Development of Lewis Base Catalyzed Stereoselective Methods for Synthesis of Beta- Lactones and Dyotropic Rearrangements of Tricyclic Beta-Lactones.
Abstract
The recent finding that the FDA-approved antiobesity agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to
pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented upregulation of FAS
in cancer cells makes this enzyme complex an interesting therapeutic target for cancer.
The described route to 3,4-dialkyl- beta -lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facialselective hydrogenation leading to cis-substituted- beta -lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling
opportunities for subsequent transformations of these optically active, reactive
intermediates. Subsequent R-epimerization and R-alkylation or acylation led to trans- beta -
lactones and beta -lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant
form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple
phenyl-substituted cis- beta -lactone, displayed an apparent Ki (2.5 ( 0.5 muM) of only 10- fold lower than that of orlistat (0.28 ( 0.06 muM). In addition, mechanistic studies of the ketene dimerization process by Reaction View infrared spectroscopy support previous findings that ketene formation is rate determining. A highly diastereoselective, nucleophile-promoted bis-cyclization process,
employing readily available and tractable keto-acid substrates, is described. This
methodology provides concise access to bicyclic- and tricyclic-beta-lactones bearing
tertiary carbinol centers and quaternary carbons, greatly extending the scope of previous routes to bicyclic-beta-lactones from aldehyde acid substrates. This and related processes may be revealing a subtle interplay between [2 plus 2] cycloaddition and nucleophilecatalyzed aldol lactonization (NCAL) reaction manifolds. An early induction period in the bis-cyclization of keto-acids is confirmed via isolation of the complex between 4- pyrrolopyridine and Modified Mukaiyama reagent N-propyl-2-bromo pyridinium triflate.
Dyotropic rearrangements of tricyclic keto beta-lactones derived in high yields and
>19:1 diastereoselectivity from readily available 1, 3-dione acids is described. Zn (II) salts were found to be most efficient for affecting dyotropic 1, 2-acyl migrations where
as sub stoichiometric TMSOTf was found to execute a delta-lactone migration providing bis
gamma-lactone in modest yields. Enantioselective desymmetrization with inexpensive (S) - tetramisole has been demonstrated to provide direct evidence of Lewis base involvement in the Nucleophile Promoted Bis-cyclization of keto-acids. Further studies using TsCl as the carboxylate activating agent instead of modified Mukaiyama reagent and catalytic tetramisole are described for achieving practical, catalytic, enantioselective synthesis of beta-lactones from keto-acids. Preliminary studies toward conjugate addition- lactonization pathway provided a hint as to the complexity involved to affect this transformation under the bis-cyclization conditions. An alternate hypotheses concerning the possibility of isomerization-dienolate formation - lactonization is experimentally proven. Additionally, applications of these
and related findings in the intramolecular Morita-Baylis-Hillman reaction with cyclic
ketones have been investigated which provide new avenues of synthetic methodology
development.
Citation
Purohit, Vikram C. (2008). Development of Lewis Base Catalyzed Stereoselective Methods for Synthesis of Beta- Lactones and Dyotropic Rearrangements of Tricyclic Beta-Lactones.. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /ETD -TAMU -2008 -12 -199.