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Enantioselective total syntheses of the proposed structures of macrolide cytotoxic agents iriomoteolide-1a and 1b have been accomplished. The synthesis was carried out in a convergent and stereoselective manner. However, the present work suggests that the reported structures have been assigned incorrectly. The synthesis features Julia-Kocienski olefination, Sharpless asymmetric epoxidation, Brown asymmetric crotylboration, a Sakurai reaction, an aldol reaction, and enzymatic resolution as the key steps.

The antibacterial activity of the cationic dimeric amphiphile octamethylene-1,8-bis(dodecyldimethylammonium bromide) (12-8-12) against the Gram-negative bacteria Escherichia coli was measured and compared with the monomeric amphiphile dodecyltrimethylammonium bromide (DTAB). The minimum inhibitory concentration (MIC) of 12-8-12 was about 1/20 of DTAB. By measuring the activity of b-galactosidase and the image of fieldemission scanning electron microscopy, it was revealed that the cationic amphiphile 12-8-12 interacted with the negatively charged membrane of E. coli and disrupted the membrane integrity, thus leading to the release of intracellular contents and the death of bacteria. To further explore the antibacterial mechanism, the interactions of cationic amphiphile 12-8-12 with biomacromolecules (bovine serum albumin (BSA) and salmon sperm DNA) were studied by measuring the intrinsic fluorescence of BSA and the zeta potential of DNA. It was shown that the antibacterial action site of cationic amphiphile was not only on the bacterial membrane but also on the intracellular contents such as protein and DNA.

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 ...

Iriomoteolide-1a and iriomoteolide-1b are very potent cytotoxic agents, isolated from marine dinoflagellates. We carried out the enantioselective syntheses of the proposed structures of these natural products. However, our analysis of the NMR spectra of the synthetic iriomoteolide-1a and the natural products revealed that the structures of iriomoteolide-1a and iriomoteolide-1b were assigned incorrectly. Based upon our detailed analysis of the spectral data of the synthetic iriomoteolide-1a and the natural products, we rationally designed three diastereomers of the proposed structure of 1 in an effort to assign the correct structures. The key steps of our syntheses of the proposed structures of iriomoteolides involved a highly diastereoselective ene reaction, a carbocupration that utilized a Gilman reagent, a Julia–Kocienski olefination to couple fragments, and Yamaguchi macrolactonization to form the target macrolactone. This synthetic route was then utilized to carry out syntheses of three diastereomers to the proposed structure of 1. These diastereomeric structures show close similarities to natural iriomoteolide-1a; however, there were differences in their spectral data. While natural iriomoteolides exhibited potent cytotoxicies, our preliminary biological evaluation of synthetic iriomoteolide-1a, iriomoteolide-1b, and all three synthetic derivatives did not show any appreciable cytotoxic properties.