Catalytic Asymmetric Five‐Component Tandem Reaction: Diastereo‐ and Enantioselective Synthesis of Densely Functionalized Tetrahydropyridines with Biological Importance
TL;DR: The first catalytic asymmetric five-component tandem reactions of β-keto esters, aromatic aldehydes and anilines have been established in the presence of a chiral phosphoric acid, affording densely functionalized tetrahydropyridines with concomitant generation of five σ bonds and two stereogenic centers in high diastereo and enantioselectivities as mentioned in this paper.
Abstract: The first catalytic asymmetric five-component tandem reactions of β-keto esters, aromatic aldehydes and anilines have been established in the presence of a chiral phosphoric acid, affording densely functionalized tetrahydropyridines with concomitant generation of five σ bonds and two stereogenic centers in high diastereo- and enantioselectivities (up to >99:1 dr, 95:5 er). In addition, the first isolation and preparation of a diene species as the key intermediate of the reaction has been successfully realized, leading to the formation of the desired tetrahydropyridine via further condensation with in situ generated imine, which supported the proposed tandem [4+2] reaction pathway to some extent. This protocol not only represents the first enantioselective example of this five-component tandem reaction, but also provides an unprecedented access to enantioenriched tetrahydropyridines with structural diversity, which holds great potential in medicinal chemistry.
Citations
More filters
1,397 citations
TL;DR: In this article, the utility of multicomponent reactions as methods for green synthesis is highlighted and the practical value of these type of reactions for meeting many of the criteria set by the green chemistry philosophy.
873 citations
TL;DR: The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet-Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester.
Abstract: The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet-Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all >95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro-β-carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple quaternary stereogenic centers.
135 citations
TL;DR: The proposed catalyst/substrate interaction shown in Figure 73 corresponds to the related sulfoxidation catalyzed by chiral phosphoric acid PA 5, and an alternative mechanism has been proposed, as discussed in the surrounding text.
Abstract: Figure 73: The proposed catalyst/substrate interaction shown in Figure 73 corresponds to the related sulfoxidation catalyzed by chiral phosphoric acid PA 5 (ref 133). Please note that this interaction will be different for PA 43. Figure 105 and surrounding text: The asymmetric reduction was achieved with 1 mol % (S)-PA 25 (ref ). Figure 176 and surrounding text: For the first example of the application of asymmetric counteranion directed catalysis with phosphoric acid salts as catalysts, see ref 29d. Figure 192: The proposed transition state corresponds to the spiroacetalization catalyzed by chiral phosphoric acid (S)-PA 25 (ref 373). Please note that this will be different for PA 43. Figure 196: The correct substrate used is TMSN3. Please note that an alternative mechanism has been proposed (ref 381), as discussed in the surrounding text. Figure 228: The correct structure of 427 is
130 citations
TL;DR: An organocatalytic asymmetric formal [3+2] cycloaddition of isatin-derived 3-indolylmethanol with 3-methyl-2-vinylindole has been established, leading to highly stereoselective construction of a spiro[cyclopenta[b]indole-1,3'-oxindole] scaffold.
127 citations
References
More filters
3,685 citations
TL;DR: MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures, however, this requires that the chemist learns the "language" of M CRs, something that this review wishes to stimulate.
Abstract: Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.
3,619 citations
2,084 citations
1,801 citations
TL;DR: Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously and has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects.
Abstract: Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.
1,479 citations