Practical asymmetric synthesis of a gamma-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition.
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.
Scott
Jeremy P
JP
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom. jeremy_scott@merck.com
Oliver
Steven F
SF
Brands
Karel M J
KM
Brewer
Sarah E
SE
Davies
Antony J
AJ
Gibb
Andrew D
AD
Hands
David
D
Keen
Stephen P
SP
Sheen
Faye J
FJ
Reamer
Robert A
RA
Wilson
Robert D
RD
Dolling
Ulf-H
UH
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
D000475:Alkenes; D000605:Amino Alcohols; D004791:Enzyme Inhibitors; D009570:Nitriles; D010087:Oxides; D013644:Tartrates; D053829:Amyloid Precursor Protein Secretases; C029768:tartaric acid