I. Total synthesis, stereochemical reassignment, and biological evaluation of (+)-neopeltolide and related stereoisomers. II. Development of chiral benzylsilanes: Reagents for stereoselective, silicon-mediated oxa-Pictet-Spengler reactions

(+)-Neopeltolide is a biologically active marine natural product that was recently isolated from a previously unknown species of deep-sea sponge. Preliminary bioactivity assays indicated (+)-neopeltolide possessed anti-cancer properties with a potency rivaling the known chemotherapeutic agent Taxol RTM. The promising pharmaceutical potential and intriguing architecture of this natural product prompted us to initiate synthetic studies towards its preparation. Two of six stereogenic centers were procured from chiral pool reagents, while a third was installed via highly stereoselective Evans-Tishchenko reduction. An organosilane-based [4+2]-annulation was critical in the asymmetric assembly of the tetrahydropyran segment while simultaneously establishing two additional stereocenters at C3 and C7. Union of the 14-membered lactone with the oxazole side chain occurred under Mitsunobu conditions to give the compound originally identified as (+)-neopeltolide. Comparison of the natural and synthetic material revealed that the two compounds were not identical. Re-evaluation of the natural material led to the supposition that the original structure was a related stereoisomer and subsequent preparation of a select subset of neopeltolide diastereomers successfully identified the correct relative and absolute stereochemistry of (+)-neopeltolide. (+)-Neopeltolide and four additional stereoisomers were evaluated for biological activity where the natural product demonstrated a remarkable tolerance for stereochemical modification.;Substituted isochromans (1H-3,4-dihydro-2-benzopyrans) are common structural archetypes in biologically active compounds. A common approach to these templates is the oxa-Pictet Spengler condensation of a carbonyl with a phenylethyl alcohol. While successfully applied towards natural product syntheses, the general reaction suffers from several constraints, including limited substrate scope and preferential formation of cis-pyrans. Incorporation of a substituted silicon group within the phenylethyl alcohol may circumvent these restrictions. To explore this possibility, several novel benzylsilane reagents were obtained from silyl glycidate openings utilizing various aryl metal nucleophiles. These new silane reagents were then evaluated in a kinetically-controlled oxa-Pictet Spengler reaction wherein they displayed exceptional cis-diastereoselectivity and yields in isochroman formation. The annulation of electron-deficient aromatic systems, as well as trans-selective pyran assembly, proved more difficult but could be achieved under alternative conditions.