HYDROGENATION OF THE ANSA-CHAIN OF RIFAMYCINS - X-RAY CRYSTAL-STRUCTURE OF (16S)-16, 17, 18, 19-TETRAHYDRORIFAMYCIN-S

The catalytic hydrogenation of rifamycin S(2) over Pd/C, followed by oxidation with K3[Fe(CN)6], generates a pair of 16,17,18,19-tetrahydrorifamycins S(3/4), epimeric at C(16). The use of PtO2 as catalyst leads to the hydrogenation also of the C(28)=C(29) bond giving, after oxidation by K3[Fe(CN)6], a mixture of the epimers (16,R)- and (16S)-16,17,18,19,28,29-hexahydrorifamycins S(5/6). Furthermore, we synthesized the (16R)- and (16S)-3-bromo derivatives 7/8 and (16,R)- and (16S)-3-(piperidin-1-yl) derivatives 9/10. The determination of the X-ray crystal structure of the most abundant epimer 4 of the tetrahydrorifamycins allowed the assignment of the absolute configuration at C(16)of all derivatives. A structure-activity relationship study showed that in general the (16R)-epimers are more potent inhibitors of bacterial RNA polymerase than the (16S)-epimers.