Total synthesis of nominal cyclocinamide B and investigation into the identity of the cyclocinamides

Abstract

The total synthesis of nominal cyclocinamide B, a cyclic peptide marine natural product, is reported together with an isomer of nominal cyclocinamide A. Initial attempts at the synthesis of the title compounds by inclusion of a turn inducer failed. However, direct synthesis succeeded in formation of the 14-membered cyclic peptide structure. Comparison of the data from all synthetic cyclocinamide A and B compounds with those of the natural products leads to the conclusion that the two natural products possess the same relative stereochemistry and that the true structures have not been defined.

Marine natural products

“…The compound's relative conguration was also determined, 726,727 while the relative conguration of the C-36 to C-42 portion of hemicalide 1107 was also solved by synthesis. 728,729 Total syntheses of polyketides gracilioether B and C 730,731 and hippolachnin, 732,733 mycothiazole, [734][735][736] aromatic renieramycin I, 737,738 and peptides cyclocinamide A, 739 corticiamide B, [740][741][742] stylissamide X 743,744 and stylissatin A 745,746 have all been realised. The total synthesis of yaku'amide A 1108, including eight possible stereoisomers of its core region, required revision of structure, and also that of congener B 1109.…”

Application of the DP4 Probability Method to Flexible Cyclic Peptides with Multiple Independent Stereocenters: The True Structure of Cyclocinamide A

“…One of us (UCSC) has prepared 1a , 6 the 4 S , 7 S , 11 R , 14 S isomer 1d , 6 2 , 7 and ent -1b 7 (i.e., the compound with the core of 2 and the glycine-pyrrole side chain of compounds 1 ). None of these compounds corresponded to either natural product as determined by comparison of the 1 H and 13 C NMR data.…”

“…However, it was determined that CC-A and CC-B were either enantiomers or identical with respect to their stereochemistry by comparison of their respective NMR data. 7…”

“…None of these compounds corresponded to either natural product as determined by comparison of the 1 H and 13 C NMR data. However, it was determined that CC-A and CC-B were either enantiomers or identical with respect to their stereochemistry by comparison of their respective NMR data …”

“…However, it was determined that CC-A and CC-B were either enantiomers or identical with respect to their stereochemistry by comparison of their respective NMR data. 7 Herein, we report the assignment of the stereochemistry of cyclocinamide A as 1e (4S, 7R, 11R, 14S) through the extension of the DP4 analysis to this 14-membered, conformationally flexible, cyclic peptide with four unrelated stereocenters. In addition, we present the total synthesis of this isomer, thus verifying the DP4 prediction.…”