N‐Heterocyclic Carbene Catalysis: Enantioselective Formal [2+2] Cycloaddition of Ketenes and N‐Sulfinylanilines

Abstract

As analogues of both b-sultams and b-lactams, 3-oxo-bsultams (1,2-thiazetidin-3-one 1,1-dioxides), are a novel class of four-membered heterocycles showing interesting biological activities.[1] However, to the best of our knowledge, there is no report for the enantioselective synthesis of these heterocycles.[1a] We envisioned that the 3-oxo-b-sultams could be easily synthesized by oxidation of the corresponding 1,2-thiazetidin-3-one 1-oxides (A), [2] which could be accessed from the [2+2] cycloaddition of ketenes with N-sulfinylamines (Scheme 1).In addition, the cycloadduct A could also undergo a ring opening to give the a-mercapto acid derivatives and bmercapto amines, which are both key structures of bioactive compounds [3] and highly useful chiral reagents or ligands for asymmetric synthesis. [4] In the last several years, we successfully demonstrated that N-heterocyclic carbenes (NHCs) [5] are efficient catalysts for enantioselective reactions of ketenes, [6] including a series of formal [2+2], [3+2], and [4+2] cycloaddition reactions of ketenes with 2-oxoaldehydes, [7] activated ketones, [8] imines, [9] oxaziridines, [10] and heterodienes.[11] Herein we report an NHC-catalyzed enantioselective reaction of ketenes and Nsulfinylanilines to give chiral 1,2-thiazetidin-3-one 1-oxides.After some initial attempts, we were happy to find that ethyl(phenyl)ketene (1 a) and N-sulfinylaniline (2 a) reacted in the presence of 10 mol % of the NHC 4 a' [10a, 12] (generated from the triazolium salt 4 a derived from l-pyroglutamic acid in the presence of 20 mol % of Cs 2 CO 3 ) to give the corresponding 1,2-thiazetidin-3-one 1-oxide (3 aa) in 93 % yield with 96 % ee ( Table 1, entry 1). The NHC 4 b', having a free hydroxy group, also worked for the reaction but resulted in somewhat lower yield (entry 2). The NHC 5', [13] derived from aminoindanol, catalyzed the reaction to give the enantiomer of the cycloadduct in 95 % yield with 99 % ee (entry 3). No significant change in yield or enantioselectivity was observed when the catalyst loading was reduced to 5 mol % (entry 4). Although the yield decreased sharply to 36 %, the excellent enantioselectivity was maintained when 2 mol % of the NHC was utilized (entry 5). Solvent screening with toluene or THF resulted in a small increase of the yield (entries 6 and 7).A dramatic improvement in the yield was realized when 4 molecular sieves (M.S.) were added as the additive. The addition of M.S. may serve to remove trace amounts of water and thus reduce the hydrolysis of the ketene and N-sulfinylamine, thereby resulting in improvement of the yield of the cycloadduct. With the addition of M.S., both enantiomers of Scheme 1. Synthesis and applications of thiazetidinone oxide (A). Entry 4 or 5 (x mol %) [a] Solvent 3 aa Yield [%] [b] ee [%][c]

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…238 Thus, activated α-ketoaldehydes reacted with aryl(alkyl)-disubstituted ketenes to provide β-lactones in good yields (78–99%) and high diastereo-(4:1 to > 20:1 dr) and enantioselectivity (4–99% ee) (Scheme 202). …”

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 .…”