New synthesis methodology for the formation of 1,1-disubstituted allenes and iron-mediated [2+2+1] carbocyclizations: Applications for the total synthesis of (+)-ileabethoxazole.

摘要

Development of novel reagents that allow bidirectional molecular construction through a sequential reactions at each reactive center has received significant attention over the last two decades. Efforts within Williams research laboratories has culminated in the development of several such reagents. Our studies have developed novel 1-trialkylsilyl-substituted-propargyl stannane reagents and have described their bifunctional utility. A 1-trimethylsilyl-3-(tri- n-butylstannyl)-1-propyne is shown to undergo regioselective Stille crosscouplings with variety of alkenyl iodides to exclusively form 1,1-disubstituted allenylsilanes. Preliminary mechanistic studies suggest possibility of interconversions of eta1 propargyl palladium complex and eta1 allenyl palladium complex prior to reductive elimination step. Remarkably, a switch in the regioselectivity was achieved through the use of 1-triisopropylsilyl-3-(tri- n-butylstannyl)-1-propyne reagent that produce skipped enyne isomers selectively. Lewis acid-catalyzed SE' reactions of 1,1-disubstituted allenylsilanes are described which has established a useful bifunctional utility for 1-trimethylsilyl-3-(tri- n-butylstannyl)-1-propyne. Our efforts have also detailed preparation and applications of 3-(tri-n-butylstannyl)-2-bromo-1-propene, in a radical-based alkylation reactions.;Iron-mediated [2+2+1] carbonylation of 1,1-disubstituted allenes has been developed which occur under extraordinarily mild conditions. A highly functionalized 4-alkylidene-2-cyclopenten-1-one are accessed stereoselectively and in excellent yields. Our studies describe characterization of reaction-competent, three-membered metallacycle exhibiting regio- and stereoselective tetracarbonyliron and allene complexation. A detailed kinetic analysis and computational studies have provided insights leading to a stereoselective mechanistic pathway, which has not been described before.;An intramolecular application of iron-mediated [2+2+1] carbonylation has led to the successful completion of the first total synthesis of (+)-ileabethoxazole, a potent inhibitor of Mycobacterium tuberculosis, via an efficient 20 linear step sequence. An effective preparation of the alkyl-substituted allenes is achieved via Stille cross-couplings of propargylic stannane. A subsequent intramolecular [2+2+1] carbonylation of allene-yne provides expeditious entry into the 5,6-ring of ileabethoxaole. Our studies describe useful substitutions at C2, C4 and C5 positions of intact oxazoles. A modification, introducing the use of (S)-H8-BINAP, in the preparation of hydridocopper species for 1,4-conjugate reductions offer improved selectivity for the asymmetric reactions of indenones. Finally, our synthetic strategy offers a well-suited route for the generation of focused libraries, and studies entailing the antitubercular activity of these marine heterocycles.