74 research outputs found
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
Stereospecific NickelāCatalyzed CrossāCoupling Reactions of Alkyl Grignard Reagents and Identification of Selective AntiāBreastāCancer Agents
Alkyl Grignard reagents that contain Ī²-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp(3))-C(sp(3)) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells
Role of Secondary Structure in the Asymmetric Acylation Reaction Catalyzed by Peptides Based on Chiral Calpha-Tetrasubstituted alpha-Amino Acids
On the Origins of Kinetic Resolution of Cyclohexane-1,2-diols Through Stereoselective Acylation by Chiral Tetrapeptides
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Mechanism and Origins of Ligand-Controlled Stereoselectivity of NiāCatalyzed SuzukiāMiyaura Coupling with Benzylic Esters: AĀ Computational Study
Nickel catalysts have shown unique
ligand control of stereoselectivity
in the SuzukiāMiyaura cross-coupling of boronates with benzylic
pivalates and derivatives involving CĀ(sp<sup>3</sup>)āO cleavage.
The SIMes ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces
the stereochemically inverted CāC coupling product, while the
tricyclohexylphosphine (PCy<sub>3</sub>) ligand delivers the retained
stereochemistry. We have explored the mechanism and origins of the
ligand-controlled stereoselectivity with density functional theory
(DFT) calculations. The oxidative addition determines the stereoselectivity
with two competing transition states, an S<sub>N</sub>2 back-side
attack type transition state that inverts the benzylic stereogenic
center and a concerted oxidative addition through a cyclic transition
state, which provides stereoretention. The key difference between
the two transition states is the substrateānickelāligand
angle distortion; the ligand controls the selectivity by differentiating
the ease of this angle distortion. For the PCy<sub>3</sub> ligand,
the nickelāligand interaction involves mainly Ļ-donation,
which does not require a significant energy penalty for the angle
distortion. The facile angle distortion with PCy<sub>3</sub> ligand
allows the favorable cyclic oxidative addition transition state, leading
to the stereoretention. For the SIMes ligand, the extra dāp
back-donation from nickel to the coordinating carbene increases the
rigidity of the nickelāligand bond, and the corresponding angle
distortion is more difficult. This makes the concerted cyclic oxidative
addition unfavorable with SIMes ligand, and the back-side S<sub>N</sub>2-type oxidative addition delivers the stereoinversion
Selection of Enantioselective Acyl Transfer Catalysts from a Pooled Peptide Library through a Fluorescence-Based Activity Assay: An Approach to Kinetic Resolution of Secondary Alcohols of Broad Structural Scope
Structure-Selectivity Relationships and Structure for a Peptide-Based Enantioselective Acylation Catalyst
Rhodium-Catalyzed Kinetic Resolution of Tertiary Homoallyl Alcohols via Stereoselective Carbon-Carbon Bond Cleavage
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