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.
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