title: A novel crystallization-induced diastereomeric transformation based on a reversible carbon-sulfur bond formation. Application to the synthesis of a gamma-secretase inhibitor.
abstract: This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.
authors.affiliation: Department of Process Research, Merck, Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom. tony-davies@merck.com
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Davies
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Scott
authors.forename: Brian C
authors.initials: BC
authors.lastname: Bishop
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Brewer
authors.forename: Jimmy O
authors.initials: JO
authors.lastname: Dasilva
authors.forename: Peter G
authors.initials: PG
authors.lastname: Dormer
authors.forename: Ulf-H
authors.initials: UH
authors.lastname: Dolling
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Gibb
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Hammond
authors.forename: David R
authors.initials: DR
authors.lastname: Lieberman
authors.forename: Michael
authors.initials: M
authors.lastname: Palucki
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Payack
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002244:Carbon / Q000737:chemistry*; D003460:Crystallization; D005461:Fluorine / Q000737:chemistry; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism; D013440:Sulfides / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry*; D013696:Temperature
chemical_list: D007651:Keto Acids; D011480:Protease Inhibitors; D013440:Sulfides; D005461:Fluorine; D013455:Sulfur; D002244:Carbon; D053829:Amyloid Precursor Protein Secretases; D008274:Magnesium