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.