Organic & Biomolecular Chemistry Blog

2023 marks twenty of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from Professor Peter Langer at the University of Rostock who first published with OBC in 2008 and he has continued to support the journal with 47 articles across the years, most recently earlier this year.

About Peter

Peter was born in Hannover, Germany in 1969. From 1989 till 1994, he studied chemistry at the University of Hannover. His diploma thesis he carried out at the Massachusetts Institute of Technology (Cambridge, USA). Between 1994 and 1997, Peter did his PhD studies at the University of Hannover. Afterwards, he spent one year in Cambridge, UK to work as a postdoc. From 1998 till 2001, he carried out his research towards habilitation of the University of Göttingen, Germany. In 2002, Peter was appointed full professor (C4) at the University of Greifswald and later in 2004, full professor (C4) at the University of Rostock where he is working as the head of the chair of organic chemistry. Peter is also affiliated to the Leibniz-Institute of Catalysis e. V. at the University of Rostock (LIKAT). He has coauthored about 800 research papers and reviews, nearly 50 of them in OBC and supervised about 100 PhD students from various countries, 100 MSc and 50 BSc students. His students come from all over the world. Besides German and English, Peter speaks French, Spanish and Russian.

His research is focused on the development of new reactions and heterocyclic molecules and their application in the field of medicine and materials science. Peter has received several awards and scholarships; he was scholar of the German Academic Scholarship Foundation, of the Chemical Industry Fund, and of the Alexander von-Humboldt foundation. In addition, he obtained a Heisenberg scholarship of the German Research Foundation (DFG). Peter has received 10 honorary doctorates, 3 honorary professorships and several medals and research awards. He is an elected member of the Academy of Sciences of the Republic of Armenia and of the Academy of Sciences of the Islamic Republic of Pakistan. In addition, he was decorated with the civil award ‘Sitara-i-Quaid-i-Azam’ given by the President of Pakistan.

First OBC paper: S. Reim, D. Michalik, K. Weisz, Z. Xiao & P. Langer, Synthesis and Solution Structure of 3,5-Dioxopimelic Acid Diesters – Stable 1,3,5,7-Tetracarbonyl Derivatives, Org. Biomol. Chem., 2008, 6, 3079-3084, DOI: 10.1039/b805808c

Most recent OBC paper: E. Ammon, P. Heine, M. A. A. Cordero, S. Lochbrunner, A. Villinger, P. Ehlers & P. Langer, Dibenzoacridines: Synthesis by Alkyne-Carbonyl-Metathesis and Properties, Org. Biomol. Chem., 2023, 21, 4504-4517, DOI: 10.1039/d3ob00407d

Favourite OBC paper: T. N. Ngo, P. Ehlers, T. T. Dang, A. Villinger & P. Langer, Synthesis of indolo[1,2-f]phenanthridines by Pd-catalyzed domino C–N coupling/hydroamination/C–H arylation reactions, Org. Biomol. Chem., 2015, 13, 3321-3330, DOI: 10.1039/c5ob00013k

How has your research developed over the last 20 years?

During an academic career in Germany, at least for my generation, it was a requirement to change the field of research when you move from dependent (PhD, postdoc) to independent research (habilitation, junior or assistant professorship). In fact, during my career, I worked in various fields of research. My diploma thesis (equivalent to a Master thesis) I did in the group of Dietmar Seyferth at Massachusetts Institute of Technology in the field of organosilicon chemistry. My doctoral degree under the supervision of H. Martin R. Hoffmann at the University of Hannover I obtained in the field of natural products, specifically Cinchona alkaloids and my postdoc with Steven V. Ley at Cambridge University I did in carbohydrate chemistry. In 1998, I started my independent career habilitation under the mentorship of Armin de Meijere at the University of Göttingen. At that time the field of bioorganic chemistry was rather new and modern. But I had no idea of this field, was a bit afraid and decided to stay with organic synthesis for my independent research.

During my habilitation, I developed cyclization reactions of free and masked dianions. The latter are electroneutral equivalents of dianions, for example 1,3-bis(silyloxy)-1,3-butadienes. This work turned out to be fruitful and importantly rather inexpensive and I continued in the area during my tenure as full professor first at the University of Greifswald and since 2004, at the University of Rostock. After having published many, maybe too many, articles in the field, we moved more and more away from it. It soon became clear it was better to start something new and it was more and more difficult to publish in high ranked journals. As a consequence, in 2006, we started to work in the field of transition metal catalysis and developed new regioselective Pd catalysed coupling reactions of a great variety of polyhalogenated heterocyclic substrates such as pentachloropyridine or tetrabromothiophene. Later, starting in 2012, we began to investigate the combination of such coupling reactions with cyclizations by twofold Buchwald-Hartwig reactions, domino C-C coupling / hydroamination reactions, cycloisomerizations and CH-activations. In this context, we became also more and more interested in the synthesis of new heterocyclic core structures and their optical, electrochemical and electronic properties and started to carry out extensive fluorescence and cyclovoltammetric studies and also started to apply computational work to complement our experimental investigations. This nowadays represents about 80% of the research in my group.

A more recent field in my group is the application of alkyne-carbonyl metathesis (ACM) reactions to new heterocyclic substrates. Starting in 2010, we started three new research areas which were recently completed. Firstly, the synthesis of fluorinated purine analogues by cyclization reactions of heterocyclic enamines with dielectrophiles. Secondly, the development of cyclization reactions of enamines with chromones. In fact, this project went back to our earlier experiences with chromones in cyclizations with 1,3-bis(silyloxy)-1,3-butadienes. Thirdly, CH activation reactions of nitro-substituted heterocycles. In addition, during my career, I had several collaborations with medicinal chemists and in the context of this work (cancerostatic and antibacterial compounds and enzyme inhibitors), we carried out various target orientated syntheses of heterocycles which include various types of molecules. In addition, after my postdoc in carbohydrate chemistry, I was convinced that this field would be too difficult for independent research studies because of tedious purification and characterisation of the products. However, never say never. In 2006, we started a project in this field, and we developed the synthesis of N-glycosides of indigo and indirubine derivatives. The latter proved to be active against skin cancer. This field of research continued until recently but only a few students were involved. In conclusion, my research was rather diverse over the years, but when we believed we had found a ‘gold mine’ we stayed and tried to explore it as much as possible. Besides all the research and teaching, it was always an important issue for me to bring people of different cultures, religions and political systems together. Therefore, chemistry can act as a bridge.

How has the encompassing field of chemistry changed over the last 2 decades and where do you see the challenges over the next 20 years?

As I worked in various fields of research, it is difficult to answer this question. Regarding my first independent field of research (development of cyclizations of free and masked dianions), there was not much competition at the time which might be due to the fact that it was somehow quite niche. But I was very happy when the French research group of Charles Mioskovski applied a synthesis of γ-alkylidenebutenolides which I had developed. In the field of regioselective Pd catalysed coupling reactions of polyhalogenated heterocycles the competition was higher. Nowadays, it is more and more difficult to find new substrates. A very high competition I observe is for the synthesis of new, especially highly symmetric, heterocyclic core structures and their applications in the field of electronic devices (e.g. OLED) and I believe that many interesting findings will come up in the area in the coming years.

In the case of ACM reactions, also a lot is known, but I am sure that interesting applications will be published in the future. The same is true for twofold Buchwald-Hartwig reactions, domino C-C coupling / hydroamination reactions and cycloisomerisations. With regard to cyclizations of enamines and chromones it will also be possible to come up with interesting results. This is especially the case for the synthesis of fluorinated purines and other heterocycles, because of their pharmacological relevance. Regarding the anti-cancer activity of indirubines it was surprising to follow the rapid development of this rather special and interesting type of biological target molecule. Therefore, I believe that new and interesting glycosylated indirubine derivatives will be an important topic in the future.

Check out the other entries in our blog series here!

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from Professor Alexandra Slawin, recently retired from the University of St. Andrews who’s first contribution to OBC was in 2003, the journal’s first year. She continued to bring her X-ray crystallography expertise to 43 research papers published in the journal across the years, most recently in 2023.

About Alex

Alex Slawin was born in Taunton in 1961 where she went to Bishop Fox School. She started her academic journey as an undergraduate at Imperial College in 1980, moving to Loughborough University to start an independent career and establish a chemical crystallography lab. In 1999 she moved to St Andrews where she was promoted to Professor in 2002 – the first female Professor of Chemistry in the University of St Andrews. She was there over 20 years, having worked at Imperial and Loughborough before. In 2013 she was recognised as a rare woman with over 50 papers in Angewandte Chemie and in 2014 she published her 1000^th paper.

She was a fellow of the RSC and RSE before retiring and stopped paying the subscriptions and is the highest ranked female on the Cambridge Crystallographic Data Centre (the international depository for X-ray structures). She has published over 1500 peer reviewed papers and has an internationally leading research profile. Whilst her children were at school in St Andrews, Alex was on the PTA then the Parent Council for Madras College in a variety of capacities. She was the manager for technicians in the School of Chemistry for a number of years and has been a pastoral advisor there for almost all her time there. Just prior to retirement, she trained (formally) to be mediator with the Mediation partnership, and was a member of the University Mediation service, participating in external and internal mediations. She has 3 children ages 29-33 so had informally mediated for many years. She retired in 2022 intending to go into dog advertising as she felt her son’s dog was endearing enough to make big bucks but decided very quickly that was a bad move.

