Stereoselective synthesis of the C1–C12 segment of iriomoteolide-1a: a very potent macrolide antitumor agent

Abstract

A stereoselective synthesis of the C 1 -C 12 segment of the potent cytotoxic macrolide, iriomoteolide 1a, has been accomplished. The key steps involve an enzymatic kinetic resolution of a β-hydroxy amide, a Pd-catalyzed cross-coupling to a substituted allylsilane, a highly regio-and stereoselective conjugate addition of lithium dimethylcopper to an α, β-acetylenic esters and an elaboration of the C 6 -C 7 trans-olefin geometry by a Julia-Kocienski olefination.Macrocyclic marine natural products are a rich source of potent and structurally novel anticancer agents with clinical potential. 1 Over the years, Kobayashi and co-workers have reported a variety of structurally diverse macrolides known as amphidinolides from marine dinoflagellates, Amphidinium Sp. 2 Recently, Tsuda and co-workers isolated iriomoteolide 1a (1), a 20-membered macrolide from Amphidinium Sp. from benthic sea sand collected off Iriomote island in Japan. 3 Iriomoteolide 1a displayed remarkably potent cytoxicity against human B lymphocyte DG-75 cells with an IC 50 value of 2 ng/mL. Furthermore, it has shown cytotoxicity against Epstein-Barr virus -infected human B lymphocyte Raji cells with IC 50 value of 3 ng/mL. Despite its potent activity, the biological mechanism of action of iriomoteolide 1a is currently unknown. The gross structure of 1 was established by extensive mass spectroscopy and NMR studies. 3 The unique structural features of iriomoteolide 1a coupled with its potent antitumor activity attracted our interest in its synthesis and structureactivity studies. Herein we report synthesis of the C 1 -C 12 segment of iriomoteolide 1a in which the key steps involve lipase catalyzed kinetic resolution of a β-hydroxy amide, a highly stereoselective conjugate addition, and a Julia-Kocienski olefination to install the C 6 -C 7 trans olefin geometry. Thus far, only Yang and coworkers reported the synthesis of C 1 -C 12 fragment of iriomoteolide 1a and the total synthesis of iriomoteolide has not yet been achieved. 4 As shown in figure 1, our synthetic strategy of iriomoteolide 1a is convergent and involves the assembly of fragments 2 (C 1 -C 12 segment) and 3 (C 13 -C 23 segment) by a Sakurai reaction 5 and subsequent macrolactonization between the C 19 -hydroxyl group and the C 1 -carboxylic acid. Segment 2 was planned to be synthesized by a Julia-Kocienski olefination reaction 6 between sulfone 4 and aldehyde 5. This reaction is expected to establish the C 6 -C 7 trans-olefin geometry.The synthesis of sulfone 4 was carried out as shown in Scheme 1. Deprotonation of N-methoxy-N-methylacetamide by lithium diisopropylamide followed by reaction of the resulting enolate * Corresponding author. Tel.: +1 765 494 5323; fax: +1 765 496 1612; akghosh@purdue.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before ...

Probing o‐Diphenylphosphanyl Benzoate (o‐DPPB)‐Directed CC Bond Formation: Total Synthesis of Dictyostatin

“…For the synthesis of the southern fragment ( 2 ), we needed enantiopure Weinreb amide 8 . Access to an enantiopure precursor of 8 had been developed by Ghosh and Yuan,46 who had employed Amano Lipase PS47 for the enzymatic resolution of the corresponding racemate (Scheme ). In our case, the desired enantiomer was the acetate.…”

Comparisons of Chemical Composition, Flavor and Bioactive Substances between Korean and Imported Velvet Antler Extracts

“…Amongst, some representative compounds such as; iriomoteolide 1a (accepted ID: CSID17627054), hovenidulcioside A2 (accepted ID: HMDB41029) and ginsenoside F3 (accepted ID: HMDB39556) in the KVA extract; Notoginsenoside I (accepted ID: HMDB31371), ganoderic acid H (accepted ID: HMDB35987) and mibefradil (accepted ID: CSID54673) in the RVA extract; Papulacandin A (accepted ID: CHEBI:72611), 2-palmitoyl-sn-glycero-3-phosphocholine (accepted ID: CSID21403165) and tetra-(3E)-3-hexen-1-yl methylenebis (phosphonate) (accepted ID: CSID4524297) in the NZVA extract, all of them have also been reported to exert the important biological functionalities (e.g., immune activity and disease healing and anti-cancer etc.) in literatures ( Elkhatee et al, 2018 ; Ghosh and Yuan, 2009 ; Zhang and Wang, 2006 ). This study, for the first time, identified and compared the bioactive substances in the VAEs from different countries, and it may be said that all the VAEs studied are rich in the bioactive substances.…”

“…It was also noted that some compounds were also found in two different VAE types for instance; 13, 13 and 11 compounds were found in both the KVA and RVA; KVA and NZVA; and RVA and NZVA extracts, respectively. Although the quantifications of the identified compounds were not done, there might be some differences existing in their levels among the three VAE types as shown in CSID54673) in the RVA extract; Papulacandin A (accepted ID: CHEBI:72611), 2-palmitoylsn-glycero-3-phosphocholine (accepted ID: CSID21403165) and tetra-(3E)-3-hexen-1-yl methylenebis(phosphonate) (accepted ID: CSID4524297) in the NZVA extract, all of them have also been reported to exert the important biological functionalities (e.g., immune activity and disease healing and anti-cancer etc.) in literatures (Elkhatee et al, 2018;Ghosh and Yuan, 2009;Zhang and Wang, 2006). This study, for the first time, identified and compared the bioactive substances in the VAEs from different countries, and it may be said that all the VAEs studied are rich in the bioactive substances.…”

Enantioselective Synthesis of the C1–C6 and C7–C23 Fragments of the Proposed Structure of Iriomoteolide 1a

“…1 Because of the attractive biological profile and the unique structural attributes of iriomoteolide 1a, several laboratories have undertaken the total synthesis of 1 . The groups of Loh, 2 Paterson, 3 Zhao, 4 Li, 5 and Dai 6 have reported creative approaches to complex fragments of 1 , while Horne, 7 Ghosh, 8 and Yang 9 have completed the total synthesis of macrolactone 1. During the course of their synthetic studies, Horne, 7 Ghosh, 8 and Yang 9 independently ascertained that the proposed structure of iriomoteolide 1a had been misassigned.…”

“…The groups of Loh, Paterson, Zhao, Li, and Dai have reported creative approaches to complex fragments of 1 , while Horne, Ghosh, and Yang have completed the total synthesis of macrolactone 1 . During the course of their synthetic studies, Horne, Ghosh, and Yang independently ascertained that the proposed structure of iriomoteolide 1a had been misassigned (Figure ).…”