Archive for the ‘Uncategorized’ Category

OBC Highlight: A new atom and mass efficient synthetic route for tamoxifen

Nowadays, chemists are increasingly interested in revealing simpler methodologies for the synthesis of various drugs with high selectivity and purity. Transition metal catalysis has opened a wide window for the synthesis of different natural products and drugs with greater ease.

Z-Tamoxifen is one such drug, which is used in the treatment of breast cancer. Although there are many well-established synthetic procedures for the synthesis of Z-tamoxifen by various research groups such as T. Stiidemann et.al. and P. L. Coe et.al. etc., there are disadvantages to current methods, such as the use of multiple synthetic steps and generation of stoichiometric amounts of waste. Thus, there is a need to overcome these drawbacks.

In their recent OBC publication, Prof. Ben L. Feringa et.al. of Stratingh Institute for Chemistry, University of Groningen, Nijenborgh develop a fantastic two step protocol for the synthesis of Z-tamoxifen from commercially available starting materials. Usually, the transmetallation of anions formed by carbolithiation of (diphenyl)acetylenes with magnesium, boron, zinc or aluminium results in an active cross coupling partner, but with low atom efficiency. Here, Feringa et.al., for the first time proposed the direct cross coupling of the formed organolithium reagent with aryl halides in the presence of an active palladium nanoparticle based catalyst, cutting down the number of synthetic steps required to two, with excellent selectivities and yields. They report the thorough screening of reaction conditions such as solvent, temperature, catalyst loading etc. and explain the effect of various reaction parameters. The 0.67 atom economy and 22% RME achieved in the study is twice as good as the previously reported best protocol, and the scientists found that THF gave the desired product without encouraging any side reactions. Another advantage of this reaction is that the formed side product (lithium halide) can be easily removed.

Hence, Prof. Ben L. Feringa laid a new efficient pathway for the synthesis of biologically important Z-tamoxifen through his works.

Read their full article now.

 

About the Blog Writer: A. Vamshi Krishna is currently pursuing a PhD  in Organic chemistry with Prof. D. B. Ramachary at University of Hyderabad. His research mainly focuses on asymmetric supramolecular catalysis and organocatalysis, where he synthesises highly functionalized biologically active novel scaffolds with excellent selectivities and yields. He is passionate about scientific writing.

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Bristol Synthesis Meeting 2019

Organic & Biomolecular Chemistry are proud to sponsor the 2019 Bristol Synthesis Meeting, to be held in the Victoria Rooms, University of Bristol, 9th April 2019.

The meeting boasts a fantastic line up of speakers including OBC Advisory Board members Helma Wennemers (ETH Zurich) and Ilan Marek (Technion, Israel Institute of Technology).

Registration is now open, so for the full list of speakers and to register, see the Bristol Synthesis Meeting webpage.

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Creating a platform for the development of photoswitchable ligand libraries

Photoswitchable small molecules have become important tools for analyzing biological systems. The discovery of light-tuneable molecules has enabled the study of intricate physiological responses within cells through precise spatial and temporal control to modulate their function. Although powerful tools, de novo design is often challenging as it requires detailed information about the structure of both the ligand and the receptor.

In a recent OBC publication, the group of Professor Ratmir Derda of the University of Alberta discusses a strategy to develop libraries of light-responsive (LR) ligands, which can be produced by grafting known LR structures, such as azobenzene, onto molecules with established biological activity. In this way, the challenges of identifying novel LR ligands can be addressed by selecting from a library of tagged LR-compounds that are already known to possess desired biological function.

Their study outlines a proof-of-concept for such a library using the synthesis of LR-bicyclic peptides, which contain a hydroxyl amine and di-chlorobenzene containing azobenzene (HADCAz) linker.

