Asymmetric Three-Component Propargyloxylation for Direct Assembly of Polyfunctionalized Chiral Succinate Derivatives

Abstract

An enantioselective three-component propargyloxylation reaction of propargyl alcohols, pyridotriazoles, and imines has been realized by cooperative catalysis with dirhodium complex and chiral phosphoric acid under mild conditions. This is the first example of a catalytic asymmetric three-component propargyloxylation reaction, which provides practical access to chiral polyfunctionalized succinate derivatives with adjacent quaternary and tertiary stereocenters in good to high yields with excellent enantioselectivity. In addition to the alkyne motif, pyridyl, alkoxy, amino, and alkenyl species are all tolerated under the reaction conditions. Notably, the utility of the current method is demonstrated by catalytic cyclization of the product alkyne into a variety of heterocyclic structures without loss of enantiomeric purity.

Enantioselective Oxidative Multi-Functionalization of Terminal Alkynes with Nitrones and Alcohols for Expeditious Assembly of Chiral α-Alkoxy-β-amino-ketones

“…A reaction mechanism is proposed in Scheme based on the aforementioned results and previous studies. − Initially, gold-catalyzed alkyne oxidation in the presence of nitrone 2 forms the gold carbene intermediate B via A , followed by addition with alcohol 3 to give a gold-associated enolate species C′ via oxonium ylide C . Then, assembly of enolate species with an imine fragment in the presence of chiral phosphoric acid produces the Mannich-type addition product 4 and regenerates the catalyst.…”

“…In our work, high to excellent enantioselectivity has been realized in the key Mannich-type addition step of an in situ formed gold enolate intermediate with imine in the presence of chiral phosphoric acid (CPA) . As a continuation of our research on catalytic alkyne functionalization via interception of reactive intermediates, , we envisioned that an asymmetric three-component reaction of alkynes with alcohols and nitrones could be enabled through an oxidation/ylide formation/Mannich-type addition sequence, providing an atom-economic method for multi-functionalization of commercially available alkynes (Scheme c). In this context, challenges lie in the control of chemo- and stereoselectivity, especially in competitive reactions with carbene intermediates.…”

Enantioselective Intermolecular Mannich-Type Interception of Phenolic Oxonium Ylide for the Direct Assembly of Chiral 2,2-Disubstituted Dihydrobenzofurans

“…On the other hand, by using 2-ethynyl-phenols as the carbene precursor under catalytic oxidative conditions, Liu and co-workers have reported a highly diastereoselective Mannich-type addition of in situ generated phenolic oxonium ylide with imine, which is a leaving fragment in the carbene formation step, enabling a diastereoselective synthesis of benzofuran-3­(2 H )-ones (Scheme b) . Inspired by these advances and as the continuation of our interest in multicomponent reactions via interception of in situ generated reactive intermediates, − we envisioned that an enantioselective intermolecular Mannich-type trapping process of phenolic oxonium ylides I that derived from 2-hydroxylaryl tethered diazoacetes, which have been reported by Zhou’s group for the asymmetric intramolecular phenolic O–H insertion in the presence of chiral copper complex (Scheme c), might be realized by using an appropriate catalytic strategy . Herein, we report our recent results in this direction, an enantioselective Mannich-type interception of in situ generated phenolic oxonium ylides with external imines, which has been enabled with combined catalysis by achiral rhodium­(II) carboxylates and CPA catalysts to circumvent the competitive intramolecular phenolic O–H bond insertion via dual H-bonding, enabling the synthesis of chiral 2,2-disubstituted dihydrobenzofurans with high yield and excellent enantioselectivity under mild conditions (Scheme d).…”

“…On the basis of these results and previous studies, − a plausible reaction pathway has been proposed in Scheme . First, carbene intermediate A was generated from diazo compound 1 in the presence of Rh-catalyst, followed by the generation of the ylide species B (or its enolate form B′ ) by addition with tethered phenolic hydroxyl group.…”

Synergistic Activation Strategy to Achieve Rh2(II)-Catalyzed Asymmetric Cycloisomerization of 1,n-Enynes

“…. 近年来, 炔烃经由卡宾过程的不对称催化转化取得 了一系列突破性进展, 如利用高炔丙醇作为卡宾前体的 不对称曼尼希加成 [4][5][6] 、不对称催化的卡宾/炔烃复分解 反应(carbene/alkyne metathesis, CAM) [7][8] 等. 通过不同 模式的串联反应、多组分反应可以高效合成结构多样的 手性杂环化合物.…”