Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation.

The development of new reactions forming asymmetric carbon-carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy--dynamic kinetic asymmetric transformation--involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods.

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.

Correction: Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes.

[This corrects the article DOI: 10.1039/D1SC06035J.].

Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes.

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known. Herein we report the Rh-catalyzed asymmetric hydrometallation of a range of meso-cyclobutenes with salicylaldehydes. The ortho-phenolic group promotes hydroacylation and can be used as a handle for subsequent transformations. The reaction proceeds via asymmetric hydrometallation of the weakly activated cyclobutene, followed by a C-C bond forming reductive elimination. A prochiral, spirocyclic cyclobutene undergoes a highly regioselective hydroacylation. This report will likely inspire the development of other asymmetric addition reactions to cyclobutenes via hydrometallation pathways.

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

This corrects the article DOI: 10.1038/ncomms15762.

Asymmetric cross-coupling of alkyl, alkenyl and (hetero)aryl nucleophiles with racemic allyl halides.

Single enantiomer molecules are important for the pharmaceutical and agrochemical industries and increasingly so in materials science. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. Dynamic asymmetric processes are powerful methods that use racemic mixtures of chiral substrates as starting material. This Feature Article focuses on asymmetric additions to racemic substrates using non-stabilized sp2- and sp3-hybridized nucleophiles. These reactions bear considerable resemblance to traditional sp2-sp2 cross-coupling reactions in terms of the starting materials used and the products obtained, but the reaction mechanisms are necessarily different.

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.

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

Csp(2)-Csp(2) 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. Csp(2)-Csp(3) 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 Csp(2)-Csp(3) 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.

Cu-catalyzed asymmetric addition of sp²-hybridized zirconium nucleophiles to racemic allyl bromides.

Alkenylzirconium nucleophiles made in situ by the hydrozirconation of terminal alkynes undergo dynamic kinetic asymmetric allylic alkenylation with racemic allyl bromides to give enantioenriched products.

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.

Iododesilylation of TIPS-, TBDPS-, and TBS-substituted alkenes in connection with the synthesis of amphidinolides B/D.

The C-Si bonds of triisopropylsilyl-substituted alkenes, 1,3-dienes, and related multifunctional substrates, as well as analogous C-TBDPS and C-TBS bonds, are readily and chemoselectively cleaved with NIS (or other sources of I(+), such as N-iodosaccharin, 1,3-diodohydantoin, and Ipy(2)BF(4)). The desired iodoalkenes are obtained stereospecifically without byproducts, provided that the reactions are carried out in CF(3)CHOHCF(3) and, in general, with 30 mol % of Ag(2)CO(3) (or AgOAc/2,6-lutidine) as an additive. Fragment C10-C18 of cytotoxic amphidinolides B1-B3 and D has been synthesized using this improved procedure.