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Keywords: amphidinolides; polyketides; total synthesis; Suzuki cross-coupling; epoxides; protecting groups EN amphidinolides polyketides total synthesis Suzuki cross-coupling epoxides protecting groups 2017 2021 5 10/09/23 20231024 NES 231024 Graph Amphidinolide U is a moderately cytotoxic macrolide isolated from dinoflagellates of an I Amphidinium i species, with reported IC SB 50 sb values on L1210 and KB cell lines of 12 and 20 g/mL, respectively. 1994, 107 24 Ley, S V. Tackett, M N. Maddess, M L. Anderson, J C. Brennan, P E. Cappi, M W. Heer, J P. Helgen, C. Kori, M. Kouklovsky, C. Marsden, S P. Norman, J. Osborn, D P. Palomero, M. Á. Pavey, J B. J. Pinel, C. Robinson, L A. Schnaubelt, J. Scott, J S. Spilling, C D. Watanabe, H. Wesson, K E. Willis, M C. Chem. Eur. J. 2009, 15: 2874 25 Cid, M B. Pattenden, G. Synlett. Chem. 2006, 71: 5826 20 Mihelich, E D. Daniels, K. Eickhoff, D J. J. Am. Chem. Soc. 1981, 103: 7690 21 Corey, E J. Fuchs, P L. Tetrahedron Lett. Int. Ed. 2001, 40: 4544 29 Berthold, D. Breit, B. Chem. Eur. J. 2018, 24: 16770 30 Geist, E. Kirschning, A. Schmidt, T. Nat. [Extracted from the article]

Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium. Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. Access to enough material is needed for these studies, but samples of these compounds are limited due to the minute amounts that can only be obtained by either large-scale cultivation of the organism that produces them or by total synthesis. Of all the amphidinolides known to date, only the targets of five of them (B1, H1, J, K, and X) have been examined and all have been found to interact with actin, a crucial cytoskeletal protein. This paper reviews what is currently known about actin-interacting amphidinolides, with a focus on the research of our group. Amphidinolides J and X are F-actin destabilizers, whereas Amphidinolides H1 and K stabilize actin filaments, likely via different mechanisms. More precise details of the interaction between amphidinolides and actin are missing. [ABSTRACT FROM AUTHOR]

dinoflagellates amphidinolide group of natural products have drawn the attention of the synthetic community owing to their natural scarcity, variation in ring size (12‐ to 27‐membered), and architectural complexity. The manifold strategies for creating the unique macrocyclic framework of amphidinolides, overcoming the entropy barrier of cyclisation, in good yields and selectivity, are highly encouraging as this platform provides an opportunity to develop compounds for structure‐activity relationship studies. This review emphasizes various methods of intramolecular C−C and C−O bond‐forming reactions for constructing the macrocyclic structure of different naturally occurring molecules of amphidinolide family. [ABSTRACT FROM AUTHOR]

Amphidinolides C, F, and U, including C2-C4 analogs, are highly cytotoxic marine macrolides, mainly isolated from dinoflagellates of the genus Amphidinium. All these polyketides share a 75 % or more similar structure, highlighted by a macrolactone ring, at least one trans-2,5-substituted-THF motif and a characteristic polyenic side chain. From their isolation and absolute configurational assignment, the total synthesis of these marine macrolides represented an intense challenge to the organic synthesis community over the last 15 years, with around 14 research groups engaged in this inspiring task. In the first part of this review, we present the different approaches to the isolation and characterization of these natural products, including the most recent analogs, which may cast doubt on the biogenetic origin of these compounds. The various synthetic approaches to the total synthesis of C, F, and U amphidinolides are presented in a second part, focusing on key reactions and/or innovative strategies. The review concludes in a third section summarizing the successful approaches leading to the total synthesis of one of the members of this amphidinolide subfamily., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Amphidinolides are cytotoxic macrolides produced by symbiotic unicellular microalgae of the genus Amphidinium. Here we describe the identification of four related molecules belonging to this macrolide family isolated from the invertebrate Stragulum bicolor. The new molecules, named amphidinolide PX1-PX3 and stragulin A (1–4), show an unprecedented carbon skeleton whose complete stereochemistry has been determined by spectroscopic and computational methods. Differences in the structures of these molecules modulate their biological activity in a panel of tumor cell lines, but the opened derivative stragulin (4) shows a very potent and specific cytotoxic activity (IC50 0.18 µM) against the aggressive human melanoma cell A2058.

Abstract: A stereoselective synthesis of a C1–C18 segment of the structure of the cytotoxic macrolides amphidinolides G and H is reported. The target compound was retrosynthetically disconnected into three fragments. In the synthetic sense, connection of the fragments was made by means of a Stille coupling and a Julia–Kocienski olefination. Precursors from the chiral pool were used as the starting materials. [Copyright &y& Elsevier]

Highlights: [•] A formal total synthesis of amphidinolide Y is reported. [•] Fragment C3–C9 was obtained via carbometalation–iodination and Negishi coupling. [•] Sharpless dihydroxylation and Hafner–Duthaler crotylation provided fragment C1–C11. [•] The C1–C11 fragment and alcohol C12–C16 were linked by Kita–Trost esterification. [•] Excess of Hoveyda–Grubbs-II complex was required for complete conversion (RCM). [Copyright &y& Elsevier]

A short approach to the tetrahydrofuran fragment of amphidinolides X and Y has been developed through the combination of iterative Sharpless asymmetric epoxidations, Pd-catalyzed regio�selective hydrogenolysis of a 4,5-epoxy-2-alkenoate and the disfavored 5-endo-tet ring closure of a β-hydroxy epoxide promoted by a double bond adjacent to the epoxide function. [ABSTRACT FROM AUTHOR]

Amphidinolides are cytotoxic macrolides produced by symbiotic unicellular microalgae of the genus Amphidinium. Here we describe the identification of four related molecules belonging to this macrolide family isolated from the invertebrate Stragulum bicolor. The new molecules, named amphidinolide PX1-PX3 and stragulin A (1–4), show an unprecedented carbon skeleton whose complete stereochemistry has been determined by spectroscopic and computational methods. Differences in the structures of these molecules modulate their biological activity in a panel of tumor cell lines, but the opened derivative stragulin (4) shows a very potent and specific cytotoxic activity (IC50 0.18 µM) against the aggressive human melanoma cell A2058. [ABSTRACT FROM AUTHOR]