Enantioselective Synthesis of 2,2‐Disubstituted Tetrahydrofurans: Palladium‐Catalyzed [3+2] Cycloadditions of Trimethylenemethane with Ketones

Abstract

An approach to 2,2-disubstituted 4-methylenetetrahydrofurans has been developed utilizing a cycloaddition of trimethylenemethane with aryl ketones, with formation of the products in up to 96% yield and 95% ee. The reaction is catalyzed by palladium in the presence of a phosphoramidite ligand possessing a stereogenic phosphorus, where only a single epimer at phosphorus yields the active catalyst. The identity of this epimer and the origin of its effect on reactivity are discussed. Keywords trimethylenemethane cycloaddition; tetrahydrofuran synthesis; asymmetric catalysis; phosphoramiditeFound throughout nature and in synthetic products, tetrahydrofurans are a ubiquitous structural motif with wide-reaching biological activity. Among the many approaches towards their synthesis, [1] cycloaddition represents a powerful and attractive strategy, [2] but catalytic enantioselective variants remain rare. [3,4] We recently disclosed one such approach involving the palladium-catalyzed cycloaddition of trimethylenemethane (TMM) with aldehydes. [4c] In this Communication, we describe the surprising success of this method in reactions with aromatic ketones, a substrate class that was previously unknown in Pd-TMM reactions using achiral ligands.First discovered over 30 years ago, [5] the palladium-catalyzed TMM cycloaddition is a versatile method for the synthesis of 5-membered rings. [6] The recent discovery that bulky phosphoramidites are effective chiral ligands has stimulated a fresh examination of Pd-TMM chemistry, leading to highly enantio-and diastereoselective cycloadditions with olefins, [7] imines, [8] and tropones. [9] A hallmark of the phosphoramidites used in these studies is an improved catalytic activity when compared to the achiral ligands used previously, allowing for reactions with highly substituted acceptors such as tetrasubstituted olefins [7b] and ketimines [8b,c] under mild conditions. However, these substrates required a TMM precursor bearing a cyano group in order to obtain high ee. [10] Given our earlier success with cycloadditions of aldehydes, we wondered whether more complex and less reactive carbonyl groups might also function in the asymmetric TMM cycloaddition, despite the fact that racemic reactions with ketones are relatively challenging and quite limited. [11,12] The reduced reactivity of the ketone coupled with the presence of relatively acidic protons [13] undoubtedly prevents a more general synthetic scope. Further, aliphatic aldehydes were not tolerated under the asymmetric conditions, presumably due to the presence of α-protons. An additional challenge involves enantioselectivity, since enantioface differentiation of ketones was expected to be more difficult than with the corresponding aldehydes. Nevertheless, such a reaction would provide rapid access to enantioenriched 2,2-disubstituted tetrahydrofurans, an important structural component [14] that is found, for example, in the antifungal drug posaconazole (1, Figure 1). [15] Despite these concerns, initial tests usin...

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N-Phosphorylated Pyrrolidines: An Overview of Synthetic Approaches

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Enantioselective Palladium‐Catalyzed [3+2] Cycloaddition of Trimethylenemethane and Fluorinated Ketones

“…[7] Despite the development of elegant strategies to access chiral trifluoromethyl-substituted tertiary alcohols, methods that directly assemble 2,2-disubstituted dihydrofurans in asingle step from available fluorinated ketones would be of high interest (Scheme 1B). [8] Our group has al ong-standing interest in [3+ +2] cycloadditions of trimethylenemethane (TMM) donors with electron-deficient acceptors. [9] Recently,w eh ave demonstrated that the s-electron-withdrawing properties of the CF 3 group could be used to promote the [3+ +2] cycloaddition, affording cyclopentanes bearing aq uaternary center, albeit without absolute control of chirality (Scheme 1C).…”