A Novel Crystallization-Induced Diastereomeric Transformation Based on a Reversible Carbon−Sulfur Bond Formation. Application to the Synthesis of a γ-Secretase Inhibitor

• Published in: Journal of organic chemistry 2007-06, Vol.72 (13), p.4864-4871
• Main Authors: Davies, Antony J, Scott, Jeremy P, Bishop, Brian C, Brands, Karel M. J, Brewer, Sarah E, DaSilva, Jimmy O, Dormer, Peter G, Dolling, Ulf-H, Gibb, Andrew D, Hammond, Deborah C, Lieberman, David R, Palucki, Michael, Payack, Joseph F
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Carbon - chemistry; Chemistry; Crystallization; Exact sciences and technology; Fluorine - chemistry; Keto Acids - chemical synthesis; Keto Acids - chemistry; Magnesium - chemistry; Molecular Structure; Organic chemistry; Oxidation-Reduction; Preparations and properties; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Solubility; Stereoisomerism; Sulfides - chemistry; Sulfur - chemistry; Temperature
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0705925

This paper describes a remarkably efficient process for the preparation of γ-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.