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Here, we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles but also for more complex heterotricycles, showing acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure-activity relationships of biologically active small molecules.

The Ugi reaction is a useful four-component coupling reaction for α-(acylamino)amide. However, selective transformation of the two amides is generally difficult. Here, we report 1-hydroxy-2-methyl-2-propyl isocyanide (HMPI) as a new member of a 'convertible isocyanide' class used to solve the problem. HMPI is odorless and shows good reactivity in the Ugi reaction to give N-(1hydroxy-2-methyl-2-propyl) amides, which are smoothly converted into esters upon Zn(OTf) 2 -mediated solvolysis. Overall, structurally diverse α-amino acid esters are readily accessible in two steps by using HMPI.

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1-Hydroxy-2-methyl-2-propyl Isocyanide (HMPI) as a New Convertible Isocyanide for the Ugi Four-Component-CouplingReaction. -The successful use of isocyanide (IV) in Ugi four-component reactions is shown. The mild chemoselective cleavage of the resulting N-(1-hydroxy-2-methyl-2-propyl) amides is achieved by alcoholysis mediated by Zn(OTf)2 and diethyl carbonate. -(OIKAWA*, M.; SUGAMATA, Y.; CHIBA, M.; FUKUSHIMA, K.; ISHIKAWA, Y.; Synlett 24 (2013) 15, 2014-2018, http://dx.