Acyl transfer of in situ-generated mixed anhydrides is an important method for amide bond formation from short linkages with the easily removed byproduct CO2. To improve our understanding of the inherently difficult acyl transfer hindered by the large ring strain, a density functional theory study was performed. The calculations indicate that the amidation of activated α-aminoesters and N-protected amino acids is more likely to proceed via the self-catalytic nucleophilic substitution of the two substrates and the subsequent 1,3-acyl transfer. By comparison, the mechanism involving 1,5-acyl transfer is less kinetically favored because of the slow homocoupling of activated α-aminoesters. Furthermore, we found that the detailed mechanism of 1,3-acyl transfer on the mixed carboxylic−carbamic anhydrides depends on the catalysts. Strong acidic catalysts and bifunctional catalysts both lead to stepwise pathways, but their elementary steps are different. Basic catalysts cause a concerted C−N b

N-(2-Hydroxybenzyl)cysteine derivatives were recently disclosed to be efficient crypto-thioesters for native chemical ligation (NCL). To elucidate the mechanism of the relevant N-to-S acyl transfer process as well as the origin of the acceleration effect of the phenol substitutes, a density functional theory (DFT) study was performed. It was found that the N-to-S acyl transfer of N-(2-hydroxybenzyl)cysteine derivatives involve four major steps: concerted nucleophilic addition of thiolate/proton transfer, inversion of an amine moiety, water-assisted proton transfer and C

N bond cleavage. The phenol substitutes promote the nucleophilic addition of thiolate by protonating the carbonyl oxygen atom synergistically and the proton transfer from hydroxyl to amide nitrogen atom is the rate-determining step of the N-to-S acyl transfer. By contrast, changing the phenolic hydroxyl to methoxyl was found to significantly slow down the nucleophilic addition of thiolate and thus hinders the N-to-S ac

The Cl-initiated atmospheric oxidation mechanism of methyl isopropenyl ketone (MIK) has been investigated at the CCSD(T)/6-311++G(d,p)//MP2/6-311G(d,p) level of theory. Two reaction types initiated from Cl-addition and H-abstraction, respectively, and the key intermediates involved, IM1, IM2 (obtained from Cl-addition) and IM6 (obtained from H-abstraction), are presented and discussed. The calculated results supported the experimental results that Cl addition dominates the initial reactions of MIK with Cl atoms, and the most energetically favorable pathway is the Cl addition to the terminal carbon of C]C bond. Among the four proposed H abstraction processes, our study clearly indicated that the H-abstraction by Cl only takes place at the methyl linking to the internal alkenfinic carbon rather than the one at the methyl linking to the carbonyl carbon, which resolves the uncertainty of Habstraction encountered in experiment. In addition, the isomerization processes involved in the Cl add

Three new arylboronate ester protected amino acids and their on-resin deprotection methods have been developed. These useful building blocks were found to exhibit favorable chemical properties that are fully compatible with Fmoc strategy solid-phase peptide synthesis. Furthermore, the formation of over-oxidation side-product methionine was minimized by using N-methyl-N-phenylaniline N-oxide as the oxidizing reagent. Effective application of the three new amino acids for the synthesis of different types of peptidomimetics has been demonstrated by high-quality preparation of lipidated peptide MP-196 C-C8, on-resin head-to-tail cyclization of desotamide B, and lactam bridging of hPTHrP-(11–19) through a facile and metal-free procedure by standard Fmoc solid-phase peptide synthesis.

Here, an unpresented non-C1 synthon function of CO2 is reported to facilitate electrochemical defluorination. The introduction of CO2 modulates the electron distribution of the radical anion intermediate generated through one-electron reduction, thereby weakening the reduction potential and facilitating reduction and defluorination. CO2 is released subsequently via spontaneous decarboxylation to complete its promotion role. The presented results shed light on a distinctive utilization of CO2, which may stimulate interest in developing non-C1 synthon functions of CO2.

