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

Abstract

We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.

Dehydration reactions in polyfunctional natural products

“…[103][104][105][106] In our laboratory's efforts to construct members of the 4-amido-2,4-pentadienoate (APD) bearing cyclolipodepsipeptide (CLD) natural products, such as rakicidin A (87) (see Scheme 15B), we have employed the combination of DSC and DIPEA to construct the trademark exocyclic double bond present in these natural products. 106 In the synthesis of rakicidin A, the elimination process requires selectivity between the secondary alcohol of the hydroxyasparagine motif in the southern part of the molecule and the primary alcohol that must be eliminated to construct the APD-functionality. The elimination process that engenders rakicidin A is low yielding, regardless of dehydration conditions employed, likely a consequence of the poor stability of the natural product.…”

Synthesis of the enantiomers of 13‐methylheptacosane, the sex pheromone of pear psylla, Cacopsylla pyricola

“…Optical rotations were determined by a Perkin-Elmer PE-341 polarimeter. 1 H, 13 C nuclear magnetic resonance (NMR), and 19 F NMR spectra were obtained from a Bruker DP-X300 MHz or ASCEND™500 spectrometer with internal tetramethylsilane for 1 H NMR and CDCl 3 for 13 C NMR. High-resolution mass spectrometry (HRMS) data were recorded on Thermo Scientific Exactive Plus (EMR) with a quadrupole mass analyzer.…”

SeMPI 2.0—A Web Server for PKS and NRPS Predictions Combined with Metabolite Screening in Natural Product Databases

“…The nMT is located between the A and PCP domain in all observed cases, e.g., BGC0001971 (C-A-nMT-PCP), BGC0000461 (C-A-nMT-PCP-TE), BGC0000384 (A-nMT-PCP), and BGC0000326 (C-A-nMT-PCP-E). The nMT domain usually leads to methylation of the nitrogen in the peptide bond of the inserted building block (e.g., retimycin and rakicidin A [24]).…”