The novel reactivity of the O-silylthionoesters with amine nucleophiles to generate oxoamides (rather than thioamides) is described. A straightforward first-generation trimethylsilylation protocol using bistrimethylsilylacetamide (BSA) combined with the unique reactivity of the O-silylthionoesters toward 1° and 2° amines to generate oxoamides provides the simplest means of activating a thiol acid for peptide bond formation at neutral pH. Excellent stereoretention is observed.
Metal binding proteins are essential to many life-sustaining processes. The non-thermodynamic binding selectivity and specificity of metals to proteins in living systems has captured the focus of much research effort. Equally essential to life-sustaining processes are the biomolecular mechanisms by which tightly bound metals are selectively transferred, or released from a thermodynamically strong coordination sphere within a protein. As mechanistic knowledge of these metal mobilizing biological processes is uncovered, occasions may arise for translating the biological processes into ones useful in chemical catalysis in the laboratory. In particular, the biomolecular mechanisms by which Nature releases catalytically important thiophilic metals like Cu from high-sulfur binding sites within proteins should be useful points of inspiration from which to develop novel preparative protocols where the catalytic turnover of a thiophilic metal in a sulfur-containing environment is essential. Opportunities for productive metal catalysis in sulfur-rich systems are found in energy-related research (metal-catalyzed desulfurization of carbon-based fuels), detoxification of nerve gas agents (metal-catalyzed transformations of phosphonothioate and phosphorothioates), as well as in the synthesis of fine chemicals through desulfitative transformations.
Reported herein is a general and efficient method to construct 2,3,6-trisubstituted piperidines in a substituent-independent fashion. From the high enantiopurity organometallic scaffold (−)-Tp(CO)2[(η-2,3,4)-(1S, 2S)-1-benzyloxycarbonyl-5-oxo-5,6-dihydro-2H-pyridin-2-yl)molybdenum (Tp = hydridotrispyrazolylborato), a variety of TpMo(CO)2-based 2,3,6-trifunctionalized complexes of the (η-3,4,5-dihydropyridinyl) ligand were easily obtained in 5 steps through a sequence of highly regio- and stereospecific metal-influenced transformations (15 examples). From the 2,3,6-trifunctionalized molybdenum complexes, either 2,6-cis-3-trans or 2,3,6-cis systems were selectively obtained through the choice of an appropriate stereodivergent demetalation protocol. The potential of this strategy in synthetic chemistry was demonstrated by the short total synthesis of four natural and one non-natural alkaloids: indolizidines (±)-209I and (±)-8-epi-219F in the racemic series, and enantiocontrolled syntheses of (−)-indolizidine 251N, (−)-quinolizidine 251AA, and (−)-dehydroindolizidine 233E.
A series of acyclic and cyclic 1-alkoxy- and 1-arylsulfonyloxy-substituted TpMo(CO)2(η3-allyl) complexes was synthesized and characterized, and exchange of the oxygenated substituent was investigated under a variety of reaction conditions. 1-Alkoxy-substituted η3-allyl and η3-butenyl complexes participated in direct, uncatalyzed exchange of the alkoxy substituent with benzylamine, but required a Lewis acid for exchange with alcohols. The 1-alkoxy-substituted η3-cyclohexenyl complex was unreactive towards exchange under all conditions investigated. The corresponding acyclic arylsulfonyloxy-substituted complexes underwent direct, uncatalyzed exchange with both benzylamine and alcohols, while the arylsulfonyloxy-substituted cyclohexenyl compounds participated in direct substitution with benzylamine, but not alcohols. High enantiopurity acyclic and cyclic alkoxy- and arylsulfonyloxy-substituted complexes provided exchange products with predominant, but incomplete, losses in enantiomeric excess in all cases examined. Mechanisms accounting for the observed reactivity trends and for the losses in enantiomeric excess are discussed. Reaction of alkoxy-substituted complexes through an associative mechanism and of arylsulfonyloxy-substituted compounds through a dissociative mechanism is suggested.
A stereocontrolled synthesis of α-amino-α′-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters and chiral nonracemic α-alkoxyalkylstannanes gives α-amino-α′-alkoxy ketones in good to excellent yields with complete retention of configuration at the α-amino- and α-alkoxy-substituted stereocenters.
The Density Functional Theory (DFT) method is used to elucidate the nature of the active species and the mechanism of the aerobic CuI-catalyzed cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids reported previously (J. Am. Chem. Soc. 2007, 129, 15734–15735; Angew. Chem., Int. Ed. 2009, 48, 1417-1421). The energetically lowest isomer of the proposed active species [LC(O)R1]Cu-(O2)-Cu[LC(O)R1]2+, 2a, (where L = thiolatosalicylamide) is found to be I1(OO,OO) with a μ-η2:η2-peroxo Cu2O2-core, while its isomers I2(OO,OO) with a bis-(μ-O) Cu2O2-core and I3(OO,OO) with a (μ-η1:η1) Cu2O2-core lie only a few kcal/mol higher and separated by 4–7kcal/mol energy barriers. In all these isomers, the thiol ester is coordinated to the Cu-centers via its two O-ends. Isomers with (SO,OO) and (SO,SO) coordination modes of the thiol esters lie slightly higher and are separated with moderate energy barriers. We found the latter isomers to be vital for the reported CuI-templated cross-coupling of S-acyl thiosalicylamide thiol esters and boronic acids under aerobic conditions. The presence of an anion (halide, carboxylate modeled as formate) in the reaction medium is found to be necessary. Its coordination to the active catalyst I1(SO,SO) is the first step of the proposed anion-assisted transmetalation by boronic acid. Overall the transmetalation reaction requires 34.0 kcal/mol and is 24.0 kcal/mol exergonic. This conclusion is in reasonable agreement with available experiments. The C-C bond formation in the transmetalation product requires a 6.3 kcal/mol lower energy barrier and is highly exergonic.
Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind−Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.
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).