First OBC paper: C. J. Moody, A. M. Z. Slawin & D. Willows, Dirhodium(ii) tetraacetate catalysed reactions of diazo thioamides: isolation and cycloaddition of anhydro-4-hydroxy-1,3-thiazolium hydroxides (thioisomünchnones), an approach to analogues of dehydrogliotoxin, Org. Biomol. Chem., 2003, 1, 2716-2722, DOI: 10.1039/b305698h

Most recent OBC paper: A. Giannoulis, K. Ackermann, A. Bogdanov, D. B. Cordes, C. Higgins, J. Ward, A. M. Z. Slawin, J. E. Taylor & B. E. Bode, Synthesis of mono-nitroxides and of bis-nitroxides with varying electronic through-bond communication, Org. Biomol. Chem., 2023, 21, 375-385, DOI: 10.1039/d2ob01863b

Favourite OBC paper: F. N. Palmer, F. Lach, C. Poriel, A. G. Pepper, M. C. Bagley, A. M. Z. Slawin & C. J. Moody, The diazo route to diazonamide A: studies on the tyrosine-derived fragment, Org. Biomol. Chem., 2005, 3, 3805-3811, DOI: 10.1039/b510653b

How did your research on organic systems structural determination develop over the last 20 years?

I have been a crystallographer since my final year as an undergraduate, and back then structures were principally the domain of the inorganic chemist – although organic structures were solved, it was mainly inorganic and organometallic chemists that used the results of X-ray crystallography. The advent of cheap computing and many clever algorithms to utilise crystallographic methods meant that the use of X-ray crystallography in – as it were – ‘pure’ organic chemistry to solve light atom structures and to give absolute structure determinations became possible. Since I started with just 1 Cu machine at Imperial college, I always utilised Cu radiation and when I could afford to expand, I added Mo. Back then preferring copper radiation was unusual, and occasionally I would get referees saying I should recollect using Mo, even if the crystal I had available to me were too small to be usefully collected with Mo radiation. Instead of celebrating we had really great results, the focus was on how they thought it could be ‘better’ – as if I wouldn’t want to try publishing the best I had done, rather than just shoving in any old result.

How has X-ray crystallography as a tool in organic chemistry changed over the last 2 decades?

Much of what I said above, applies to this. I suppose the real change is that organic chemists are now used to being able to get results with smaller crystals, get absolute structure determination, marry up the results with other techniques. For instance, for a couple of groups, I would run a crystal that gave an absolute structure determination, save the crystal and transfer it to a vial. Then they would take that crystal and do clever NMR experiments on what could be a very small sample size in order to show that the absolute structure could verify the NMR results of not only that particular structure but perhaps a whole string of results. Although you would have to speak to the chemists about that – in the altered words of Austin Powers “NMR is not my bag”.

Where do you foresee the challenges being in this area over the next 20 years?

Oh, if I could answer that accurately I would be using my powers to live in a tax haven such as Bermuda – where actually one of my sons does live legitimately (he’s an actuary). So maybe my answer would be to quit chemistry and go into finance, which actually might help one finance the ongoing costs of obtaining, running and maintaining high end research equipment in the face of spiralling energy costs, decreasing public interest and fashions in chemistry that bend not according to scientific need but to political initiatives. The challenges in the area I spent my working life in are not that different to all ongoing challenges in science and it needs people with passion and interest to keep going against the system rather than going with it. I am now of an age where I didn’t feel like keeping up the fight so have retired to spend my energy doing things I enjoy, rather than struggle against stuff.

A word on the paper you selected as your favourite in OBC

For my favourite paper I have picked one I collaborated on with Chris Moody on an early structure from the Rigaku Rotating anode/CCD system which was a small pure organic crystal collected using Mo radiation. He was a lecturer at Imperial when I was an undergraduate, I started my independent career at Loughborough when he was Head of School there and we carried on collaborations after he and I both moved to different locations. There are very many people I had long and fruitful collaborations with, but I feel Chris’ contributions are sometimes overlooked.

Check out the other entries in our blog series here!

Proof of why Momo, my son’s dog, could make big bucks in advertising

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from Professor Lei Wang at Taizhou University who first published with OBC in 2009 and he has continued to support the journal with 31 articles across the years, most recently earlier this year.

About Lei

Education and Employment:

2019.9 – Present Distinguished Professor of Chemistry, Taizhou University, P. R. China

2012.4 – 2019.3 Secretary of the Communist Party of China, Huaibei Normal University, P. R. China

2005.2 – 2019.9 Professor of Chemistry, Huaibei Normal University, P. R. China

2005.2 – 2012.4 President of Huaibei Normal University, P. R. China

2004.6 – 2005.2 Visiting Professor of Chemistry, Mississippi State University, USA

2001.8 – 2004.6 Professor of Chemistry, Huaibei Normal University, P. R. China

1999.6 – 2001.8 Postdoctoral Research Associate at University of Tennessee, Knoxville, USA

1996.9 – 1999.6 Ph. D., Department of Chemistry, Zhejiang University, P. R. China

1995.3 – 1996.9 Professor of Chemistry, Huaibei Normal University, P. R. China

1994.2 – 1995.3 Visiting Professor of Chemistry, Western Kentucky University, USA

1982.7 – 1995.3 Assistant, Associate and Full Professor at Huaibei Normal University, China

1978.9 – 1982.7 B.S., Huaibei Normal University, P. R. China, Major in Chemistry

Research Interests:

Organic synthesis; Organometallic chemistry; Green synthetic methodology; Organic photosynthesis; Organic electrosynthesis; Organic photoelectrosynthesis

First OBC paper: K. Ren, M. Wang & L. Wang, Lewis acid InBr₃-catalysed arylation of diorganodiselenides and ditellurides with arylboronic acids, Org. Biomol. Chem., 2009, 7, 4858-4861, DOI: 10.1039/b914533h

Most recent OBC paper: X. Hu, H. Guo, H. Jiang, R. Zheng, Y. Zhou & L. Wang, Visible-light-induced C(sp³)-H thiocyanation of pyrazoline-5-ones: a practical synthesis of 4-thiocyanated 5-hydroxy-1H-pyrazoles, Org. Biomol. Chem., 2023, 21, 2232-2235, DOI: 10.1039/d3ob00092c

Favourite OBC paper: X. Xie, P. Li, Q. Shi & L. Wang, Visible-light-induced tandem cyclization of 2-alkynylanilines with disulfides: a convenient method for accessing benzothiophenes under transition-metal-free and photocatalyst-free conditions, Org. Biomol. Chem., 2017, 15, 7678-7684, DOI: 10.1039/c7ob01747b

How has your research developed over the last 20 years?

In 2001, after finishing my postdoctoral research associate at the University of Tennessee, Knoxville, USA, I returned to my home university, Huaibei Coal Industry Teachers College, starting my independent research career. At that time, I began my research from zero, overcoming a variety of unimaginable difficulties in my arduous scientific research journey, including setting up my own laboratory from nothing, with only one or two undergraduate students in my group and limited money and facilities. With the support of the Chinese government, encouragement by my co-workers and the hard work of my colleagues, my research group gradually grew and grew, and my research projects began to go very smoothly in the last two decades. Now there is a big team with more than 30 post-doctorates and graduate students in my group, well equipped with instruments including 600 MHz NMR and HPLC-HRMS with generous research funding. I have now since published more than 300 papers in J. Amer. Chem. Soc., Angew. Chem. Int. Ed., Org. Lett. et al., especially including over 30 papers published in Org. Biomol. Chem. with the first paper in 2009¹. As a result of this, I was selected as one of the Highly Cited Researchers (Chemistry) from 2020 to 2022 in Elsevier’s list and in the World’s Top 2% of Scientists by Stanford University. In addition, I served as the President of Huaibei Normal University (originally Huaibei Coal Industry Teachers College) from 2005 to 2012, and the Secretary of the Communist Party of China in Huaibei Normal University from 2012 to 2019. During my time in those positions, we have promoted the rapid development of the university in scientific research and the quality of graduate and undergraduate students under the support of our faculties and staffs.

How has the encompassing field of your research changed over the last 2 decades?

Over the last two decades, my research has been focused on the methodology of organic synthesis. However, this was originally classified as analytical chemistry until 1996. Developments in organic chemistry has meant my research field has also adjusted from organometallic chemistry directed towards organic synthesis (OMCOS) to activation/functionalisation of inert chemical bonds including C-H, C-O, and C-halogen bonds, organic photosynthesis, organic electrosynthesis and organic photoelectrosynthesis to meet the need of green chemistry with atom economy, concise synthetic routes, green solvents, non-precious transition-metal catalysis and renewable energy. Our most recent publications in OBC are an example of this, focusing on organic photosynthesis and electrosynthesis^2,3. However, my favourite paper that has been published in OBC is on a convenient method for accessing benzothiophenes using visible light induced tandem cyclization of 2-alkynylanilines with disulfides⁴ which was highlighted by SYNFACTS in 2017⁵.

