Diastereoselective Synthesis of Silyl-Substituted Pyrrolidines

In this paper, we report the synthesis and structural investigation of enantioenriched methylene isosteres of Hayashi-Jørgensen catalysts, and their application in organocatalysis. <i>N</i>-protected pyrrolidines <b>7b</b>-<b>d</b> were prepared in high yields and excellent diastereoselectivity using a new one-pot, four-step synthetic protocol involving: (a) the formation of a silyllithium reagent (<b>1</b>), (b) its addition to a diaryl olefin (<b>2</b>) to generate a silyl-substituted diphenylethyllithium intermediate (<b>3</b>), (c) the highly diastereoselective addition of this intermediate to a chiral sulfinimine (<b>4</b>), and (d) intramolecular cyclization to the desired products. After <i>N</i>-deprotection, the new catalysts <b>8</b> were further evaluated in benchmark Michael additions of aliphatic aldehydes to β-nitrostyrene, under various conditions, demonstrating reactivity and stereoselectivity comparable to the Hayashi catalyst. Notably, the trimethylsilyl derivative (<i>S</i>)-<b>8d</b> showed superior enantioselectivity, transferring its stereochemical information with remarkable efficiency (up to 99% <i>ee</i>). Structural studies through 2D-NMR and DFT calculations revealed different conformational preferences for the corresponding enamines, providing insight into the observed catalytic performance.