50 Years of Zweifel Olefination:A Transition-Metal-Free Coupling

The Zweifel olefination is a powerful method for the stereoselective synthesis of alkenes. The reaction proceeds in the absence of a transition-metal catalyst, instead taking place by iodination of vinyl boronate complexes. Pioneering studies into this reaction were reported in 1967 and this short review summarizes developments in the field over the past 50 years. An account of how the Zweifel olefination was modified to enable the coupling of robust and air-stable boronic esters is presented followed by a summary of current state of the art developments in the field, including stereodivergent olefination and alkynylation. Finally, selected applications of the Zweifel olefination in target-oriented synthesis are reviewed.1 Introduction2.1 Zweifel Olefination of Vinyl Boranes2.2 Zweifel Olefination of Vinyl Borinic Esters2.3 Extension to Boronic Esters3.1 Introduction of an Unsubstituted Vinyl Group3.2 Coupling of α-Substituted Vinyl Partners3.3 Syn Elimination4 Zweifel Olefination in Natural Product Synthesis5 Conclusions and Outlook</jats:p

Interrogating the Configurational Stability of Atropisomers

Atropisomers are molecules whose stereogenicity arises from restricted rotation about a single bond. They are of current importance because of their applications in catalysis, medicine and materials science. The defining feature of atropisomeric molecules is that their stereoisomers are related to one another by bond rotation: as a result, evaluating their configurational stability (i.e., the rate at which their stereoisomers interconvert) is central to any work in this area. Important atropisomeric scaffolds include C–C linked biaryls, such as the ligand BINAP and the drug vancomycin, and C–N linked amine derivatives such as the drug telenzepine. This article focuses on the three most widely used experimental methods that are available to measure the rate of racemization in atropisomers, namely: (i) kinetic analysis of the racemization of an enantioenriched sample, (ii) dynamic HPLC and (iii) variable-temperature NMR. For each technique, an explanation of the theory is set out, followed by a detailed experimental procedure. A discussion is also included of which technique to try when confronted with a new molecular structure whose properties are not yet known. None of the three procedures require complex experimental techniques, and all can be performed by using standard analytical equipment (NMR and HPLC). The time taken to determine a racemization rate depends on which experimental method is required, but for a new compound it is generally possible to measure a racemization rate in <1 d

Stereodivergent Olefination of Enantioenriched Boronic Esters

A stereodivergent coupling reaction between vinyl halides and boronic esters is described. This coupling process proceeds without a transition‐metal catalyst, instead proceeding by electrophilic selenation or iodination of a vinyl boronate complex followed by stereospecific syn or anti elimination. Chiral, nonracemic boronic esters could be coupled with complete enantiospecificity. The process enables the highly stereoselective synthesis of either the E or Z alkene from a single isomer of a vinyl coupling partner

Synthesis of Functionalized Alkenes by a Transition-Metal-Free Zweifel Coupling

The Zweifel reaction is a powerful method for the synthesis of alkenes, serving as a transition-metal-free alternative to the Suzuki–Miyaura reaction. To date, the scope of the Zweifel coupling has been rather narrow and has focused mainly on the coupling of vinyllithium reagents to synthesize simple aryl- and alkyl-substituted olefins. Herein, the development of a general transition-metal-free coupling process enabling the coupling of Grignard reagents or organolithiums is described. This method enables the enantiospecific synthesis of a wide variety of functionalized acyclic and cyclic olefin products

Conjunctive functionalization of vinyl boronate complexes with electrophiles:A diastereoselective three-component coupling

A conjunctive functionalization process enables a diastereoselective three-component coupling of vinyl boronate complexes with a range of electrophiles.</p

Synthesis, structure and stereodynamics of atropisomeric N-chloroamides

Atropisomeric N-chloroamides were efficiently accessed by electrophilic halogenation of ortho-substituted secondary anilides. The stereodynamics of atropisomerism in these novel scaffolds was interrogated by detailed experimental and computational studies, revealing that racemization is correlated with amide isomerization. The stereoelectronic nature of the amide was shown to significantly influence racemization rates, with potentially important implications for other C–N atropisomeric scaffolds

Control of absolute stereochemistry in transition-metal-catalyzed hydrogen borrowing reactions

Hydrogen borrowing catalysis represents a powerful method for the alkylation of amine or enolate nucleophiles with unactivated alcohols. This approach relies upon a catalyst which can mediate a strategic series of redox events, enabling the formation of C–C and C–N bonds and producing water as the sole by‐product. In the majority of cases these reactions have been employed to target achiral or racemic products. In contrast, the focus of this minireview is upon hydrogen borrowing catalyzed reactions in which the absolute stereochemical outcome of the process can be controlled. Asymmetric hydrogen borrowing catalysis is rapidly emerging as a powerful approach for the synthesis of enantioenriched amine and carbonyl containing products and examples involving both C–N and C–C bond formation are presented. A variety of different approaches are discussed including use of chiral auxiliaries, asymmetric catalysis and enantiospecific processes