Where do you see the challenges being for this field over the next 20 years?

The past decade has witnessed an explosive growth in the use of photocatalytic and electrocatalytic techniques in organic synthesis, and organic photocatalysis and electrocatalysis are two powerful strategies for the construction of organic molecules that have received much attention in recent years. Electrophotocatalysis, which at its best combines to most advantageous aspects of these two approaches, has in the last five years begun to offer new avenues for synthetic chemists. Electrophotocatalysis has the ability to perform photoredox reactions without the need for large quantities of stoichiometric or superstoichiometric chemical oxidants or reductants by making use of an electrochemical potential as the electron source under relatively mild conditions. In the next 20 years, electrophotocatalysis will be a rapidly growing research frontier combining with scale-up reactions, continuous flow chemistry for high reproducibility and high-throughput experimentation. It is becoming a powerful tool for both academic and industrial chemists.

Check out the other entries in our blog series here!

¹K. Ren, M. Wang & L. Wang, Lewis acid InBr₃-catalysed arylation of diorgano diselenides and ditellurides with arylboronic acids, Org. Biomol. Chem., 2009, 7, 4858-4861, DOI: 10.1039/b914533h

²X. Hu, H. Guo, H. Jiang, R. Zheng, Y.-Q. Zhou & L. Wang, Visible-light-induced C(sp³)-H thiocyanation of pyrazoline-5-ones with ammonium thiocyanate to 4-thiocyanated 5-hydroxy-1H-pyrazoles, Org. Biomol. Chem., 2023, 21, 2232-2235, DOI: 10.1039/d3ob00092c

³Y. Lv, Z.-W. Hou, Y. Wang, P. Li & L. Wang, Electrochemical monofluoroalkylation cyclization of N-arylacrylamides to construct monofluorinated 2-oxindoles, Org. Biomol. Chem., 2023, 21, 1014-1020, DOI: 10.1039/d2ob01883g

⁴X. Xie, P. Li, Q. Shi & L. Wang, Visible-light-induced tandem cyclization of 2-alkynylanilines with disulfides: a convenient method for accessing benzothiophenes under transition-metal-free and photocatalyst-free conditions, Org. Biomol. Chem., 2017, 15, 7678-7684, DOI: 10.1039/c7ob01747b

⁵V. Snieckus & M. Miranzadeh, Visible-lighted-induced iron-catalyzed synthesis of 3,3-disubstituted oxindoles, Synfacts, 2017, 13, 0802, DOI: 10.1055/s-0036-1590741

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

Our next entry to the series comes from Professor Dhevalapally B. Ramachary at the University of Hyderabad who first published with OBC in 2006 and has continued to support the journal with 27 articles across the years, most recently in 2022.

About Ramachary

Prof. Ramachary graduated with a MSc degree in Chemistry from the University of Hyderabad and obtained a PhD in synthetic organic chemistry from the Indian Institute of Science, Bangalore in 2001. He subsequently held a postdoctoral position at the Scripps Research Institute for Catalysis, prior to joining the University of Hyderabad in January 2005, where presently he is a full professor of organic chemistry.

He has been the recipient of many awards including Fellow of the National Academy of Sciences (Allahabad, 2021), Fellow of the Royal Society of Chemistry (London, 2020) and Fellow of Indian Academy of Sciences (Bangalore, 2018). He has guided 20 PhD students, 13 PDFs and out of them, 5 got Eli Lilly & Company Asia Outstanding Thesis Awards. He is an Editorial Advisory Board Member for Organic & Biomolecular Chemistry (2013-present), European Journal of Organic Chemistry (2017-present) and Tetrahedron Chem (2021-present). He serves as a reviewer for many national and international reputed journals and is a member of many national funding committees (DST, SERB). Prof. Ramachary has published more than 113 research papers, 2 books on emerging organocatalysis areas, delivered over 130 lectures in national/international conferences and has a few chemical reactions named after him.

First OBC paper: D. B. Ramachary, M. Kishor & G. B. Reddy, Development of drug intermediates by using direct organocatalytic multi-component reactions, Org. Biomol. Chem., 2006, 4, 1641-1646, DOI: 10.1039/b602696f

Most recent OBC paper: A. V. Krishna & D. B. Ramachary, The seven-step, one-pot regioselective synthesis of biologically important 3-aryllawsones: scope and applications, Org. Biomol. Chem., 2022, 20, 3948-3954, DOI: 10.1039/d2ob00438k

Favourite OBC paper: D. B. Ramachary, M. Shiva Prasad, S. Vijaya Laxmi & R. Madhavachary, Asymmetric synthesis of drug-like spiro[chroman-3,3′-indolin]-2′-ones through aminal-catalysis, Org. Biomol. Chem., 2014, 12, 574-580, DOI: 10.1039/c3ob42100g

How has your research developed over the last 20 years?

I am incredibly pleased to share some of my thoughts on how our research began in 2005 upon joining the School of Chemistry, University of Hyderabad as faculty after my post-doctoral studies at The Scripps Research Institute. With the knowledge gained on total synthesis from my PhD days, followed by having exposure to developing reactions in newly thriving molecular catalysis during my post-doctoral research, I decided to commence my early investigation on the area of organocatalysis, which derived inspiration from the reactions performed in biological systems designed by nature and that are occurring sequentially in a consistent medium.

We, therefore, envisioned developing new organocatalytic domino cascade sequential one-pot multi-component and multi-catalytic cascade reactions. With this objective, several questions arose about how to mimic the biological systems in already existing reactions that use harsh conditions, metals, tedious workups and column purifications with the accompanying functional group intolerance in most cases. To address these challenges, we had to develop the reactions that maintain lenity with conditions useful in sequential one-pot methods by forming bonds in a greener manner by using solvents, catalysts and conditions that ensure that the conditions employed in the first reaction are affable to the following sequence of reactions. With this rationale, we were able to develop a new method for the alkylation of cyclic-1,3-diketones, a reaction not feasible with existing conditions. The soft nucleophilic centre present in cyclic-1,3-diketones when treated with a soft electrophile like methyl iodide, allyl bromide, benzyl bromide and propargyl bromide resulted in a maximum 70% yield of the desired C-alkylation product. However, when using a hard electrophile, it resulted in only O-alkylated products. With our systematic efforts, we developed a three-component reductive alkylation of CH-acids with aldehydes/ketones in the presence of an amine or amino acid catalyst by using Hantzsch ester as a reducing agent. This is a preliminary reaction to the designed sequential one-pot combination of MCRs/MCC reactions. This method has become a beneficial tool in creating various highly functionalized biologically active molecules with wide pharmaceutical applications. This diversity-orientated green one-pot synthetic strategy has received much acclaim and is recognised as the “Ramachary Reductive Coupling Reaction”.

We later added a new dimension to our research by developing push-pull dienamine catalysis to synthesise complex organic molecules. We developed a novel regioselective, one-step, cascade Claisen-Schmidt/ iso-aromatisation reaction that could furnish highly functionalized phenols in a regio-specific manner using a simple aldehyde possessing a non-enolizable carbonyl functional group with highly substituted Hagemann’s esters under diamine catalysis. It is the first example of its kind in literature where push-pull dienamines have been generated in situ and it has stood out as an excellent platform for cascade reactions.

The discovery of copper-catalysed [3+2]-cycloaddition (the 2022 Chemistry Noble Prize-Winning Reaction) for the selective synthesis of 1,2,3-triazoles evoked interest among the synthetic community due to the significance of functionalized 1,2,3-triazoles and studies of their properties being widespread. Even though the copper-catalysed click reaction has broad utility, it has some drawbacks. To address the drawbacks imminent with existing click reactions, we have developed a common metal-free, green enamine- or enolate-mediated organocatalytic click reaction for the synthesis of 1,4-disubstituted, 1,5-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles in a more sustainable manner. Unlike the copper catalyst for [3+2]-cycloaddition of different terminal alkynes with azides, we have used relatively greener conditions by using organocatalyst like proline/DBU and were able to demonstrate the [3+2]-cycloaddition between alpha-methylene carbonyl compounds (because of their wide availability, stability and acidity) as the dipolarophile source and the aryl/alkyl-azides to synthesise the substituted 1,2,3-triazoles.

In 2012, we developed an asymmetric synthesis for drug-like spiranes through reflexive-Michael reaction using 2-aminobuta-1,3-enyne catalysis under mild conditions. Functionalized spirooxindoles were furnished in good yields with excellent stereoselectivities by using an effective Tomita zipper cyclisation reaction through organophosphine catalysis on the ynones and active olefins. Later we developed asymmetric supramolecular-organocatalysis; a bio-inspired tool for high asymmetric induction where two catalysts were used synergistically to induce high enantioselectivity for constructing enantiomerically pure drug-like hexahydroxanthenes and spriodihydrocoumarins with three contiguous stereocenters from simple precursors under mild conditions. This vital tool demonstrates the synthesis of various compounds showing potent biological activities. It has become significant in understanding the pre-transition state theory in organic chemistry. The in situ generated chiral supramolecular assembly catalysts could become great future catalytic systems for more functionalized substrates.

