Total synthesis of herboxidiene/GEX 1A and development of chiral organosilane based [5+2] annulations

Herboxidiene/GEX 1A is a secondary metabolite originally isolated from Streptomyces sp. A7847. This natural product displays an array of diverse biological activities that include selective phytotoxicity against broadleaf annual weeds, activation of the low density lipoprotein (LDL) receptor, and more recently discovered antitumor activity against several human tumor cell lines. The natural product possesses several synthetically challenging structural features, including a trisubstituted tetrahydropyran core, a conjugated diene moiety and a poly-oxygenated side chain. In that regard, a convergent enantioselective synthesis of herboxidiene/GEX 1A was accomplished utilizing organosilanes-based bond construction methodology in three crucial stages: (1) the functionalized pyran core was constructed through our stereoselective [4+2]-annulation methodology; (2) synthesis of the acyclic side chain relied on a double stereodifferentiating crotylation using a newly developed crotylsilane reagent bearing a quaternary stereocenter; (3) union of the pyran core and the acyclic side chain was accomplished through a silicon-assisted sp 2-sp2 cross-coupling reaction.;Seven-membered oxygen heterocycles constitute an important class of molecules with well-documented biological properties. The stereocontrolled synthesis of medium sized cyclic ethers continues to be a significant challenge to synthetic chemists. Here, we have demonstrated a convenient and flexible approach to prepare stereochemically well-defined oxepenes based on Bronsted acid-catalyzed [5+2]-annulations of chiral crotylsilanes bearing a primary alcohol. Inspired by the unique structural features of rogiolenyne family of natural products, a highly stereoselective epoxidation and epoxide-ring opening reaction sequence was applied for the rapid access to diversified oxepanes.;Spirocyclic oxindoles are commonly occurring heterocyclic ring systems found in numerous natural products and recent pharmaceuticals. We have developed an efficient protocol for directly accessing spirooxindoles with high diastereo- and enantioselectivity by mild Lewis acid-promoted [5+2]-annulation of chiral silyl alcohols. Enhanced complexity of the spirooxindole scaffold was achieved by employing different combinations of functionalized silyl alcohols and substituted isatin reaction partners. Products were further elaborated to fused polycyclic oxindoles utilizing intramolecular Heck cyclization.