Syntheses of New Phosphorus-Containing Azabicycloalkanes and Their Microbial Hydroxylation Using Beauveria bassiana

Representative novel phosphorus-containing azabicyclic substrates have been synthesized and subsequently microbially hydroxylated in fair to good yields using the microorganism Beauveria bassiana . (7-Azabicyclo[2.2.1]hept-7-yl)phosphonic acid diethyl ester was hydroxylated at the unactivated methylene carbon to give (2- endo -hydroxy-7-azabicyclo[2.2.1]hept-7-yl)phosphonic acid diethyl ester in 43% yield and 64% ee, while N -(diphenylphosphinoyl)-7-azabicyclo[2.2.1]heptane was similarly hydroxylated to give 2- endo -hydroxy-7-(diphenylphosphinoyl)-7-azabicyclo[2.2.1]heptane in 35% yield and 20% ee. (7-Azabicyclo[2.2.1]hept-7-yl)phosphonic acid diphenyl ester yielded two distinct hydroxylated products: monohydroxylated (2- endo -hydroxy-7-azabicyclo[2.2.1]-hept-7-yl)phosphonic acid diphenyl ester in 7% yield and 7% ee and dihydroxylated (2- endo -hydroxy-7-azabicyclo[2.2.1]hept-7-yl)phosphonic acid phenyl, p -hydroxyphenyl ester in 37% yield and 77% ee. HPLC studies indicated that the monohydroxylated metabolite is formed first during fermentation, and becomes a substrate for a second enzymatic hydroxylation at one of the aromatic rings with induced enantioselection, to give the dihydroxylated metabolite. All microbially hydroxylated metabolites were easily N -deprotected using TFA−CH 2 Cl 2 (1:1). Thus, N -phosphinyl groups are good facilitators of hydroxylation reactions with B. bassiana and offer a new choice for an N -substituent when substrates are hydroxylated with this microorganism. By offering a new N -substituent, this work extends the general utility of B. bassiana as a preparatively useful unactivated methylene hydroxylator.