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A Chirality-returning Sequence for the Synthesis of an Unnatural Isomer of Hirsutellone B

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Abstract

Previously we had reported the total synthesis of the anti-tuberculosis agent hirsutellone B. The key step in the synthesis was the direct construction of a highly strained 13-membered macrocycle utilizing an intramolecular Ullmann reaction. In this work, we studied the influence of configuration at the C19 position on the 13-membered macrocyclization. The central chirality of the C19 position of cyclization precursor was specifically transferred to the planar chirality of the enol ether moiety of 13-membered macrocycle, and the planar chirality was then transferred back to the central chirality at the C19 position of the final product. This "chirality-returning" sequence enabled stereoselective construction of -hydroxylactam on the 13-membered macrocycle. By utilizing this stereochemical sequence, we achieved synthesis of a new unnatural isomer of hirsutellone B.

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