanol (BMS-986104) as a Potent S1P1 Receptor Modulator

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient...

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Published in:Journal of medicinal chemistry 2016-12, Vol.59 (24), p.11138-11147
Main Authors: Yang, Michael G, Xiao, Zili, Dhar, T. G. Murali, Xiao, Hai-Yun, Gilmore, John L, Marcoux, David, Xie, Jenny H, McIntyre, Kim W, Taylor, Tracy L, Borowski, Virna, Heimrich, Elizabeth, Li, Yu-Wen, Feng, Jianlin, Fernandes, Alda, Yang, Zheng, Balimane, Praveen, Marino, Anthony M, Cornelius, Georgia, Warrack, Bethanne M, Mathur, Arvind, Wu, Dauh-Rurng, Li, Peng, Gupta, Anuradha, Pragalathan, Bala, Shen, Ding Ren, Cvijic, Mary Ellen, Lehman-McKeeman, Lois D, Salter-Cid, Luisa, Barrish, Joel C, Carter, Percy H, Dyckman, Alaric J
Format: Article
Language:English
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Summary:We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidyl­choline (LPC) induced demyelination in a three-dimensional brain cell culture assay.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01433