Synthesis and absolute configuration of the stereoisomers of [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate,a muscarinic antagonist

The compound [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate 1 is a muscarinic antagonist characterized by the presence of three chiral atoms and eight possible stereoisomers. The binding affinities to the five cloned m₁–m₅ muscarinic receptors of the stereoisomers of 1 were previously investigated and proved to be related to the chirality of the molecules. The eight isomers are prepared through the synthesis of their racemates followed by chemical resolution as (+) and (−) tartrate or (+) and (−) dibenzoyltartrate salts. The isomers with cis-configuration of OH and COOH substituents of the cyclohexane are also obtained by coupling optically active (1S, 2S) or (1R,2R)-1-hydroxy-[1,1′-bicyclohexyl]-2-carboxylic acid with (S)- or (R)-1-diethylamino-2-propanol. Chiral GC and HPLC methods are used to determine their optical purity. The absolute configurations of the four cis- and four trans-isomers are established by stereospecific synthesis and X-ray crystallographic data. Chirality 9:713–721, 1997. © 1997 Wiley-Liss, Inc.     

Utilizing hydrolases of opposite enantiopreference for the preparation of both enantiomers of (1R,7aR)-(-)- and (1S,7aS)-(+)-3,6,7,7a-tetrahydro-1-hydroxy-7a-methyl-1H-inden-5(2H)-one

Four racemic esters of (1R*,7aR*)-3,6,7,7a-tetrahydro-1-hydroxy-7a-methyl-1H-inden-5(2H)-one were prepared and subjected to hydrolysis with two types of hydrolases, including alcalase and three lipases. Alcalase and lipase showed opposite enantiopreference on these esters. Based on this result, we developed a gram-scale procedure using butanoate as the substrate, which was treated consecutively with alcalase and lipase from Candida rugosa (CRL), to give both enantiomers of the title compound in high yields and high enantiomeric excess.     

New route to enantiopure MalphaNP acid, a powerful resolution and chiral 1H NMR anisotropy reagent

MalphaNP acid (+/-)-1, 2-methoxy-2-(1-naphthyl)propionic acid, was enantioresolved by the use of phenylalaninol (S)-(-)-4; a diastereomeric mixture of amides formed from acid (+/-)-1 and amine (S)-(-)-4 was easily separated by fractional recrystallization and/or HPLC on silica gel, yielding amides (R;S)-(-)-5a and (S;S)-(+)-5b. Their absolute configurations were determined by X-ray crystallography by reference to the S configuration of the phenylalaninol moiety. Amide (R;S)-(-)-5a was converted to oxazoline (R;S)-(+)-8a, from which enantiopure MalphaNP acid (R)-(-)-1 was recovered. In a similar way, enantiopure MalphaNP acid (S)-(+)-1 was obtained from amide (S;S)-(+)-5b. These reactions provide a new route for the large-scale preparation of enantiopure MalphaNP acid, a powerful chiral reagent for the enantioresolution of alcohols and simultaneous determination of their absolute configurations by (1)H NMR anisotropy.     

Synthesis of 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives and their screening for antimicrobial and antioxidant properties

Novel 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives have been synthesized using boron trifluoride diethyl etherate catalyzed Diels–Alder reaction. This method presents considerable synthetic advantages in terms of high atom economy, mild reaction condition and good yields. The synthesized compounds have been screened for their antibacterial and antioxidant activities.     

MalphaNP acid, a powerful chiral molecular tool for preparation of enantiopure alcohols by resolution and determination of their absolute configurations by the (1)H NMR anisotropy method

A novel methodology using a chiral molecular tool of MalphaNP acid (1), 2-methoxy-2-(1-naphthyl)propionic acid, useful for preparation of enantiopure secondary alcohols and determination of their absolute configurations by the (1)H NMR anisotropy method was developed; racemic MalphaNP acid (1) was enantioresolved with (-)-menthol, and the enantiopure MalphaNP acid (S)-(+)-(1) obtained was allowed to react with racemic alcohol, yielding a mixture of diastereomeric esters, which was clearly separated by HPLC on silica gel. By applying the sector rule of (1)H NMR anisotropy effect, the absolute configuration of the first-eluted MalphaNP ester was unambiguously determined. Solvolysis or reduction of the first-eluted MalphaNP esters yielded enantiopure alcohols.     

Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist

A novel neurokinin-1 receptor antagonist, (±)-(1R^*,3S^*,4S^*,5S^*)-4-[(N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane (1), was synthesized stereoselectively using Padwa’s intramolecular 1,3-dipolar cycloaddition methodology as the key step. Compound (±)-1 showed high affinity for the NK-1 receptors in human IM-9 cells with an IC₅₀ value of 0.22 nM. This new structural scaffold demonstrated significant in vivo antagonistic activity in the guinea pig ureter capsaicin-induced plasma extravasation model with an ED₅₀ value of 1–10 mg/kg, po.     

Synthesis, absolute configuration, and application of enantiopure trans-1-aminobenz[f]indan-2-ol

Both novel enantiopure trans-1-aminobenz[f]indan-2-ols (4) were obtained from the racemate by the diastereomeric salt formation with (+)- and (-)-dibenzoyltartaric acids (8), respectively, and the absolute configuration of the enantiomer 4 in the less-soluble diastereomeric salt of racemic 4 with (+)-8 was determined to be (1S,2S) by an X-ray crystallographic analysis. The chiral recognition ability of the enantiopure amino alcohol was examined for the enantioseparation of racemic 2-arylalkanoic acids by the diastereomeric salt formation. The role of the naphthylene group of the amino alcohol was found to be closely associated with the stabilization of the crystal by CH/pi interactions on the basis of an X-ray crystallographic study.     

Parallel kinetic resolution of an oxazolidinone using a quasi-enantiomeric combination of [D,13C]-isotopomers of pentafluorophenyl 2-phenyl propionate

Parallel kinetic resolution of Evans' phenylglycine derived oxazolidinone using an equimolar combination of quasi-enantiomeric active esters (derived from [D,13C]-labeled 2-phenylpropionic acid) was achieved. The levels of stereocontrol were high, leading to products with predictable configurations.     

Melatonin receptor agents: synthesis, resolution by HPLC on polysaccharides chiral stationary phases, absolute configuration, and pharmacology of the enantiomers of (+/-)-N-[[2[(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide

In order to obtain milligram amounts of the enantiomers of tetrahydronaphthalenic derivative 5 to be tested for binding to the melatonin sites, preparative HPLC employed a mobile phase consisting of n-hexane-alcohol and a silica-based cellulose tris-methylbenzoate (Chiralcel OJ) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size from a scale-up of the analytical method. The enantiomeric elution order was reversed by the change from the carbamate type phase (Chiralcel OD-H) to the benzoate type phase (Chiralcel OJ) in analytical mode. The optical rotation and the circular dichroism spectra of the single enantiomers were determined after separation. The absolute stereochemistry of the two enantiomers of (+/-)-N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide 5 was established by X-ray crystallographic analysis. The purity obtained was sufficient for a first screen of their biochemical properties: the (-)-(S) enantiomer shows more affinity for melatonin receptors MT1, MT2 and is responsible of the selectivity towards MT2.     

Design and synthesis of novel 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one derivatives as telomerase inhibitors

Eight novel 4,5-tetrahydropyrazolo[1,5-d][1,4]oxazepine derivatives have been synthesized and purified to be screened for anticancer activity. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound 4a showed the most potent inhibitory activity with IC₅₀ value at 0.78 ± 0.22 μM. Western blot assays showed that compounds 4a and 4b could inhibit expression of Cyclin D1, TERT, phospho-AKT and PI3K/AKT pathway.     

A newly synthesized 6-methyl-7H,8H,9H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8-one for potential inhibitor of adenosine A1 receptor: a combined experimental and computational studies

Abstract

6-Methyl-7H,8H,9H-[1,2,4]triazolo[4,3-b][1,2,4]triazepin-8-onehas been synthesized, characterized by spectroscopic techniques (FT-IR, ¹H and ¹³C NMR) and finally the structure was confirmed by single crystal X-ray diffraction studies. In the title molecule, C₆H₇N₅O, the 7-membered ring adopts a bowl-like conformation. In the crystal, the molecules form stacks along the c-axis direction through offset π-stacking interactions between the 5-membered rings and C–H···N hydrogen bonds. The stacks are associated via a combination of N–H···N, C–H···O and C–H···N hydrogen bonds. Further, the Hirshfeld surface analysis reveals the nature of molecular interactions and the fingerprint plot provides information about the percentage contribution from each individual molecular contact to the surface. In addition, due to its biological interest the target molecule adenosine A1 receptor was found based on Structural Activity Relationship (SAR) analysis and, further, subjected into molecular docking and molecular dynamics analysis to understand the binding interaction and stability of the molecule in adenosine A1 receptor system. Furthermore, the Density Functional Theory (DFT) calculations were carried for free compound and the compound in active site (single point DFT), to know the internal stability.

