title: 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 S1P1Receptor Modulator.
abstract: 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Michael G
authors.identifier: 0000-0003-2908-4060
authors.initials: MG
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: John L
authors.initials: JL
authors.lastname: Gilmore
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: David
authors.initials: D
authors.lastname: Marcoux
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Xie
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Taylor
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Virna
authors.initials: V
authors.lastname: Borowski
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Heimrich
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Feng
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Alda
authors.initials: A
authors.lastname: Fernandes
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marino
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Cornelius
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Bethanne M
authors.initials: BM
authors.lastname: Warrack
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Dauh-Rurng
authors.initials: DR
authors.lastname: Wu
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Bala
authors.initials: B
authors.lastname: Pragalathan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Ding Ren
authors.initials: DR
authors.lastname: Shen
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Lois D
authors.initials: LD
authors.lastname: Lehman-McKeeman
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.affiliation: Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543-4000, United States.
authors.forename: Alaric J
authors.identifier: 0000-0002-1050-2077
authors.initials: AJ
authors.lastname: Dyckman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000620393:1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol; D009281:Naphthalenes; D049349:Receptors, Lysosphingolipid