Michael Harmata

Herein, we report a DFT study of a 4+3 cycloaddition reaction involving a theoretically proposed oxyallylic cation stabilized by a chiral sulfoximine group. The growing importance of the sulfoximine functional group in chemistry cannot be overstated. Computed energy profiles indicate that the reaction is feasible, and geometric and topological analyses (QTAIM, ESP, and NCI) of all transition‐states elucidate bonding and the non‐covalent interactions stabilizing the favored pathway. The results reveal a strong preference for the endo pathway with modest diastereoselectivity.

Sulfoximines are valuable scaffolds in pharmaceuticals, yet their aqueous-phase stability and reactivity remain underexplored. We report a systematic study of sulfoximine–carboxylic acid coupling in water using hydroxypropyl methylcellulose (HPMC) as a microenvironment. In situ ¹⁹F NMR revealed potential key intermediates and the critical role of LiCl in their stabilization in water. The optimized protocol tolerates diverse functional groups, operates under mild conditions, and scales efficiently. These findings enable efficient sulfoximine functionalization and provide mechanistic insights.

An efficient, two-step synthetic route for PS-750-M has been developed, offering significant improvements in terms of sustainability, scalability, and operational simplicity compared to the conventional four-step process. The new methodology eliminates hazardous reagents, toxic solvents, and chromatography, while enabling solvent recovery and catalyst reuse. Quantitative green metrics reveal dramatic reductions in environmental impact, with E-factor and process mass intensity (PMI) decreasing by over 90% and 85%, respectively. Importantly, PS-750-M, synthesized via this greener route, retains its micellar catalytic efficiency tested on a variety of transformations, including palladium-catalyzed C–C couplings, Buchwald–Hartwig aminations, biaryl ketone formation, and rapid amide couplings. These results support the industrial viability of the redesigned process and its alignment with the principles of green chemistry, potentially facilitating the large-scale adoption of this approach in pharmaceutical and fine chemical manufacturing.

Selected azabicyclo[4.3.1]deca-3,8-dienes react with NIS in HFIP to form bridgehead ethers via a net oxidative C–H activation.

The ABCE tetracyclic ring system of daphnicyclidin A was prepared using an intramolecular (4 + 3) cycloaddition of an oxidopyridinium ion as the key step.

N‐alkylation of 5‐hydroxynicotinic acid esters with electrophiles containing diene functionality produces salts that undergo intramolecular (4+3) cycloaddition reactions upon heating in the presence of base. Initial studies used a three‐carbon tether to join the pyridinium ion and diene, revealing some aspects of the inherent selectivity of the reaction with such substrates. Much more challenging was the synthesis of related species possessing only a two‐carbon tether. Nevertheless, the cycloaddition of such compounds was successful, leading directly to the ABC ring system of the alkaloid daphnicyclidin A.

Easily prepared cycloadducts derived from the (4+3) cycloaddition of oxidopyridinium ions with dienes reacted intramolecularly in a [2+2] cycloaddition process to afford complex polycyclic species in which the tropane skeleton was embedded.

The (4 + 3) cycloaddition of 2-trialkylsilyl-4-alkylbutadienes with an N-methyloxidopyridinium ion affords cycloadducts with high regioselectivity and excellent endo selectivity.

Oxidopyridinium ions bearing an ester group at the 5-position undergo (4 + 3) cycloaddition reaction to afford congeners of 7-azabicyclo[4.3.1]decane. The reaction generally proceeds in high yield, although an excess of diene is often required to achieve such yields. The reaction is highly regioselective, but not endo/exo selective. It appears the cycloaddition process can be either kinetically or thermodynamically controlled, depending on the nature of the diene used and the reaction time. An intramolecular Heck reaction was used to demonstrate that some chemistry is possible with the cycloadducts.