Total Synthesis of Platensimycin - DeepDyve
N2 - Oxatropanes from oxiranes: An expedient assembly of the compact platensimycin core is described. The synthetic approach relies on a Suzuki cross-coupling, a late-stage dearomatization reaction, and a copper-catalyzed vinyl oxirane ring expansion for accessing the oxatropane moiety of the natural product.
Total Syntheses of Natural Products
With a viable route to the core structure (12) of platensimycin in hand, we turned our attention to the installation of the side chain and completion of the total synthesis. Enone 12 could be methylated in excellent yield by exposure to KHMDS followed by addition of MeI in a THF-HMPA mixture (). The methyl group was introduced with almost complete stereoselectivity, giving 72 as essentially a single diastereoisomer, as judged by 1H NMR spectroscopic analysis. A second alkylation was then investigated using various electrophiles. As might be expected, the enolate of 72 was found to be rather unreactive, and all attempts to install a side chain using 3-oxygenated propyl iodides (e.g. 73 or 74) failed. Treatment of the potassium enolate of 72 with bromide 75 rapidly transferred the ester group to the enolate oxygen of the substrate to form the corresponding enol carbonate. However, this enolate did react with allyl bromide to provide the desired allylated compound 76 along with significant quantities of the O-allylated product. Recourse to allyl iodide overcame this complication, giving 76 in good yield (83%) and, again, essentially as a single diastereoisomer, verifying our retrosynthetic hypothesis. The conversion of 76 into platensic acid (2) was also problematic at first. The allyl side chain was not reactive toward bulky hydroboration reagents; treatment with BH3•THF led to hydroboration of the allyl group with concomitant reduction of the enone carbonyl moiety, allowing isolation of diol 77 in low yield, along with several by-products. Oxidation of 77 with DMP then furnished aldehyde 78 in low overall yield from 76 (steps a and b were carried out with both racemic and enantiopure materials; steps c and d were carried out only with racemic compounds).
Since 1975 my group has been engaged in research in the total synthesis of natural products and three areas of synthetics method development: (1) Lewis acid-catalyzed ene reactions, Prins reactions, and cycloadditions, especially those using alkylaluminum halides as Lewis acids that are Brønsted bases,,,116 (2) intramolecular cycloaddition reactions of ketenes and keteniminium salts with alkenes, and (3) Mn(OAc)3 based oxidative free radical cyclizations., Targets synthesized include cylindrospermopsin, guanacastepene A, SCH 642305, berkelic acid,, chaetominine, haterumalide, abyssomycin C, symbioimine, polygalolide A, platensiymycin, and vibralactone. Further information is provided in the Research section.
Total synthesis of complex heterocyclic natural products
The discovery of platensimycin was reported just this May by biologist Jun Wang, structural biologist Stephen M. Soisson, and Director of Natural Products Chemistry Sheo B. Singh of , in Rahway, N.J., and coworkers (Nature 2006, 441, 358; ). "Most antibiotics used today fall into four different categories in terms of how they kill bacteria," Singh says, "and platensimycin uses a fifth mechanism-inhibition of fatty acid biosynthesis."
More Dead Ends and Detours : En Route to Successful Total Synthesis.
"This expedient total synthesis opens an important chapter in antibiotic research," says assistant professor of chemistry of the National University of Singapore, whose group also has been trying to synthesize platensimycin. "The synthetic approach is cleverly planned, and routes to asymmetric variants and designed analogs for drug development look conceivable."