Our group is continuously striving to develop new catalytic reactions that can become valuable tools to make organic reactions greener and sustainable while demonstrating the synthesis of more drugs and natural products in a sequential one-pot manner.

How has the field of organocatalysis changed over the last 2 decades?

Over the last two decades, there has been an exponential proliferation of organocatalysis in every domain of chemistry, which is evident from the ~1500 articles per year. The role of organocatalysis in the synthesis of chiral organic compounds makes it a fundamental tool in catalytic asymmetric organic synthesis, which has several advantages over metal-catalysed and enzyme-catalysed reactions like the use of elementary organic molecules such as amino acids, the use of extraordinarily mild conditions with operational simplicity, functional group tolerance and broad applicability. The contributions from Professors Carlos F. Barbas III, David W. C. MacMillan and Benjamin List in the late 2000s laid the way for a paradigm shift in expanding the area from making simple asymmetric C-C bonds to a much wider scope of bond formations (C-O, C-N, C-X, C-S, C-P, C-H) and an eventual Chemistry Nobel Prize for the area in 2021.

In organic chemistry, achieving excellent diastereo- / enantio-selectivity and construction of pure single enantiomers is not easy, except for a few reactions like the Sharpless epoxidation, Noyori hydrogenation etc. Organocatalysis is solving challenging stereoselective transformations in vital areas which include aminocatalysis, Brønsted-acid catalysis, H-bonding catalysis, N-heterocyclic carbene catalysis, ion-pairing catalysis, oligopeptide (foldamers) catalysis, SOMO-catalysis, organosuperbases/frustrated Lewis pairs promoted catalysis, bifunctional catalysis and synergistic catalysis to name a few. Numerous valuable challenging chemical asymmetric transformations are unveiled with this tool making chemical industries chiral, greener and more sustainable.

Much more is yet to be discovered with this beautiful asymmetric platform. Unifying this platform with other fields like photoredox catalysis, electrochemistry, nanochemistry, flow chemistry and solid phase synthesis will undoubtedly be revolutionary in chiral drug discovery, natural product synthesis and material chemistry. The shortcoming of organocatalysis is that it is less efficient that metal or enzyme catalysis at low parts-per-million (ppm) level catalyst loadings. Moreover, the organocatalysts are usually required in higher quantities (up to 30 mol%). Asymmetric organocatalysed reactions with extremely low catalyst loadings are one step higher in their evolution. They are the need of the hour as they would be highly appreciable in pharmaceutical industries. General challenges associated with developing low ppm-level organocatalysed reactions include the requirement of very high reaction rates, preventing catalyst poisoning from impurities/by-products, rapidity of catalyst regeneration, catalyst stability and product stability under the reaction conditions.

Where do you see the challenges being for this field over the next 20 years?

Although we can reaffirm that organocatalysis has become an efficient tool capable of replacing metal and enzyme catalysis, we cannot completely rule out some of its drawbacks. The most important feature of this catalysis is that it has cleverly solved most typical problems which were once thought impossible. Nevertheless, this rapidly developing catalysis has suffered disadvantages like high catalyst loading and less efficiency than the highly explored metal or enzyme catalysis at ppm level loading. Furthermore, in comparison to intricate transition metal complexes, the simple organic molecules as catalysts were thought to once be incapable of performing all types of reactions. The deliberation in employing organocatalysis is evident in several areas but it cannot achieve excellent enantioselectivities with some of the highly functionalised substrates.

Therefore, it becomes necessary for synthetic chemists to design catalytic systems and conditions in such a way that they are useful with a wide variety of substrates. Thus, the design of functionally rich catalysts is essential, and it may only be possible with in situ combining some of the known catalysts because of cost effectiveness. However, this drawback is addressed by developing reactions employing an in situ supramolecular organocatalysis approach where more than two or three catalysts are employed in the reaction and act synergistically to produce high enantioselectivities than their single catalytic counterparts. In order to develop such types of technologies, a detailed understanding of the pre-transition states, reaction mechanisms and reactivity’s of the molecules, just like the molecular designing at the cellular level becomes highly essential.

One more challenge is recycling and reusing the employed organocatalyst, especially in the case of very costly catalysts, which stands as a severe issue that needs attention. The problem of high catalytic loading comes only with costly catalysts. Therefore, wisely switching PPM and PPB level catalyst loading to achieve good turnover numbers is the need of the hour to make organocatalysis thrive ahead in the evolution of greener and more sustainable reactions.

Another challenge and advantage of organocatalysis is the ability to not require protection and de-protection of functional groups when designing sequential one-pot strategies which increases the applicability of this tool, mainly at the industrial scale-up level. Organocatalysts often employ dilute solutions, which makes the reaction industrially less feasible. Alternatively, flow/solid support systems can find an advantage in solving this problem of catalyst loading and dilution problems. Though this catalytic approach can solve many problems, there is much room still left for further exploration in solving the fascinating mysteries of organocatalysis.

Check out the other entries in our blog series here!

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from Professor Guan-Wu Wang at the University of Science and Technology of China who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 18 articles across the years, most recently in 2022.

About Guan-Wu

Guan-Wu Wang obtained his BS, MS and PhD degrees from Lanzhou University in 1987, 1990, 1993, respectively. He then did his postdoctoral work at Fudan University, Kyoto University, University of Kentucky, University of Chicago and Yale University. In May of 2000 he joined the University of Science and Technology of China as a full professor. His research interests include fullerene chemistry and mechanochemistry.

First OBC paper: T.-H. Zhang, P. Lu, F. Wang & G.-W. Wang, Reaction of [60]fullerene with free radicals generated from active methylene compounds by manganese(iii) acetate dihydrate, Org. Biomol. Chem., 2003, 1, 4403-4407, DOI: 10.1039/b309939c

Most recent OBC paper: Q.-S. Liu, W.-J. Qiu, W.-Q. Lu & G.-W. Wang, Copper-mediated synthesis of fullerooxazoles from [60]fullerene and N-hydroxybenzimidoyl cyanides, Org. Biomol. Chem., 2022, 20, 3535-3539, DOI: 10.1039/d2ob00239f

Favourite OBC paper: J.-X. Li & G.-W. Wang, Novel multicomponent reaction of [60]fullerene: the first example of 1,4-dipolar cycloaddition reaction in fullerene chemistry, Org. Biomol. Chem., 2006, 4, 4063-4064, DOI: 10.1039/b612641c.

How has your research developed over the last 20 years?

I established my independent research group at University of Science and Technology of China in 2000. Since then, our research interests have been focused on fullerene chemistry and green organic synthesis. We initiated the free radical reactions of fullerenes mediated by Mn(OAc)₃, Fe(ClO₄)₃ and other metal salts. Fortunately, our early papers in this field were published in the first four successive years of OBC^1,2,3,4. At the same time, we also investigated the mechanochemical reactions of fullerene and non-fullerene molecules and published papers on this in OBC^5,6,7. Most recently, we are interested in electrosynthesis of fullerene derivatives by employing the starting materials synthesized by our own developed methodologies and published papers in recent years in OBC reporting this^8,9,10. OBC is one of my favourite journals, and we have published 18 papers in the last 20 years.

How has the field of mechanochemistry changed over the last 2 decades?

Mechanochemistry was not popular at all 2 decades ago, and few scientists were working on mechanochemical reactions. However, more and more scientists are gradually interested in mechanochemistry, which is now a hot research topic. Various types of mechanochemical reactions of fullerenes and non-fullerene molecules have been developed, and even applied to the synthesis of supramolecular structures including calixarenes, rotaxanes, cage compounds, and functional materials such as MOFs, COFs, Co-crystals.

Where do you see the challenges being for this field over the next 20 years?

The challenges in the field of mechanochemistry over the next 20 years would be the deep understanding of the reaction mechanisms probed by more state-of-art monitoring techniques and high-level theoretical computations. Another issue would be the large-scale preparation of materials which have great potential in industries.

Check out the other entries in our blog series here!

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from previous Editorial Board member Dame Margaret Brimble at the University of Auckland, who first published with OBC in 2003, the journal’s first year. She has continued to support the journal across the years with 61 articles across the years, the most any author has published with OBC.

About Margaret

Dame Margaret Brimble FRS is the Director of Medicinal Chemistry and a Distinguished Professor at the University of Auckland. She is an Associate Editor for Organic Letters, Deputy Director of the Maurice Wilkins Centre of Molecular Biodiscovery, Past-President of IUPAC Organic and Biomolecular Division III and Past-President of the International Society of Heterocyclic Chemistry. She has published >560 papers, 96 reviews and is an inventor on >50 patents.

