Organic & Biomolecular Chemistry Blog

In this HOT paper Mark C. Elliott and colleagues at Cardiff University present an investigation on the deprotonation and alkylation of 1-methylcyclohexa-2,5-diene-1-carboxylic acid under a range of conditions. The culmination of the investigation shows that deprotonation of 1-methylcyclohexa-2,5-diene-1-carboxylic acid with n-BuLi in the presence of TMEDA, followed by alkylation, offers a direct and highly diastereoselective route to the corresponding 4-substituted products in which the alkyl group introduced is transto the carboxylic acid.

Mark C. Elliott et al. comment that this result “complements previous findings of H. van Bekkum in which a 4-substituted benzoic acid is reductively alkylated and where, when any selectivity is observed, the alkyl group and the carboxylic acid are preferentially cis.”

Click here for the complete study…..

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Diastereoselective alkylation reactions of 1-methylcyclohexa-2,5-diene-1-carboxylic acid
Nicholas J. Bennett, Mark C. Elliott, Natalie L. Hewitt, Benson M. Kariuki, Clare A. Morton, Steven A. Raw and Simone Tomasi
Org. Biomol. Chem., 2012
DOI: 10.1039/C2OB25211B

In this HOT paper Martine Largeronand co-workers at CNRS-Université Paris Descartes report the first total synthesis of S-(+)-HHMA in 45% overall yield (six steps) and 99% ee. Along with their previously reported method for making R-(−)-HHMA, Largeron et al. go on to prepare large amounts of optically active thioether conjugates viaa straightforward one-pot electrochemical procedure. This new availability of optically active thioether conjugates allows future studies into their exact role in the neurotoxic effects of MDMA to be carried out.

MDMA, also known as “ecstasy”, is a psychoactive drug with selective neurotoxic potential toward brain serotonin neurons. Despite intensive research, the precise mechanism by which MDMA selectively damages brain neurons in most species remains unknown. One hypothesis is that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In particular, O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic catechol–thioether conjugates.

As MDMA enantiomers have different pharmacological properties, it is reasonable to predict that the thioether conjugates of the HHMA enantiomers similarly display distinct neurotoxicity profiles. However, such studies have yet to be carried out because HHMA exists as a pair of enantiomers so its thioether conjugates exist as a mixture of diastereoisomers and current analytical and semipreparative methodologies for the diastereoisomeric separation of HHMA thioether conjugates only furnish small quantities of both diastereoisomers. Now, thanks to this work by Largeron et al. such studies can be undertaken.

 A convenient biomimetic synthesis of optically active putative neurotoxic metabolites of MDMA (“ecstasy”) from R-(−)- and S-(+)-N-methyl-α-methyldopamine precursors
Claire-Marie Martinez, Anne Neudörffer and Martine Largeron
Org. Biomol. Chem., 2012,
DOI: 10.1039/C2OB25245G

Rajagopal Nagarajan and colleagues at University of Hyderabad have synthesized a series of pyrimido[4,5-b]-carbazolone derivatives using cascade Ullmann N-arylation and aerobic oxidative C–H amidation reactions that allow the assembly of readily accessible building blocks into diverse (heteroarylannulated) pyrimido[4,5-b]carbazolones with the aid of CuBr as a catalyst without any additives or ligands.

An attractive feature of this synthetic approach is that it not only provides a new approach for constructing pyrimido[b]carbazoles but also offers an efficient method for preparation of synthetically and medicinally important hetero-arylated carbazoles.

For all the details of their investigation simply CLICK HERE. This HOT article is FREE to access for 4 weeks!

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Copper-mediated domino synthesis of pyrimido[4,5-b]carbazolones via Ullmann N-arylation and aerobic oxidative C–H amidation
Devanga K. Sreenivas, Nagarajan Ramkumar and Rajagopal Nagarajan
Org. Biomol. Chem., 2012,
DOI: 10.1039/C2OB07179G