Ambient Pressure Ir@Hal-Catalyzed Hydrogenation of Aryl Aldehydes, Ketones, and Phenol.

A reliable method for encapsulation of iridium nanoparticles (6-8 nm particles) in halloysite Ir@Hal has been developed. The Ir@Hal nanocomposite was found to be a highly efficient catalyst for the hydrogenation and transfer hydrogenation of the carbonyl group of aryl aldehydes, aryl ketones, and aliphatic ketones to afford alcohols in high yields. In addition, phenol could be hydrogenated to furnish cyclohexanol (93-95% yield) at ambient pressure at 50 °C.

Synthesis of Simple 3,3-Diarylazetidines from -Boc-3-arylazetidinols Using Friedel-Crafts Arylation Conditions.

A synthesis of 3,3-diarylazetidines from -Boc-3-aryl-3-azetidinols using Friedel-Crafts arylation conditions with AlCl is described. A series of substituted diarylazetidines were readily prepared and isolated as the oxalate salts in high yield and high purity. The 3,3-diarylazetidine oxalates were then easily converted into -alkyl and -acyl analogues (RX, NaHCO/DMF/100 °C) in high overall yields.

Halloysite-Catalyzed Esterification of Bio-Mass Derived Acids.

Halloysite, a natural clay with a hollow tubular structure, was studied as a catalyst for the esterification of biomass-derived carboxylic acids (levulinic acid, fumaric acid, maleic acid, and succinic acid) with four different alcohols (MeOH, EtOH, -PrOH, and -BuOH). Reaction conditions were optimized (10 mol % halloysite, 170 °C, 24 h) and gave high yields of the corresponding esters and diesters (>90%). The halloysite was easily recovered and recycled after washing and drying.

Room-Temperature Aqueous Suzuki-Miyaura Cross-Coupling Reactions Catalyzed via a Recyclable Palladium@Halloysite Nanocomposite.

A reliable method for encapsulation of palladium nanoparticles (6-8 nm particles) in halloysite (Pd@Hal) has been developed. The Pd@Hal was found to be a highly efficient room-temperature catalyst for Suzuki-Miyaura cross-coupling reactions that gave high yields of a diverse array of coupling products in 5:2 n-PrOH/HO within 1 h. The catalytic system was remarkably effective with a broad substrate scope.

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors.

Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. Although the structural bases of these compounds are scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity.

Synthesis, hepatotoxic evaluation and antipyretic activity of nitrate ester analogs of the acetaminophen derivative SCP-1.

A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6).

2-Substituted 3β-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations.

Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3β-aryltropanes with 2β-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2α-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.

3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters.

A series of 3-aryl-3-arylmethoxy-azetidines were synthesized and evaluated for binding affinities at dopamine and serotonin transporters. The 3-aryl-3-arylmethoxyazetidines were generally SERT selective with the dichloro substituted congener 7c (Ki=1.0 nM) and the tetrachloro substituted derivative 7i (Ki=1.

Further structure-activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters.

The synthesis and structure-activity relationships of 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives were investigated at the dopamine transporter (DAT), the serotonin transporter (SERT) and norepinephrine transporter (NET).

Synthesis and structure-activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands.

A series of benzyl esters of meperidine and normeperidine were synthesized and evaluated for binding affinity at serotonin, dopamine and norepinephrine transporters. The 4-methoxybenzyl ester 8b and 4-nitrobenzyl ester 8c in the meperidine series and 4-methoxybenzyl ester 14a in the normeperidine series exhibited low nanomolar binding affinities at the SERT (K(i) values <2nM) and high SERT selectivity (DAT/SERT >1500 and NET/SERT >1500).

Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H.

The efficient and expeditious syntheses of both enantiomers of the amphibian alkaloid cis-225H have been achieved. Utilizing a common cis-2,5-disubstituted pyrrolidine building block derived from (+)-2-tropinone, the enantioselective syntheses have established the absolute configuration of these alkaloids as (+)-(2R,5S) and (-)-(5S,2R).

First Multi-gram Preparation SCP-123, A Novel Water Soluble Analgesic.

A short multi-gram process for the preparation of the analgesic compound SCP-123 (4) and its sodium salt has been developed.

Synthesis and monoamine transporter affinity of 3alpha-arylmethoxy-3beta-arylnortropanes.