Margaret is a Fellow of the Royal Society London, Dame Companion of the New Zealand Order of Merit and has been inducted into the American Chemical Society Medicinal Chemistry Hall of Fame. She was awarded the Rutherford, Hector and MacDiarmid medals (Royal Society NZ), the 2023 American Chemical Society Ernest Guenther Award for Natural Products Chemistry, the 2022 Royal Society of Chemistry Pedler Award for Innovation in Organic Chemistry and the BNZ Kiwinet Supreme Commercialization Award. She was also named the 2007 L’Oreal-UNESCO Women in Science laureate in Materials Science for Asia-Pacific and a 2015 IUPAC Distinguished Women in Chemistry/Chemical Engineering.

Margaret’s research focuses on the synthesis of novel bioactive natural products/antimicrobial peptides, antibody-drug conjugates and lipopeptides for cancer vaccines and new biomaterials. She discovered the drug ‘Trofinetide’ (NNZ2566) for Neuren Pharmaceuticals (www.neurenpharma.com) that was then successful in phase 3 clinical trials conducted by Acadia Pharmaceuticals (www.acadia.com) and approved by the US Food and Drug Administration (FDA) for the treatment of Rett syndrome on March 10, 2023. The drug, marketed under the name DAYBUE™, is now available for prescription in the United States.

 A second unique neurotrophic drug candidate NNZ-2591 also discovered by Professor Brimble’s lab has been demonstrated to give positive results in pre-clinical models of four additional neurodevelopmental disorders – Angelman syndrome, Pitt Hopkins syndrome, Phelan-McDermid syndrome and Prader-Willi syndrome and is entering phase 2 clinical trials for these disorders. She also co-founded the cancer immunotherapy company SapVax (Cleveland, Ohio; www.sapvaxllc.com) with US$7 million funding from BioMotiv USA that licensed her CLipPA peptide lipidation technology to develop self-adjuvanting peptide-based cancer vaccines.

First OBC Paper: M. A. Brimble, R. M. Davey, M. D. McLeod & M. Murphy, Synthesis of 3-azido-2,3,6-trideoxy-β-D-arabino-hexopyranosyl pyranonaphthoquinone analogues of medermycin, Org. Biomol. Chem., 2003, 1, 1690-1700, DOI: 10.1039/b301449p

Most recent OBC Paper: A. D. W. Earl, F. F. Li, C. Ma, D. P. Furkert & M. A. Brimble, Stereoselective synthesis of the spirocyclic core of 13-desmethyl spirolide C using an aza-Claisen rearrangement and an exo-selective Diels–Alder cycloaddition, Org. Biomol. Chem., 21, 1222-1234, DOI: 10.1039/d2ob01992b

Favourite OBC Paper: J. Robinson & M. A. Brimble, Synthesis of the anti-Helicobacter pylori Agent (+)-Spirolaxine Methyl Ether and the Unnatural (2″S)-Diastereomer, Org. Biomol. Chem., 5, 2572-2582, DOI: 10.1039/b708265g

How has your research developed over the last 20 years?

I started my academic career at a small agricultural university in New Zealand with limited resources and few graduate students. I worked on the synthesis of members of the pyranonaphthoquinone antibiotics that are bioreductive alkylating agents e.g kalafungin, frenolicin, nanaomycin, actinorhodin, medermycin, griseusin, cardinalin. I then moved to larger universities – first the University of Sydney for 4 years then the University of Auckland where I have worked for over 20 years. Whilst at Auckland I expanded my research to work on the synthesis of benzannulated spiroketals such as rubromycin, berkelic acid, peniphenone, paecilospirone, chaetoquadrin, spirolaxine and shellfish toxins such as spirolides, gymnodimine, pectenotoxins and portimine. In my early days at Auckland University I also carried out some peptidomimetic work that led to the discovery of the drug candidate ‘Trofinetide’ for Neuren Pharmaceuticals that was successful in phase 3 clinical trials for Rett Syndrome and has recently been approved by the FDA. This venture into peptidomimetic chemistry led me to establish a solid phase peptide chemistry group that has now become an integral part of our research programme. We are working on antibody-drug conjugates, antimicrobial and antiviral peptides, peptide-based biomaterials and peptide-based vaccines for infectious disease and cancer.

How has the encompassing field of your research changed over the last two decades?

Moving into peptide chemistry prompted me to combine this with my natural products synthesis work and establish a programme to synthesize complex peptide natural products that exhibit antimicrobial activity such as cadaside, malacidin, teixobactin, paenipeptin, laterocidine, brevicidine and glycopeptides (tikitericin, glycocin F and EPO). We also developed a new patented method to effect the lipidation of peptides using a thiol-ene reaction on cysteines coin ‘CLipPA’ (Cysteine Lipidation of Peptides and Amino acids). We have applied this to the field of self-adjuvanting cancer vaccines (co-founded SapVax Ltd), peptide hormones, antimicrobial lipopeptides (the polymyxins, antiviral peptides e.g anti-HBV peptides) and peptide hydrogels.

Where do you see the challenges being for this field over the next 20 years?

It will be interesting to see how AI impacts the design of synthetic routes to complex natural products and how automation techniques continue to help the field of natural product synthesis. Incorporation of chemoenzymatic methods into natural products synthesis will also become routine. As for solid phase peptide synthesis we have initiated some flow chemistry work to enable fast efficient production of neoantigens for personalised vaccines.

Check out the other entries in our blog series here!

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

The next entry to the series comes from Professor Philip Gale at the University of Technology Sydney who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 21 articles across the years, most recently in 2023.

About Phil

Phil Gale is the Deputy Dean of Science at the University of Technology Sydney. Phil was born and raised in Woolton, Liverpool (there are an unusually high number of academic chemists who originate from L25) and attended Gateacre Community Comprehensive School. He moved to the University of Oxford in 1988 to study Chemistry and remained there to undertake a DPhil under the supervision of Paul Beer in 1992. He moved as a Fulbright Scholar to the University of Texas at Austin in 1995 to work with Jonathan Sessler and subsequently was awarded a Royal Society University Research Fellowship which he took up at Oxford in 1997. While at Oxford, he co-wrote an Oxford Chemistry Primer on Supramolecular Chemistry with Paul Beer and David Smith which resulted in the Inorganic Editor of that series, Prof. John Evans from the University of Southampton inviting Phil down to give a seminar. Southampton offered Phil a continuing position as a Lecturer and Royal Society University Research Fellow, and he rose through the ranks becoming Professor of Supramolecular Chemistry in 2007 and serving as Head of Chemistry at Southampton between 2010 and 2016.

Phil then moved as Head of Chemistry to the University of Sydney in early 2017. He served as Head from 2017 to 2022 and Associate Dean International from 2020 to 2023. In April 2022 he became interim Dean of Science at Sydney and in February 2023, moved to the University of Technology Sydney as Deputy Dean of Science.

Phil and his research team have won several awards for their work including the RSC Bob Hay Lectureship, the Corday Morgan Medal and Prize, the RSC Supramolecular Chemistry Award and the 2018 Izatt-Christensen Award in Macrocyclic and Supramolecular Chemistry.

First OBC paper: S. Camiolo, P. A. Gale, M. B. Hursthouse & M. E. Light, Nitrophenyl derivatives of 2,5-diamidopyrroles: structural behaviour, anion binding and colour change signaled deprotonation, Org. Biomol. Chem., 2003, 1, 741-744, DOI: 10.1039/b210848h

Most recent OBC paper: M. Fares, X. Wu, D. A. McNaughton, A. M. Gilchrist, W. Lewis, P. A. Keller, A. Arias-Betancur, P. Fontova, R. Pérez-Tomás & P. A. Gale, A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death, Org. Biomol. Chem., 2023, DOI: 10.1039/d3ob00128h

Favourite OBC paper: C. J. E. Haynes, N. Busschaert, I. L. Kirby, J. Herniman, M. E. Light, N. J. Wells, I. Marques, V. Félix & P. A. Gale, Org. Biomol. Chem., 2014, 12, 62-72, DOI: 10.1039/c3ob41522h

How has your research developed over the last 20 years?

When I began my independent career in the late 1990s with my own research group, many anion receptor systems reported in literature were structurally complex, containing macrocyclic components and often carrying a positive charge. We focused on simplifying the structures of these systems and reported a series of acyclic receptors, including 2,5-diamidopyrroles, ortho-phenylene-based bis-ureas, dipyrromethene bis-amides and 1,3-diamidoanthraquinones. We showed that simple acyclic receptors could still retain high affinity and selectivity for particular anions. My first paper in OBC was published in 2003 in the 4^th issue of volume 1. At the time I was a relatively new academic at the University of Southampton in the UK, looking at designing hydrogen bond donor motifs to bind anions. We’d noticed that pyrrole 2,5-dicarboxamides containing electron-withdrawing groups would deprotonate upon addition of fluoride which in some cases would cause a colour change. At that time (and for a while after) there were many examples of colorimetric fluoride sensors reported in the literature – this paper together with contemporaneous work from Thorri Gunnlaugsson’s group at Trinity College Dublin demonstrated that the colour changes observed with these systems may also be due to deprotonation processes. We kept an eye out for these types of acid-base reactions and reported further examples over the following years – including in 2010 an example of a receptor containing multiple hydrogen bonds affecting the pKa of a bound anion resulting in deprotonation of the anionic guest.

