Associate Professor, Laboratory of Organic Chemistry, Showa Pharmaceutical University, Japan

Speech Title: Strategic Use of Gold(I)/(III)-Catalysts for Synthesis of 2-Substituted Piperidines and Azepanes; Valency-Controlled Cyclization Modes
Abstract: Gold catalysts were initially recognized as ∏-acidic catalysts that activate unsaturated bond (alkynes, allenes and alkenes) for nucleophilic attack to form C-C, C-O, C-N, and C-S bonds. Later, some groups reported the oxophilic character of gold(III) catalysts, which efficiently activate oxygen functinalities even in the presence of an unsaturated bond. We rationalized these observations in terms of the hard and soft acids and bases (HSAB) principle, which states that metal ions in low valence states soft character, whereas metal ions in high positive oxidation states show hard character. Thus, gold(I) catalysts may behave as soft acids and gold(III) catalysts as hard acids. On the basis of this working hypothesis, we developed a syntheic method to obtain two types of cyclic ethers from the same propargylic alcohols by means of valency-controlled gold-catalyzed regiodivergent activation. In order to extend our strategy, we turned our attention to the use of nitrogen nucleophile in place of oxygen nucleophile and explored the synthesis of piperidines and azepanes from propargylic alcohols bearing sulfonamide at the terminal position [R–C≡C–CH(OH)-(CH₂)n–NHSO₂R’]. Thus, use of hard gold(III) catalyst for the reaction of the propargylic alcohols (n = 4) results in cyclization to furnish piperidines having an acetylenic moiety, due to coordination of hard gold(III) to the oxygen atom at propargylic position. On the other hand, treatment of the same propargylic alcohols with soft gold(I) catalyst induces Meyer-Schuster rearrangement by activation of the triple bond by coordination of soft gold(I). The resulting α,β-unsaturated ketones undergo intramolecular aza-Michael addition to give piperidines bearing carbonyl gorup. In contrast to pyrrolidines or piperidines, development of the method for construction of azepanes, 7-membered ring amines, from flexible linear substrates still remains a challenging task becuase enthalpic and entropic factors impede the cyclization. Although the hard gold(III) catalyst brought about the cyclization of the propargylic alcohols (n = 5), the yield of azepane bearing acetylenic moiety was relatively low. On the other hand, the same propargylic alcohols in the presence of soft gold(I) catalyst undergo Meyer-Schuster rearrangement to give α,β-unsaturated ketones, which in turn undergo aza-Michael addition by adding a hard gold(III)-catalyst for activation of carbonyl oxigen to afford azepanes bearing carbonyl group.