title: Practical asymmetric synthesis of a gamma-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition.
abstract: A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.
authors.affiliation: Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom. jeremy_scott@merck.com
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Scott
authors.forename: Steven F
authors.initials: SF
authors.lastname: Oliver
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Brewer
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Davies
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Gibb
authors.forename: David
authors.initials: D
authors.lastname: Hands
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Keen
authors.forename: Faye J
authors.initials: FJ
authors.lastname: Sheen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reamer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Wilson
authors.forename: Ulf-H
authors.initials: UH
authors.lastname: Dolling
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000605:Amino Alcohols / Q000138:chemical synthesis / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry; D010087:Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013644:Tartrates / Q000737:chemistry
chemical_list: D000475:Alkenes; D000605:Amino Alcohols; D004791:Enzyme Inhibitors; D009570:Nitriles; D010087:Oxides; D013644:Tartrates; D053829:Amyloid Precursor Protein Secretases; C029768:tartaric acid