Novel Multi-component Reactions Based On Ylide Trapping And Exploration Of Selectivity Control

Multi-component reactions (MCRs) provide an efficient methodology for the synthesis of complex, polyfunctional compounds from simple materials (three or more starting materials), and offer an efficient starting point for the construction of diverse, complex molecules with improved atom economy. Selectivity control is the greatest challenge in MCRs. It is difficult to achieve an ordered, sequential assembly of the substrates in the reaction system and smoothly deliver the target compounds.In this work, we have designed and realized a series of novel MCRs based on trapping two types of active ylides through an asymmetric, co-catalytic strategy and exploration of selectivity control. The first approach used ammonium-ylide-trapping aldol, Mannich and Michael-type MCRs; the second used onium-ylide-trapping domino MCRs; the third used exploration of selectivity control.First of all, we developed the ammonium-ylide-trapping aldol, Mannich and Michael-type MCRs.We have developed RhⅡ/ZrⅣ-co-catalyzed asymmetric three-component reactions that combine aryl diazoacetates, amines and aldehydes. The reaction provides a convenient and highly enantioselective route to the construction of an important class of compounds for both organic and medicinal chemistry; namely, a-amino-β-hydroxy acid derivatives containing chiral tetrasubstituted carbon centers. Using the Rh(Ⅰ) catalyst in the three-component Mannich-type reaction of a-alkyldiazo esters, amines, and aromatic aldehydes, a-amino-β-hydroxy acid derivatives were obtained with high diastereo-selectivity. Additionally, diazo compounds were successfully converted into a-alkyldiazo esters.The use of a synergistic catalysis strategy using an intriguing Rh2(OAc)4and chiral Brφnsted acid co-catalyzed three-component Mannich-type reaction between a diazo compound, a carbamate, and an imine provides rapid and efficient access to both a, β-diamino acid derivatives with a high level of control of chemo-, diastereo-, and enantio-selectivity (up to93%yield,>99:1dr and99%ee). By the judicious choice of chiral phosphoric acid catalysts combined with differentially sterically substituted3,3-BINOL components, the diastereoselectivity can be inverted and each of the four stereoisomers of the a,p-diamino esters could be made at will. The novel, easily deprotected carbamate was initially evaluated in ammonium-ylide-based MCRs. In addition, a highly enantioselective trapping of protic phosphoramidate ammonium ylides with a-imino esters is reported; it is based on the Rh2(OAc)4and chiral Brφnsted acid system. The Rh2(OAc)4and chiral Brφnsted acid co-catalyzed three-component Mannich-type reaction between a diazo compound, a phosphoramidate, and an a-imino ester provides rapid and efficient access to2,3-diaminosuccinic acid derivatives with a high degree of diastereo-and enantio-selective control. It also provides an opportunity to fine tune the stereoselectivity by adjusting the side chain of the phosphoramides. Furthermore, imines derived from aromatic aldehydes were successfully converted to alkyl aldehydes, which have both scientific and practical significance in drug discovery.We describe the first application of the three-component Michael-type reaction for trapping ammonium ylides with β-nitrostyrenes. With Rh(Ⅰ) and metal-organic molecule catalysis, a,y-amino acid derivatives were obtained with high chemo-and diastereo-selectivity.Secondly, we developed novel domino MCRs based on trapping onium ylide.Based on the synergistic catalysis strategy using Rh2(OAc)4and the chiral Brφnsted acid co-catalyzed three-component Mannich-type reactions described, we designed an asymmetric four-component domino reaction. A ruthenium complex/chiral Brφnsted acid system was developed for the enantioselective synthesis of fully substituted tetrahydroisoquinolines in moderate yields and with high stereoselectivities.Similarly, oxonium ylides could be also trapped in the novel domino reactions. A domino cyclization/three-component reaction of2-alkylaryaldehydes with diazo compounds and alcohols is described, which affords isochromenes using metal-metal synergistic catalysis. The reaction could not be achieved using traditional monocatalysts. Using a control reaction, we indirectly proved that the domino reaction occurs via a process of cyclization/ylide trapping.We describe the development of the first oxonium-ylide-trapping, intramolecular three-component Michael-aldol-type cascade reaction of an oxonium ylide, formed from a metal carbene and an alcohol, and an electrophile through a delayed proton-transfer process. The intermediate obtained can be successfully trapped by another electrophile or electrophilic group, and the delayed proton-transfer process. In a promising pathway to chirality induction, this MCR was used to construct optically pure, functionalized,1-indanol derivatives containing multiple chiral centers, with complete stereocontrol (>20:1dr). In addition, through a deuterium-labeling experiment, we proved that the domino reaction was a concerted process.In the end, we addresses three types of synergistic catalysis systems for the synthesis of a-hydroxy-β-amino, a-amino-β-amino, and a-amino-β-hydroxy ester derivatives with high stereoselective control, using the same three starting materials: diazo compounds, aromatic aldehydes, and amines. Through the use of the synergistic metal-organic catalysis strategy, a-hydroxy-β-amino and a-amino-β-amino ester derivatives were obtained with>20:1dr and85-96%ee. The methodology not only offers an effective approach to constructing stereochemically complex and structurally diverse amino acid compounds, but also provides an insight into the construction of biological macromolecules in Nature.