Stereoselective Synthesis of Spiropiperidines as BACE-1 Aspartyl Protease Inhibitors via Late Stage N-Arylation of a 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore

Che-Wah Lee; Ricardo Lira; Jason Dutra; Kevin Ogilvie; Brian T O’Neill; Michael Brodney; Christopher Helal; Joseph Young; Erik Lachapelle; Subas Sakya; John C Murray

doi:10.1021/jo400016m

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Stereoselective Synthesis of Spiropiperidines as BACE-1 Aspartyl Protease Inhibitors via Late Stage N-Arylation of a 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore

Journal article

Peer reviewed

Stereoselective Synthesis of Spiropiperidines as BACE-1 Aspartyl Protease Inhibitors via Late Stage N-Arylation of a 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore

Che-Wah Lee, Ricardo Lira, Jason Dutra, Kevin Ogilvie, Brian T O’Neill, Michael Brodney, Christopher Helal, Joseph Young, Erik Lachapelle, Subas Sakya, …

Journal of organic chemistry, Vol.78(6), pp.2661-2669

03/15/2013

DOI: 10.1021/jo400016m

PMID: 23438191

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Abstract

A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey–Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.

Details

Title: Subtitle: Stereoselective Synthesis of Spiropiperidines as BACE-1 Aspartyl Protease Inhibitors via Late Stage N-Arylation of a 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore
Creators: Che-Wah Lee - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Ricardo Lira - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Jason Dutra - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Kevin Ogilvie - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Brian T O’Neill - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Michael Brodney - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Christopher Helal - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Joseph Young - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Erik Lachapelle - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Subas Sakya - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
John C Murray - Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
Resource Type: Journal article
Publication Details: Journal of organic chemistry, Vol.78(6), pp.2661-2669
DOI: 10.1021/jo400016m
PMID: 23438191
NLM abbreviation: J Org Chem
ISSN: 0022-3263
eISSN: 1520-6904
Language: English
Date published: 03/15/2013
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094576802771

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