HADCAz behaves as a 3-point linchpin and can be used in the bicyclization of peptides through its orthogonally reactive ‘thiol-reactive’ and ‘aldehyde-reactive’ attachment points. The authors successfully demonstrated the synthesis of a small library of bicyclic peptides from linear, unprotected peptides (~20 amino acids in length) in a one-pot, two step reaction involving double intramolecular nucleophilic addition and oxime formation to form the two loops. The peptide-bound HADCAz linkers were shown to reversibly switch to their cis-conformers after irradiation with 365 nm light and molecular dynamic (MD) simulation was used to assess conformational changes, the properties of which were seemingly dependent on the peptide’s length.

While optimizations are still required for broad application, this work provides a versatile platform from which numerous avenues within the realms of optochemical genetics and photo-pharmacology can be explored.

To find out more see:

Light-responsive bicyclic peptides
Mohammad R. Jafari, 
DOI:10.1039/C7OB03178E


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at the University of Toronto. Her research is centred on the synthesis of kinetically amphoteric building blocks which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Organic & Biomolecular Chemistry partners with Publons

Organic & Biomolecular Chemistry has partnered with Publons (a third-party reviewer recognition service) so you can keep a record of every review you complete.

We really value your reviewing and editorial contributions and want to ensure you get more recognition for them.

How it works
When you submit a review to a participating journal you will be asked if you want to opt in to Publons, you can then instantly start building your verified peer review and editorial record to showcase the full extent of your contributions and influence in your field. Publons tracks your reviews without compromising reviewer anonymity, by default, only the year of the review and the journal title will be shown on reviewer profiles for our journals.

Read more about the partnership on our news pages

For more information about Publons, visit publons.com/benefits/researchers

 

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Diversity-oriented synthesis of biaryl-containing macrocycles

Developing efficient protocols for the synthesis of macrocycle-containing molecules has been a longstanding challenge in chemistry. In a recent OBC publication, collaborative efforts between Prof. Tomás Torroba of the University of Burgos and Prof. Luis Miranda of Universidad Nacional Autónoma de México have resulted in a diversity oriented synthetic strategy for the synthesis of biaryl-containing macrocycles.

Macrocyclic structures have utility in many different areas of chemistry and have significant applications in medicine due to their broad range of biological activities. Compared to small molecules, macrocycles offer unique functional advantages in terms of selectivity and potency as their cyclic framework enables a high degree of structural preorganization such that key functional groups can interact across extended binding pockets without a major loss of entropy. Moreover, macrocycles display favourable drug-like properties such as improved solubility, lipophilicity, membrane penetration and stability.

Of interest are peptide macrocycles containing an endo aryl-aryl bond which constitute an important class of biologically active macrocyclic natural products. In terms of established synthetic approaches, two strategies have been commonly implemented 1) construction of the biaryl unit followed by a cyclization and 2) ring closure through the formation of the aryl-aryl bond.

These routes are limited however by the synthesis of the peptide backbone which typically requires challenging multi-step sequences.

To circumvent this issue, Torobba and Miranda proposed a sequence combining a Ugi four component reaction (Ugi-4CR) with a Suzuki-Miyaura cross-coupling for rapid access to the desired macrocycles in a diversity oriented approach. This synthetic strategy is composed of four steps: 1) Ugi-4CR using two bifunctional building blocks, the mono-Boc protected diamine and iodine containing carboxylic acid; 2) Boc cleavage; 3) a second Ugi-4CR involving a MIDA protected boron-containing carboxylic acid and finally 4) Suzuki-Miyaura cross-coupling-based macrocyclization.

After optimisation, the synthesis of a small collection of biaryl-containing macrocycles was carried out with good overall yields (35-65% isolated yield) and their cytotoxicity evaluated against eight human cancer cell lines.

The ease with which this synthetic sequence can be reproduced in combination with their preliminary biological results will no doubt open doors for the future evaluation of larger collections of this class of biaryl-containing macrocycles and in determining their full potential in drug discovery.

To find out more see:

Diversity-oriented synthesis and cytotoxic activity evaluation of biaryl-containing macrocycles
Karell Pérez-Labrada, Marco A. Cruz-Mendoza, Alejandra Chávez-Riveros, Eduardo Hernández-Vázquez, Tomás Torroba and Luis D. Miranda
DOI: 10.1039/C6OB02726A


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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