Three constituents of Alpinia blepharocalyx, namely calyxin I, calyxin J and epicalyxin J, are the subject of this proposal owing to their in vitro activity against human fibrosarcoma HT-1080 and murine colon 26-L5 carcinoma cells. The long-term objective of this research is to verify the absolute structures of these compounds by independent synthesis. Specifically this proposal will focus on one part of the puzzle, that being to develop a stereocontrolled approach to the fused ring system common to each compound. The research design is divided into three major sections. In section one, hetero Diels-Alder reactions between substituted dihydropyrans and N-acyl imines, leading to fused ring bicyclic acetals, will be studied. Section two focuses on Lewis acid ring cleavage reactions of these [4 + 2] cycloadducts with a variety of nucleophiles. The intended C-aryl pyranoside products will arise from nucleophilic addition of electron rich aromatic rings to oxocarbenium ions generated from these bicyclic acetals. The third section will concentrate on the application of this methodology to synthesis. Each product of ring cleavage should contain a side chain on C-2 of the tetrahydropyran ring which bears an amide moiety. A set of experiments will be designed to gradually increase the electron deficiency of this amide moiety by adding groups with increasing electron withdrawing capabilities. We hypothesize that in a Lewis acid environment, and with sufficient stabilization from neighboring groups, unimolecular dissociation of the amide functionality will lead to carbocation formation, allowing intramolecular substitution from a near-by nucleophilic center. This step is designed to provide the aforementioned three-membered fused ring system. The in vitro anti-cancer activity of these constituents makes them potential drug candidates for the treatment of human tumors. In collaboration with biologists on campus, their laboratory synthesis would eventually lead to the determination of how they kill cancer cells. Using this information, the design of analogues with superior and more selective cancer fighting properties should be possible. ? ? ?
| Cakir, Sidika Polat; Stokes, Sean; Sygula, Andrzej et al. (2009) Evidence for pi-stacking as a source of stereocontrol in the synthesis of the core pyranochromene ring system common to calyxin I, calyxin J, and epicalyxin J. J Org Chem 74:7529-32 |
