Aryloxide‐Facilitated Catalyst Turnover in Enantioselective α,β‐Unsaturated Acyl Ammonium Catalysis

Abstract

A new general concept for α,β‐unsaturated acyl ammonium catalysis is reported that uses p‐nitrophenoxide release from an α,β‐unsaturated p‐nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea‐catalyzed Michael addition of nitroalkanes to α,β‐unsaturated p‐nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β‐unsaturated p‐nitrophenyl ester, and a recently reported variable‐time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

The Importance of 1,5‐Oxygen⋅⋅⋅Chalcogen Interactions in Enantioselective Isochalcogenourea Catalysis

“…[18a] Isourea 1-O gave the desired lactone 29 in am oderate 46 %y ield and 87:13 dr, but with negligible enantiocontrol (53:47 er). Catalysis using either 1-S or 1-Se was again effective,y ielding 29 in 80 %y ield, 84:16 dr, and 95:5 er when using 1-S,a nd 95 %y ield, 84:16 dr, and 98:2 er when using 1-Se.A gain, as ignificant increase in the rate of product formation (30)was observed using 1-Se (t 1/2 = 11 min) compared to 1-S (t 1/2 = 122 min) when the reaction was monitored by 19 F{ 1 H} NMR spectroscopy ( Figure 6B).…”

“…[29] To determine whether intramolecular 1,5-O···Ch interactions govern catalysis beyond acyl transfer processes,t he activity of the 1-Ch series was examined in reactions proposed to proceed via a,b-unsaturated acyl isothiouronium and C(1)isothiouronium enolate intermediates ( Figure 1A,center and right). [30,18] Thei sochalcogenourea-catalyzed Michael addition of nitromethane to ester 23 gave the amide product in less than 5% yield and 45:55 er when 1-O was used ( Figure 6A). In contrast, both the 1-S and 1-Se catalysts gave 24 in 55 %y ield and ca.…”

Aryloxide‐Facilitated Catalyst Turnover in Enantioselective α,β‐Unsaturated Acyl Ammonium Catalysis

“…Reduction of g-nitro methyl esters 15, 29 and 31 and subsequent cyclization was achieved with no loss in enantiopurity to give pyrrolidinone derivatives 32-34 in excellent yield and highly enantioenriched form (Table 4). [19] The biological importance of pyrrolidinones,and g-aminobutryric acid (GABA) derivatives in general, is well precedented. [20] To provide greater insight into this methodology,t he reaction mechanism and kinetics were investigated to identify reaction intermediates and determine the reaction order with respect to each component.…”

“…[20] To provide greater insight into this methodology,t he reaction mechanism and kinetics were investigated to identify reaction intermediates and determine the reaction order with respect to each component. Quantitative reaction monitoring was achieved by in situ 19 F{ 1 H} NMR spectroscopy using 19 Flabeled PNP ester 35 and (2R,3S)-8F-HyperBTM 36 in MeNO 2 using PhF as internal standard and aC 6 D 6 -filled capillary reference (Figure 1a,b). Attempts to interrogate the kinetic data revealed as ubstantial reduction in reaction rate over the course of the reaction, suggesting deactivation of the catalyst.…”

“…Thea bsolute configuration of 19 was confirmed by single crystal X-ray analysis, with all other examples assigned by analogy. [17] Limitations of this methodology include incompatibility of substrates such as g-keto ester derivative 22,w hich gave ac omplex mixture of products,a nd cinnamic acid derivative 23,w hich was completely unreactive.Aderivative bearing b-alkyl substitution however gave product 21 with excellent enantiocontrol, albeit in low yield. Thesynthesis of aquaternary stereogenic carbon centre was also attempted, however application of b,bdisubstituted derivative 24 failed to give the desired Michael addition product.…”