Enantioselective Construction of Pyrrolidines by Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Trimethylenemethane with Imines

Abstract

A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with imines has been developed. Central to this effort were the novel phosphoramidite ligands developed in our laboratories. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of imine acceptors to provide the corresponding pyrrolidine cycloadducts with excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of substituted donors with N-tosyl aldimines and ketimines in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine ligand allows the complimentary synthesis of the exocyclic nitrile product shown, and we demonstrate control of the regioselectivity of the product based on manipulation of the reaction parameters.

Direct Synthesis of Enolizable N‐Sulfonyl Ketimines Under Microwave Irradiation

“…We began our investigation on a model reaction, namely the condensation between acetophenone 1a and p-toluenesulfonamide (Ts-NH 2 ), using Ti(OEt) 4 as both Lewis acid and drying agent. Titanium ethoxide was chosen rather than the commonly used chlorides in order to avoid the HCl formed upon quenching, which can catalyze imine hydrolysis.…”

“…Procedure for the Synthesis of N-Sulfonyl Imines: A 10 mL microwave vial equipped with a stirrer was charged with the ketone (1 mmol), the sulfonamide (1.2 mmol), dry toluene (0.5 mL) and Ti(OEt) 4 (1 mmol). The vial was closed and heated at 150°C for 1 h using microwave irradiation.…”

“…The crucial role of Ti(OEt) 4 was exemplified when Ti(OiPr) 4 Having solved one of the major issues in the synthesis of enolizable ketimines, namely the conversion, we moved to the next problem: product isolation. The kinetic instability of imines often causes low isolated yields even when the conversion is high.…”

“…[1] As a consequence, N-sulfonyl imines, in particular N-tosyl imines, are ubiquitous in organic transformations. To name but a few, they have been used as substrates for cycloadditions, [2][3][4][5][6] aziridines [7] and oxazolines [8] preparations, as well as nucleophilic additions [9][10][11][12] and reductions. [13,14] Due to their widespread use, several methodologies for preparing N-sulfonyl imines have been described.…”

Enantioselective Construction of Highly Substituted Vinylidenecylopentanes by Palladium‐Catalyzed Asymmetric [3+2] Cycloaddition Reaction

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The transition-metal catalyzed [3+2] trimethylenemethane (TMM) cycloaddition reaction is a versatile method for the construction of highly substituted five-membered rings with high chemo-, regio-, and diastereoselectivity.[1] Since 2006, the first asymmetric TMM reactions utilizing a series of chiral phosphoramidite ligands to form substituted carbocycles [2] and heterocycles [3] with high enantioselectivity have been reported.The search for novel TMM donors bearing diverse functionalities represents an important dimension to enhance the power of this methodology. Recently, asymmetric methodologies for cyano- [4] and vinyl-substituted [5] donors to generate tetrasubstituted cyclopentanes with three contiguous stereocenters were reported.

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