N‐Heterocyclic Carbene‐Catalyzed Umpolung Formal [3+3] Cycloaddition of Enals with Isatogens: Access to Fused Indolin‐3‐ones with a Tetrasubstituted Carbon Stereocenter

A novel synthetic method to access fused indolin‐3‐ones with a tetrasubstituted carbon stereocenter has been developed via NHC‐catalyzed umpolung formal [3+3] cycloaddtion of enals with isatogens. This methodology could be also applied for the quick construction of the 6‐5‐5 tricyclic pyrrolo[1,2‐a]indole skeleton which is frequently found as a core structure of many indole alkaloids.

     

浅谈切断法中羰基化合物的极性转换

在有机合成的切断法逆合成分析中,经常碰到“不合逻辑”的极性颠倒的反常合成子,本文综述了切断法中羰基化合物常见的合成子的极性转换及其对应的等价物或者潜在的官能团提供试剂,这对于更加深刻地理解现有的有机反应以及设计新的合成路线都有指导意义.     

Cyanide‐Catalyzed Additions of Acyl Phosphonates to Aldehydes: A New Acyl Donor for Benzoin‐Type Reactions

Acyl phosphonates have been utilized as new acyl donors for cyanide‐catalyzed benzoin‐type reactions. Cyanation of acyl phosphonates, followed by a [1,2]‐phosphoryl migration generates the active acyl anion intermediate. The presumed (cyano)phosphate anion reacts with a variety of aryl aldehydes to yield phosphate ester‐protected, unsymmetrical benzoins in good to excellent yields. The unsymmetrical benzoin product can be obtained after deprotection of the phosphate ester with an aqueous amine solution.     

Enantioselective Synthesis of a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 5 (mGluR5) Receptor via Dynamic Kinetic Resolution of α‐Amino Ketones

The concise synthesis of a pharmaceutical candidate is described. The chiral core of the molecule is assembled using an aza‐benzoin condensation and a dynamic kinetic resolution (DKR) as the key reactions. This enables superb control of the regio‐, diastereo‐ and enantioselectivity of the synthesis. Both biocatalysts and transition metal catalysts are remarkably effective in the key asymmetric reduction step. Similar approaches could be considered in the synthesis of other 1,2‐amino alcohols where traditional approaches based on functionalization of alkenes, epoxides or aziridines may suffer from selectivity issues.

     

Synthesis of 2‐Aryl‐Substituted Indole‐3‐acetic Acid Derivatives via Intramolecular Imino‐Stetter Reaction of Aldimines with Cyanide

A general method to generate umpolung of aldimines with cyanide was developed via the addition of cyanide to aldimines followed by a proton transfer from the carbon atom to the nitrogen atom in the resulting cyanide adducts. This novel method was successfully applied to the first imino‐Stetter reaction of aldimines obtained from 2‐aminocinnamic acid derivatives and aromatic aldehydes with cyanide, affording 2‐aryl‐substituted indole‐3‐acetic acid derivatives. Furthermore, the usefulness of this method was successfully demonstrated by the synthesis of an FPTase inhibitor, one of the biologically important 2‐arylindole‐3‐acetic acid derivatives.

     

Organocatalytic Upgrading of Furfural and 5-Hydroxymethyl Furfural to C10 and C12 Furoins with Quantitative Yield and Atom-Efficiency

There is increasing interest in the upgrading of C₅ furfural (FF) and C₆ 5-hydroxymethyl furfural (HMF) into C₁₀ and C₁₂ furoins as higher energy-density intermediates for renewable chemicals, materials, and biofuels. This work utilizes the organocatalytic approach, using the in situ generated N,S-heterocyclic carbene catalyst derived from thiazolium ionic liquids (ILs), to achieve highly efficient self-coupling reactions of FF and HMF. Specifically, variations of the thiazolium IL structure have led to the most active and efficient catalyst system of the current series, which is derived from a new thiazolium IL carrying the electron-donating acetate group at the 5-ring position. For FF coupling by this IL (0.1 mol %, 60 °C, 1 h), when combined with Et₃N, furoin was obtained in >99% yield. A 97% yield of the C₁₂ furoin was also achieved from the HMF coupling by this catalyst system (10 mol % loading, 120 °C, 3 h). On the other hand, the thiazolium IL bearing the electron-withdrawing group at the 5-ring position is the least active and efficient catalyst. The mechanistic aspects of the coupling reaction by the thiazolium catalyst system have also been examined and a mechanism has been proposed.     

Umpolung Synthesis of Diarylmethylamines via Palladium‐ Catalyzed Arylation of N‐Benzyl Aldimines

An umpolung synthesis of diarylmethylamine derivatives is presented. This reaction entails a palladium‐catalyzed arylation of 1,3‐diaryl‐2‐azaallyl anions, in situ generated from N‐benzyl aldimines. A Pd(NIXANTPHOS)‐based catalyst together with hindered silylamide bases enabled the coupling of aldimines with aryl bromides in good to excellent yields without product isomerization. Moreover, regioselectivity in the arylation of unsymmetrical 1,3‐diaryl‐2‐azaallyl anions was studied. This method is suitable for a gram scale synthesis of diarylmethylamine derivatives at room temperature without use of a glove box.

     

Asymmetric Synthesis of 2′‐Trifluoromethylated Spiro‐pyrrolidine‐3,3′‐oxindoles via Squaramide‐Catalyzed Umpolung and 1,3‐Dipolar Cycloaddition

The introduction of a trifluoromethyl group into the 2′‐position of spiro‐pyrrolidine‐3,3′‐oxindoles is described. By using 1 mol% of a quinine‐derived squaramide as catalyst, the 2,2,2‐trfluoroethylamine (CF₃CH₂NH₂)‐derived ketimine is transformed initially into a trifluoromethylimine through an umpolung reaction. The subsequent 1,3‐dipolar cycloaddition gives the pharmaceutical important target compounds in excellent yields, enantioselectivities and diastereoselectivies.

     

N-杂环卡宾催化Stetter反应的研究进展

N-杂环卡宾作为一类新型的催化剂,已广泛应用于有机合成领域.综述了N-杂环卡宾催化Stetter反应的研究进展,包括分子间的Stetter反应、分子内的Stetter反应、聚合物支撑的Stetter反应、Stetter-Paal-Knorr反应及其在天然产物合成中的应用.     

Ethynylbenziodoxolones (EBX) as Reagents for the Ethynylation of Stabilized Enolates

Herein, we report a detailed study on the electrophilic alkynylation of cyclic keto esters and amides with e thynyl b enziodo x olone (EBX) reagents. The structure and stability of this class of reagents is first described more in details. Differential scanning calorimetry (DSC) experiments showed a strong exothermic decomposition with EBX reagents, leading to guidelines for the safe use of these compounds. The extension of the method to aromatic alkynes and a broad range of benziodoxol(on)e reagents is then reported. Based on our preliminary results using Cinchona‐based phase‐transfer catalysts, the enantioselective alkynylation of cyclic keto esters could be achieved. Binaphthyl‐derived ammonium catalysts developed by Maruoka and co‐workers gave the highest asymmetric induction with up to 79% ee for an indanone‐derived keto ester. Throughout this work, asymmetric induction was observed only in the case of benziodoxolone reagents, demonstrating their superiority over conventional alkynyliodonium salts. The deeper understanding gained about the factors leading to higher asymmetric induction will be very useful in the future to develop a truly general and highly enantioselective alkynylation method.