Synthesis, Radiolabeling, and Biological Evaluation of the trans-Stereoisomers of 1-Amino-3-(fluoro-18F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents.

The enantiomeric non-natural cyclic amino acids (3R,4R)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid and (3S,4S)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([ 18 F]5) have been prepared as a racemic mixture in 1.3% decay corrected radiochemical yield and in greater than 99% radiochemical purity. [ 18 F]5 is transported primarily via system L with some transport occurring via system ASC, as assessed in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells. In rats bearing intracranial 9L gliosarcoma, [ 18 F]5 gave tumor to contralateral brain tissue ratios of up to 2.8. Biodistribution studies in healthy rats demonstrated that bladder accumulation is delayed until 10 min postinjection.

Synthesis, Radiolabeling, and Biological Evaluation of the cis Stereoisomers of 1-Amino-3-Fluoro-4-(fluoro-18F)Cyclopentane-1-Carboxylic Acid as PET Imaging Agents.

The non-natural cyclic amino acids (1S,3R,4S)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F]9) and (1S,3S,4R)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F]28) have been prepared in 10 and 1.7% decay corrected radiochemical yield, respectively, and in greater than 99% radiochemical purity. Cell assays in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells indicated that both compounds are substrates for amino acid transport primarily by system L, with some transport taking place via system ASC. In rats with 9L gliosarcoma, [18F]9 and [18F]28 provided high tumor to normal brain tissue ratios, with maximal ratios of 3.5 and 4.1, respectively. Biodistribution studies in healthy rats confirmed that both compounds are BBB permeable and that bladder accumulation is low until at least 5 min post injection.

Biased modulators of NMDA receptors control channel opening and ion selectivity.

Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. Here we describe a new 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 and cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel-open probability, slows receptor deactivation and decreases 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.

Esterification by Redox Dehydration Using Diselenides as Catalytic Organooxidants.

Ortho-functionalized aryl diselenides are catalytic (5.0 mol %) oxidants for the construction of esters from carboxylic acids and alcohols in the presence of stoichiometric triethyl phosphite and dioxygen in air as the terminal redox reagents (redox dehydration conditions). The reaction proceeds through the intermediacy of the anhydride and requires the presence of 10% DMAP to drive the esterification.

Aerobic, Diselenide-Catalyzed Redox Dehydration: Amides and Peptides.

At 2.5 mol % loadings using reaction temperatures between 30-55 °C, ortho-functionalized diaryl diselenides are highly effective organocatalytic oxidants for aerobic redox dehydrative amidic and peptidic bond formation using triethyl phosphite as a simple terminal reductant. This simple-to-perform organocatalytic reaction relies on the ability of selenols to react directly with dioxygen in air without recourse to metal catalysts. It represents an important step toward the development of a general, economical, and benign catalytic redox dehydration protocol.

Mechanism of Acylative Oxidation-Reduction-Condensation Reactions Using Benzoisothiazolones as Oxidant and Triethylphosphite as Stoichiometric Reductant.

We previously described a new organocatalytic oxidation-reduction-condensation for amide/peptide construction. The reaction system relies on triethylphosphite as the stoichiometric reductant and organocatalytic benzoisothiazolone/O2 in air as the oxidant. The reaction was assumed to generate catalytic quantities of S-acylthiosalicylamides as electrophiles, which are rapidly intercepted by amine reactants to generate amides/peptides and o-mercaptobenzamides. The latter are then gently reoxidized to the benzoisothiazolones under Cu-catalyzed aerobic conditions to complete the catalytic cycle. To gain a mechanistic understanding, we describe herein our studies of the stoichiometric generation of S-acylthiosalicylamides under oxidation-reduction-condensation conditions from a variety of benzoisothiazolones and carboxylic acids using triethylphosphite as the terminal reductant. These studies have revealed the presence of more than one reaction pathway when benzoisothiazolones react with triethylphosphite (including a rapid, direct deoxygenation of certain classes of benzoisothiazolones by triethylphosphite) and allow the identification of optimal reaction characteristics (benzoisothiazolone structure and solvent) for the generation of thioesters. These explorations will inform our efforts to develop highly effective and robust organocatalytic oxidation-reduction-condensation reactions that are based on the benzoisothiazolone and related motifs.

Benzoisothiazolone Organo/Copper-Cocatalyzed Redox Dehydrative Construction of Amides and Peptides from Carboxylic Acids using (EtO)3P as the Reductant and O2 in Air as the Terminal Oxidant.

Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5-36 h at 50 °C using catalytic quantities of a redox-active benzoisothiazolone and a copper complex. These catalytic "oxidation-reduction condensation" reactions are carried out open to dry air using O2 as the terminal oxidant and a slight excess of triethyl phosphite as the reductant. Triethyl phosphate is the easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C-N bonds.

Carboxyl activation via silylthioesterification: one-pot, two-step amidation of carboxylic acids catalyzed by non-metal ammonium salts.

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.

Mechanistic Insights into the Aerobic Cu(I)-Catalyzed Cross-Coupling of S-Acyl Thiosalicylamide Thiol Esters and Boronic Acids.

