Total Synthesis of Marinomycins A-C and of TheirMonomeric Counterparts Monomarinomycin A andiso-Monomarinomycin AK. C. Nicolaou,* Andrea L. Nold, Robert R. Milburn, Corinna S. Schindler,Kevin P. Cole, and Junichiro YamaguchiContribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, andthe Department of Chemistry and Biochemistry, UniVersity of California, San Diego,9500 Gilman DriVe, La Jolla, California 92093Received November 10, 2006; E-mail: [email protected]:Marinomycins A-C (1-3), and their monomeric analogues monomarinomycin A (m-1) andiso-monomarinomycin A (m-2), were synthesized by a convergent strategy from key building blocksketophosphonate 5, aldehyde 6, and dienyl bromide carboxylic acid 7. The first attempt to constructmarinomycin A [1, convertible to marinomycins B (2) and C (3) by light] by direct Suzuki-type dimerization/cyclization of boronic acid dienyl bromide 4 led to premature ring closure to afford, after global desilylation,monomarinomycin A (m-1) andiso-monomarinomycin A (m-2) in good yield and only small amounts (e2%)of the desired product. A subsequent stepwise approach based on Suzuki-type couplings improvedconsiderably the overall yield of marinomycin A (1), and hence of marinomycins B (2) and C (3). Alternativedirect dimerization approaches based on the Stille and Heck coupling reactions also led to monomarino-mycins A (m-1 and m-2), but failed to deliver useful amounts of marinomycin A (1).IntroductionThe need for new antibiotics has never been greater sincethe discovery of penicillin,1owing to the rather dramaticproliferation of drug-resistant bacteria and the frequent occur-rence of untreatable infections. Actinomycetes have providedmore than 10000 bioactive compounds and have generated morethan 70% of the antibacterial natural products found to date.2However, the discovery of new antibiotics, especially those withnovel mechanisms of action, has been steadily declining.3Manygroups have shifted their efforts from terrestrial actinomycetestoward those of the ocean, which have, until now, been largelyoverlooked.4The Fenical group in particular has been successfulin cultivating new colonies of actinomycetes from marine deepsea sediment samples, efforts that resulted in the isolation ofseveral biologically active natural products.5MarinomycinsA-C (1-3, Figure 1) have recently been isolated from a novelmarine actinomycete, Marinispora strain CNQ-140, collectedoffshore of La Jolla, California.6Possessing novel moleculararchitectures, these natural products exhibit pote n t anti b i o t i cactivity against methicillin-resistant Staphylococcus aureus(MRSA) and vancomycin-resistant Enterococcus faecium (VREF),with MIC90values ranging from 0.1 to 0.6 µM, with marino-mycin A (1) being the most active.6In addition to theirsignificant antibacterial activity, the marinomycins show potentcytotoxicities against the National Cancer Institute’s panel of60 cell lines, with an average LC50value of 2.7 µM, andremarkable selectivity against six of the eight melanoma celllines, where SK-MEL-5 is about 500 times more sensitive thanthe other cell lines, with an LC50value of 5.0 nM.6Because ofthis selectivity, it has been suggested that these secondarymetabolites inhibit tumor proliferation by a novel mode ofaction.6The marinomycins were also suspected, because of theirpolyene functionalities, and hence resemblance to amphotericinB,7to be potent antifungal agents. However, only marinomycinA (1) showed activity against Candida albicans (MIC90) 10µM).6These important biological activities of the marino-mycins, combined with their challenging structures, elicited ourattention with regards to their total synthesis. Herein, wedescribe the full account of our total synthesis of marinomycinsA-C (1-3)8as well as their unnnatural monomeric homo-logues, monomarinomycin A (m-1) and iso-monomarinomycinA (m-2).(1) Fleming, R. H. Brit. J. Exp. Pathol. 1929, 10, 226.(2) Berdy, J. J. Antibiot. 2005, 58, 1.(3) A notable example of an antibiotic with a new mechanism of action is therecently discovered platensimycin. Isolation and biology: (a) Wang, J.; etal. Nature, 2006, 441, 358. (b) Singh, S. B.; et al. J. Am. Chem. Soc. 2006,128, 11916. Total synthesis: (c) Nicolaou, K. C.; Li, A.; Edmonds, D. J.Angew. Chem., Int. Ed. 2006, 45, 7086.(4) Jensen, P. R.; Mincer, T. J.; Williams, P. G.; Fenical, W. Antoni e VanLeeuwenhoek 2005, 87, 43.(5) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P.R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355.(6) Kwon, H. C.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Am. Chem.Soc. 2006, 128, 1622. We thank Professor William Fenical for a preprintof this article; for the original publication of marinomycin structures, seereference 4.(7) Vandeputte, J.; Wachtel, J. L.; Stiller, E. T. Antibiot. Ann. 1956, 587.(8) For a preliminary communication, see: Nicolaou, K. C.; Nold, A.L.; Milburn, R. R.; Schindler, C. S. Angew. Chem., Int. Ed. 2006, 45,6527.Published on Web 01/24/200717609J. AM. CHEM. SOC. 2007,129, 1760-1768 10.1021/ja068053p CCC: $37.00 © 2007 American Chemical SocietyResults and DiscussionRetrosynthetic Design. In searching for a suitable strategyto deliver all three marinomycins (A-C, 1-3) we werecognizant of the fact that a total synthesis of marinomycin A(1), the presumed true natural product,6would constitute a totalsynthesis of the others, in view of its known photoisomerizationto marinomycins B (2) and C (3).6A cursory inspection of thestructure of 1 reveals its many sites for retrosynthetic discon-nection based on well-known processes such as the Suzuki, theStille, and the Heck coupling reactions, the olefin metathesisreaction, the Mitsunobu reaction, and the Yamaguchi macro-lactonization reaction. Taking advantage of the symmetry ofthe structure, our first retrosynthetic analysis of 1 (see Figure2) relied on a dimerization strategy to construct the 44-membered macrocycle from two identical monomeric units.While any of the above-mentioned reactions could, in principle,achieve such a dimerization, we chose the Suzuki coupling asa possible means to achieve this goal, not only because of itsreliability and the mild conditions it requires, but also becauseof its high stereoselectivity. Additional advantages included thefact that the required boronic acids could be generated
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