Phase-Transfer and Ion-Pairing Catalysis of Pentanidiums and Bisguanidiniums

Catalysts accelerate biological processes and organic reactions in a controlled and selective fashion. There are continuing efforts in asymmetric catalysis to develop efficient catalysts with broad reaction scope and industrial practicability. Among the various modes of asymmetric catalysis, phase-transfer catalysis has attracted intense interest due to its facile scale up and low catalyst loading. Chiral quaternary ammonium and phosphonium salts are well-studied classes of chiral phase-transfer catalysts, and they are typically composed of sp³-hybridized quaternary onium salts. In this Account, we describe our recent attempts to develop N-sp²-hybridized guanidinium-type salts as efficient phase-transfer catalysts as well as ion-pair catalysis based on N-sp² hybridized bisguanidinium-type salts. The sp²-quaternized ammonium salts, pentanidiums, which contain five nitrogen atoms in conjugation, displayed remarkable phase-transfer catalytic efficiency. We have shown that pentanidium can catalyze Michael additions of tert-butyl glycinate-benzophenone Schiff bases with various α,β-unsaturated acceptors, such as vinyl ketones, acrylates, and chalcones, in high enantioselectivities. The structurally amendable pentanidium phase-transfer catalysts supply diverse reactivity and selectivity to various other organic transformations, such as α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins. Pentanidium salts are applicable to enantioselective transformations on a preparative scale at low catalyst loading, allowing for the synthesis of a broad range of enantiopure compounds. From computational and experimental results, we also proposed that the halogenated pentanidium catalysts participated in halogen bonding and that this contributed to the excellent stereocontrol in alkylation reactions. Subsequently, we determined that chiral cations can direct functional anions besides basic anions in traditional Brønsted basic phase-transfer reactions, including metal-centered anions. We identified dicationic bisguanidinium as an excellent ion-pairing catalyst, first demonstrating that bisguanidinium formed an ion pair with permanganate and directed the anion in enantioselective dihydroxylation and oxohydroxylation of a,β-unsaturated esters. This initial success led us to explore chiral cationic ion-pairing catalysis as a general mode of catalysis. This mode of catalysis is at the interphase between organocatalysis, phase-transfer catalysis and organometallic catalysis. We then identified bisguanidinium diphosphatobisperoxotungstate and bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pairs as the active catalysts in enantioselective sulfoxidations using aqueous H₂O₂ as the oxidant. The structure of the bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair was elucidated using single-crystal X-ray analysis. Bisguanidinium-catalyzed sulfoxidations emerged as a practical methodology for the synthesis of enantioenriched sulfoxides including armodafinil and lansoprazole, which are commercial drugs. Finally, we are also able to show that pentanidium and bisguanidinium hypervalent silicates are intermediates in enantioselective alkylations using silylamide as a Brønsted probase.