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.

In situ carboxyl activation using a silatropic switch: a new approach to amide and peptide constructions.

The novel reactivity of 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.

Stereocontrolled synthesis of α-amino-α'-alkoxy ketones by a copper-catalyzed cross-coupling of peptidic thiol esters and α-alkoxyalkylstannanes.

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.

Mobilizing Cu(I) for carbon-carbon bond forming catalysis in the presence of thiolate. Chemical mimicking of metallothioneins.

Copper(I) is rendered catalytically viable in the presence of thiolate by the design of a small molecule chemical analogue of the metallothionein system in which an N-O reactant serves the same conceptual purpose of the S-S reactant of the biological system.

Organometallic enantiomeric scaffolding: a strategy for the enantiocontrolled construction of regio- and stereodivergent trisubstituted piperidines from a common precursor.

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.

Novel synthesis and biological evaluation of enigmols as therapeutic agents for treating prostate cancer.

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.

Novel Substitutions of 1-Alkoxy- and 1-Arylsulfonyloxy-η-Allylmolybdenum Complexes. A Case for η-Alkenyl Carbene Complexes as Intermediates.

A series of acyclic and cyclic 1-alkoxy- and 1-arylsulfonyloxy-substituted TpMo(CO)(2)(η(3)-allyl) complexes was synthesized and characterized, and exchange of the oxygenated substituent was investigated under a variety of reaction conditions. 1-Alkoxy-substituted η(3)-allyl and η(3)-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 η(3)-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.

Synthesis and evaluation of novel proton exchange membranes containing the semisquaric Acid group.

We focus our attention here on semisquaric acid, which is known to show high acidity, as a new proton dissociating group for proton exchange membranes (PEMs). The introduction of a squaric acid group into aromatic polymers was conducted by the reaction of lithiated aromatic polymers and diisopropoxy squarate, followed by treatment with hydrochloric acid. A resulting polyphenylsulfone membrane with the squaric acid group introduced (PPSf-SQ, IEC = 4.1 meq·g(-1) ) showed proton conductivity of 1.0 × 10(-1) S·cm(-1) at 80 °C under 95% relative humidity, which indicates that the semisquaric acid has the potential to become an alternative proton-conducting group for PEMs.

A new reaction motif: "homo-S(N)2'-like" direct nucleophilic addition to neutral eta(3)-allylmolybdenum complexes. total synthesis of the antimalarial (+)-isofebrifugine.

Charge neutral TpMo(CO)(2)(5-acyloxy-eta(3)-pyranyl) and TpMo(CO)(2)(5-acyloxy-eta(3)-pyridinyl) scaffolds undergo a novel intermolecular "homo-S(N)2'-like" reaction with a variety of carbon nucleophiles. Combined with an annulative demetalation, the homo-S(N)2'-like substitution/annulative demetalation sequence rapidly generates 2,7-dioxabicyclo[4.3.0]nonane and 2-aza-7-oxabicyclo[4.3.0]nonane frameworks in good to excellent yields with high enantiopurity. An enantiocontrolled total synthesis of the antimalarial alkaloid (+)-isofebrifugine was achieved utilizing this reaction cascade.

Organometallic enantiomeric scaffolding. A molybdenum-mediated intramolecular nucleophilic ketalization-demetalation cascade. Total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin.

TpMo(CO)(2)(5-oxo-eta(3)-pyranyl) scaffolds bearing an internal alkoxide undergo a novel intramolecular nucleophilic ketalization reaction. The anionic intermediate is easily demetalated, rapidly providing the 6,8-dioxabicyclo[3.2.1]oct-3-en-2-one framework in moderate to good yields with high enantiopurity. An enantiocontrolled total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin was accomplished utilizing the reaction sequence.

A copper-catalyzed, pH-neutral construction of high-enantiopurity peptidyl ketones from peptidic s-acylthiosalicylamides in air at room temperature.

A copper-catalyzed transformation of peptidic thiol esters and boronic acids gives peptidyl ketones and takes place in DMF or DMF/H(2)O at room temperature in air (see scheme). This aerobic reaction only occurs at a thiol ester group capable of coordinating to Cu through its appendage on the sulfur center and is not hampered by racemization of the reactants or products.

Organometallic enantiomeric scaffolding. Sequential semipinacol/1,5-"Michael-like" reactions as a strategic approach to bridgehead-quaternary center aza[3.3.1]bicyclics: application to the total synthesis of (-)-adaline.

A nontraditional approach to the enantiocontrolled construction of quaternary center-bearing heteroatom-bridged bicyclo[3.3.1]nonanes (homotropanes) is reported that is based on organometallic enantiomeric scaffolding. This strategy takes advantage of the unique reactivity profiles of TpMo(CO)(2)(5-oxo-eta(3)-pyranyl) and TpMo(CO)(2)(5-oxo-eta(3)-pyridinyl) scaffolds, and features a molybdenum-mediated semipinacol/1,5-"Michael-like" reaction sequence to establish the quaternary center and synthesize the bridged bicyclic structure. An asymmetric total synthesis of (-)-adaline highlights this methodology.