维蒂希反应在精细化工中应用进展

维蒂希反应(Wittig Rection)是合成烯烃的重要反应之一,以良好的立体选择性、产率在精细有机合成领域举足轻重的地位,但目前反应机理、影响因素等尚不明确。科学家们在此基础上发展了维蒂希-霍纳尔反应（Wittig-Horner Reaction）以及氮杂-维蒂希反应（aza-Wittig）弥补了维蒂希反应的不足。首先从空间位阻、电子效应等方面介绍了维蒂希反应在环外双键、α,β-不饱和羰基化合物、共轭多烯、杂环化合物等结构设计合成,然后系统综述了其在生命科学、医疗制药、农业生产、功能材料等领域的应用,最后对其发展趋势进行了展望。     

One-pot synthesis of stable phosphonium ylides using 2-mercaptopyrimidine derivatives

The reaction of dialkyl acetylenedicarboxylates with 2-mercaptopyrimidine and 2-mercapto-4,6-dimethylpyrimidine in the presence of triphenylphosphine leads to stable phosphorus ylides in excellent yields. These stable ylides exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon-carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbon group.     

The behavior of some Wittig reagents toward 4,5,6,7-tetrahydro-3H-1,2-benzo[1,2]dithiole-3-thione

ABSTRACT

Novel synthetic route for phosphanylidene-benzothiophenethione, benzothiaphosphinine-4-thione, triphenylphosphoranylidenecyclobutane and benzodithiolylidenephosphonate derivatives has been proposed through reactions of 4,5,6,7-tetrahydro-3H-1,2-benzodithiole-3-thione with different Wittig and Wittig–Horner reagents. All new synthesized compounds were fully characterized with elemental and spectroscopic analysis.     

Regioselective Asymmetric Formal (3+2) Cycloadditions of Nitrone Ylides from Isatins and Enals

A highly regio‐, diastereo‐ and enantioselective formal (3+2) cycloaddition reaction of nitrone ylides from isatins and α,β‐unsaturated aldehydes was developed via iminium catalysis in the presence of an additional base, furnishing a spectrum of 1′‐hydroxy‐3,2′‐pyrrolidinylspirooxindole frameworks. Interestingly, the regioselectivity could be finely switched in the reactions between nitrone ylides and crotonaldehyde by adding catalytic amounts of lithium perchlorate and copper(II) bromide.

     

Targeted Synthesis of Complex Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96_MDM2. The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2′-pyrrolo[2,3-c]pyrrole]-2,4′-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on-target adverse effects.     

Catalytic Asymmetric Construction of Spirocycles Containing Pyrrolidine Motifs and Spiro Quaternary Stereogenic Centers via 1,3‐Dipolar Cycloaddition of Azomethine Ylides with 2‐Alkylidene‐Cycloketones

The first catalytic asymmetric 1,3‐dipolar cycloaddition of azomethine ylides with various sterically hindered α,α,β‐trisubstituted 2‐alkylidene‐cycloketones has been developed successfully with silver acetate/TF‐BiphamPhos complex for the construction of spiro heterocyclic compounds containing pyrrolidine motifs and a spiro quaternary stereogenic carbon center. The highly efficient catalytic system exhibited high reactivity, excellent diastereoselectivity, good enantioselectivity and broad substrate scope under mild conditions. Subsequent transformations led to the expedient preparation of synthetically useful spiro[pyrrolidine‐tetrahydropyranone] and spiro[pyrrolidine‐isochroman‐1‐one] without loss of the diastereo‐ and enantiomeric excesses.     

Silver Acetate/TF‐BiphamPhos‐Catalyzed endo‐Selective Enantioselective 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Vinyl Phenyl Sulfone

The first catalytic endo‐selective 1,3‐dipolar cycloaddition of azomethine ylides and vinyl phenyl sulfone has been developed successfully. The highly efficient silver acetate (AgOAc)/TF‐BiphamPhos catalytic system exhibited high reactivity, excellent diastereoselectivity (>98:2), good enantioselectivity (67–92% ee) and broad substrate scope under mild conditions.     

Copper-Catalyzed α-Arylation of Sulfoxonium Ylides Using Hypervalent Iodine Compounds

A Cu(I)-catalyzed synthesis of α-arylated sulfoxonium ylides has been achieved from mesitylene-derived diaryliodonium salts and α-carbonyl sulfoxonium ylides. The reaction is believed to proceed via an electrophilic Cu(III)-aryl intermediate that can be trapped upon nucleophilic attack of the sulfoxonium ylide precursor. The reaction was tolerant to both α-keto and α-ester-derived sulfoxonium ylides, to drug-derived ylide motifs and to electronically-diverse arenes, and enabled the direct synthesis of 32 α-aryl-sulfoxonium ylides in 42–85% yield.     

Rhodium‐Catalyzed,Three‐Component Reaction of Diazo Compounds with Amines and Azodicarboxylates

A novel, three‐component C N bond forming reaction is described. Reaction of diazo compounds with both azodicarboxylates and arylamines in the presence of dirhodium acetate catalyst gives good yields of the corresponding aminal with high selectivity and, in most cases, N H insertion side products were suppressed. This is the first example of a C N bond formation from the addition of ammonium ylides to azodicarboxylates.     

11H-Benzo[4,5]imidazo[1,2-a]indol-11-one as a New Precursor of Azomethine Ylides: 1,3-Dipolar Cycloaddition Reactions with Cyclopropenes and Maleimides

The possibility of generating azomethine ylides from 11H-benzo[4,5]imidazo[1,2-a]indol-11-one and amino acids is shown for the first time. Based on the cycloaddition reactions of these azomethine ylides with cyclopropenes and maleimides, cyclopropa[a]pyrrolizines, 3-azabicyclo[3.1.0]hexanes, and pyrrolo[3,4-a]pyrrolizines spiro-fused with a benzo[4,5]imidazo[1,2-a]indole fragment were synthesized. Spirocyclic compounds were obtained in moderate to good yields, albeit with poor diastereoselectivity. Density functional theory calculations were performed to obtain an insight into the mechanism of the 1,3-dipolar cycloaddition of 11H-benzo[4,5]imidazo[1,2-a]indol-11-one-derived azomethine ylides to cyclopropenes. The cytotoxic activity of some of the obtained cycloadducts against the human erythroleukemia (K562) cell line was evaluated in vitro by MTS-assay.