Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts

Abstract

The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-BTM – to pyridinium salts bearing an electron withdrawing substituent in...

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

“…The use of alternative aryl esters was next probed, with pentafluorophenyl ester 2 and bis(trifluoromethyl)phenyl ester 3 giving amide products 7 and 8 in high yield, but with lower enantioselectivity than when using PNP ester 1 (Entries 4 and 5). The use of 2,4,6-trichlorophenyl ester 4 resulted in only 31% yield (Entry 6), which is consistent with previous studies in this field [65,72,76,79], and most likely reflects the increased steric hindrance of the aryloxide attenuating its nucleophilicity. Finally, using PNP ester 1, the catalyst loading could be reduced to 5 mol% with only a small drop in stereoselectivity (Entry 7), while heating the reaction to 40 • C provided a slight improvement in yield (Entry 8).…”

“…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].…”

Organocatalysis: A Tool of Choice for the Enantioselective Nucleophilic Dearomatization of Electron-Deficient Six-Membered Ring Azaarenium Salts

“…Very recently, the group of Smith has studied the synthesis of 1,4-dihydropyridines 120 by addition of aryl ester 105 to N-alkyl pyridinium salts 47 bearing an electron-withdrawing group at the 3-position catalyzed by (R)-BTM isothiourea chiral catalyst C25 (Scheme 37). [78] In the presence of 20 mol% of C25, 1.5 equivalent of DABCO in toluene at 0 °C, the reaction proceeded smoothly to provide several 1,4-addition products in low to moderate isolated yields (29-70%), good diastereoselectivities (80:20 to 95:5 dr) and variable level of enantioselectivity (0-96% ee) (Scheme 37a). For stability purposes, the 1,4addition product 120 bearing a phenolic moiety must be transformed into the corresponding amide prior to purification by treatment of the crude mixture with amine nucleophile (benzyl amine, piperidine, morpholine or N-Boc piperazine) (Scheme 37b).…”

“…In addition, some interesting features were noticed by the authors: 1) contrarywise to most others reported approaches which have been shown to be sensitive to variation of the EWG group of the pyridinium salt, CN, PhSO2 and CO2Et-substituted pyridinium salts were efficient in terms of reactivity and selectivity (except for CO2Et which result in the production of a racemate); (2) the R 1 group must be a benzyl (pyridinium salt with Me substituent being unreactive) presumably to provide stabilization of the transition state thanks to - or cation interactions; (3) the nature of the counter-cation of the pyridinium salt is crucial for the reaction to occur. Non-coordinating anions (BF4 or PF6) were less efficient both in Very recently, the group of Smith has studied the synthesis of 1,4-dihydropyridines 120 by addition of aryl ester 105 to N-alkyl pyridinium salts 47 bearing an electronwithdrawing group at the 3-position catalyzed by (R)-BTM isothiourea chiral catalyst C25 (Scheme 37) [78]. In the presence of 20 mol% of C25, 1.5 equivalent of DABCO in toluene at 0 • C, the reaction proceeded smoothly to provide several 1,4-addition products in low to moderate isolated yields (29-70%), good diastereoselectivities (80:20 to 95:5 dr) and variable level of enantioselectivity (0-96% ee) (Scheme 37a).…”