Chiral pyran-based ring systems (e.g. tetrahydropyrans, dihydropyrans, 4-lactols, and 4-lactones) are ubiquitous in nature. These substructures are found in numerous biologically active natural products, including such well-known synthetic targets as FK- 506, discodermolide, palytoxin, the bryostatins, and the spongistatins. The overall objective of these studies is to develop an efficient general strategy for the asymmetric synthesis of pyranoid functionality found in numerous biologically relevant natural product classes, and to extend these methods to the efficient synthesis of other complex polyketide systems. A method involving the direct displacement of thione- based chiral auxiliaries from the products of asymmetric aldol reactions, using a variety of carbon nucleophiles, will be explored for the rapid assembly of substituted pyranone derivatives. These methods, in combination with a catalytic asymmetric hydroformylation, will be directed toward an expeditious formal synthesis of the antineoplastic agent, acutiphycin. By way of this approach, we will prepare in nine steps or fewer what previously required nineteen. The scope of these methods will be further extended by application to the marine natural product, Tedanolide C, a recently disclosed member of the tedanolide family all members of which exhibit nanomolar cytotoxicity against cancer cell lines. Using the methods developed herein, the structurally distinct C1-C12 half of this molecule will be rapidly prepared. This fragment intersects successful routes to the original tedanolides and, thus, could be used for SAR studies of this extremely potent class of natural products. Moreover, this fragment will form the basis of a simplified model for the macrolide core of tedanolide C, which will be used to verify stereochemical relationships in the natural product that remain uncertain based upon NMR analysis alone. Finally, the asymmetric total synthesis of a novel marine natural product, enigmazole A, will be undertaken. Key to this synthesis again will be the creative functionalization of thione-based aldol adducts, along with the deoxygenation of a complex dipropionate segment, an esterification-based fragment coupling, and a ring-closing metathesis. Overall, these projects have the potential to make a genuine contribution to the methodology of pyran-based natural products synthesis. ? ? This research is concerned with the development of new methods that will allow for the efficient preparation of anticancer compounds. Three natural products having promising medicinal value, acutiphycin, tedanolide C, and enigmazole A, will be investigated using these methods. ? ? ?
| Smith, Thomas E; Fink, Sarah J; Levine, Zebulon G et al. (2012) Stereochemically versatile synthesis of the C1-C12 fragment of tedanolide C. Org Lett 14:1452-5 |
