Among the nine functionals benchmarked, the most accurate γ are obtained by Tα-LC-BLYP, reducing about half the errors of LC-BLYP.

Reactions that enable selective functionalization of strong aliphatic C−H bonds open new synthetic paths to rapidly increase molecular complexity and expand chemical space. Particularly valuable are reactions where site-selectivity can be directed toward a specific C−H bond by catalyst control. Herein we describe the catalytic site-and stereoselective γ-lactonization of unactivated primary C−H bonds in carboxylic acid substrates. The system relies on a chiral Mn catalyst that activates aqueous hydrogen peroxide to promote intramolecular lactonization under mild conditions, via carboxylate binding to the metal center. The system exhibits high site-selectivity and enables the oxidation of unactivated primary γ-C−H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at αand β-carbons. With substrates bearing nonequivalent γ-C−H bonds, the factors governing site-selectivity have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, γ-lactonization at methyl groups in gem-dimethyl structural units of rigid cyclic and bicyclic carboxylic acids can be achieved with unprecedented levels of diastereoselectivity. Such control has been successfully exploited in the late-stage lactonization of natural products such as camphoric, camphanic, ketopinic, and isoketopinic acids. DFT analysis points toward a rebound type mechanism initiated by intramolecular 1,7-HAT from a primary γ-C−H bond of the bound substrate to a highly reactive Mn IV -oxyl intermediate, to deliver a carbon radical that rapidly lactonizes through carboxylate transfer. Intramolecular kinetic deuterium isotope effect and 18 O labeling experiments provide strong support to this mechanistic picture.

We employ density functional theory (DFT) and time-dependent DFT (TDDFT) calculations to investigate the structural, energetic and optical properties of a new computationally designed RNA alphabet, where the nucleobases, A,G, C, andU (ts-bases), have been derived by replacing sulfur with selenium in the previously reported tz-bases, based on the isothiazolo[4,3-d]pyrimidine heterocycle core. We find out that the modeled non-natural bases have minimal impact on the geometry and energetics of the classical Watson-Crick base pairs, thus potentially mimicking the natural bases in a RNA duplex in terms of H-bonding. In contrast, our calculations indicate that H-bonded base pairs involving the Hoogsteen edge of purines are destabilized as compared to their natural counterparts. We also focus on the photophysical properties of the non-natural bases and correlate their absorption/emission peaks to the strong impact of the modification on the energy of the lowest unoccupied molecular orbital. It is indeed stabilized by roughly 1.1-1.6 eV as compared to the natural analogues, resulting in a reduction of the gap between the highest occupied and the lowest unoccupied molecular orbital from 5.3-5.5 eV in the natural bases to 3.9-4.2 eV in the modified ones, with a consequent bathochromic shift in the absorption and emission spectra. Overall, our analysis clearly indicates that the newly modelled ts-bases are expected to exhibit better fluorescent properties as compared to the previously reported tz-bases, while retaining similar H-bonding properties. In addition, we show that a new RNA alphabet based on size-extended benzo-homologated ts-bases can also form stable Watson-Crick base pairs with the natural complementary nucleobases.