Final Report Summary - SEQ-MCR (New Sequential Multicomponent Reactions)
Development of selective, safe, ecologically benign, resource effective, atom economical, operationally simple and readily scalable processes has been at the forefront in the quest for ideal organic synthesis. Multicomponent reactions (MCR) tend to fulfill many of the stringent criteria of ideal organic synthesis. MCRs have attracted a considerable attention of organic chemists in recent times. These valuable methodology encompasses several criteria; e.g. minimum use of solvent and reagents, minimum of operation (a single or no purification step), atom-economy and of course step-economy and finally possible automation of the process when efficient. The consequences are immediate, reducing the time-costs of operators and when applied to large scale processes, they constitute one of the best environmentally benign approaches for organic synthesis. These different reasons make clear why pharmaceutical and agrochemical companies have been at the onset of these developments, with MCR allowing the everyday preparation of large collections of drug candidates as well as high throughput screening of thousands of lead compounds.The MCR strategy is thus used as a powerful tool to prepare complex molecules with multiple bonds formation in a single operation, which is of paramount importance in contemporary organic synthesis. As the principle objective of this research program, efforts on development of new multicomponent processes involving consecutive free-radical and ionic transformations using readily available starting materials have been pursued.
A sequential carboformylation protocol involving three-component radical reaction-hydrolysis process was developed for the synthesis of a variety of keto-aldehydes that led to substituted cyclohexenones on acid as well as base mediated aldol condensation. An efficient protocol was developed and successfully applied for the hydrolysis of benzyl oximes to corresponding aldehydes. We have also developed an efficient three-component carbo-oximation process with a new SEM oxime, which can then be hydrolyzed under mild conditions. This sequence provides new and functionalized aldehydes in reasonable yields. The aldehydes were then engaged in various nucleophilic processes, including Mukaiyama aldol reactions, Sakurai allylation and cyanation of imines. Pictet-Spengler reactions of these functionalized aldehydes with homoveratylamine and tryptamine delivered a number of piperidinones bearing tricyclic, tetracyclic and pentacyclic framework. A model study focused on the total syntheis of (-)-eburnamine and related alkaloids was also conducted. A variety of reactions such as Mannich reaction, Petasis-borono Mannich reaction, radical three-component intermolecular carboformylation and carboacylation were also explored and evaluated.
A sequential carboformylation protocol involving three-component radical reaction-hydrolysis process was developed for the synthesis of a variety of keto-aldehydes that led to substituted cyclohexenones on acid as well as base mediated aldol condensation. An efficient protocol was developed and successfully applied for the hydrolysis of benzyl oximes to corresponding aldehydes. We have also developed an efficient three-component carbo-oximation process with a new SEM oxime, which can then be hydrolyzed under mild conditions. This sequence provides new and functionalized aldehydes in reasonable yields. The aldehydes were then engaged in various nucleophilic processes, including Mukaiyama aldol reactions, Sakurai allylation and cyanation of imines. Pictet-Spengler reactions of these functionalized aldehydes with homoveratylamine and tryptamine delivered a number of piperidinones bearing tricyclic, tetracyclic and pentacyclic framework. A model study focused on the total syntheis of (-)-eburnamine and related alkaloids was also conducted. A variety of reactions such as Mannich reaction, Petasis-borono Mannich reaction, radical three-component intermolecular carboformylation and carboacylation were also explored and evaluated.