Communicated by Ramaswamy H. Sarma     

Analysis of warfarin enantiomers: Chromatographic separation of six stereoisomeric esters prepared from (−)-(1S,2R,4R)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2- carboxylic acid

Reaction of rac-warfarin, (?)-(1S,2R,4R)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2- carboxylic acid [(?)-HCA] and carbodiimide reagents gave two noncyclic ketonic diastereoisomeric derivatives whereas rac-warfarin and (?)-HCA acid chloride with 4-(dimethylamino)pyridine gave four cyclic hemiketal diastereoisomeric ester derivatives. The structure and stereochemistry of diastereoisomeric esters prepared from warfarin and p-chlorowarfarin were determined from ¹H- and ¹³C-NMR spectra, mass spectra, and hydrolysis to warfarin and p-chlorowarfarin enantiomers. The structure and stereochemistry of one of the cyclic hemiketal diastereoisomeric derivatives of warfarin are supported by an X-ray crystallographic determination. Mechanisms for the formation of all products are proposed. © 1994 Wiley-Liss, Inc.     

4-[18F]Fluoro-N-methyl-N-(propyl-2-yn-1-yl)benzenesulfonamide ([18F]F-SA): a versatile building block for labeling of peptides, proteins and oligonucleotides with fluorine-18 via Cu(I)-mediated click chemistry

Cu(I)-mediated [3+2]cycloaddition between azides and alkynes has evolved into a valuable bioconjugation tool in radiopharmaceutical chemistry. We have developed a simple, convenient and reliable radiosynthesis of 4-[¹⁸F]fluoro-N-methyl-N-(propyl-2-yn-1-yl)benzenesulfonamide ([ ¹⁸ F]F-SA) as a novel aromatic sulfonamide-based click chemistry building block. [ ¹⁸ F]F-SA could be prepared in a remotely controlled synthesis unit in 32 ± 5 % decay-corrected radiochemical yield in a total synthesis time of 80 min. The determined lipophilicity of [ ¹⁸ F]F-SA (logP = 1.7) allows handling of the radiotracer in aqueous solutions. The versatility of [ ¹⁸ F]F-SA as click chemistry building block was demonstrated by the labeling of a model peptide (phosphopeptide), protein (HSA), and oligonucleotide (L-RNA). The obtained radiochemical yields were 77 % (phosphopeptide), 55–60 % (HSA), and 25 % (L-RNA), respectively. Despite the recent emergence of a multitude of highly innovative novel bioconjugation methods for ¹⁸F labeling of biopolymers, Cu(I)-mediated click chemistry with [ ¹⁸ F]F-SA represents a reliable, robust and efficient radiolabeling technique for peptides, proteins, and oligonucleotides with the short-lived positron emitter ¹⁸F.     

Synthesis of ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxy-bicyclo[3.1.0]hexane-carboxylate from L-ribose: a versatile chiral synthon for preparation of adenosine and P2 receptor ligands

Substitution of the ribose moiety of various nucleosides and nucleotides with the (N)-methanocarba ring system increases the potency and selectivity as ligands at certain subtypes of adenosine and P2 receptors. We have prepared a key intermediate in the synthesis of these derivatives, ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxybicyclo[3.1.0]hexane-carboxylate (15), starting from L-ribose (8) as a readily available, enantiopure building block. L-ribose was converted to the corresponding 5'-iodo derivative (9), which was cleaved reductively with Zn. Improvements were made in subsequent steps corresponding to a published route to biologically important (N)-methanocarba 5'-uronamido nucleosides, and new steps were added to prepare related 5'-nucleotides.     

