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

• Published in: Journal of organic chemistry Vol. 64; no. 17; pp. 6312 - 6318
• Main Authors: Hemenway, Michael S, Olivo, Horacio F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.08.1999; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; REMOTE DOUBLE-BOND; SULFURESCENS; ENANTIOMERIC EXCESS; SITE-SELECTIVE OXIDATION; N-PHENYL CARBAMATE; MICROBIOLOGICAL OXYGENATION; ASYMMETRIC REDUCTION; PEPTIDE-SYNTHESIS; RHIZOPUS-ARRHIZUS ATCC-11145; TRANSFORMATIONS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo9904664

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−CH2Cl2 (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.