A KOtBu-mediated C2-benzylation of quinoline N-oxides with benzylboronates under mild reaction conditions has been developed. The reaction shows broad scope for both of the quinoline N-oxides and benzylboronates, especially, secondary and tertiary benzylboronates are also compatible with this reaction. DFT calculations indicate that the reaction is promoted by the nucleophilic addition of KOtBu to boronate rather than the deprotonation of benzylic C−H bond with KOtBu.

A 1,1-hydroboration of alkynylgermanes with unique transGe/B stereochemistry under transition-metal-free conditions is reported. Mechanistic studies suggest that a pathway involving α boration followed by a stepwise 1,2-Ge/H shift on the intermediate structurally lies between an alkyne−Ge+ π complex and a typical vinyl cation. The resulting Ge/B bimetallic modules, along with a Ge*/Ge/B trimetallic variant, can be conveniently transformed into trisubstituted olefins through iterative divergent cross-coupling. This work demonstrates that incorporating metalloids into classical organic reactions may offer unconventional chemical selectivity and efficient synthetic applications.

Nickel/photoredox dual catalyzed cross-coupling of aryl halides with alkylboron compounds is one of the effective methodologies for the construction of C(sp2) C(sp3) bonds. Although elegant results have been achieved by using alkyl trifluoroborates as alkyl radical precursors, the generation of alkyl radicals from readily available alkyl boronic esters is still limited due to their high oxidation potential. We disclosed here that activation of alkyl boronic esters by MeOLi is highly efficient for the generation of alkyl radicals under photocatalysis conditions. The reaction featured with a wide substrate scope, high functional group tolerance, and late-stage modification of bioactive substances. In addition, the method was also successfully extended to alkyl boronic acids. Experimental and computational mechanistic studies indicated that the crosscoupling likely proceeds via a Ni(I)-catalyzed pathway.

Here, an unpresented non-C1 synthon function of CO2 is reported to facilitate electrochemical defluorination. The introduction of CO2 modulates the electron distribution of the radical anion intermediate generated through one-electron reduction, thereby weakening the reduction potential and facilitating reduction and defluorination. CO2 is released subsequently via spontaneous decarboxylation to complete its promotion role. The presented results shed light on a distinctive utilization of CO2, which may stimulate interest in developing non-C1 synthon functions of CO2.

A KOtBu-mediated C2-benzylation of quinoline N-oxides with benzylboronates under mild reaction conditions has been developed. The reaction shows broad scope for both of the quinoline N-oxides and benzylboronates, especially, secondary and tertiary benzylboronates are also compatible with this reaction. DFT calculations indicate that the reaction is promoted by the nucleophilic addition of KOtBu to boronate rather than the deprotonation of benzylic C−H bond with KOtBu.

A 1,1-hydroboration of alkynylgermanes with unique transGe/B stereochemistry under transition-metal-free conditions is reported. Mechanistic studies suggest that a pathway involving α boration followed by a stepwise 1,2-Ge/H shift on the intermediate structurally lies between an alkyne−Ge+ π complex and a typical vinyl cation. The resulting Ge/B bimetallic modules, along with a Ge*/Ge/B trimetallic variant, can be conveniently transformed into trisubstituted olefins through iterative divergent cross-coupling. This work demonstrates that incorporating metalloids into classical organic reactions may offer unconventional chemical selectivity and efficient synthetic applications.

Nickel/photoredox dual catalyzed cross-coupling of aryl halides with alkylboron compounds is one of the effective methodologies for the construction of C(sp2) C(sp3) bonds. Although elegant results have been achieved by using alkyl trifluoroborates as alkyl radical precursors, the generation of alkyl radicals from readily available alkyl boronic esters is still limited due to their high oxidation potential. We disclosed here that activation of alkyl boronic esters by MeOLi is highly efficient for the generation of alkyl radicals under photocatalysis conditions. The reaction featured with a wide substrate scope, high functional group tolerance, and late-stage modification of bioactive substances. In addition, the method was also successfully extended to alkyl boronic acids. Experimental and computational mechanistic studies indicated that the crosscoupling likely proceeds via a Ni(I)-catalyzed pathway.