Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A
convergent strategy required methodologies for preparation of
an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and
a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner.
A [3+2] cycloaddition of an enantiopure azomethine ylide
followed by a diastereoselective crystallization was employed
to prepare the benzopyranopyrrolidine in high diastereomeric
and enantiomeric purity. Conditions for reduction of an O-aryl
lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished
in high yield. The thienopyrazine was prepared by condensation
of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen
substitutive deamination to prepare regiospecific trisubstituted
pyrazines will be described.
Recently, we described a new method for the deprotection of acetals using tin dichloride dihydrate (SnCl2• 2H2O).1 Under neutral or even mildly basic conditions, both nonconjugated and conjugated acetals are converted to aldehydes when treated with 1 equiv of this stannylene. Yields range from 62-94% for dimethoxy and diethoxy acetals and 84-95% for conjugated dioxolanes; poorer yields were obtained for conjugated 1,3-dioxanes and nonconjugated dioxolanes.
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