Enantioselective Synthesis of a Tricyclic,sp3-Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold

6-, 7-, and 8-membered rings are assembled from a linear precursor by successive cyclisation reactions to construct a tricyclic diazatricyclo[6.5.1.0^{4, 9}]-tetradecanedione scaffold. Advanced building blocks based on d -aspartic acid and l -pyroglutamic acid were combined by a sp³−sp² Negishi coupling. A carbamate-guided syn-diastereoselective epoxidation followed by an intramolecular epoxide opening allowed the construction of the piperidine ring. An efficient one-pot hydroxyl-group protection twofold deprotection reaction prepared the ground for the cyclisation to the bicycle. A final deprotection of the orthogonal protecting groups and lactamisation led to the novel, sp³-rich tricycle. The final compound is a substrate mimic of peptidyl-prolyl cis-trans isomerases featuring a locked trans-amide bond. Cheminformatic analysis of 179 virtual derivatives indicates favourable physicochemical properties and drug-like characteristics. As proof of concept we, show a low micromolar activity in a fluorescence polarisation assay towards the FK506-binding protein 12.     

Late-Stage Diversification of Tryptophan-Derived Biomolecules

Pd-mediated reactions have emerged as a powerful tool for the site-selective and bioorthogonal late-stage diversification of amino acids, peptides and related compounds. Indole moieties of tryptophan derivatives are susceptible to C²H-activation, whereas halogenated aromatic amino acids such as halophenylalanines or halotryptophans provide a broad spectrum of different functionalisations. The compatibility of transition-metal-catalysed cross-couplings with functional groups in peptides, other biologically active compounds and even proteins has been demonstrated. This Review primarily compiles the application of different cross-coupling reactions to modify halotryptophans, halotryptophan containing peptides or halogenated, biologically active compounds derived from tryptophan. Modern approaches use regio- and stereoselective biocatalytic strategies to generate halotryptophans and derivatives on a preparative scale. The combination of bio- and chemocatalysis in cascade reactions is given by the biocompatibility and bioorthogonality of Pd-mediated reactions.     

Second Comes First: Switching Elementary Steps in Palladium-Catalyzed Cross-Coupling Reactions

The electron-poor palladium(0) complex L₃Pd (L=tris[3,5-bis(trifluoromethyl)phenyl]phosphine) reacts with Grignard reagents RMgX and organolithium compounds RLi via transmetalation to furnish the anionic organopalladates [L₂PdR]⁻, as shown by negative-ion mode electrospray-ionization mass spectrometry. These palladates undergo oxidative additions of organyl halides R′X (or related S_N2-type reactions) followed by further transmetalation. Gas-phase fragmentation of the resulting heteroleptic palladate(II) complexes results in the reductive elimination of the cross-coupling products RR′. This reaction sequence corresponds to a catalytic cycle, in which the order of the elementary steps of transmetalation and oxidative addition is switched relative to that of palladium-catalyzed cross-coupling reactions proceeding via neutral intermediates. An attractive feature of the palladate-based catalytic system is its ability to mediate challenging alkyl–alkyl coupling reactions. However, the poor stability of the phosphine ligand L against decomposition reactions has so far prevented its successful use in practical applications.     

新型绿色有机合成反应设计:Pd/β-环糊精催化的纯水相铃木-宫浦偶联反应*

以环境友好的β-环糊精代替毒性膦配体、纯水代替有机溶剂,设计了4-溴苯乙酮和苯硼酸的绿色铃木-宫浦偶联反应。通过单因素实验,探讨了氯钯酸钠用量、氯钯酸钠/β-环糊精配比、苯硼酸用量、反应温度以及反应时间等对产率的影响。通过引导学生对β-环糊精结构的认识和机理探讨,让学生深刻感受到了绿色化学在有机合成中的重要性,并激发了他们对科学研究的兴趣。该实验环境友好,反应条件温和,反应时间短,产率高,重复性好,适宜于本科实验教学。     

Acyl Fluorides in Late‐Transition‐Metal Catalysis

In this Review, we summarize the current state of the art in late‐transition‐metal‐catalyzed reactions of acyl fluorides, covering both their synthesis and further transformations. In organic reactions, the relationship between stability and reactivity of the starting substrates is usually characterized by a trade‐off. Yet, acyl fluorides display a very good balance between these properties, which is mostly due to their moderate electrophilicity. Thus, acyl fluorides (RCOF) can be used as versatile building blocks in transition‐metal‐catalyzed reactions, for example, as an “RCO” source in acyl coupling reactions, as an “R” source in decarbonylative coupling reactions, and as an “F” source in fluorination reactions. Starting from the cleavage of the acyl C?F bond in acyl fluorides, various transformations are accessible, including C?C, C?H, C?B, and C?F bond‐forming reactions that are catalyzed by transition‐metal catalysts that contain the Group 9–11 metals Co, Rh, Ir, Ni, Pd, or Cu.     

