Mireia Sidera

Formation of Quaternary Centers by Copper‐Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Pure and simple: Alkylzirconocenes generated in situ from simple alkenes are used in highly enantioselective copper-catalyzed 1,4-addition reactions to trisubstituted cyclic enones to generate quaternary centers. These reactions operate at room temperature under a range of conditions and tolerate many functional groups. Cp=cyclopentadienyl, Tf=trifluoromethanesulfonyl. Copyright

Copper-catalyzed asymmetric conjugate addition of alkylzirconium reagents to cyclic enones to form quaternary centers

This protocol describes the catalytic asymmetric formation of all-carbon quaternary centers—a distinctive feature of many natural products and pharmaceuticals—via conjugate addition of alkylzirconium reagents to a tertiary enone. This methodology uses alkenes as starting materials and enables the incorporation of functional groups. The alkylzirconium reagent is generated in situ by mixing the alkene with the Schwartz reagent. The alkylzirconium is added to a solution containing a copper-ligand complex, and then the enone is added to the mixture. The addition of pent-4-en-1-ylbenzene to 3-methyl-2-cyclohexenone is detailed herein as a generic example. This procedure works at room temperature (∼25 °C), and it is scalable to at least 1.5 g. The setup of the reaction takes 3–5 h and the reaction goes to completion within 4–20 h.

Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids

Csp2−Csp2 cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp2−Csp3 cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. Here we report a highly enantioselective Csp2−Csp3 bond-forming method that couples arylboronic acids to racemic allyl chlorides. Both enantiomers of a cyclic chloride are converted into a single enantiomer of product via a dynamic kinetic asymmetric transformation. This Rh-catalysed method uses readily available and inexpensive building blocks and is mild and broadly applicable. For electron-deficient, electron-rich or ortho-substituted boronic acids better results are obtained with racemic allyl bromides. Oxygen substitution in the allyl halide is tolerated and the products can be functionalized to provide diverse building blocks. The approach fills a significant gap in the methods for catalytic asymmetric synthesis. Cross-couplings between boronic acids and halides are a mainstay of synthetic organic chemistry but enantioselective Csp2−Csp3 couplings are rare, and simply retaining the stereochemistry of the starting material is problematic. Now, it is shown that racemic allylic halides can converted to single enantiomer products by a rhodium(I)-catalysed asymmetric allylic arylation using arylboronic acids

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

Using asymmetric catalysis to simultaneously form carbon–carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib—an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.

Mechanistic Studies on a Cu-Catalyzed Asymmetric Allylic Alkylation with Cyclic Racemic Starting Materials

Mechanistic studies on Cu-catalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide electrophiles were conducted using a combination of isotopic labeling, NMR spectroscopy, kinetic modeling, structure-activity relationships, and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric Cu-ligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cu-counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide intermediate. We quantify the rate of Cu-catalyzed allyl iodide isomerization and identify a series of conditions under which the formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitable substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic seven-membered-ring allyl chlorides for the first time. 1H and 2H NMR spectroscopy experiments on reactions using allylic phosphates showed the importance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantiomer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copper-catalyzed asymmetric reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly.

Author Correction: Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

This corrects the article DOI: 10.1038/ncomms15762.