Substituent and Solvent Effect Studies of N-Alkenylnitrone 4π Electrocyclizations.

The roles of substituent and solvent effects in promoting the 4π electrocyclization of N-alkenylnitrones to give azetidine nitrones have been investigated by experimental examination of relative rates, activation energies, and linear free energy relationships. These transformations are synthetically important because they favor the formation of a strained heterocyclic ring with imbedded functionality and stereochemical information for versatile derivatization. Mechanistic investigations, including Hammett studies, solvent-dependent Eyring studies, and solvent isotope effects, provide insight into the steric and electronic factors that control these electrocyclizations and identify trends that can be used to advance this approach towards the rapid synthesis of complex azetidines.

Lewis Basic Salt-Promoted Organosilane Coupling Reactions with Aromatic Electrophiles.

Lewis basic salts promote benzyltrimethylsilane coupling with (hetero)aryl nitriles, sulfones, and chlorides as a new route to 1,1-diarylalkanes. This method combines the substrate modularity and selectivity characteristic of cross-coupling with the practicality of a base-promoted protocol. In addition, a Lewis base strategy enables a complementary scope to existing methods, employs stable and easily prepared organosilanes, and achieves selective arylation in the presence of acidic functional groups. The utility of this method is demonstrated by the synthesis of pharmaceutical analogues and its use in multicomponent reactions.

Synthesis of Spirocyclic 1-Pyrrolines from Nitrones and Arynes through a Dearomative [3,3']-Sigmatropic Rearrangement.

A dearomative [3,3']-sigmatropic rearrangement that converts N-alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N-alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically-active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.

Generation and Rearrangement of N,O-Dialkenylhydroxylamines for the Synthesis of 2-Aminotetrahydrofurans.

A new diastereoselective route to 2-aminotetrahydrofurans has been developed from N,O-dialkenylhydroxylamines. These intermediates undergo a spontaneous C-C bond-forming [3,3]-sigmatropic rearrangement followed by a C-O bond-forming cyclization. A copper-catalyzed N-alkenylation of an N-Boc-hydroxylamine with alkenyl iodides, and a base-promoted addition of the resulting N-hydroxyenamines to an electron-deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base-promoted ring-opening and Mannich reaction has been discovered to covert 2-aminotetrahydrofurans to cyclopentyl ß-aminoacid derivatives or cyclopentenones.

Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines.

An electrocyclization route to azetidine nitrones from N-alkenylnitrones was discovered that provides facile access to these unsaturated strained heterocycles. Reactivity studies showed that these compounds undergo a variety of reduction, cycloaddition, and nucleophilic addition reactions to form highly substituted azetidines with excellent diastereoselectivity. Taken together, these transformations provide a fundamentally different approach to azetidine synthesis than traditional cyclization by nucleophilic displacement and provide novel access to a variety of underexplored strained heterocyclic compounds.

Cascade Reactions of Nitrones and Allenes for the Synthesis of Indole Derivatives.

Cascade reactions involving nitrones and allenes are known to facilitate the rapid synthesis of several indole derivatives. The chemoselectivity of these complicated transformations can be influenced by substrate functionalization, reaction conditions, and catalyst control. While seminal studies established primary reactivity patterns, recent work has illustrated the impact of these cascade reactions for creating diverse libraries, increased the breadth of these methods with facilitated access to challenging nitrones, and shown that these transformations can be controlled by asymmetric catalysis.

Catalytic Asymmetric Synthesis of Dihydropyrido[1,2-a]indoles from Nitrones and Allenoates.

An asymmetric method for the synthesis of dihydropyrido[1,2-a]indoles from mixtures of nitrones and allenoates has been developed. This transformation showcases the use of squaramide catalysis in a complicated cascade system that has been shown to be highly sensitive to reaction conditions and substituent effects. The new method provides access to enantiomerically enriched dihydropyridoindoles from modular, non-indole reagents. The optimization and scope of the new transformation is discussed in addition to initial mechanistic experiments that indicate the role of the catalyst.