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Studies toward the total synthesis of lydiamycin A




Sabodash, Tatyana C., author
Williams, Robert Michael, advisor
Prieto, Amy Lucia, committee member
Inamine, Julia M., committee member

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The isolation of lydiamycin A from Streptomyces lydicus (strain HKI0343) was reported by Sattler and coworkers in 2006. Lydiamycin A showed potent activity against slow-growing and pathogenic mycobacteria, suggesting a novel mode of action in comparison with existing therapeutics. In addition to having no assigned absolute configuration at C-2 and C-3, the interesting structural complexity of the thirteen-membered cyclodepsipeptide makes it an attractive synthetic target. To this date there has been two synthesis reported-- lydiamycin B (Ma 2009) and lydiamycin A (Xu and Ye 2010) but none of the synthetic compounds matched the reported isolation data suggesting incorrect assignment of stereocenter(s) in the ring portion of the lydiamycins. Current work has been focused on closing the macrocyclic core of lydiamycin A using standard coupling conditions. Once the method for effective cyclization is developed, synthesis of diastereomers would be approached to aid in the correct assignment of natural lydiamycin A. Once we have identified the correct structure of natural lydiamycin A, we plan to use the macrocyclic core to make a series of side-chain analogs of the lydiamycins with the goal of improving potency against drug-resistant strains of Mycobacteria tuberculosis in collaboration with Prof. McNeil's laboratory. The ultimate goal is to synthesize dozens of analogs of lydiamycin to be assayed for in vitro activity against non-pathogenic, pathogenic and drug-resistant strains of Mycobacteria sp.


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Lydiamycin A


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