Synthesis of a smoothened cholesterol: 18,19-di-nor-cholesterol.
Herein, we report the first synthesis of a demethylated form of cholesterol (18,19-di-nor-cholesterol), in which the C18 and C19 methyl groups of the β-face were eliminated. Recent molecular simulations modeling 18,19-di-nor-cholesterol have suggested that cholesterol's opposing rough β-face and smooth α-face play necessary roles in cholesterol's membrane condensing abilities and, additionally, that specific facial preferences are displayed as cholesterol interacts with different neighboring lipids and transmembrane proteins. Inspired by these poorly characterized biochemical interactions, an extensive 18-step synthesis was completed as part of a collaborative effort, wherein synthesizing a "smoothened" cholesterol analogue would provide a direct way to experimentally measure the significance of the β-face methyl groups. Starting from known perhydrochrysenone A, the synthesis of 18,19-di-nor-cholesterol was accomplished with an excellent overall yield of 3.5%. The use of the highly stereoselective Dieckmann condensation and the employment of Evans' chiral auxiliary were both key to ensuring the success of this synthesis.
Department of Developmental Biology, ‡Anesthesiology, and §Psychiatry, Washington University School of Medicine , St. Louis, Missouri 63110, United States.
Laurel
L
Mydock-McGrane
Nigam P
NP
Rath
Douglas F
DF
Covey
D002783:Cholestenones / Q000138:chemical synthesis* / Q000737:chemistry; D002784:Cholesterol / Q000138:chemical synthesis* / Q000737:chemistry; D058635:Lipid-Linked Proteins / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002783:Cholestenones; D058635:Lipid-Linked Proteins; D002784:Cholesterol