Over the last twenty years we have stayed with the theme of anions but moved from designing receptors to designing and testing anionophores to facilitate the transport of anions across lipid bilayer membranes. This has been a collaborative effort with many colleagues including Tony Davis and David Sheppard in Bristol, Jeff Davis in Maryland, Bradley Smith at Notre Dame, Jonathan Sessler in Austin, Roberto Quesada in Burgos, Vitor Félix in Aveiro, Rob Elmes at Maynooth University, Kate Jolliffe at the University of Sydney, Yun-Bao Jiang at Xiamen University, Ricardo Pérez-Tomás at Barcelona, and Injae Shin at Yonsei University. My group has moved during this time, first to the University of Sydney in 2017 and this year to the University of Technology Sydney.

Early work focused on producing analogues of the natural product prodigiosin – one of the most potent HCl co-transporters known. However, as with our work on anion receptors, we simplified the design of anion transporters to understand the factors that govern efficient transport. Work focused both on encapsulating tripodal tris-ureas and -thioureas and planar single ureas, thioureas and squaramides that we demonstrated are very effective transporters when fluorinated. In 2013, we published a quantitative structure activity relationship study, showing that in a series of simple thioureas with one n-hexyl substituent and a phenyl substituent with different groups in the 4-position, the lipophilicity of the receptor is the dominant molecular parameter determining effective transport, with smaller contributions from the receptors’ volume and affinity for chloride.

With our collaborators, we’ve found that anion transport into cells can trigger apoptosis and interfere with autophagy and hence these compounds may potentially have anti-cancer properties. We’ve also demonstrated that our compounds can facilitate the transport of chloride across epithelial cell membranes. This is an interesting result as chloride transport is reduced or stopped across epithelial cell membranes in patients with cystic fibrosis. The development of chloride anionophores offers the prospect of replacing the faulty chloride channels in these cells with small molecules that can perform the same function. Our latest paper in OBC, published in 2023, twenty years after the first, is a collaboration with Ricardo Pérez-Tomás where we investigate where fluorescently tagged versions of one of the most effective anion transport motifs (ortho-phenylene bis-ureas) localise in cells.

How has the field of supramolecular chemistry changed over the last 2 decades?

The field of supramolecular chemistry has grown and developed significantly over the last 20 years. One of the most fascinating areas has been the development of systems chemistry and the study of dissipative self-assembly. The use of fuels to form transient assemblies far from equilibrium resembles processes found in biological systems with complex dynamic behaviour. Of course, one of the highlights of the last two decades has been the award of the Nobel Prize in Chemistry in 2016 to Jean-Pierre Sauvage, Fraser Stoddart and Ben Feringa for the development of molecular machines. Another pioneer in this area is Dave Leigh at the University of Manchester, whose work on molecular knots, synthetic chemically-fuelled molecular motors and molecular robotics is always inspiring with the ingenuity and elegance of his supramolecular creations. Another leader in supramolecular chemistry is Wolf prize winner Makoto Fujita at the University of Tokyo. A standout achievement for me has been Fujita’s development of crystalline sponges which allow micrograms of compounds to be soaked into crystals and subsequent X-ray structural determination. This has allowed single crystal X-ray diffraction structures of liquids and very small quantities of materials to be obtained.

I think importantly recently we have seen a generational shift in the field with many of the first generation of supramolecular chemists approaching retirement or having already retired, a new more diverse cohort of researchers is picking up the mantle. A positive international development has been the establishment of the Women in Supramolecular Chemistry network (www.womeninsuprachem.com) which is providing a support network for women and marginalised groups working in supramolecular chemistry. A growing recognition of the importance of supramolecular chemistry is reflected in the recent decision by the Royal Australian Chemical Institute to form a new division of supramolecular chemistry alongside the more traditional areas of chemistry.

Where do you see the challenges being for this field over the next 20 years?

Obtaining research funding is always challenging and supramolecular chemistry is at its core, a fundamental area of chemistry which requires discovery type support to make progress. However, I think it’s important that we as a field can point to applications of supramolecular chemistry in technological processes and in medicine. This will allow us to illustrate to funders and to our academic colleagues, the cross-cutting nature of supramolecular chemistry and the many real-world problems that can be addressed using supramolecular approaches. A group of us wrote a review¹ in 2021 highlighting some of these which covered medicine, sensors, remediation of chemical warfare agents, hydrometallurgy, separations and extractions, environmental remediation, self-healing materials and coatings, adhesives, and batteries. The continued translation of supramolecular chemistry to technological applications in the real-world is vital for the long-term health of our discipline.

Check out the other entries in our blog series here!

¹G. T. Williams, C. J. E. Haynes, M. Fares, C. Caltagirone, J. R. Hiscock & P. A. Gale, Advances in applied supramolecular technologies, Chem. Soc. Rev., 2021, 50, 2737-2763, DOI: 10.1039/d0cs00948b

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

Our next entry to the series comes from Professor Luis R. Domingo at the University of Valencia who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 27 articles across the years, most recently in 2021.

About Luis

Luis R. Domingo obtained his PhD in Organic Chemistry in 1987. In 2010 he attained his current position as a Full Professor at the Department of Organic Chemistry of the University of Valencia. In 2014 he was admitted as a Fellow of the Royal Society of Chemistry. His research interest is the study of organic chemical reactivity by using quantum chemical procedures based on the analysis of the molecular electron density. He has published more than 370 articles and 8 book chapters, being reviewer of more than 690 articles. Today, he has reached an h index of 61, receiving more than 16,450 citations.

In 2009, Domingo proposed the mechanism of polar Diels-Alder reactions against the ‘pericyclic mechanism’, which is followed by many of the experimental reactions and in 2019 he established the relationship between the structure and reactivity of the three-atom-components participating in [3+2] cycloaddition reactions, proposing four different reaction mechanisms. In 2014, he proposed a new model for the C-C bond formation based on the quantum chemical topology of electron density. He emphasised the significance of the global electron density transfer (GEDT) in the activation energies of polar reactions. After the study of relevant organic reactions classified in 1969 as pericyclic reactions, in 2019 the corresponding mechanism was rejected. He has introduced several concepts widely used today as non-concerted two-stage one-step mechanisms, which involve high asynchronous transition state structures, pseudoradical centres, which participate in many organic reactions involving the formation of new C-C single bonds, and the GEDT which discards the arrow curves used in many textbooks to explain the electronic displacement in polar reactions.

In the present century, Domingo and co-workers have developed several reactivity indices within the Conceptual Density Functional Theory, such as the local electrophilicity ω_k index in 2002, the empirical nucleophilicity N index in 2008, the reactivity difference index in 2012, and the electrophilic and nucleophilic Parr functions in 2013, commonly used nowadays in the study of polar organic reactions.

After 20 years and more than 250 publications in the field of Theoretical Organic Chemistry, in 2016 Domingo proposed a new reactivity theory named Molecular Electron Density Theory (MEDT), which opposes all theories developed in the past century based on analysis of molecular orbitals such as the Frontier Molecular Orbital (FMO) theory. Domingo’s MEDT proposes the study of organic chemical reactivity based on the analysis of electron density changes during a chemical reaction.

First OBC Paper: A. Manuel & L. R. Domingo, Theozyme for antibody aldolases. Characterization of the transition-state analogue, Org. Biomol. Chem., 2003, 1, 637-643, DOI: 10.1039/b209636f

Most recent OBC Paper: M. Ríos-Gutiérrez, P. Pérez, L. R. Domingo & J. Soto-Delgado, The catalytic effects of a thiazolium salt in oxa-Diels-Alder reaction between benzaldehyde and Danishefsky’s diene: A molecular electron density theory study, Org. Biomol. Chem., 2021, 19, 9306-9317, DOI: 10.1039/d1ob01415c

Favourite OBC Paper: L. R. Domingo & J. A. Sáez, Understanding the mechanisms of polar Diels-Alder reactions, Org. Biomol. Chem., 2009, 7, 3576-3583, DOI: 10.1039/b909611f

How has your research developed over the last 20 years?

The development at the end of the last century of quantum chemistry tools capable of performing molecular electron density analysis has made significant advances in the field of Theoretical Organic Chemistry during the last 20 years.

After the proposal in 1999 of Parr’s electrophilicity ω index, which provides a quantitative measure of an important reactivity concept in organic chemistry in 2002, the first electrophilicity ω scale of organic molecules able to explain the reactivity of experimental Diels-Alder reactions was presented¹. The local electrophilicity ω_k index, proposed in 2002, allowed explaining the chemo and regioselectivity in polar cycloaddition reactions². Later in 2008, the empirical nucleophilicity N index was proposed^3,4. Today, the electrophilicity ω and the nucleophilicity N indices allow the quantitative study of polar reactions. Finally, in 2013, the electrophilic and nucleophilic Parr functions were introduced, allowing the understanding of the local reactivity, i.e., the chemo and regioselectivities, in polar reactions⁵.