Measurement of rate constants for quenching singlet oxygen with a Cypridina luciferin analog (2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-a]pyrazin-3-one) and sodium azide

The rate constants for [¹O₂] [MCLA] and [¹O₂][NaN₃] were measured by quenching the near-infrared emission (¹Δ_g→³∑_g) in steady state with MCLA and NaN₃, respectively. ¹O₂ was constantly generated by energy transfer to O₂ from Ar laser-excited Rose Bengal. The Stern—Volmer plots yielded the second-order rate constants of 2.94 × 10⁹ M^?1 S^?1 and 3.83 × 10⁸ M^?1 S^?1 for quenching ¹O₂ with MCLA and NaN₃ in water at pH 5.4, respectively. The ¹O₂ + MCLA reaction emitted light with maximum at 465 nm at pD 4.5 identical to the O₂^? + MCLA reaction.     

Absolute configuration of the thyroid hormone analog KAT-2003 as determined by the 1H NMR anisotropy method with a novel chiral auxiliary, MalphaNP acid

The absolute configuration of the chiral thyroid hormone analog KAT-2003 (+)-2, showing hypocholesterolemic activities, decreases of hepatic triglyceride contents with lowering cardiac side effects, and significant inhibitory effect for the second primary hepatocellular carcinoma, was determined as S by the (1)H NMR anisotropy method using a novel chiral auxiliary, 2-methoxy-2-(1-naphtyl)propionic acid (MalphaNP acid).     

The biosynthesis of lubimin from [1-14C]isopentenyl pyrophosphate by cell-free extracts of potato tuber tissue inoculated with an elicitor preparation from Phytophthora infestans

A cell-free enzyme system, which catalyses the incorporation of radiolabel from [$\text{1}\text{2}$-¹⁴C]isopentenyl pyrophosphate into the sesquiterpenoid phytoalexin lubimin, has been prepared from tuber tissue of Solanum tuberosum inoculated with an elicitor preparation from Phytophthora infestans. Biosynthesis of lubimin is optimum at pH 7.$\text{3}\text{2}$-7.5 and is dependent upon Mg²⁺ and NADPH. Lubimin labelling by cell-free enzyme system prepared from tissue 48 hr after treatment with elicitor rises rapidly to a maximum over the first 30 min of incubation and does not decline for a further 150 min. The biosynthetic capacity for lubimin in cell free extracts can be observed as early as 3 hr after inoculation of tuber tissue, and rises to a maximum at about 48 hr after treatment, declining thereafter. Lubimin labelling is inhibited by iodoacetamide, the effect of which is reversed by 3,3-dimethylallylpyrophosphate. Preliminary observations on the cell-free system show that it will also catalyse the incorporation of [2-¹⁴C]mevalonic acid into lubimin in the presence ofan ATP-generating system.     

Synthesis,characterisation and reactivity of oxodiperoxo-[2-(1-pyrazolyl)-6-menthylpyridine]molybdenum(VI): The first chiral 2-(1-pyrazole)pyridineoxodiperoxomolybdenum(VI) complex

We have obtained a novel chiral enantiomerically pure molybdenum complex of the type MoO(O₂)₂LL′ which has been fully characterised, including structural determination by X-ray crystallography and screened in a series of epoxidation reactions with simple olefins giving satisfactory conversions, but low enantioselectivities. It’s mode of epoxidation has been investigated.     

Synthesis, characterization, and anticonvulsant activity of enaminones. Part 5: Investigations on 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-one derivatives

A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones is herein reported. 2-Aminothiophenols underwent cyclocondensation with 4-carboalkoxy-5-methylcyclohexane-1,3-diones in refluxing dimethylsulfoxide (DMSO) to yield 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones, 4a–k. In the case of the carbo-tert-butoxy derivatives (4c and 4k) prolonged reaction times led to the isolation of the respective 3-unsubstituted-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones (4l and 4m) instead. Significant anticonvulsant activity was displayed by these analogues, most particularly 4k, which was active at 30 mg/kg intraperitoneally (ip) in mice in the maximal electroshock seizure (MES) evaluation, with no toxicity noted at dosages up to 300 mg/kg. Oral (po) rat evaluation of 4k in the MES evaluation provided an ED₅₀ of 17.60 mg/kg, with no toxicity noted at dosages up to 500 mg/kg, providing a protective index (PI = TD₅₀/ED₅₀) > 28.40. These compounds represent the first reported series of phenothiazines which possess anticonvulsant activity.