ABSTRACT
The catalytic, undirected borylation of alkyl C-H bonds typically occurs at high reaction temperatures or with excess substrate, or both, because of the low reactivity of alkyl C-H bonds. Here we report a new iridium system comprising 2-anilino-1,10-phenanthroline as the ligand that catalyzes the borylation of alkyl C-H bonds with little to no induction period and with high reaction rates. This superior activation and reactivity profile of 2-aminophenanthroline-ligated catalysts leads to broader reaction scope, including reactions of sensitive substrates, such as epoxides and glycosidic acetals, enhanced diastereoselectivity, and higher yields of borylated products. These catalysts also enable the borylation of alkanes, amines, and ethers at room temperature for the first time. Mechanistic studies imply that facile N-borylation occurs under the reaction conditions and that iridium complexes containing N-boryl aminophenanthrolines are competent precatalysts for the reaction.
ABSTRACT
The natural product himastatin has an unusual homodimeric structure that presents a substantial synthetic challenge. We report the concise total synthesis of himastatin from readily accessible precursors, incorporating a final-stage dimerization strategy that was inspired by a detailed consideration of the compound's biogenesis. Combining this approach with a modular synthesis enabled expedient access to more than a dozen designed derivatives of himastatin, including synthetic probes that provide insight into its antibiotic activity.
Subject(s)
Chemistry Techniques, Synthetic , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacillus subtilis/ultrastructure , Cell Membrane/drug effects , Cell Membrane/ultrastructure , Dimerization , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , StereoisomerismABSTRACT
The direct α-sulfidation of tertiary amides using sulfoxide reagents under electrophilic amide activation conditions is described. Employing convenient and readily available reagents, selective functionalization takes place to generate isolable sulfonium ions en route to α-sulfide amides. Mechanistic studies identified activated sulfoxides as promoters of the desired transformation and enabled the extension of the methodology from benzylic to aliphatic amide substrates.
ABSTRACT
Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two nâπ* interactions, each with large energies (3-5 kcal/mol). The nâπ* interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the nâπ* interaction in molecular design.
Subject(s)
Density Functional Theory , Disulfides/chemistry , Piperazines/chemistry , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Oxidation-Reduction , ThermodynamicsABSTRACT
A method for activation of unprotected ceramides towards stereo- and site-selective glycosylation is described. Two-point binding of a diarylborinic acid catalyst to the ceramide accelerates its reactions with 'armed' glycosyl methanesulfonate donors, resulting in the formation of a ß-glycosidic linkage at the primary OH group.
ABSTRACT
In the presence of a diarylborinic acid catalyst, glycosyl methanesulfonates engage in regio- and stereoselective couplings with partially protected pyranoside and furanoside acceptors. The methanesulfonate donors are prepared in situ from glycosyl hemiacetals, and are coupled under mild, operationally simple conditions (amine base, organoboron catalyst, room temperature). The borinic acid catalyst not only influences site-selectivity via activation of 1,2- or 1,3-diol motifs, but also has a pronounced effect on the stereochemical outcome: 1,2-trans-linked disaccharides are obtained selectively in the absence of neighboring group participation. Reaction progress kinetic analysis was used to obtain insight into the mechanism of glycosylation, both in the presence of catalyst and in its absence, while rates of interconversion of methanesulfonate anomers were determined by NMR exchange spectroscopy (EXSY). Together, the results suggest that although the uncatalyzed and catalyzed reactions give rise to opposite stereochemical outcomes, both proceed by associative mechanisms.