Organocatalytic Enantioselective One‐Pot Synthesis and Application of Substituted 1,4‐Dihydropyridines—Hantzsch Ester Analogues

Abstract

An easy and simple one-pot approach for the formation of optically active substituted 1,4-dihydropyridines by using asymmetric organocatalysis is presented. The one-pot reaction of alpha,beta-unsaturated aldehydes with beta-diketones or beta-ketoesters and primary amines gives optically active 2,3-substituted 1,4-dihydropyridines in moderate yields and with enantioselectivities up to 95 % ee. It is also demonstrated that the optically active 1,4-dihydropyridines can be used in situ for the direct enantioselective reduction of, for example, alpha-ketoesters with high enantioselectivity.

H8-BINOL chiral imidodiphosphoric acids catalyzed cyclization reactions of β,γ-unsaturated α-ketoesters, arylamines and 1,3-dicarbonyl compounds: enantioselective synthesis of 1,4-dihydropyridines

“…In 2008, Jørgensen et al successfully used the pyrrolidine catalyst in this reaction and obtained chiral 1,4-dihydropyridines with moderate yields and high enantioselectivities. 9 At the same time, chiral phosphoric acids were applied in this reaction by Gong et al and moderate to good yields and high enantioselectivities were obtained. 10 Not long after, chiral thiourea-ammonium salts and pyrrolidine were used in cyclization reactions of a,b-unsaturated aldehydes and b-enamino esters.…”

“…c o m / l o c a t e / t e t a s y enantioselective syntheses are currently available. [7][8][9][10][11] Besides chiral phosphoric acids catalytic enantioselective Hantzsch reactions 7 and YCl 3 together with chiral silver phosphate catalytic asymmetric aza-Diels-Alder reactions, 8 enantioselective cyclization reactions of a,b-unsaturated aldehydes, primary amines and 1,3-dicarbonyl compounds could effectively produce chiral 1,4-dihydropyridines. In 2008, Jørgensen et al successfully used the pyrrolidine catalyst in this reaction and obtained chiral 1,4-dihydropyridines with moderate yields and high enantioselectivities.…”

“…2). [9][10][11] The substituents at the C-2 and C-6 positions of 1,4-dihydropyridines make a crucial contribution to their conformation and are very important for their biological activities. 1a,c Enones could introduce a substituent at C-6 position directly and afford 1,2,3,4,6-penta-substituted chiral 1,4-dihydropyridines.…”

1,3-Dicarbonyl compounds in stereoselective domino and multicomponent reactions

“…A similar sequence was developed contemporaneously also for the synthesis of enantioenriched dihydropyridines. 124 However, this reaction is not considered as a multicomponent reaction since the addition of the third reagent (primary amine) is not simultaneous but takes place after the formation of the Michael adduct (between a β-ketoester or a β-diketone and an α,β-unsaturated aldehyde). Thus, in this specific case, the term of consecutive reaction is more appropriate.…”

Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation of Enantioenriched Piperidines

“…Several methods have been developed for formal aza [3+3] cycloaddition reactions, such as reactions of 1,3-cyclic sulfonates with C/N dianions, [4] vinylogous amides with a,b-unsaturated iminium ions, [5] and aziridines with Pd-trimethylenemethane complexes.[6] In spite of these formal aza [3+3] cycloaddition methods, and to the best of our knowledge, an enantioselective catalytic version has not been reported.Asymmetric catalytic reactions promoted by organocatalysts is a rapidly growing area of research.[7] Our group developed diarylprolinol silyl ether as an effective catalyst in the Michael reaction, [8] the ene reaction, [9] the Diels-Alder reaction, [10] the tandem Michael/Henry reaction, [11] and the Michael reaction of nitroalkanes.[12] At the time of our first report, the group of Jørgensen also developed the same type of catalyst; [13] the diarylprolinol silyl ether catalyst has been widely used in enantioselective reactions. [14] We have applied diphenylprolinol silyl ether to the reaction of a,b-unsaturated aldehydes with enecarbamates and found that a formal aza [3+3] cycloaddition reaction proceeds in a highly enantioselective manner as reported herein (Figure 1).…”