Stereocontrolled diversity oriented synthesis of 2H-benzopyran-based natural product-like polycyclics

Abstract

Over the years, it has been shown that natural products that act as highly specific modulators of protein function are complex in nature, highly functionalized and contain few stereogenic centers. There are several examples in literature, where benzopyran-based natural products have been utilized as small molecule chemical probes in understanding protein function. Inspired by the "privileged benzopyrans", the studies reported in this thesis are centred on the development of a novel method leading to the synthesis of functionalized benzopyran-derived scaffolds. Further, several attempts have been made to obtain natural product-like polycyclic compounds as derivatives of these scaffolds. Our approach has been to develop the synthetic methods initially by solution synthesis. In one case, a partial solid phase synthesis has been achieved that could further be extended to library generation. The synthetic efforts to obtain several benzopyran-based analogs are reported. These include the development of a novel, stereoselective synthetic route to obtain functionalized benzopyran templates (71a,b) and further extensions leading to diverse tricyclic derivatives having medium sized rings with few asymmetric diversity sites. An intramolecular Mitsunobu-based approach was explored to obtain benzopyran-derived tricyclic derivatives having a cis- and trans-fused lactone moiety ( 72, 73). Although we were successful in making the amino acid conjugates (387, 392, 395), we were not successful in making their tricyclic derivatives. Several ring closing metathesis (RCM)-based approaches were also developed to obtain benzopyran-based tricyclic derivatives having functionalized 6- and 8-membered rings, and were successful in making the polyethers ( 74, 75). Also reported in this chapter is the preliminary work on solid phase synthesis in which benzopyran-based tricyclic compounds with 6- and 8-membered rings were obtained by a RCM approach (541a,b).