Aryloxide-facilitated catalyst turnover in enantioselective α,β-unsaturated acyl ammonium catalysis

The authors thank the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) ERC grant agreement no. 279850 (A.D.S) and the EPSRC (EP/J018139/1, A.M.) for funding. A.D.S. thanks the Royal Society for a Wolfson Research Merit Award.A new general concept for α,β-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,β-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,β-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79% yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.Publisher PDFPeer reviewe

Four into One: Organocatalyzed Stereoselective Conjugate Addition of Unprotected and Unactivated Carbohydrates

This paper proposes a new and stereoselective access to glycosides. This operationally simple approach achieved via base-catalyzed conjugate additions of unprotected and unactivated carbohydrates to activated alkenes or alkynes is described

Aryloxide-facilitated catalyst turnover in enantioselective α,β-unsaturated acyl ammonium catalysis

A new general concept for α,β-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,β-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,β-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79% yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics

Enantioselective stereodivergent nucleophile-dependent isothiourea-catalysed domino reactions

α,β-Unsaturated acyl ammoniums generated from the reaction of α,β-unsaturated 2,4,6-trichlorophenol (TCP) esters bearing a pendent enone with an isothiourea organocatalyst are versatile intermediates in a range of enantioselective nucleophile-dependent domino processes to form complex products of diverse topology with excellent stereoselectivity. Use of either 1,3-dicarbonyls, acyl benzothiazoles, or acyl benzimidazoles as nucleophiles allows three distinct, diastereodivergent domino reaction pathways to be accessed to form various fused polycyclic cores containing multiple contiguous stereocentres

Data underpinning - Enantioselective Stereodivergent Nucleophile-Dependent Isothiourea-Catalyzed Domino Reactions

All FID of 1H and 13C NMR spectra, HPLC data and other analytical data for compounds produced in this manuscrip

Unanticipated Silyl Transfer in Enantioselective α,β-Unsaturated Acyl Ammonium Catalysis Using Silyl Nitronates

We thank the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013), ERC Grant Agreement 279850 (A.D.S.), the EPSRC (EP/J018139/1, A.M.), and the Royal Society of Chemistry (Researcher Mobility Grant). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. D.W.L. thanks the Australian Research Council for a Discovery Award (DP170103567). We also thank the EPSRC UK National Mass Spectrometry Facility at Swansea University.The use of silyl nitronates is reported for the isothiourea-catalyzed synthesis of γ-nitro-substituted silyl esters containing up to two contiguous stereocenters in good yields with excellent enantioselectivities (up to 93% yield and 99:1 er). The serendipitously discovered formation of silyl ester products in this reaction demonstrates a novel platform for catalyst turnover in α,β-unsaturated acyl ammonium catalysis.PostprintPeer reviewe

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance