Synthetic Applications and Methodological Developments of Donor−Acceptor Cyclopropanes and Related Compounds

Donor−acceptor cyclopropanes are convenient precursors to reactive and versatile 1,3-dipoles, and have found application in the synthesis of a variety of carbo- and heterocyclic scaffolds. This perspective review details our laboratory's use of donor−acceptor cyclopropanes as intermediates toward the total synthesis of various natural products. We also discuss our work in the development of novel cycloadditions and rearrangements of donor−acceptor cyclopropanes and aziridines, as well as an example of an aryne insertion proceeding via fragmentation of a transient donor−acceptor cyclobutane.     

Repurposing the Pummerer Rearrangement: Determination of Methionine Sulfoxides in Peptides

The reversible oxidation of methionine residues in proteins has emerged as a biologically important post-translational modification. However, detection and quantitation of methionine sulfoxide in proteins is difficult. Our aim is to develop a method for specifically derivatizing methionine sulfoxide residues. We report a Pummerer rearrangement of methionine sulfoxide treated sequentially with trimethylsilyl chloride and then 2-mercaptoimidazole or pyridine-2-thiol to produce a dithioacetal product. This derivative is stable to standard mass spectrometry conditions, and its formation identified oxidized methionine residues. The scope and requirements of dithioacetal formation are reported for methionine sulfoxide and model substrates. The reaction intermediates have been investigated by computational techniques and by ¹³C NMR spectroscopy. These provide evidence for an α-chlorinated intermediate. The derivatization allows for detection and quantitation of methionine sulfoxide in proteins by mass spectrometry and potentially by immunochemical methods.     

Regioselective synthesis of pentacyclic heterocycles by the thermal and Lewis acid catalyzed Claisen rearrangement

[6,6]- and [6,5]-fused hithero unreported pentacyclic heterocycles have been regioselectively synthesized from 4-(4′-aryloxybut-2′-ynylthio)thiocoumarin in good yields by the application of thermal as well as catalytic Claisen rearrangement.     

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

Hydroxamate‐based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that “pan‐HDAC inhibitors” may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate‐containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high‐potency HDACIs, is not necessarily the best zinc‐binding group for HDACI drug discovery.     

发烟硫酸条件下环己酮肟贝克曼重排工艺进展

综述了环己酮肟在发烟硫酸条件下液相重排生成己内酰胺的相关新工艺、新设备及新技术,并对其进行了概括和分析.     

Formation of Furan Fatty Alkyl Esters from their Bis‐Epoxide Fatty Esters

Reactions of epoxidized alkyl soyate with four different alcohols: ethanol, isopropyl alcohol, 2‐ethylhexanol, benzyl alcohol, in the presence of Brønsted acid catalyst, were investigated. Products, not reported in prior studies of similar reactions, were found. These were furan fatty acid alkyl esters (FFE, mixture of alkyl 8‐(5‐hexyl‐2‐furyl) octanoate and alkyl 9‐(5‐pentyl‐2‐furyl)nonanoate) which were unambiguously identified by means of GC–MS and two‐dimensional NMR. Evidence suggests that the FFE are formed by an acid‐catalyzed rearrangement of the epoxidized linoleates. The FFE were formed in presence of all four alcohols tested and in the presence of either sulfuric acid or Amberlyst 15 catalyst. Yields of up to 13 %, as quantified by GC and NMR spectroscopies, were observed.     

Gold(I)‐Catalyzed Tandem Reaction of γ‐Amino‐Substituted Propargylic Esters to Pyrrolines and its Application in the Formal Synthesis of (±)‐Aphanorphine

An effective synthesis of structurally diverse pyrroline derivatives has been accomplished by a gold(I)‐catalyzed tandem 1,3‐acyloxy rearrangement/intramolecular azacylization reaction of γ‐amino‐substituted propargylic esters in good to excellent chemical yields (52–98%). The reaction proceeds under extremely mild conditions and has also demonstrated its potential in a concise formal synthesis of (±)‐aphanorphine with a catalyst loading as low as 0.5 mol% to provide the key intermediate 5‐(4‐methoxybenzyl)‐1‐tosyl‐2,5‐dihydro‐1H‐pyrrol‐3‐yl pivalate on a gram scale.

     

3-乙酰基-4-羟基苯甲酸的合成及正交工艺优化

以4-乙酰氧基苯甲酸甲酯为原料,经无溶剂的Fries重排法合成了3-乙酰基-4-羟基苯甲酸,并对其结构进行了表征.采用L9(34)正交实验,考察了物料投料比、反应温度和反应时间等参数对目标产物收率的影响,并对重排反应机理进行了探讨.结果表明,3-乙酰基-4-羟基苯甲酸的最佳合成工艺为:n(4-乙酰氧基苯甲酸甲酯):n(...     

“一锅三步法”合成苯基-2-吡啶基甲醇

以2-苄基吡啶氮氧化物和三氟乙酸酐为原料,通过“一锅三步法”（串联“酰化、[3,3]σ重排和水解”反应）合成了关键药理活性中间体苯基-2-吡啶基甲醇,并对反应条件进行了优化。结果表明：当n（2-苄基吡啶氮氧化物）：n（三氟乙酸酐）=1 : 1.2、N, N-二异丙基乙胺（DIPEA）为碱、甲苯为反应溶剂,室温反应6小时,经硅胶柱层析分离即可得到苯基-2-吡啶基甲醇,收率为81.0%。产物经1H NMR,13C NMR 和HRMS进行结构表征。本文以原子经济学的理念首次实现了由2-苄基吡啶氮氧化物到苯基-2-吡啶基甲醇的直接转化。     

5-氨基-1,4-苯并二恶烷盐酸盐的合成

以2,3-二羟基苯甲酸为原料,经酚羟基烷基化保护、羧酸叠氮化、Curtius重排、水解成盐四步反应以35%的总收率合成了5-氨基-1,4-苯并二恶烷盐酸盐,其结构经1H-NMR确认。由于合理的反应溶剂选择和反应温度控制,减少了副反应的发生、简化了工艺操作、降低了分离难度、提高了收率和产品纯度,使得该路线适合于工业化生产。