A novel crystallization-induced diastereomeric transformation based on a reversible carbon-sulfur bond formation. Application to the synthesis of a gamma-secretase inhibitor.
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.
Davies
Antony J
AJ
Department of Process Research, Merck, Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, United Kingdom. tony-davies@merck.com
Scott
Jeremy P
JP
Bishop
Brian C
BC
Brands
Karel M J
KM
Brewer
Sarah E
SE
Dasilva
Jimmy O
JO
Dormer
Peter G
PG
Dolling
Ulf-H
UH
Gibb
Andrew D
AD
Hammond
Deborah C
DC
Lieberman
David R
DR
Palucki
Michael
M
Payack
Joseph F
JF
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
D007651:Keto Acids; D011480:Protease Inhibitors; D013440:Sulfides; D005461:Fluorine; D013455:Sulfur; D002244:Carbon; D053829:Amyloid Precursor Protein Secretases; D008274:Magnesium