Decarboxylative Alkyl–Alkyl Cross‐Coupling Reactions

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137566/1/anie201605593_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137566/2/anie201605593.pd

Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers with Isotopically-Labeled Grignard Reagents

In this manuscript we highlight the potential of stereospecific nickel-catalyzed cross-coupling reactions for applications in the pharmaceutical industry. Using an inexpensive and sustainable nickel catalyst, we report a gram-scale Kumada cross-coupling reaction. Reactions are highly stereospecific and proceed with inversion at the benzylic position. We also expand the scope of our reaction to incorporate isotopically labeled substituents

Silver-Catalyzed Enantioselective Propargylation Reactions of N-Sulfonylketimines.

The enantioselective silver-catalyzed propargylation of N-sulfonylketimines is described. This reaction proceeds in high yield and excellent enantiomeric ratio and is compatible with a wide variety of diaryl- and alkylketimines. Synthetic transformations of homopropargylic products via enyne ring-closing metathesis, Sonogashira cross-coupling, and reduction reactions proceed with high stereochemical fidelity. Both allenyl and propargyl borolane reagents can be used to obtain homopropargylic products, a distribution most consistent with a mechanism involving transmetalation of the silver catalyst with the borolane reagent

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers and esters.

This Account presents the development of a suite of stereospecific alkyl-alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal. The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination. Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details. Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent

Selective synthesis of either enantiomer of an anti-breast cancer agent via a common enantioenriched intermediate

A stereoselective synthesis of a bioactive triarylmethane is described. Key to the synthesis is a nickel-catalyzed Suzuki-Miyaura coupling which proceeds with retention at the benzylic center. This method is complementary to our previously reported nickel-catalyzed Kumada coupling which proceeds with inversion. Together, the two methods allow for efficient access to either enantiomer of biologically relevant triarylmethanes from a common enantioenriched intermediate

Functional-Group-Tolerant, Nickel-Catalyzed Cross-Coupling Reaction for Enantioselective Construction of Tertiary Methyl-Bearing Stereocenters

The first Negishi nickel-catalyzed stereospecific cross-coupling reaction of secondary benzylic esters is reported. A series of traceless directing groups is evaluated for ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially available 2-(methylthio)­acetic acid are most effective. The products are formed in high yield and with excellent stereospecificity. A variety of functional groups are tolerated in the reaction including alkenes, alkynes, esters, amines, imides, and <i>O</i>-, <i>S</i>-, and <i>N</i>-heterocycles. The utility of this transformation is highlighted in the enantioselective synthesis of a retinoic acid receptor agonist and a fatty acid amide hydrolase inhibitor

Enantiospecific Intramolecular Heck Reactions of Secondary Benzylic Ethers

Enantioenriched methylene­cyclo­pentanes are synthesized by stereospecific, nickel-catalyzed Heck cyclizations of secondary benzylic ethers. The reaction proceeds in high yield and enantiospecificity for benzylic ethers of both π-extended and simple arenes. Ethers with pendant 1,2-disubstituted olefins form trisubstituted olefins with control of both absolute configuration and alkene geometry. Diastereoselective synthesis of a polycyclic furan is demonstrated