Chiral Sulfinamide Bisphosphine Catalysts: Design,Synthesis, and Application in Highly Enantioselective Intermolecular Cross‐Rauhut–Currier Reactions

A novel type of highly efficient chiral sulfinamide bisphosphine catalysts (Wei‐Phos) were developed. These could be easily prepared from commercially available starting materials. Wei‐Phos has shown good performance in the very challenging intermolecular cross‐Rauhut–Currier reactions of vinyl ketones and 3‐acyl acrylates or 2‐ene‐1,4‐diones, leading to the R‐C products in high yields with up to 99 % ee under 2.5–5 mol% catalyst loading. The highly regio‐ and enantio‐selective cross‐Rauhut–Currier reactions of 2‐ene‐1,4‐diones and vinyl ketone have yet reported so far.     

Design,Synthesis, and Application of a Chiral Sulfinamide Phosphine Catalyst for the Enantioselective Intramolecular Rauhut–Currier Reaction

A novel class of chiral sulfinamide phosphine catalysts (Xiao‐Phos) are reported, which can be easily prepared from inexpensive commercially available starting materials. The Xiao‐Phos catalysts showed good performance in enantioselective intramolecular Rauhut–Currier reactions, generating α‐methylene‐γ‐butyrolactones in high yields with up to 99 % ee under mild conditions. Moreover, kinetic resolution and parallel kinetic resolution were also observed with the use of two different substituted racemic precursors.     

The Roles of Counterion and Water in a Stereoselective Cysteine‐Catalyzed Rauhut–Currier Reaction: A Challenge for Computational Chemistry

The stereoselective Rauhut–Currier (RC) reaction catalyzed by a cysteine derivative has been explored computationally with density functional theory (M06‐2X). Both methanethiol and a chiral cysteine derivative were studied as nucleophiles. The complete reaction pathway involves rate‐determining elimination of the thiol catalyst from the Michael addition product. The stereoselective Rauhut–Currier reaction, catalyzed by a cysteine derivative as a nucleophile, has also been studied in detail. This reaction was experimentally found to be extremely sensitive to the reaction conditions, such as the number of water equivalents and the effect of potassium counterion. The E1cB process for catalyst elimination has been explored computationally for the eight possible stereoisomers. The effect of explicit water solvation and the presence of counterion (either K⁺ or Na⁺) has been studied for the lowest energy enantiomer pair (1S, 2R, 3S)/(1R, 2S, 3R).     

多功能手性膦催化活泼烯烃的不对称分子间Rauhut-Currier反应

研究实现了多功能手性膦催化的3-芳酰基丙烯酸酯和烯酮的不对称分子间Rauhut-Currier反应,为多羰基手性化合物的构建提供了一种新方法.在使用（S,R_S）-X8作为催化剂和甲苯作为溶剂的条件下,一系列含有不同取代基团的3-芳酰基丙烯酸酯和烯酮均可顺利地发生不对称Rauhut-Currier反应,从而高产率且高对映选择性地生成相应的产物.对照实验表明多功能手性膦催化剂中的N-H键对反应的对映选择性的控制起到了至关重要的作用;膦谱监测实验结果表明手性膦催化剂对烯酮的Michael加成是该反应的启动步骤.     

Organocatalytic Enantioselective Cross‐Vinylogous Rauhut–Currier Reaction of Methyl Coumalate with Enals

The organocatalytic enantioselective intermolecular cross‐vinylogous Rauhut–Currier (RC) reaction of methyl coumalate with α,β‐unsaturated aldehydes is reported, and the enals are activated by iminium catalysis to serve as the Michael acceptors and methyl coumalate is used as an activated diene to generate a latent enolate. The excellent selectivity is driven by the aromaticity of methyl coumalate, and the post transformation of this heterocyclic structure into other electron‐deficient arenes and heterocycles have addressed, in part, the challenging selectivity issues of the intermolecular cross‐RC reactions and the limited scope of iminium catalysis.     

Lewis Base Catalyzed Stereo‐ and Regioselective Bromocyclization

Oxygen‐ and nitrogen‐containing heterocyclic compounds are widely recognized as key components in many natural products and biologically relevant molecules, but often the problem comes down to methodologies in synthesizing them. Halocyclization of olefinic substrates is a promising strategy in the construction of O‐ and N‐heterocyclic compounds, which further signifies the development of their asymmetric variants. Over the past years, our group has been devoted to this particular area of asymmetric electrophilic halocyclization with chalcogen‐containing molecules as catalysts. In this account, the main focus is on the development of our novel chiral catalysts and applications derived from the reaction products.     

exo‐Selective Asymmetric Diels–Alder Reaction Catalyzed by Diamine Salts as Organocatalysts

An organocatalyst formed from a binaphthyl‐substituted diamine and trifluoromethanesulfonic acid exhibited unprecedented levels of exo selectivity in the Diels–Alder reaction of α,β‐unsaturated aldehydes with cyclopentadiene. A novel axially chiral diamine was also designed as an organocatalyst for an asymmetric variant of this reaction, in which the desired cycloadducts were formed with high diastereo‐ and enantioselectivities. The highest diastereoselectivity observed was greater than 20:1 in favor of the exo cycloadduct in the asymmetric Diels–Alder reaction of crotonaldehyde with cyclopentadiene.     

