The first organo-catalyzed silylthioesterification of a carboxylic acid and a commercially available mercaptoorganosilane results in the in situ production of an O-silylthionoester. Subsequent amine addition forms amides in an operationally simple one-pot procedure without removal of water. The scope and efficiency of these reactions with respect to the catalyst, carboxylic acid, amine, [Si─S] moiety, and solvent are investigated. A number of functionalities are tolerated in the two-step amidation including alkene, alkyne, alkyl and aryl halides, benzylic ethers, and heterocycles with free coordinating sites.
Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. We describe here a novel class of positive allosteric modulators of N-methyl D-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential roles in learning, memory, cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel open probability, slows receptor deactivation, in addition to decreasing both single channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium influx, and shows that allosteric modulators can act as biased modulators of ion channel permeation.
A new method for the synthesis of nitriles is described. As a complement to the classic cyanation of aryl halides using cyanide sources and a transition metal catalyst, the palladium-catalyzed cross-coupling of thiocyanates with boronic acids in the presence of copper(I) thiophene-2-carboxylate (CuTC) affords nitriles in good to excellent yields.
TpMo(CO)2(5-alkenyl-η-2,3,4-pyranyl) diene complexes function as excellent chiral scaffolds for the efficient regio- and enantiocontrolled synthesis of highly functionalized 1-oxadecaline derivatives through a novel transition metal-mediated Diels-Alder reaction. Very good to excellent yields and excellent levels of endo-selectivity are obtained and the reaction gives products with complete retention of enantiomeric purity when carried out with chiral, non-racemic scaffolds. A subtle structural modification on the diene (replacement of an H by a trans-CH3 group) leads to a complete change of regiochemistry, which is discussed from a mechanistic point of view. The role of the η3-coordinated TpMo(CO)2 moiety is also critical to the further functionalization of the [4+2] cycloadducts, as illustrated by the preparation of 20 variously functionalized 1-oxadecaline derivatives (>98% ee when carried out with high enantiopurity scaffolds).
A short and efficient synthesis of high enantiopurity (−)-D-erythro-sphingosine has been achieved in 71% yield over 6 steps from N-Boc-L-serine. The key steps are high yield, racemization-free, palladium-catalyzed, copper(I)-mediated coupling of the thiophenyl ester of N-Boc-O-TBS L-serine with E-1-pentadecenyl boronic acid and the highly diastereoselective reduction of the resulting peptidyl ketone with LiAl(O-t-Bu)3H. Using this concise route (−)-D-erythro-sphingosine can be prepared on large scale and in high enantio and diastereopurity (ee >99%, de up to 99%).
Catalytic quantities of copper (I) or copper (II) sources catalyze the N-imination of boronic acids and organostannanes through reaction with oxime O-carboxylates under non-basic conditions. This method tolerates various functional groups and takes place efficiently using aryl, heteroaryl, and alkenyl boronic acids and stannanes.
α-Amino acid thiol esters derived from N-protected mono-, di-, and tripeptides couple with aryl, π-electron-rich heteroaryl, or alkenyl boronic acids in the presence of stoichiometric Cu(I) thiophene-2-carboxylate (CuTC) and catalytic Pd2(dba)3/triethylphosphite to generate the corresponding N-protected peptidyl ketones in good to excellent yields and in high enantiopurity. Triethylphosphite plays a key role as a supporting ligand by mitigating an undesired palladium-catalyzed decarbonylation-β-elimination of the α-amino thiol esters. The peptidyl ketone synthesis proceeds at room temperature under non-basic conditions and demonstrates a high tolerance to functionality.
A unified strategy for the high throughput synthesis of multigram quantities of the η3-oxopyranyl- and η3-oxopyridinylmolybdenum complexes TpMo(CO)2(η3-oxopyranyl) and TpMo(CO)2(η3-oxopyridinyl) is described (Tp = hydridotrispyrazolylborato). The strategy uses the oxa- and aza-Achmatowicz reaction for the preparation of these organometallic enantiomeric scaffolds, in both racemic and high enantiopurity versions.
A simple, modular method to prepare highly substituted pyridines is disclosed. The method employs a cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the N—O bond of α, β-unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization of the resulting 3-azatriene, and (3) air oxidation affording highly substituted pyridines in moderate to excellent isolated yields (43–91%). Starting materials are readily available and functional group tolerance is very good.
A general non-oxidative N-amidation of organostannanes and boronic acids has been developed. Under non-basic conditions a wide variety of aryl, alkenyl, and heteroaryl organostannanes and boronic acids couple efficiently with O-acetyl hydroxamic acids in the presence of Cu(I) sources.