Mechanistic Insights into the Racemization of Fused Cyclopropyl Isoxazolines.

Experimental and computational studies of the unexpected racemization of enantiopure fused cyclopropyl isoxazolines are reported. These studies offer insights into the mechanism of racemization, quantify the position of the transition state on the dipolar-diradical continuum, and establish a relationship between the structure and stability of this class of compounds. Experimental and computed energy barriers for racemization are also presented.

Fragment Coupling and the Construction of Quaternary Carbons Using Tertiary Radicals Generated From tert-Alkyl N-Phthalimidoyl Oxalates By Visible-Light Photocatalysis.

The coupling of tertiary carbon radicals with alkene acceptors is an underdeveloped strategy for uniting complex carbon fragments and forming new quaternary carbons. The scope and limitations of a new approach for generating nucleophilic tertiary radicals from tertiary alcohols and utilizing these intermediates in fragment coupling reactions is described. In this method, the tertiary alcohol is first acylated to give the tert-alkyl N-phthalimidoyl oxalate, which in the presence of visible-light, catalytic Ru(bpy)3(PF6)2, and a reductant fragments to form the corresponding tertiary carbon radical. In addition to reductive coupling with alkenes, substitution reactions of tertiary radicals with allylic and vinylic halides is described. A mechanism for the generation of tertiary carbon radicals from tert-alkyl N-phthalimidoyl oxalates is proposed that is based on earlier pioneering investigations of Okada and Barton. Deuterium labeling and competition experiments reveal that the reductive radical coupling of tert-alkyl N-phthalimidoyl oxalates with electron-deficient alkenes is terminated by hydrogen-atom transfer.

Catalytic enantioselective synthesis of quaternary carbon stereocentres.

Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

Direct construction of quaternary carbons from tertiary alcohols via photoredox-catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates.

A convenient method for the direct construction of quaternary carbons from tertiary alcohols by visible-light photoredox coupling of tert-alkyl N-phthalimidoyl oxalate intermediates with electron-deficient alkenes is reported.

Total synthesis of oxidized welwitindolinones and (-)-N-methylwelwitindolinone C isonitrile.

We report the total synthesis of (-)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.

Total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate.

We report the first total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. Our route features a number of key transformations, including an indolyne cyclization to assemble the [4.3.1]-bicyclic scaffold, as well as a late-stage intramolecular nitrene insertion to functionalize the C11 bridgehead carbon en route to the natural product.

Suzuki-Miyaura cross-coupling of aryl carbamates and sulfamates: experimental and computational studies.

The first Suzuki-Miyaura cross-coupling reactions of the synthetically versatile aryl O-carbamate and O-sulfamate groups are described. The transformations utilize the inexpensive, bench-stable catalyst NiCl(2)(PCy(3))(2) to furnish biaryls in good to excellent yields. A broad scope for this methodology has been demonstrated. Substrates with electron-donating and electron-withdrawing groups are tolerated, in addition to those that possess ortho substituents. Furthermore, heteroaryl substrates may be employed as coupling partners. A computational study providing the full catalytic cycles for these cross-coupling reactions is described. The oxidative addition with carbamates or sulfamates occurs via a five-centered transition state, resulting in the exclusive cleavage of the aryl C-O bond. Water is found to stabilize the Ni-carbamate catalyst resting state, which thus provides rationalization of the relative decreased rate of coupling of carbamates. Several synthetic applications are presented to showcase the utility of the methodology in the synthesis of polysubstituted aromatic compounds of natural product and bioactive molecule interest.

Suzuki-Miyaura coupling of aryl carbamates, carbonates, and sulfamates.

The first Suzuki-Miyaura cross-couplings of carbamates, carbonates, and sulfamates is described. The method provides a powerful means of using simple derivatives of phenol as precursors to polysubstituted aromatic compounds, as exemplified by a concise synthesis of the anti-inflammatory drug flurbiprofen.

Cross-coupling reactions of aryl pivalates with boronic acids.

The first cross-coupling of acylated phenol derivatives has been achieved. In the presence of an air-stable Ni(II) complex, readily accessible aryl pivalates participate in the Suzuki-Miyaura coupling with arylboronic acids. The process is tolerant of considerable variation in each of the cross-coupling components. In addition, a one-pot acylation/cross-coupling sequence has been developed. The potential to utilize an aryl pivalate as a directing group has also been demonstrated, along with the ability to sequentially cross-couple an aryl bromide followed by an aryl pivalate, using palladium and nickel catalysis, respectively.