Highly Enantioselective Bromocyclization of Allylic Amides with a P/P=O Double‐Site Lewis Base Catalyst

The enantioselective bromocyclization of allylic amides catalyzed by phosphorus‐containing Lewis bases was examined in detail. A series of control experiments and NMR studies showed that a partially oxidized bis‐phosphine generated in situ serves as the actual enantioselective catalyst. The reaction mechanism involves distinct roles of two Lewis basic sites, P and P=O, with P⁺Br serving as a fine‐tuning element for substrate fixation in the chiral environment, and P⁺OBr as the Br⁺ transfer agent to the olefin. Catalyst loading could be reduced to as little as 1 mol %, and the reaction affords enantioenriched oxazolines with up to >99.5 % ee.     

Theoretical study on the reaction mechanisms and stereoselectivities of DABCO‐catalyzed Rauhut–Currier/cyclization reaction of methyl acrylate with 2‐benzoyl‐3‐phenyl‐acrylonitrile

With the aid of density functional theory (DFT) calculations, we have investigated the mechanisms and stereoselectivities of the tandem cross Rauhut–Currier/cyclization reaction of methyl acrylate R₁ with (E)‐2‐benzoyl‐3‐phenyl‐acrylonitrile R₂ catalyzed by a tertiary amine DABCO. The results of the DFT calculations indicate that the favorable mechanism (mechanism A) includes three steps: the first step is the nucleophilic attack of DABCO on R₁ to form intermediates Int1 and Int1‐1, the second step is the reaction of Int1 and Int1‐1 with R₂ to generate intermediate Int2(SS,RR,SR&RS), and the last step is an intramolecular S_N2 process to give the final product P(SS,RR,SR&RS) and release catalyst DABCO. The S_N2 substitution is computed to be the rate‐determining step, whereas the second step is the stereoselectivity‐determining step. The present study may be helpful for understanding the reaction mechanism of similar tandem reactions.     

Lewis Base Catalyzed Aerobic Oxidative Intermolecular Azide–Zwitterion Cycloaddition

The discovery of a novel aerobic oxidative intermolecular azide–zwitterion reaction catalyzed by an organocatalyst is presented. It is demonstrated that the merger of the Lewis base 1,8‐diazabicyclo[5.4.0]undec‐7‐ene and electron‐deficient olefins generates reactive zwitterion intermediates, which readily participate in cycloaddition reactions with an array of azides, thus providing facile entry to fully or highly substituted 1,2,3‐triazole frameworks. The reaction features an excellent substrate scope, and the products are obtained with high yields and excellent regioselectivities. It is demonstrated that some of these products can be transformed into pharmaceutically important agents. In addition to the experimental results, a detailed mechanistic survey is also provided, including MS studies rationalizing the origin of regioselective control.     

Temperature Dual Enantioselective Control in a Rhodium‐Catalyzed Michael‐Type Friedel–Crafts Reaction: A Mechanistic Explanation

By changing the temperature from 283 to 233 K, the S (99 % ee) or R (96 % ee) enantiomer of the Friedel–Crafts (FC) adduct of the reaction between N‐methyl‐2‐methylindole and trans‐β‐nitrostyrene can be obtained by using (S_Rh,R_C)‐[(η⁵‐C₅Me₅)Rh{(R)‐Prophos}(H₂O)][SbF₆]₂ as the catalyst precursor. This catalytic system presents two other uncommon features: 1) The ee changes with reaction time showing trends that depend on the reaction temperature and 2) an increase in the catalyst loading results in a decrease in the ee of the S enantiomer. Detection and characterization of the intermediate metal–nitroalkene and metal–aci‐nitro complexes, the free aci‐nitro compound, and the FC adduct‐complex, together with solution NMR measurements, theoretical calculations, and kinetic studies have allowed us to propose two plausible alternative catalytic cycles. On the basis of these cycles, all the above‐mentioned observations can be rationalized. In particular, the reversibility of one of the cycles together with the kinetic resolution of the intermediate aci‐nitro complexes account for the high ee values achieved in both antipodes. On the other hand, the results of kinetic measurements explain the unusual effect of the increment in catalyst loading.     

Chiral Sulfinamide Bisphosphine Catalysts: Design,Synthesis, and Application in Highly Enantioselective Intermolecular Cross‐Rauhut–Currier Reactions

A novel type of highly efficient chiral sulfinamide bisphosphine catalysts (Wei‐Phos) were developed. These could be easily prepared from commercially available starting materials. Wei‐Phos has shown good performance in the very challenging intermolecular cross‐Rauhut–Currier reactions of vinyl ketones and 3‐acyl acrylates or 2‐ene‐1,4‐diones, leading to the R‐C products in high yields with up to 99 % ee under 2.5–5 mol% catalyst loading. The highly regio‐ and enantio‐selective cross‐Rauhut–Currier reactions of 2‐ene‐1,4‐diones and vinyl ketone have yet reported so far.     

Design,Synthesis, and Application of a Chiral Sulfinamide Phosphine Catalyst for the Enantioselective Intramolecular Rauhut–Currier Reaction

A novel class of chiral sulfinamide phosphine catalysts (Xiao‐Phos) are reported, which can be easily prepared from inexpensive commercially available starting materials. The Xiao‐Phos catalysts showed good performance in enantioselective intramolecular Rauhut–Currier reactions, generating α‐methylene‐γ‐butyrolactones in high yields with up to 99 % ee under mild conditions. Moreover, kinetic resolution and parallel kinetic resolution were also observed with the use of two different substituted racemic precursors.