Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide‐2a

Abstract

Iriomoteolide‐2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG‐75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide‐2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide‐2a featured a late‐stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring‐closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2–5 as candidates for the correct structure. Accordingly, total syntheses of 2–5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2–5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide‐2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent‐5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent‐5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

Silylation of Alcohols, Phenols, and Silanols with Alkynylsilanes – an Efficient Route to Silyl Ethers and Unsymmetrical Siloxanes

“…[6][7][8][9][10] to their most known function as a temporary protective group for hydroxyl moieties (e.g., natural products synthesis, derivatization, etc.). [11][12][13][14] There are several methods of their synthesis, starting with classical condensation between alcohols and halosilanes, [15] and finishing on catalytic coupling reactions with hydro-, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] vinyl- [33] or allylsilanes, [34,35] and more recently also with silyl formates. [36][37][38] However, in the case of O-silylation of alcohols with alkynylsilanes -this process has never been comprehensively studied, and previous investigations have mainly referred to the problem of C sp -Si bond stability rather than the application of this transformation as an efficient method for obtaining silyl ethers.…”

Synthesis-Driven Stereochemical Assignment of Marine Polycyclic Ether Natural Products

“…Nonetheless, configurational assignment of acyclic portions and remotely isolated stereogenic centers is still a daunting task. The JBCA method is effective for the configurational assignment of non-biased acyclic systems, but its application to more or less biased acyclic systems appears to need special care [ 136 , 137 , 138 ]. Genome sequence information of the producer organisms may be useful for assigning the configuration of natural products on the basis of biosynthetic predictions, although the biosynthetic genes are difficult to obtain from marine dinoflagellates.…”

The Tetrahydrofuran Motif in Polyketide Marine Drugs

“…Despite their biological interest, there is no total synthesis reported for the 21-membered macrolide 95, nor the 22-membered macrolide 96, probably due to their complexity. On the contrary, the synthesis of 94 was accomplished by Fuwa and co-workers recently and it led to a structural revision [68,69].…”

“…Thanks to this total synthesis it was possible to establish the absolute configuration of iriomoteolide-2a and to re-study the biological activity of synthetic compounds [69]. By comparing the spectral data, the correct stereochemistry of the natural compound could be assigned, which differed from the first proposed assignment [65].…”