After numerous theoretical studies of reaction mechanisms in the period 2002-2014 based on the topological analysis of the molecular electron density, a model for the formation of new C-C single bonds experienced by many organic reactions was proposed in 2014⁶. On the other hand, the recognition of the decisive role of the global electron density transfer (GEDT)⁶ in the activation energies of polar organic reactions provided a new vision of relevant reactions such as the polar Diels-Alder reactions⁷, inadequately classified as a pericyclic reaction in 1969.

[3+2] cycloaddition (32CA) reactions are a class of fascinating organic reactions. After 20 years of studying 32CA reactions, an excellent correlation between the electronic structure of the three-atom-components (TACs) and their reactivity was established in 2019. Unlike the 1,2-dipolar structure proposed by Huisgen, four different electronic structures, which experience four different reactivity types, were characterized⁸. Recent studies have shown that although the electronic structure of the TAC can be modified with substitution, the four types of reactivity can be characterized in most 32CA reactions.

After 20 years of working in the field of Theoretical Organic Chemistry, in 2016, Domingo proposed a new reactivity theory named Molecular Electron Density Theory (MEDT)⁹, which establishes that changes in electron density along an organic reaction, and not molecular orbital interactions, are responsible for the chemical reactivity of organic molecules.

Many recent MEDT studies of relevant organic reactions have allowed us to reinterpret the organic reactivity based on electron density analysis. A recent study of the four reactions classified in 1969 by Woodward and Hofmann as pericyclic reactions has proved that this mechanism does not exist since the bonding changes in organic reactions are sequential and non-concerted¹⁰.

How has the field of theoretical organic chemistry changed over the last 2 decades?

The advances carried out in the last 2 decades in the field of theoretical organic chemistry based on the analysis of the molecular electron density, which is the only physical observable, have allowed us to establish new concepts in organic chemistry. This has caused the rejection of models developed in the past such as the FMO theory, the symmetry rules and energy decomposition analyses based on molecular orbitals, all of them proposed in the past century before the possibility to perform any topological analysis of the molecular electron density obtained from Schrödinger’s wavefunction.

On the other hand, the electrophilicity ω and the nucleophilicity N indices, together with the Parr functions have become easy and powerful tools in studying local reactivity in polar reactions for experimental organic chemists.

Finally, the recent topological analysis of the ELF of the reagents in relevant organic reactions such as 32CA reactions has established a good correlation between the electronic structure and chemical reactivity.

Where do you see the challenges being for this field over the next 20 years?

The establishment of Schrödinger’s equation in 1926 was one of the more relevant advances in the field of theoretical organic chemistry as it provides the molecular electron density distribution, which determines the structure and reactivity of organic molecules. Still unfortunately, it cannot be resolved even for the simplest organic molecules. In 1932, the molecular orbital theory was established as a mathematical approach to the wavefunction, but inappropriately molecular orbitals were taken as a reality, proposing in 1931 the Hückel’s p-bonds in unsaturated compounds and 1956 Fukui’s FMO theory to explain organic chemical reactivity. Many concepts, such as pericyclic reactions or concerted reactions are still used today in many organic chemistry textbooks.

Extensive work developed in the present century, based on the analysis of the molecular electron density, has allowed the understanding of many organic reactions, rejecting those concepts based on molecular orbital analyses. Unfortunately, there is still strong influence by research groups that continue working with molecular orbital theories to study reaction mechanisms. But in the last two decades, they have not introduced any advances in chemical understanding.

MEDT proposed in 2016, suggests that the analysis of the molecular electron density, which is the only physical observable, is accurate for understanding organic molecules’ electronic structure and reactivity. Today, theoretical and experimental organic chemists have a great variety of quantum chemical tools able to perform a rigorous analysis of the molecular electron density obtained by any computational level, thus rejecting any obsolete molecular orbital analysis. Note that molecular orbitals were defined to approach the wavefunction, the square of which provides the molecular electron density.

The relationship of HOMO and LUMO energies with the ionization potential and the electron affinity used in Conceptual Density Functional Theory to attain the reactivity indices and that between molecular orbital coefficients and the Fukui functions used to study the local reactivity allows explaining the good correlations found between experimental data and FMO analyses, but non HUMO-LUMO interactions, but rather nucleophilic/electrophilic interactions between molecules of different electronegativity are responsible for the chemical reactivity in polar reactions.

These similitudes make it that unfortunately, many people continue using models based on the updated FMO theory, but it is essential to remember that Schrödinger’s wavefunction was proposed only to describe the electron distribution in a molecule and that electronic interactions between particles constituting a molecule, i.e., nuclei and electrons are responsible for electronic energies.

Check out the other entries in our blog series here!

2023 marks twenty years of Organic & Biomolecular Chemistry publications. As part of the celebrations, OBC has invited some of the most prominent authors across our history to give their thoughts on the last twenty years of their career alongside their predictions for the next two decades.

Our first entry to the series comes from Professor Hirokazu Tamamura at the Tokyo Medical and Dental University who first published with OBC in 2003, the journal’s first year. He has continued to support the journal with 12 articles across the years, most recently in 2021.

About Hirokazu

Prof Hirokazu Tamamura graduated from the Faculty of Pharmaceutical Sciences, Kyoto University in 1988 (Supervisor: Prof Haruaki Yajima), and received his Ph.D. from Kyoto University in 1995. He became an Assistant Professor of the Faculty of Pharmaceutical Sciences, Kyoto University in 1989 (Boss: Prof Nobutaka Fujii), and then a Lecturer of the Graduate School of Pharmaceutical Sciences, Kyoto University in 1997.

He became a Visiting Fellow at the National Cancer Institute/NIH, USA in 1999-2000 (Lab. Medicinal Chemistry, Boss: Dr Victor E. Marquez) before becoming an Associate Professor of the Graduate School of Pharmaceutical Sciences, Kyoto University in 2005, and then a Full Professor at the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU) in 2005. His research fields extend to peptide & protein chemistry, chemical biology, medicinal chemistry and organic chemistry.

Hirokazu Tamamura

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

First OBC Paper: H. Tamamura, T. Kato, A. Otaka & N. Fujii, Synthesis of Potent β-Secretase Inhibitors Containing a Hydroxyethylamine Dipeptide Isostere and Their Structure-Activity Relationship Studies, Org. Biomol. Chem., 2003, 1, 2468-2473, DOI: 10.1039/b304842j

Most recent OBC paper: K. Tsuji, T. Ishii, T. Kobayakawa, N. Ohashi, W. Nomura & H. Tamamura, Fluorescence resonance energy transfer-based screening for protein kinase C ligands using 6-methoxynaphthalene-labeled 1,2-diacylglycerol-lactones, Org. Biomol. Chem., 2021, 19, 8264-8271, DOI: 10.1039/d1ob00814e

Favourite OBC paper: H. Tamamura, K. Hiramatsu, M. Mizumoto, S. Ueda, S. Kusano, S. Terakubo, M. Akamatsu, N. Yamamoto, J. O. Trent, Z. Wang, S. C. Peiper, H. Nakashima, A. Otaka & N. Fujii, Enhancement of the T140-based Pharmacophores Leads to the Development of More Potent and Bio-stable CXCR4 Antagonists, Org. Biomol. Chem., 2003, 1, 3663-3669, DOI: 10.1039/b306613b

How has your research developed over the last 20 years?

My research has been focused on peptide-based medicinal chemistry over the last 20 years. I started on the development of methodologies for peptide synthesis in 1988 at the Graduate School of Pharmaceutical Sciences, Kyoto University. After receiving my PhD and finishing a postdoctoral fellowship at the National Institutes of Health/National Cancer Institute (NIH/NCI), USA, my research got closer to medicinal chemistry and chemical biology, using peptides and their derivatives. As drug leads for chemotherapy of Alzheimer’s disease, we developed potent beta-secretase inhibitors based on peptide derivatives containing a mimic structure of the enzyme-substrate transition state: a hydroxyethylamine dipeptide isostere. Thus, in 2003, my first paper with OBC on the development of beta-secretase inhibitors was published¹. In addition, we had research for the development of antagonists for the chemokine receptor CXCR4, which is correlated with several diseases such as HIV-1/AIDS, cancer and rheumatoid arthritis. Through structure-activity relationship studies on polyphemusin-related peptides, we developed peptidic CXCR4 antagonists, which were designated as T140 derivatives, with high CXCR4-binding affinity, low cytotoxicity and improved biostability. The lead compound, Motixafortide has been progressing through to Phase III clinical studies. In the finding of these CXCR4 antagonists, we published two consecutive papers in 2003 with OBC^2,3.

In association with this research, we established a fluorescence-based assay system for CXCR4 binding of compounds using a fluorophore-labeled T140 derivative⁴. So far we have developed novel CXCR4 antagonists based on nonpeptides as well as cyclic pentapeptide derivatives, which we published in several journals^5-10, mostly OBC^5,7-10. This target receptor CXCR4 forms dimers in the cell surface because it belongs to the G protein-coupled receptor family. So we developed bivalent CXCR4 ligands with polyproline linkers to catch the dimers in cells¹¹. These bivalent CXCR4 ligands are remarkably more potent than the corresponding monomers. In addition, trivalent CXCR4 ligands highly recognise CXCR4-expressed cells because of accumulation of ligands, which we published with OBC in 2015¹². The concept of multimerised peptides has been applied to HIV-1 envelope proteins related to membrane fusion, hence dimeric C34 derivatives showed much more potent anti-HIV-1 activity compared to the monomer C34 peptide¹³.

