Stereocontrolled preparation of a nonpeptidal (-)-spirobicyclic NK-1 receptor antagonist.
The synthesis of a spirobicyclic NK-1 receptor (Substance-P) antagonist 1 antipode is described. Retrosynthetic analysis reveals an allylic halide A bearing the cyclopropoxy-substituted aryl group and a 2-phenyl-3-piperidone B. The stereochemistry in the spirobicyclic system bearing three chiral centers is initially set via a highly diastereoselective zinc-mediated coupling of the allylic bromide 23 to the optically active ketopiperidine 3. The remaining benzylic asymmetric center is set by a diastereoselective hydroboration followed by cyclization to the spirobicyclic system.
Maligres
Peter E
PE
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Merck & Co., Inc., Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK. peter_maligres@merck.com
Waters
Marjorie M
MM
Lee
Jaemoon
J
Reamer
Robert A
RA
Askin
David
D
Ashwood
Michael S
MS
Cameron
Mark
M
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry; D001895:Boron / Q000737:chemistry; D002728:Chlorohydrins / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D008274:Magnesium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors; D014961:X-Ray Diffraction; D015032:Zinc / Q000737:chemistry
C449759:6-phenyl-1-oxa-7-azaspiro(4,5)decane; D001372:Aza Compounds; D001555:Benzene Derivatives; D002728:Chlorohydrins; D064729:Neurokinin-1 Receptor Antagonists; D009942:Organometallic Compounds; D013141:Spiro Compounds; D013373:Substance P; D008274:Magnesium; D015032:Zinc; D001895:Boron