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 (16R)- 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 (16R)- 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 derivative. A Structure-activity relationship study showed that in general the (16R)-epimers are more potent inhibitors of bacterial RNA polymerase than the (16S)-epimers.

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