In my postdoctoral fellowship at NIH/NCI, I had started to develop ligands of protein kinase C (PKC) based on conformationally constrained gamma-lactone derivatives of 1,2-diacylglycerol (DAG). This led to research on the development of DAG-lactones with potent binding affinity for PKC. Initially, we had adopted a competitive assay using radio isotope tritium-labeled phorbol 12,13-dibutyrate to evaluate PKC-binding activity of synthesised DAG-lactones. But from the point of view of environmental health and safety, radio isotope-based screening has been replaced with fluorescene-based screening. Therefore, we developed a fluorescence resonance energy transfer (FRET)-based screening method for PKC ligands, which we published with OBC in 2021⁴. It was an honour that this paper was chosen as the Inside Front Cover of the issue. Taken together my research has focused on medicinal chemistry and chemical biology using peptides, their derivatives and other functional molecules over the last two decades.

How has the field of Medicinal Chemistry changed over the last 2 decades?

Two decades ago, it was common sense that drugs were mostly low molecular weight (small-size) compounds. Through the progress of organic and synthetic chemistry, small-size drugs based on synthesised compounds have been conventionally developed against several diseases. Small molecules have some useful advantages including oral availability and low immunogenicity but serious drawbacks such as low specificity and high possibility of side effects. In this century, high molecular weight biologics (large-size molecules) including human monoclonal antibodies have been developed. Macromolecules have some merits such as high specificity and low possibility of side effects but critical shortages containing low applicability and possible immunogenicity. Accordingly, both small- and large-size drugs have their mutual advantages and drawbacks. In addition, it has been noticed that there is an important drug-like chemical space in the mid-size region between small- and large-size regions. Middle-size molecules, which are categorised between small- and large-size molecules and designated as mid-size drugs, might avoid drawbacks but contain the above advantages possessed by small- and large-size molecules. Therefore, mid-size drugs are ideal as new drug modalities, which encompasses peptides and their derivatives because of their location in this middle-size region.

Small-size drugs can recognise small regions on targeted proteins and usually bind to active centres of enzymes and pockets of receptors. The interface between the drugs and the targeted proteins is relatively narrow. Recently, the number of newly found proteins relevant to several diseases is decreasing since the whole human genome was disclosed in 2003/04. Thus, it has been difficult to find first-in-class drugs (brand-name drugs), which have novel action mechanisms that give new therapeutic approaches to treat diseases. Generic drugs, which can be presented for sale if the patent protection for a brand-name drug expires, or next-in-drugs, which have similar action mechanisms to existing drugs, have come to the forefront as small-size drugs. The concept of molecular target drugs, which bind to only specific molecules relevant to objective diseases and inhibit their functions has come to the fore over the last 20 years. Large-size drugs including human monoclonal antibodies can recognise broad regions on targeted proteins and usually bind to extracellular regions on cell surface receptors. The interface between the drugs and the targeted proteins is relatively expansive. Due to the expansive interface, large-size drugs can specifically recognise targeted proteins and achieve inhibition of protein-protein interaction, hence reducing off-target binding and side effects.

Mid-size drugs containing mostly peptides and their derivatives can have these broad interface regions with targeted proteins, the same as large-size drugs. In addition, mid-size drugs such as peptide derivatives might penetrate cell membranes if the conformation is constrained, therefore can target not only extracellular regions on cell surface receptors but also molecules inside of cells. Accordingly, mid-size drugs can target protein-protein interaction as well as active centres of enzymes and pockets of receptors. They are the current focus for development of next generation drugs. Altogether, the field of medicinal chemistry has been much changed over the last two decades, with medicinal chemists drawing attention to these mid-size drugs.

Where do you see the challenges being for the Medicinal Chemistry field over the next 20 years?

I think in the next two decades the field of medicinal chemistry will have been changed even more. In the design of small-size and mid-size drugs, computer calculation and artificial intelligence (AI) will be applied to a greater extent. There are still meaningful targets for small-size drug development, such as the central nervous system along with virus-related diseases including emerging and re-emerging infectious diseases. Currently these drugs are designed based on the structures of the lead compounds complexed with their targeted proteins determined by the X-ray structure analysis and/or NMR analysis accompanied with docking simulations. Recently, cryo-electron microscopy (cyro-EM) has been used for structural analysis with great success. In the future, cryo-EM will be used for more structure analysis and other spectroscopies might be adopted. Even though the practical structures of the lead compounds bound to the targeted proteins sometimes are not discoverable, computer calculation and AI can produce the plausible structures. These techniques are now already useful for the design of potent drugs and will advance more in the future, to much greater levels. Based on bioinformatics, including genome information and chemoinformatics of libraries, AI drug discovery will advance more and more with application of big data of lead compounds and in silico screening. AI and robotics, in which data from each working step can be obtained by the robots’ sensors and then judged by the AI to make progress towards the next steps, will also be developed in the near future.

Peptides and new drug modalities will also become more prominent, especially cyclic peptide derivatives, which possess many advantages as drug candidates. Antibody drug conjugates (ADCs) are ideal compounds, which are conjugates of monoclonal antibodies and small drugs tethered by linkers. In ADCs, the monoclonal antibody can specifically recognise targeted extracellular regions on cell surface receptors while the small drug is then able to reach intracellular target molecules to inhibit their functions. Many ADCs will be developed, mainly for the application for cancer chemotherapy.

An alternative to drugs is chemical protein knockdown. In this strategy, molecules containing ligands of targeted proteins and E3 ligase are synthesised to attack the targeted protein and induce degradation of them by the ubiquitin-proteasome system in vivo, based on specific and non-genetic IAP-dependent protein eraser (SNIPER), proteolysis targeting chimeras (PROTAC) and other similar mechanisms. These molecules can access undruggable targets, which cannot be bound by small size drugs. In the future, I think chemical protein knockdown will be applied to many targets.

Nucleic acid medicine, another drug modality, is now very popular. RNA-dependent polymerease RNA inhibitors and mRNA vaccines have been useful for treatment and prevention of COVID-19 respectively. Thus, these drugs will be expected for the treatment and prevention of new infectious diseases. Research on other gene therapies involving small interfering RNA (siRNA) and antisense nucleotides along with genome editing will become a hot area. Concomitantly, development of vectors for nucleic acid and genome medicine will be actively pursued. In addition, regenerative medicine including cell therapy will make progress in close association with embryonic (ES cells) and induced pluripotent stem cells (iPS cells). Chimeric antigen receptor-therapy (CAR-T) will also be another next generation therapy for cancer. Altogether, I believe various drug modalities will be utilised to have the right drugs for the right targets in the future.

Check out the other entries in our blog series here!

This year we are proud to be celebrating the 20 years since the launch of Organic & Biomolecular Chemistry. 

Although the first issue of OBC was published in 2003, the journal is part of a proud history of publications stretching back over 170 years beginning with Journal of the Chemical Society (1849-1965) via Journal of the Chemical Society B and C (1966–1971), and Journal of the Chemical Society, Perkin Transactions 1 and 2 (1972–2002). The vision behind OBC‘s creation was to bring together the synthetic and physical organic strands of Perkin 1 and 2, while incorporating more material relevant to biology. Since that first issue OBC has continued to publish a diverse range of high quality and impactful research in the organic chemistry community. 

We are delighted to announce a range of activities to celebrate the 20th anniversary of OBC. You can find out more about each of these activities below:

20th Anniversary Activities

Introductory Editorial

Editorial Board Chair Anthony Davis and Executive Editor Becky Garton introduce the anniversary celebrations with an Editorial: Celebrating the 20^th anniversary of Organic & Biomolecular Chemistry

20th anniversary collection

We have published an ongoing themed collection featuring work from members of the community who have served on the Editorial and Advisory Boards of OBC across the last two decades. We would like to thank everyone who has been a part of the journal as it would not be where it is today without the support they provided and we appreciate them sharing their latest discoveries with us! Hopefully you enjoy the range of articles featured in the collection.

OBC 20th anniversary collection

Community Spotlight Interviews

We will be publishing a series of blogs featuring interviews with authors who have prominently supported OBC by publishing in the journal from our early volumes through to the present day. These blog posts are an opportunity for our authors to give their thoughts on the past twenty years of their research and the encompassing field alongside their insights towards the next two decades.

Professor Hirokazu Tamamura

Professor Luis Domingo

Professor Philip Gale

Professor Dame Margaret Brimble

Professor Guan-Wu Wang

Professor Dhevalapally B. Ramachary

Professor Lei Wang

Professor Alexandra Slawin

Professor Peter Langer

Keep an eye out on our blogs platform and on our socials for future interviews!