Total synthesis of leucascandrolide A and apicularen A and synthesis of natural product-like macrodiolides

An efficient and reliable method has been developed to synthesize 2,6-substituted dihydropyrans through the strategy of [4+2] annulation of enantiomerically enriched syn-allylsilanes with aldehydes. A turnover of stereoselectivity was observed with the change of the protecting group on the primary alcohol of silane reagents. Mechanistic interpretations for this turnover were discussed. Stereocontrolled synthesis of both 2,6-cis- and 2,6- trans-dihydropyrans was carried out using syn-allylsilanes with the appropriate choice of protecting groups. This methodology was utilized in the total syntheses of the complex natural products leucascandrolide A and apicularen A.; The total synthesis of leucascandrolide A was achieved and highlighted by an efficient and stereocontrolled formation of an advanced bis -tetrahydropyran intermediate. The synthesis of the C1-C16 fragment relies on two consecutive [4+2] annulations of a chiral allylsilane and crotylsilane, respectively. Macrolactonization of the acyclic intermediate was achieved via a documented macroacetalization and oxidation sequence. Union of the macrolide and an oxazole-containing side chain using the Mitsunobu esterification method concluded the total synthesis of leucascandrolide A.; The total synthesis of apicularen A also demonstrates the utility of our organosilane based pyran annulation methodology. The synthesis of the C1-C15 fragment involved a [4+2] annulation of an allylsilane to afford a 2,6-trans-dihydropyran, followed by subsequent diastereoselective epoxidation and a regioselective reductive opening of epoxide to install the C11 hydroxyl group. The macrolactone of apicularen A was obtained using a sodium hydride (NaH)-promoted transesterification of an acyclic hydroxyl cyanomethylester. The final appendance of the enamide side chain to the macrolide employing copper(I) thiophene-2-carboxylate (CuTC)-catalyzed coupling of vinyl iodide and unsaturated (Z,Z)-conjugated amide completed the total synthesis of apicularen A.; Rapid generation of complexity was achieved by the cyclodimerization of enantiomerically enriched hydroxyl methyl esters, which led to the formation of macrodiolides. The synthesis of diverse chiral starting hydroxyl esters was carried out employing highly stereoselective condensations of aldehydes and functionalized (E)-crotylsilane reagents. Cyclodimerizations of these chiral building blocks were accomplished via a transesterification catalyzed by Otera's distannoxanes to produce a collection of 14-, 16- and 22-membered macrodiolides.