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

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…A Merck group described a CIDT based on a reversible formation of carbon‐sulfur bonds (Scheme 29). [81] They found out that epimeric mixture of carbinols epi ‐ 76 readily dehydrated if dissolved in MeSO 3 H and upon addition of a slight excess of thiol 77 provided cis / trans ‐ 78 in ca 1:1 dr. Fortunately, the desired cis ‐stereoisomer had a higher mp than trans ‐ 78 (144 versus 127 °C) and was less soluble in the used solvent system. Addition of water in a rather narrow volumetric window (9–13 vol%) was determined to be critical for optimal rate and yields of CIDT.…”

Synthesis of an H3 Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition

“…Davies showed that Grignard reagents can be added to the ketones of ketoacids if the acids are first converted to their magnesium salts by treatment with Et 3 N and MgCl 2 in THF, followed by filtration of Et 3 N·HCl . Accordingly, treatment of acid 17 with MgCl 2 and Et 3 N furnished carboxylate 18 , which was treated with 9 .…”

Diastereoselective Palladium-Catalyzed α-Arylation of 4-Substituted Cyclohexyl Esters

“…During the course of a recent research program, we required a concise and selective method to access 4-substituted cyclohexyl aryl ester 1 . Although 1,4 disubstituted cyclohexane derivatives are achiral due to the presence of a C 2 -symmetry element, the selective preparation of either of the two possible achiral diastereomers represents a significant synthetic challenge …”