Au-Catalyzed Asymmetric Formal [3 + 2] Cycloaddition of Isocyanoacetates with Maleimides

An efficient protocol for the Au^I-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with phenylmaleimide has been developed. In the presence of cationic Au^I/DTBM-segphos complex, excellent diastereoselectivity and high levels of enantioselectivity (up to 97% ee) have been attained with a variety of α-substituted isocyanoacetates. The synthetic potential of the resulting enantioenriched 1-pyrrolines has been demonstrated by the preparation of highly substituted pyrrolidines bearing a quaternary stereocenter

Au-Catalyzed Asymmetric Formal [3 + 2] Cycloaddition of Isocyanoacetates with Maleimides

An efficient protocol for the Au^I-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with phenylmaleimide has been developed. In the presence of cationic Au^I/DTBM-segphos complex, excellent diastereoselectivity and high levels of enantioselectivity (up to 97% ee) have been attained with a variety of α-substituted isocyanoacetates. The synthetic potential of the resulting enantioenriched 1-pyrrolines has been demonstrated by the preparation of highly substituted pyrrolidines bearing a quaternary stereocenter

Cu^I‑Catalyzed Asymmetric [3 + 2] Cycloaddition of Azomethine Ylides with Cyclobutenones

The catalytic asymmetric 1,3-dipolar cycloaddition of cyclobutenones with azomethine ylides provides straightforward access to densely substituted 3-azabicyclo[3.2.0]­heptanes. In the presence of Cu^I/(R)-Fesulphos as the catalytic system, high levels of diastereoselectivity and enantioselectivity were achieved (up to 98% enantiomeric excess (ee))

Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Hydroamination Sequence: Expeditious Access to Enantioenriched Pyrroloisoquinoline Derivatives

A three-step reaction sequence has been developed to prepare a variety of enantioenriched pyrroloisoquinoline derivatives. The process involves a catalytic asymmetric azomethine ylide 1,3-dipolar cycloaddition followed by an intramolecular Au^I-catalyzed alkyne hydroamination and enamine reduction

Enantioselective Synthesis of α‑Heteroarylpyrrolidines by Copper-Catalyzed 1,3-Dipolar Cycloaddition of α‑Silylimines

α-Heteroarylpyrrolidines have been efficiently prepared via 1,3-dipolar cycloaddition between silylimines and activated olefins. In the presence of Cu­(CH₃CN)₄PF₆/Walphos as catalytic system, high levels of enantioselectivity (up to ≥99% ee) and diastereoselectivity were achieved (major formation of C-2/C-4 <i>trans</i>-substituted pyrrolidines). The reaction is compatible with a broad variety of dipolarophiles including maleimides, maleates, fumarates, nitroalkenes, and vinylsulfones. The resulting cycloadducts can be transformed into bioactive pyrrolidine derivatives

Regiocontrolled Cu^I-Catalyzed Borylation of Propargylic-Functionalized Internal Alkynes

Good to excellent reactivity and regiocontrol have been achieved in the Cu^I-catalyzed borylation of dialkyl internal alkynes with bis­(pinacolato)­diboron. The presence of a propargylic polar group (OH, OR, SAr, SO₂Ar, or NHTs), in combination with PCy₃ as ligand, allowed maximizing the reactivity and site-selectivity (β to the propargylic function). DFT calculations suggest a subtle orbitalic influence from the propargylic group, matched with ligand and substrate size effects, as key factors involved in the high β-selectivity. The vinylboronates allowed the stereoselective synthesis of trisubstituted olefins, while allylic substitution of the SO₂Py group without affecting the boronate group provided access to formal hydroboration products of unbiased dialkylalkynes

Palladium-Catalyzed Coupling of Arene C–H Bonds with Methyl- and Arylboron Reagents Assisted by the Removable 2-Pyridylsulfinyl Group

The Pd^II-catalyzed direct coupling of arene C–H bonds with organoboron reagents assisted by the 2-pyridylsulfinyl group is reported. Methylboronic acid and arylboronic acid neopentyl esters proved to be efficient coupling partners, furnishing methylated arenes and biaryl products in moderate to good yields. The 2-pyridylsulfinyl group can be easily removed to provide the free biaryls. The essential role of the 2-pyridyl unit in stabilizing the cyclopalladation complex was demonstrated by X-ray diffraction analysis of the palladacycle intermediate

Palladium-Catalyzed Coupling of Arene C–H Bonds with Methyl- and Arylboron Reagents Assisted by the Removable 2-Pyridylsulfinyl Group

The Pd^II-catalyzed direct coupling of arene C–H bonds with organoboron reagents assisted by the 2-pyridylsulfinyl group is reported. Methylboronic acid and arylboronic acid neopentyl esters proved to be efficient coupling partners, furnishing methylated arenes and biaryl products in moderate to good yields. The 2-pyridylsulfinyl group can be easily removed to provide the free biaryls. The essential role of the 2-pyridyl unit in stabilizing the cyclopalladation complex was demonstrated by X-ray diffraction analysis of the palladacycle intermediate

Pd-Catalyzed Directed <i>ortho</i>-C–H Alkenylation of Phenylalanine Derivatives

A practical Pd-catalyzed <i>ortho</i>-olefination of enantioenriched <i>N</i>-(SO₂Py)-protected aryl-alanine and norephedrine derivatives with electron-deficient alkenes has been developed using <i>N</i>-fluoro-2,4,6-trimethyl­pyridinium triflate as the terminal oxidant. The reaction occurs efficiently with excellent monosubstitution selectivity and without loss of enantiopurity. This cross-coupling proved to be broad in scope, tolerating a variety of steric and electronic changes to both coupling partners. Removal of the directing group under mild conditions provides access to optically active tetrahydro­isoquinoline-3-carboxylic acid derivatives (Tics) with good diastereocontrol and with very small erosion of enantiomeric purity

Palladium-Catalyzed Carbonylative Cyclization of Amines via γ‑C(sp³)–H Activation: Late-Stage Diversification of Amino Acids and Peptides

The selective γ-C­(sp³)–H carbonylation of <i>N</i>-(2-pyridyl)­sulfonyl (<i>N</i>-SO₂Py)-protected amines has been accomplished by using palladium catalysis and Mo­(CO)₆ as carbonyl source. The reaction provides a powerful approach for derivatization of amine-based moieties, including amino acids, into richly functionalized γ-lactams. Not only methyl groups, but also methylene C–H bonds of cyclopropanes and conformationally biased molecules can be activated to provide ring-fused γ-lactam derivatives. This carbonylation protocol is also amenable to the late-stage diversification of more-complex multifunctional molecules such as dipeptides and tripeptides, demonstrating the key role of the <i>N</i>-SO₂Py as directing group and its capacity to override other inherent substrate coordinating elements. In addition to providing an attractive solution to the difficulties in handling hazardous CO gas, the use of Mo­(CO)₆ as an air-stable solid source of CO in substoichiometric amount (0.33 equiv) ensures Pd^II-catalytic activity by preventing its decomposition or deactivation under excess of CO via reduction of Pd^II to Pd⁰ or saturation of the metal coordination sphere. Indeed, significantly lower efficiency is observed when the reactions are carried out under CO atmosphere (1 atm), or in the presence of increased amounts of Mo­(CO)₆. A series of experimental and DFT mechanistic studies provide important insights about the reaction mechanism