Zbigniew Czarnocki

Identification and synthesis of some contaminants present in 4-methoxyamphetamine (PMA) prepared by the Leuckart method

The clandestine synthesis of ring and side chain modified phenylisopropylamines continues to be a major source of these drugs of abuse. One method used for the synthesis of the amphetamine and related compounds involves the treatment of the appropriate ketone with formamide or ammonium formate followed by acid hydrolysis of intermediate N-formyl derivative. In this paper the synthesis of 4-methoxyamphetamine (PMA, 1) by the Leuckart method is investigated. The identification by means of gas chromatography-mass spectrometry (GC-MS) of methoxy derivative of N-(beta-phenylisopropyl)benzaldimine 9, methoxy derivative of N-(beta-phenylisopropyl)benzyl methyl ketimine 5, 1-(4-methoxyphenyl)-N-(4-methoxybenzyl)-2-propanamine 10, (RR/SS) and (RS) 1-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 6a-6c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-methyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 7a-7c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-formyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 8a-8c in crude PMA, are reported. The identity of these compounds was confirmed by independent synthesis of reference compounds. The NMR, MS, IR data, stereochemistry and some chromatographic properties of synthesized compounds are discussed. Finally, the results of the GC-MS analysis of illicitly prepared tablets, containing PMA 1 and 4-methoxymethamphetamine (PMMA, 2), are outlined. The presence of 4-methoxydimethylamphetamine 11, 4-methoxyethylamphetamine 12, and 4-hydroxymethamphetamine 13 are reported in these tablets. The identity of 2, 11, and 12 was confirmed by their independent synthesis.

Pictet-Spengler reaction of biogenic amines with (2R)-N-Glyoxyloylbornane-10,2-sultam. Enantioselective synthesis of (S)-(+)-N-methylcalycotomine

Abstract (2 R )- N -Glyoxyloylbornane-10,2-sultam reacted with dopamine hydrochloride, forming the Pictet-Spengler condensation product, which was further converted into ( S )-(+)- N )-methylcalycotomine of high enantiomeric purity. The same kind of reaction with tryptamine hydrochloride gave the condensation product with 100% d.e.

Highly selective inhibition of butyrylcholinesterase by a novel melatonin–tacrine heterodimers

Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin–tacrine heterodimers via the carbamate bond. Compounds 14a‐i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nm for acetylcholinesterase (AChE) and 0.24 nm for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4‐ to 256‐fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.

(S)-(−)-α-Methylbenzylamine as an efficient chiral auxiliary in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine

Abstract ( S )-(−)-α-Methylbenzylamine 2 was used as a chiral auxiliary in the enantiodivergent synthesis of simple isoquinoline alkaloids. The prochiral imine moiety in compound 4 was reduced with different reagents, giving diastereomeric amines 5a or 5b , which subsequently were transformed to either ( S )-(−)- N -acetylcalycotomine 6 or ( R )-(+)- N -acetylcalycotomine ent - 6 in good enantiomeric excess. 19 F NMR of its Moshers acid ester was used to establish the purities of final compounds.

Molecular cloning of melatonin 3-hydroxylase and its production of cyclic 3-hydroxymelatonin in rice (Oryza sativa).

Melatonin is metabolized in animals to cyclic 3‐hydroxymelatonin (3‐OHM) not by an enzymatic pathway, but by interaction with hydroxyl radicals. The production of 3‐OHM in animals suggests the possible presence of 3‐OHM in plants. Prior to the identification of 3‐OHM in plants, we directly cloned the corresponding gene(s) responsible for 3‐OHM synthesis using Escherichia coli library strains expressing genes belonging to the 2‐oxoglutarate‐dependent dioxygenase (2‐ODD) superfamily from rice. Three of 35 E. coli library strains supplemented with 1 mmol/L melatonin were found to produce 3‐OHM in their extracellular medium, suggestive of three 2‐ODD genes involved in 3‐OHM production. The purified recombinant 2‐ODD 11, 2‐ODD 26, and 2‐ODD 33 proteins were shown to catalyze the metabolism of melatonin to 3‐OHM, with 2‐ODD 11 showing the highest melatonin 3‐hydroxylase (M3H) catalytic activity. Consistent with the presence of M3H genes, rice leaves supplemented with 5 mmol/L melatonin produced 3‐OHM [233 μg/g fresh weight (FW)], 2‐hydroxymelatonin (21 μg/g FW), and N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine (5 μg/g FW). Three M3H transcripts were induced upon the treatment of rice leaves with cadmium followed by an increase in M3H enzyme activity. Cloning of M3H genes in plants has paved the way for the studies of melatonin in plants in terms of its multiple physiological roles.

α-Phenylethylamine in illegally produced amphetamine

The possibility of simultaneous synthesis of α-phenylethylamine and amphetamine from mixture of acetophenone and benzylmethylketone was studied. The structures of specific impurities were predicted and these compounds were synthesized and finally found in reaction mixtures, as well as in the final product. The data collected by gas chromatography, proton and carbon magnetic resonance, Fourier transform infrared spectrometry and mass spectrometry are presented.

Electrospray ionization, accurate mass measurements and multistage mass spectrometry experiments in the characterization of stereoisomeric isoquinoline alkaloids

Mass spectrometry has been employed for the characterization of diastereoisomeric isoquinoline alkaloids. Electrospray ionization was used to generate MH(+) ions, and multistage collisionally activated spectra allowed differentiation among the different compounds via specific fragmentation patterns, whose mechanisms have also been elucidated by accurate mass measurements.

Stereoselective synthesis of (R)-(−)-mianserin

Abstract (14bR)-2-Methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, (R)-(−)-mianserin 1a was synthesised in several steps in good enantiomeric purity with the use of (S)-(−)-α-methylbenzylamine 5. The absolute configuration was assigned on the basis of X-ray data.

The oxidation products of melatonin derivatives exhibit acetylcholinesterase and butyrylcholinesterase inhibitory activity

Abstract:  It is already well documented that melatonin exhibits strong antioxidant properties. It traps several reactive oxygen species including singlet oxygen, peroxyl and hydroxyl radicals. Also, peroxynitrite‐induced reactions are inhibited by melatonin. The oxidation of melatonin by singlet molecular oxygen [O2 (1Δg)] may produce cyclic 3‐hydroxymelatonin whose structure we have already studied. In this investigation we report on the synthesis of several melatonin analogues having a carbamate substituent instead of the methoxy group at 5 position of the indole ring. These compounds behave analogously to melatonin with respect to singlet oxygen and produce the corresponding cyclic 3‐hydroxymelatonin analogues. The structures of the products were investigated with spectral methods and X‐ray crystallography. The compounds obtained possess the 2,3,8,8a‐tetrahydropyrrolo[2,3‐b]indole heterocyclic system which is a structural motif characteristic of alkaloids, physostigmine and phenserine, that are potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors used in the Alzheimer’s disease treatment. We measured the inhibitory activity of the obtained compounds against AChE and BChE from human erythrocytes and serum. In the case of the compounds having a phenylcarbamate and methoxyphenylcarbamate substituents, the inhibitory activity (IC50) ranged from 0.252 ± 0.033 to 3.804 ± 0.581 μm. Other compounds were less active and showed rather complex interactions with the structure–activity relationship in need of further investigation.

The use of l-(+)-tartaric acid in the enantioselective synthesis of isoquinoline alkaloids

l-(+)-Tartaric acid was used in an enantioselective synthesis of (S)-(−)-N-acetylcalycotomine.