Development of a tandem, three-component synthesis of tetrahydrofurans via silylated beta-lactone intermediates in the tandem Mukaiyama aldol-lactonization
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Although initial attempts to convert (R)-4-trichloromethyl-β-lactone to ketoaldehydes or keto-β-lactones for stereoselective tetrahydrofuran (THF) synthesis were unsuccessful, several novel transformations of this malic acid surrogate were discovered. Radical alkylations and α-silylations of optically active (R)-trichloromethyl- 2-oxetanone are described that maintain the integrity of the β-lactone. Alternate methods for selective dechlorinations of both the β-lactone and the derived Weinreb amide are presented. The development of a diastereoselective, three-step strategy for the construction of substituted tetrahydrofurans from alkenyl-aldehydes based on the tandem Mukaiyama aldol-lactonization (TMAL) process and Mead reductive cyclization of keto-β-lactones is reported. Stereochemical outcomes of the TMAL process are consistent with models established for Lewis acid-mediated additions to α-benzyloxy and β-silyloxy aldehydes while reductions of the five-membered oxocarbenium ions are consistent with Woerpel’s models. Further rationalization for observed high diastereoselectivity in reductions of α- silyloxy five-membered oxocarbenium ions based on stereoelectronic effects is posited. A diagnostic trend for coupling constants of γ-benzyloxy-β-lactones was observed that should enable assignment of the relative configuration of these systems. A single stereocenter generates as many as two C-C bonds, one C-O bond, and three stereocenters in a single reaction leading to substituted tetrahydrofurans (THFs) in a three-component process. This process utilizes the tandem Mukaiyama aldollactonization (TMAL) and proceeds through a silylated β-lactone intermediate. The results build on Mead’s reductive cyclization (MRC) of keto-β-lactones and are in accordance with Woerpel’s model for “inside attack” of oxocarbenium ions. Application to a THF fragment of colopsinol B is described. A universal model was set forth that rationalizes the stereochemical outcome of the reaction between α- and β-substituted aldehydes and (E)- and (Z)-substituted ketene acetals in the ZnCl2-mediated tandem Mukaiyama aldol-lactonization (TMAL).
Mitchell, Timothy Andrew 1979- (2008). Development of a tandem, three-component synthesis of tetrahydrofurans via silylated beta-lactone intermediates in the tandem Mukaiyama aldol-lactonization. Doctoral dissertation, Texas A & M University. Available electronically from