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Recent Publications from the Aggarwal Group

Collection of lab notebooks with raw experimental data for α-cyclopiazonic acid University of Bristol

22 January 2018

The group of Professor Varinder Aggarwal performed a publication strike, with three papers accepted to the journal Angewandte Chemie over just a few weeks.

Chromium enables efficient cross-coupling reactions: The introduction of enantioenriched chiral centres into organic molecules is of utmost importance, due to their prevalence in a plethora of biologically relevant molecules, natural products and drug targets. Over the last five years, the group of Professor Varinder Aggarwal has developed methods to couple enantioenriched secondary and tertiary boronic esters with aromatic groups, where the chirality in the starting boronic esters is efficiently transferred into the product molecule. These coupling methods, however, were limited to specific types of aromatic molecule, such as electron-rich aromatics, phenols, and pyridines. In the group’s latest work, this limitation has been overcome through the use of chromium arene complexes, which allows the coupling of sp3-hybridised carbon atoms with a broad range of electronically diverse aromatics and provides an efficient method for the introduction of valuable enantioenriched chiral centres into organic molecules.

Synthesis of α-cyclopiazonic acids: α-Cyclopiazonic acid and its congener, α-iso-cyclopiazonic acid, are natural products of fungal origin. Their producing organisms are ubiquitous in grains, dairy products and other foodstuffs. For example, P. camemberti and P. roqueforti fungi, as their names suggest, are responsible for the production of two of the world’s most famous cheeses, camembert and roquefort.

The molecules are wolves in sheep's clothing. Despite their apparent simplicity, they represent a significant synthetic challenge. The combination of stereochemical challenges, undesired reactivity and product instability resulted in several approaches failing. It took a team of 11 collaborators working over almost 17 years to achieve the synthesis of α-cyclopiazonic acid. They designed a route that is both convergent and short. The sensitive functionality is kept masked until the end of the synthesis and then revealed.

The two building blocks were stitched together using an enantioselective sulfur-ylide-mediated aziridination reaction previously developed in Professor Varinder Aggarwal’s group. The polycyclic core is then constructed by a Lewis-acid-catalysed intramolecular aziridine-alkene cycloaddition. An unprecedented Pd-mediated lactamisation/N–O reduction cascade then installs the final ring and unleashes the unstable tetramic acid unit.

The paper marks the completion of a 17-year saga. It has been selected as Hot Paper by Angewandte Chemie International Edition. A “behind-the-scenes” story has been submitted for inclusion in the Strategies and Tactics in Organic Synthesis book series.

Synthesis of valuable organoboron products with visible light: Boronic acids are becoming increasingly important in medicinal chemistry because of their ability to form reversible covalent bonds with biological targets. They can also mimic the hydrogen-bonding geometries displayed by carboxylic acids, which further enhances their binding capabilities within biological systems. In fact, replacing the carboxylic acid group of certain α-amino acids with a boronic acid group has led to the development of the peptide anticancer drugs bortezomib and ixazomib.

To improve the availability of amino boronic acids for widespread application in medicinal chemistry, the group of Professor Varinder Aggarwal has developed a visible-light-mediated reaction to transform readily available α-amino acids to γ-amino boronic acid derivatives. The reaction uses a photoredox catalyst, which captures the energy of visible light and uses it to promote a decarboxylative reaction between the amino acid and a vinyl boron reagent. The methodology makes use of readily available starting materials, proceeds under mild reactions conditions and demonstrates high functional group tolerance. Furthermore, it provides a one-step method to access the boron-analogues of γ-amino butyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system. Given the previous successful application of boronic acids in medicine, this new methodology may find use in the development of a novel class of boron-based GABA analogue drugs.

Further information

"Ortho-Directing Chromium Arene Complexes as Efficient Mediators for Enantiospecific C(sp2)–C(sp3) Cross-Coupling Reactions" by Dr. Raphael Bigler and Prof. Varinder K. Aggarwal in Angew. Chem. Int. Ed.


"Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides" by Dr. Oleksandr Zhurakovskyi, Dr. Yunus E. Türkmen, Lorenz E. Löffler, Vijayalakshmi A. Moorthie, C. Chun Chen, Michael A. Shaw, Mark R. Crimmin, Marco Ferrara, Dr. Mushtaq Ahmad, Dr. Mehrnoosh Ostovar, Johnathan V. Matlock and Prof. Varinder K. Aggarwal in Angew. Chem. Int. Ed.


"Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ-Amino Boronic Esters" by Dr. Adam Noble, Riccardo S. Mega, Dr. Daniel Pflästerer, Dr. Eddie L. Myers and Prof. Varinder K. Aggarwal in Angew. Chem. Int. Ed.

 

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