Asymmetric Synthesis of Methylenetetrahydrofurans by Palladium-Catalyzed [3 + 2] Cycloaddition of Trimethylenemethane with Aldehydes – A Novel Ligand Design

“…Because the BINOL derivative in L1 is unsymmetric, the ligand is chiral at phosphorus (R P and S P ). In our previous work, [4] we found that only a single diastereomer of L1 was active. Thus, the chirality at phosphorus serves as a unique control element for the reactivity of the catalyst, a phenomenon which to the best of our knowledge has not been previously described in the chemical literature.…”

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confidence: 74%

“…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] Herein, we describe the surprising success of this method in reactions with aromatic ketones, a substrate class which was previously unknown in Pd/TMM reactions using achiral ligands.…”

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confidence: 99%

“…Thus, the chirality at phosphorus serves as a unique control element for the reactivity of the catalyst, a phenomenon which to the best of our knowledge has not been previously described in the chemical literature. By appropriate selection of the reaction conditions, [4] we were able to synthesize L1 in < 1: > 20 d.r., and the major (and active) diastereomer appears to possess the R,R,R,S P configuration based on its 31 P NMR spectrum, since the major signal (at d = 144.2 ppm) appears upfield of the minor signal (at d = 148.0 ppm). [17] Although we were unsuccessful in crystallizing L1 directly, this assignment is corroborated by X-ray crystal analysis of L4 (see the Supporting Information), which clearly depicts the S P configuration and also shows the major diastereomer (at d = 148.9) upfield of the minor diastereomer (at d = 149.6) in the 31 P NMR spectrum.…”

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confidence: 99%

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

Trost

Bringley

2013

Angewandte Chemie

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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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“…Recently, Trost and co-workers coupled trimethylenemethane with aromatic aldehydes and ketones in a palladium catalyzed process leading to methylene tetrahydrofuran structures in good yield (Scheme 59). 209,210 Excellent enantioselectivity could be obtained using chiral phosphoramidite ligands. Other possible 1,3-dipole equivalents are 3-chloropropylphenylsulfones or sulfoxides, activated by a Brønsted base, used by the group of Mąkosza to form trans-2,3 disubstituted oxolanes.…”

Section: Other Annulation Reactionsmentioning

confidence: 99%

Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis

et al. 2016

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Mousseron. His research interests include the total synthesis of oxygenated cyclic and non cyclic metabolites of polyunsaturated fatty acids, mainly leukotrienes, iso-, phyto-and neuroprostanes, as well as dihydroxylated PUFAs and more recently lipophenols and the understanding of the role of such bioactive lipids and lipophenols by developing collaborations with chemists, biochemists, biologists and clinicians across the world. Jean-Marie Galano studied chemistry at Paul Cézanne Université Marseille and obtained his PhD under the supervision of Honoré Monti in 2001. He then moved to the University of Oxford to pursue a postdoctoral fellowship with David H. Hodgson on the development of new methods for the total synthesis of natural products. In October 2005 he joined the CNRS as a Chargé de Recherche at Université of Montpellier. His research focuses on the total synthesis and discovery of new lipid metabolites, and to discover their potential implications in human health. AbstractMany natural products contain tetrahydrofuran (THF) moieties. Those molecules, often biologically active, may be structurally diverse, e.g. cis or trans THF, mono-, di-, tri-or tetrasubstituted on the furan ring. Thus, the construction of THF is of great interest for the community of organic chemists; especially in developing new methodologies, and applying them in the total synthesis of natural products. The aim of this review is to report recent advances in the field of THF synthesis, as well as the application of these methods to the synthesis of bioactive compounds.

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Asymmetric Synthesis of Methylenetetrahydrofurans by Palladium-Catalyzed [3 + 2] Cycloaddition of Trimethylenemethane with Aldehydes – A Novel Ligand Design

Cited by 75 publications

References 25 publications

Enantioselective Palladium-Catalyzed [3 + 2] Cycloadditions of Trimethylenemethane with Nitroalkenes

Enantioselective Palladium-Catalyzed [3 + 2] Cycloadditions of Trimethylenemethane with Nitroalkenes

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

Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis

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