A series of 3-arylnortrop-2-enes and 3alpha-arylmethoxy-3beta-arylnortropanes were synthesized and evaluated for binding affinity at monoamine transporters. The 3-(3,4-dichlorophenyl)nortrop-2-ene (6e) exhibited high affinity for the SERT (K(i)=0.3 nM).

Enantioselective syntheses of both enantiomers of noranabasamine.

Both the R and S enantiomers of the amphibian alkaloid noranabasamine were prepared in >30% overall yield with 80% ee and 86% ee, respectively. An enantioselective iridium-catalyzed N-heterocyclization reaction with either (R)- or (S)-1-phenylethylamine and 1-(5-methoxypyridin-3-yl)-1,5-pentanediol was employed to generate the 2-(pyridin-3-yl)-piperidine ring system in 69-72% yield.

Synthesis and CB1 cannabinoid receptor affinity of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles.

A series of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles were synthesized regioselectively using click chemistry and evaluated at CB1 cannabinoid receptors. The n-propyl ester 11 (K(i)=4.6 nM) and phenyl ester 14 (K(i)=11 nM) exhibited the most potent affinity of the series.

General strategy for the construction of enantiopure pyrrolidine-based alkaloids. Total synthesis of (-)-monomorine.

An enantiopure cis-2,5-disubstituted pyrrolidine building block was prepared from cocaine. The synthetic utility of this compound as a chiral building block was demonstrated by a short and efficient synthesis of the pyrrolidine-based alkaloid (-)-monomorine (six steps, 37% overall yield).

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs.

A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP.

Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives.

A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3alpha derivatives were found to be the most potent compounds with the 3alpha-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.

Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters.

The structure-activity relationships of 3',4'-dichloro-meperidine were investigated at dopamine (DAT) and serotonin transporters (SERT). Large ester substituents and lipophilic groups at the 4-position favored molecular recognition at the SERT. The benzyl ester of 3',4'-dichloro-meperidine exhibited high potency and high selectivity for the SERT (DAT/SERT=760).

Synthesis and biological evaluation of meperidine analogues at monoamine transporters.

A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at mu-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (K(i) = 0.

Novel chromium(VI) catalyzed oxidation of N-alkylamides to imides with periodic acid.

A novel and practical procedure for preparation of imides is described using chromium(VI) oxide to catalyze the oxidation of N-alkylamides with periodic acid in the presence of acetic anhydride in acetonitrile.

Synthesis and monoamine transporter binding of 2-(diarylmethoxymethyl)-3 beta-aryltropane derivatives.

3 beta-Aryltropane analogues wherein the 2-position was substituted with various diarylmethoxyalkyl groups were synthesized and evaluated for binding at the dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and muscarinic (M(1)) receptors. The 2 beta-analogues 9a-i generally demonstrated high to moderate binding affinities (K(i) = 34-112 nM) at the DAT with good selectivity over SERT, NET, and M(1) receptors. Alternatively, the 2 alpha-isomers 10a-i were 10-fold less potent at the DAT with poor selectivity over SERT.

Synthesis and nicotinic acetylcholine receptor binding affinities of 2- and 3-isoxazolyl-8-azabicyclo[3.2.1]octanes.

A series of epiboxidine homologues, 2- and 3-isoxazole substituted 8-azabicyclo[3.2.1]octane derivatives was synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors in [(3)H]cytisine labeled rat brain.

Chromium(VI) oxide catalyzed oxidation of sulfides to sulfones with periodic acid.

A highly efficient and selective oxidation of sulfides to sulfones with periodic acid catalyzed by CrO(3) is described. A variety of electron-rich and electron-deficient sulfides were oxidized to sulfones with 2 mol % CrO(3) in acetonitrile at room temperature in excellent yields. Sulfides with other readily oxidized functional groups were selectively oxidized to sulfones in high yields with 10 mol % CrO(3) in ethyl acetate/acetonitrile at -35 degrees C.

Spinally mediated analgesia and receptor binding affinity of epibatidine analogs.

Two epibatidine derivatives, (1R, 2R, 5S)-A-(2-chloropyridinyl) azabicyclo [3.2.1] octane; A=2 beta: analog 1, 2 alpha: analog 2, were investigated for their spinally mediated analgesic effects and binding affinity to nicotinic acetylcholine receptors.