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Total synthesis and determination of the absolute configuration of rakicidin A
Feng Sang1, Dongmei Li, Xiaolong Sun
1College of Pharmacy, State Key Laboratory of Elemento-Organic Chemistry, State Key Laboratory of Medicinal Chemical Biology, Nankai University , Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071 P. R. China.
Abstract:
Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target were consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547, and vinylamycin, and facilitates the investigations of rakicidin A as an anticancer stem cell agent.
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Structures of Carboxylic Acid Derivatives
Carboxylic acid derivatives contain an acyl group attached to a heteroatom such as chlorine, oxygen, or nitrogen. The carbonyl carbon and oxygen are both sp2-hybridized with an unhybridized p orbital.
The three sp2 orbitals of the carbonyl carbon form three σ bonds, one each with the carbonyl oxygen, the α carbon, and the heteroatom, whereas the other two sp2 orbitals of the carbonyl oxygen are occupied by the lone pairs. Further, the...

