Enantioselective Synthesis of α‐Aryl‐β²‐Amino‐Esters by Cooperative Isothiourea and Brønsted Acid Catalysis

Abstract

The synthesis of α‐aryl‐β2‐amino esters through enantioselective aminomethylation of an arylacetic acid ester in high yields and enantioselectivity via cooperative isothiourea and Brønsted acid catalysis is demonstrated. The scope and limitations of this process are explored (25 examples, up to 94 % yield and 96:4 er), with applications to the synthesis of (S)‐Venlafaxine⋅HCl and (S)‐Nakinadine B. Mechanistic studies are consistent with a C(1)‐ammonium enolate pathway being followed rather than an alternative dynamic kinetic resolution process. Control studies indicate that (i) a linear effect between catalyst and product er is observed; (ii) an acyl ammonium ion can be used as a precatalyst; (iii) reversible isothiourea addition to an in situ generated iminium ion leads to an off‐cycle intermediate that can be used as a productive precatalyst.

Enantioselective Synthesis of α‐Aryl‐β2‐Amino‐Esters by Cooperative Isothiourea and Brønsted Acid Catalysis

“…Theabsolute configuration of (S)-13 was determined by single crystal X-ray crystallography,w ith all other products assigned by analogy. [29] This stereochemical outcome is consistent with the expected configuration at C(2) if this process proceeds through aC (1)-ammonium enolate intermediate. [19c] Only the introduction of a4 -nitro-substituent led to the product 17 in reduced yield and enantioselectivity.F urther variation of the arylacetic ester showed that incorporation of substituents at both the 3-position (such as 3,4-dimethoxy-, 3-methoxy-and 3-bromo-to give 18-21)and the 2-position (2-methoxy-and 2-bromo-to give 22-23)gave products with consistently high yields and er.…”

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides

“…Finally, regeneration of catalyst 6, and concurrent release of product 37, is proposed to be facilitated by para-nitrophenoxide 86,87]. Although not essential for reactivity, the addition of Et 3 N as an auxiliary base may be beneficial as a proton shuttle, and to maintain the isothiourea catalyst in its non-protonated form 6 [77,86]. The enantioselectivity of the transformation indicates the C-C bond forming event takes place on the Si-face of the ammonium enolate.…”

“…The enantioselectivity of the transformation indicates the C-C bond forming event takes place on the Si-face of the ammonium enolate. This selectivity can be rationalized through preferential formation of the (Z)-ammonium enolate [76][77][78][79]85], which is conformationally-restricted by an intramolecular 1,5-O• • • S interaction [61,[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104] and results in the phenyl stereodirecting group of the catalyst blocking the enolate Re-face. The observed poor diastereoselectivity can be tentatively rationalized by a simple stereochemical model that assumes a favored, open pre-transition state assembly where steric interactions are minimized about the forming C-C bond.…”

“…In both cases, an isothiourea-derived C(1)-ammonium enolate is intercepted by an electrophilic transition metal complex to affect an allylation or benzylation reaction. We have expanded the scope of electrophiles applicable within this catalyst turnover strategy to include iminium ions generated under either photoredox conditions or Brønsted acid catalysis, as well as bis-sulfone Michael acceptors, and pyridinium salts (Scheme 1e) [76][77][78][79]. Recently, Waser also reported an elegant example of this turnover strategy for the enantioselective α-chlorination of pentafluorophenyl esters [80], while Zheng and co-workers reported a related approach using diphenyl methanol as an external turnover reagent for the fluorination of carboxylic acids [81,82].…”

Design, Synthesis, and Application of Chiral Bicyclic Imidazole Catalysts

“…Tertiary amine catalysts can be classified by the catalytic skeleton bearing an sp 3 - N atom or sp 2 - N atom. The catalysts bearing a catalytic sp 3 - N atom mainly include quinuclidine and dimethylalkyl amine, while the catalysts bearing a catalytic sp 2 - N atom include dimethylaminopyridine (DMAP), N -methylimidazole (NMI), amidine, etc. (Figure ).…”