Development of a tandem, three-component synthesis of tetrahydrofurans via silylated beta-lactone intermediates in the tandem Mukaiyama aldol-lactonization
Abstract
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).
Subject
beta-lactonetetrahydrofuran
oxocarbenium
reductive cyclization
tandem
Mukaiyama aldol
radical
Citation
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 https : / /hdl .handle .net /1969 .1 /174656.