Chiral N-Heterocyclic Carbene Catalyzed Staudinger Reaction of Ketenes with Imines:  Highly Enantioselective Synthesis of N-Boc β-Lactams

Abstract

N-heterocyclic carbenes (NHCs) were demonstrated to be efficient catalysts for the Staudinger reaction of ketenes with N-tosyl, N-benzyloxycarbonyl, or N-tert-butoxycarbonyl imines. Chiral NHC 8b, conveniently prepared from L-pyroglutamic acid, catalyzed the reactions of arylalkylketenes with a variety of N-tert-butoxycarbonyl arylimines to give the corresponding cis-beta-lactams in good yields with good diastereoselectivities and excellent enantioselectivities (up to 99% ee). Two possible catalytic pathways, initiated by the addition of NHC to ketenes or imines, were discussed.

Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates

“…1a, for example, Benzoin condensation 21 and the Stetter reaction 22,23 ). NHCs can also react with acyl halides/anhydrides/esters 24,25 , electron-deficient olefins 26,27 and ketenes 28,29 , forming either highly reactive acylating agents or Baylis-Hillman-type intermediates through a nucleophilic addition reaction (Fig. 1b,c) 30 .…”

Investigation of the Role of Electrogenerated N-Heterocyclic Carbene in the Staudinger Synthesis in Ionic Liquid

“…In fact, it seems that in these conditions (disubstituted ketene and electrophilic imine in aprotic solvent) a NHC activation of ketene is probable, as confirmed by Ye and coworkers, [16] while the reaction NHC-electrophilic imine leads to a stable adduct (in some cases isolated). On the other hand, Wilhelm and coworkers [38] add all reagents (N-pNs imine, ketene and NHC) in toluene and obtain the desired -lactam, proposing that both activation of ketene and of imine are, in principle, possible and their studies could not rule out one of them.…”

“…In fact, recently the "non innocent" nature of imidazolium ILs has been described by many authors, [6,7] as, in particular experimental conditions, these cations can give rise to the formation of Nheterocyclic carbenes (NHC). NHC can be easily prepared by deprotonation of imidazolium cations [8] not substituted in the 2-position (Scheme 1) [9][10][11][12][13][14][15][16][17].…”

“…N-Heterocyclic carbenes have been frequently used in organic chemistry as ligands and, more recently, as organocatalysts [18][19][20][21] in many reactions, such as the annulation of enals and sulfonylimines, [10,11] the Aza-Morita-Baylis-Hillman reaction of cyclic enones and N-tosylimines, [12] the benzoin condensation, [9,13] the Stetter reaction, [9,13] the Mannich Reaction [15] and the Staudinger reaction [16,17]. These stabilized singlet carbenes behave as nucleophilic organic catalysts, due to the presence of p-donor heteroatoms adjacent to the divalent carbon atom [22].…”

“…However, usually this is a reaction that needs catalysis. [35][36][37] Among the catalysts, NHCs have been recently used in the Staudinger synthesis [10,16,17,[38][39][40] starting from highly electrophilic imines (e.g., N-Boc, N-Ts and N-pNs imines). These reactions are successfully carried out in classical VOCs, using a disubstituted ketene (pre-prepared) and an electrophilic imine, in the presence of an NHC as organocatalyst.…”