Phosphate Tether-Mediated Synthetic Studies- Applications in Natural Products Synthesis.

Abstract

The focus of this dissertation is the utilization of phosphate tether mediated approaches to synthesize bioactive natural products and their analogs in аn efficient and effective manner. The several salient features, which are inherent to phosphate triesters, include: (i) orthogonal stability under acid conditions, (ii) leaving group ability, (iii) multivalent activation of carbinol centers, (iv) protecting group attributes, and serving as a (v) temporary tether that can be removed under various conditions. Taken collectively various transformations, including chemoselective reductions as well as oxidations of the exocyclic olefin, a diastereoselective cuprate addition and successful cross-metathesis of type I and type II olefins with the exocyclic double bond, all mediated by phosphate tether, have provided the facile synthetic routes towards the synthesis of several natural products. Application of this protocol toward the total synthesis of fostriecin and 8-epi-fostriecin are reported. Fostriecin, an antitumor antibiotic isolated from Streptomyces pulveraceus, is the most selective and potent inhibitor of protein phosphatases 2A and 4, known to-date (IC50s 3.2 nM and 3 nM, respectively). It has been shown to be active against L1210 and P388 leukemia cells in vivo and in vitro against leukemia, lung, breast, and ovarian cancer cells. Synthetic studies related to diastereoselective ring-closing metathesis reaction, regioselective oxidation, diastereoselective Grignard addition and cross metathesis, all mediated by a temporary phosphate tether, have established a scalable route toward the goal of total and analog synthesis of fostriecin and 8-epi-Fostriecin. In addition to the aforementioned transformations, the coupling of orthogonal transformations in a multi-step, one-pot, sequential RCM/CM/H2 process has also allowed for facile synthesis of advanced intermediates en route to the total synthesis of natural products. Application of three step, one-pot, sequential RCM/CM/H2 protocol in a library amenable, efficient and modular synthesis of strictifolione and (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one are also discussed. Both anti-fugal natural products were synthesized in seven linear steps starting from readily available 1,3-anti-diene-diol without incorporating additional protecting groups.