Enantioselective Synthesis of Axially Chiral Tetrasubstituted Allenes via Lipase-Catalyzed Desymmetrization

Abstract

Lipase from Pseudomonas fluorescens efficiently catalyzes the transesterification of prochiral tetrasubstituted allenic diols yielding highly enantioenriched axially chiral allenyl monoesters. In combination with subsequent 5-endo-trig cyclizations geminally disubstituted dihydrofurans are accessible in high optical purity.In constant search of highly selective protocols for the preparation of optically pure chiral molecules, organic chemists have shown growing interest in the use of biocatalysts 1 -and lipases in particular 2 -to accomplish this ever-demanding task. Naturally designed to break down fats and thus well adjusted to perform in a hydrophobic environment, lipases offer a high tolerance towards nonaqueous media and provide considerable activity and stability in strictly organic solvent systems. 3 But by far the most striking features are the remarkably broad acceptance of different substrate structures and the variety of transformations catalyzed by this class of enzymes. 2,4 In quest of novel, synthetically valuable, nonclassical targets for biocatalytic investigations, we and others became interested in the use of allenes as potential hydrolase substrates and in recent years, a number of successful procedures for the enzymatic kinetic resolution of axially chiral allenic derivatives have been reported. 5 Though being an efficient and preparatively simple approach to obtain optically active compounds, resolution always comprises a yield limitation of 50% of the enantiopure material. To address this issue, we recently presented an alternative approach by employing prochiral allenic diols. 6 Using lipase from porcine pancreas, the enantioselective desymmetrization proceeded smoothly and axially chiral allenyl esters were isolated in high yield and with excellent enantiopurity.Based on our studies regarding the desymmetrization of trisubstituted allenic diols, our aim was to further investigate the extended substrate scope of this reaction and in particular, turn our attention to related tetrasubstituted derivatives. Hence, a series of allene diols 2 were prepared from propargylic acetate precursors 1a-c in moderate to good yields (Scheme 1). Depending on the desired substitution pattern, the synthesis was accomplished by either S N 2′-type substitution using alkyl cuprates 7 or through a palladium-catalyzed Tsuji-type coupling with the respective arylzinc nucleophiles, 8 followed by acid-catalyzed acetonide cleavage. Scheme 1 Synthesis of tri-and tetrasubstituted allenic diolsWith the diol substrates in hand, we turned our attention to the intended biocatalytic transformation. As lipase from porcine pancreas (PPL) proved to be well suited for this purpose in the desymmetrization of trisubstituted allenes we supposed that this enzyme would also be able to catalyze transesterifications of related tetrasubstituted substrates to some extent. However, under the conditions elaborated before, using vinyl butyrate as acyl donor in 1,4-dioxane at 40°C, the reaction with diol 2b proceeded sluggishly, and after th...

Pd((R)-DTBM-SEGphos)Cl2-catalyzed kinetic resolution of tertiary propargylic alcohols

“…7 e On the other hand, due to the axial allenes serving as versatile precursors in organic transformations and material science, 8 development of expeditious paths for constructing optically active tetrasubstituted allenes has been receiving increasing attention in the synthetic community. Representative catalytic methods for axially chiral tetrasubstituted allenes 9,10 are as follows (Scheme 1b): (a) direct asymmetric functionalization of trisubstituted allenes. 9 f–i These reported strategies are generally based on the formation of allenic carbanion analogues through the deprotonation of trisubstituted allenes to react with electrophiles, which demand the potential acidity of trisubstituted allenes such as trisubstituted allenoates and allenamides.…”