Total Synthesis and Determination of the Absolute Configuration of Rakicidin A

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.

APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells

“…See also Figure S1. compared with 1 ( Figure 1B) (Villadsen et al, 2017) (for other studies of the natural products see, e.g., Sang et al, 2014;Sun et al, 2017). Both 1 and 2 feature an electrophilic 4-amido-2,4pentadienote (APD) functionality (blue, Figure 1) embedded within a cyclic lipodepsipeptide (CLD) scaffold, and this combination (APD-CLD) is necessary for hypoxia-selective toxicity (Tsakos et al, 2016a).…”

“…Integrating the necrotic cell death profile with the metabolomics and transcriptomics data (combination of GSH/GSSG loss, ROS formation, and induction of ER stress) suggested a degree of mechanistic similarity of 1 and 2 to erastin, whose mode of action has been unveiled in a series of reports over the last decade (Dixon et al, 2012;Yang et al, 2014;Lewerenz et al, 2018). It is now understood that erastin blocks the cellular uptake of cystine, which is required for GSH synthesis, and thereby triggers ferroptosis/oxytosis (Lewerenz et al, 2018), driven by formation of polyunsaturated lipid hydroperoxides.…”

Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue

“…This analyses converged upon (2 R , 3 R , 14 R , 15 R , 16 S ) as the most likely configuration of natural rakicidin A, and we initially targeted this particular isomer. Recently, two reports appeared, both claiming assignment of the configuration of rakicidin A . Through synthesis of a compound with spectroscopic data matching those of the natural product, Chen and co‐workers arrived at a (2 S , 3 S , 14 S , 15 S , 16 R ) configuration, whereas Igarashi and co‐workers paradoxically concluded the stereochemistry to be (2 R , 3 R , 14 S , 15 S , 16 R ) by direct degradation of the natural product and comparison with authentic standards (Figure A) .…”

“…Recently, two reports appeared, both claiming assignment of the configuration of rakicidin A . Through synthesis of a compound with spectroscopic data matching those of the natural product, Chen and co‐workers arrived at a (2 S , 3 S , 14 S , 15 S , 16 R ) configuration, whereas Igarashi and co‐workers paradoxically concluded the stereochemistry to be (2 R , 3 R , 14 S , 15 S , 16 R ) by direct degradation of the natural product and comparison with authentic standards (Figure A) . This latter assignment, however, was corrected earlier this year to corroborate a (2 S ,3 S ,14 S ,15 S ,16 R ) configuration for rakicidin A, and it was thus clear that our initial synthesis in fact had targeted ent ‐rakicidin A. Herein, we report our unique route to the natural isomer of rakicidin A, along with biological evaluation and the discovery of a simplified bioactive rakicidin A analogue.…”

Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue

“…Recently,t wo reports appeared, both claiming assignment of the configuration of rakicidin A. [13,14] Through synthesis of ac ompound with spectroscopic data matching those of the natural product, Chen and co-workers arrived at a( 2 S,3S,14S,15S,16R)c onfiguration, [13] whereas Igarashi and co-workers paradoxically concluded the stereochemistry to be (2R,3R,14S,15S,16R)b yd irect degradation of the natural product and comparison with authentic standards ( Figure 1A). [14] This latter assignment, however, was corrected earlier this year to corroborate a( 2 S,3S,14S,15S,16R) configuration for rakicidin A, and it was thus clear that our initial synthesis in fact had targeted ent-rakicidin A. Herein, we report our unique route to the natural isomer of rakicidin A, along with biological evaluation and the discovery of asimplified bioactive rakicidin Aanalogue.…”