The Persistent Radical Effect in Organic Synthesis

Radical–radical couplings are mostly nearly diffusion‐controlled processes. Therefore, the selective cross‐coupling of two different radicals is challenging and not a synthetically valuable transformation. However, if the radicals have different lifetimes and if they are generated at equal rates, cross‐coupling will become the dominant process. This high cross‐selectivity is based on a kinetic phenomenon called the persistent radical effect (PRE). In this Review, an explanation of the PRE supported by simulations of simple model systems is provided. Radical stabilities are discussed within the context of their lifetimes, and various examples of PRE‐mediated radical–radical couplings in synthesis are summarized. It is shown that the PRE is not restricted to the coupling of a persistent with a transient radical. If one coupling partner is longer‐lived than the other transient radical, the PRE operates and high cross‐selectivity is achieved. This important point expands the scope of PRE‐mediated radical chemistry. The Review is divided into two parts, namely 1) the coupling of persistent or longer‐lived organic radicals and 2) “radical–metal crossover reactions”; here, metal‐centered radical species and more generally longer‐lived transition‐metal complexes that are able to react with radicals are discussed—a field that has flourished recently.     

Silaboration of [1.1.1]Propellane: A Storable Feedstock for Bicyclo[1.1.1]pentane Derivatives

The silaboration of [1.1.1]propellane enables direct introduction of B and Si functional groups onto the bicyclo[1.1.1]pentane (BCP) scaffold in high yield under mild, additive‐free conditions. The silaborated BCP can be obtained on a gram‐scale in a single step without the need for column‐chromatographic purification, and is storable and easy to handle, providing a versatile synthetic intermediate for BCP derivatives. We also describe various conversions of the C?B/C?Si bonds on the BCP scaffold, including development of a modified Suzuki–Miyaura cross‐coupling reaction at the highly sterically hindered bridgehead sp³ carbon center of the BCP skeleton using a combination of highly activated BCP boronic esters, copper(I) oxide, and a PdCl₂(dppf) catalyst system.     

Stereoselective Csp3−Csp2 Cross‐Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides

We report palladium‐catalyzed cross‐coupling reactions of chiral secondary non‐stabilized dialkylzinc reagents, prepared from readily available chiral secondary alkyl iodides, with alkenyl and aryl halides. This method provides α‐chiral alkenes and arenes with very high retention of configuration (dr up to 98:2) and satisfactory overall yields (up to 76 % for 3 reaction steps). The configurational stability of these chiral non‐stabilized dialkylzinc reagents was determined and exceeded several hours at 25 °C. DFT calculations were performed to rationalize the stereoretention during the catalytic cycle. Furthermore, the cross‐coupling reaction was applied in an efficient total synthesis of the sesquiterpenes (S)‐ and (R)‐curcumene with control of the absolute stereochemistry.     

Visible‐Light‐Enabled Stereodivergent Synthesis of E‐ and Z‐Configured 1,4‐Dienes by Photoredox/Nickel Dual Catalysis

A stereodivergent reductive coupling reaction between allylic carbonates and vinyl triflates to furnish both E‐ and Z‐configured 1,4‐dienes has been achieved by visible‐light‐induced photoredox/nickel dual catalysis. The mild reaction conditions allow good compatibility of both vinyl triflates and allylic carbonates. Notably, the stereoselectivity of this synergistic cross‐electrophile coupling can be tuned by an appropriate photocatalyst with a suitable triplet‐state energy, providing a practical and stereodivergent means to alkene synthesis. Preliminary mechanistic studies shed some light on the coupling step as well as the control of the stereoselectivity step.     

Catalytic Enantioselective Synthesis of anti‐Vicinal Silylboronates by Conjunctive Cross‐Coupling

Chiral 1,2‐bimetallic reagents are useful motifs in synthetic chemistry. Although syn‐1,2‐bimetallic compounds can be prepared by alkene dimetallation, anti‐1,2‐bimetallics are still rare. The stereospecific 1,2‐metallate shift that occurs during conjunctive cross‐coupling is shown to enable a practical and modular approach to the catalytic synthesis of enantioenriched anti‐1,2‐borosilanes. In addition to reaction development, the synthetic utility of anti‐1,2‐borosilanes was investigated, including applications to the synthesis of anti‐1,2‐diols and anti‐1,2‐amino alcohols