The biomimetic vitamin D3 analog synthesis that was recently disclosed, based on an
earlier reported route for the commercial synthesis of alfacalcidol,
will be discussed here.
An Oppenauer oxidation converted commercially available cholesterol
141 to enone 142 in 80% yield. A second oxidation event
with DDQ provided dienone 143 in 75% yield. Treatment of 143
with sodium ethoxide in ethanol triggered migration of the enone
double bond into the B-ring, giving olefin 144 in 53% yield. Stereospecific
reduction of ketone 144 with sodium borohydride gave
alcohol 145 in 53% yield, which was then immediately protected
as the corresponding acetate with acetic anhydride to furnish
146. Next, further dehydrogenation of the B-ring was accomplished
using radical bromination of the olefin within 146 through
the use of NBS and catalytic AIBN, followed by elimination with
collidine. A subsequent saponification step ultimately gave rise to
the key diene 147. Next, in order to selectively epoxidize the A-ring
olefin, a unique ??protection?ˉ strategy was employed using phenyl-
1,2,4-triazole-3,5-dione (PTAD). Diels¨CAlder reaction between
diene 147 and PTAD produced cycloadduct 148 in 80% overall yield
from acetate 146. Protection of the alcohol as the corresponding
TBS ether preceeded a regio- and stereospecific epoxidation with
m-CPBA to afford 1,2a-epoxide 150 in 78% yield. Diels¨CAlder adduct
150 was then subjected to thermal conditions to affect a retro-[
4+2] reaction to give diene 151. Fluoride-mediated removal
of the TBS group prepared 3b-alcohol 152 in 95% yield. Subsequent
ring-opening reaction with 1,3-propane diol in the presence of
potassium t-butoxide, provided 3-hydroxy propoxy ether 153 in
29% yield. Microbial oxidation of intermediate 153 was accomplished
using an Amycolata autotrophica ATCC 33796 culture to obtain
eldecalcitol derivative 154 in 64% yield. Subjection of 154 to
400 watt light followed by thermolysis provided eldecalcitol (XII)
in 29% yield.
