Organic & Biomolecular Chemistry Blog

From left to right: Takakura, Koyama, Yamada, Sajiki and Sawama

Introducing the researchers:

Ryoya Takakura obtained his B.S. (2016) from Gifu Pharmaceutical University. At present, he is pursuing his Ph.D. at Gifu Pharmaceutical University. He is developing new chemical methodologies for the convenient synthesis of medicine.

Kaho Koyama obtained her B.S. (2020) from Gifu Pharmaceutical University. Her B.S. research focused on the development of organic transformation catalyzed by hydroquinone and benzoquinone. She is currently working as a pharmacist in Japan.

Dr. Tsuyoshi Yamada was received his Ph.D. in 2017 from Gifu Pharmaceutical University under the direction of Prof. Hironao Sajiki. After serving as a Postdoctoral Fellow at Heidelberg University (Prof. A. Stephen K. Hashmi, 2017–2018), he moved to Gifu Pharmaceutical University as an Assistant Professor. His research interests include the development of acid-catalyzed rearrangement, cyclization reactions and flow reactions using heterogeneous catalysts.

Prof. Dr. Hironao Sajiki received his PhD from Gifu Pharmaceutical University in 1989 under the direction of Prof. Yoshifumi Maki. After serving as a Postdoctoral Fellow at the State University of New York at Albany (Prof. Frank M. Hauser, 1990–1991) and Massachusetts Institute of Technology (Prof. Satoru Masamune, 1991–1992), he joined Metasyn, Inc. (subsequently Epix Pharmacueticals), MA, USA as a group leader. In 1995, he moved to Gifu Pharmaceutical University as an Assistant Professor. He became an Associate Professor in 1999 and Professor in 2006. He has also been the president of the Japanese Society for Process Chemistry since 2017.

Dr. Yoshinari Sawama obtained his Ph.D. degree at Osaka University in 2006 under the supervision of Professor Yasuyuki Kita. After working as the postdoctoral fellows, he was appointed as an Assistant Professor at Gifu Pharmaceutical University (Professor Hironao Sajiki) in 2010. He was promoted to Lecturer in 2015 and Associate Professor at same university in 2017. His research interests include mechanochemical reaction, hydrogen generation, carbon capture and reuse, Lewis acidic chemistry, green sustainable chemistry, isotopic labeling and total synthesis of natural products.

What inspired your research in this area?

Our research group continuously developed the deuterium-labeling methods of organic compounds, which are widely utilized in various scientific fields, such as the mechanistic investigation of organic reactions, tracer in microanalyses, elucidation of drug metabolism, heavy drugs, quantitative mass spectrometry analysis, etc. To achieve the one-pot reaction of the deuteration of aldehyde and Knoevenagel condensation, it was necessary to develop the Knoevenagel condensation, which can proceed under milder reaction conditions in the aqueous phase.

What do you personally feel is the most important outcome of your study?

Although we have tested the aqueous Knoevenagel condensation using weak acidic hydroquinone at an earlier investigation stage, we found that the benzoquinone, slightly contaminated in hydroquinone, effectively facilitated the present desired reaction. This serendipity produced the first organic reaction catalyzed by the combination of hydroquinone and benzoquinone.

What directions are you planning to take with your research in future?

Another of our interests is green sustainable chemistry using the heterogeneous and reusable solid catalysts. Our plan is to create the functional supermoleculars bearing both of hydroquinone and benzoquinone skeletons, which are applicable to various organic reactions including the Knoevenagel condensation.

Read the full article: Hydroquinone and benzoquinone-catalyzed aqueous Knoevenagel condensation

See the other articles showcased in this month’s Editor’s Collection

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Left to right: Mc Carthy, Zhu

Introducing the researchers:

Cian Mc Carthy obtained his B.Sc. degree in Medicinal Chemistry from University College Dublin. He is currently a final year PhD student under the guidance of Xiangming Zhu, investigating the role of N-trifluoromethylthiosaccharin as a promoter for thioglycoside activation.

Xiangming Zhu was born in Yiwu City, China. He received his PhD from Shanghai Institute of Organic Chemistry in 2001. He then moved to Konstanz to take up a postdoctoral position at the University of Konstanz with Prof Richard Schmidt. In 2005, he joined Prof. Geert-Jan Boons’ group in the Complex Carbohydrate Research Centre at UGA to work on the stereoselective synthesis of arabinofuranosides. He is currently a PI in the School of Chemistry at UCD and his research interests are in the areas of carbohydrate chemistry.

What inspired your research in this area?

A direct and highly stereoselective procedure for the synthesis of α-glycosyl thiols (J. Org. Chem. 2011, 76, 10187-10197) has been developed recently in our laboratory. α-Glycosyl thiols could be used to make various α-S-linked glycosides or glycoconjugates including α-thioglycoside donors, are thus very valuable building blocks in thioglycoside chemistry. This work was therefore initiated as part of our research program aimed to investigate glycosylation property of α-thioglycoside donors.

What do you personally feel is the most important outcome of your study?
I believe the most significant finding of this study is the simplicity of the reaction condition that achieves high chemoselectivity between two most commonly used thioglycoside donors. Our study highlights the importance of finding new activation protocols which may bring new and interesting applications to glycosylation.

What directions are you planning to take with your research in future?

We would like to expand our study beyond phenyl and ethyl thioglycosides to the commonly used S-tolyl glycoside donors. This will give an even more comprehensive overview of our new promoter’s ability in chemoselective activation. Additionally, we would like to see how effective N-trifluoromethylthiosaccharin will serve as an extension to already established reactivity-based one-pot strategies.

Read the full article: Chemoselective Activation of Ethyl vs Phenyl Thioglycosides: One-pot Synthesis of Oligosaccharides

See the other articles showcased in this month’s Editor’s Collection

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The Organic & Biomolecular Chemistry Editor’s collection is a showcase of some of the best articles published in the journal, hand selected by our Associate Editors and Editorial Board members. For this month’s selection, Associate Editor Elizabeth Krenske has highlighted some of her favourite recent works. Take a look at what she thought of the articles below, and find out more about the research and the researchers behind the papers in our interviews with the authors.

Elizabeth’s Selection:

Photochemical [2+2] Cycloaddition Reaction of Carbonyl Compounds with Danishefsky Diene

Dian Agung Pangaribowo and Manabu Abe

Elizabeth’s comments: “This work by Abe and Pangaribowo reveals that photochemistry can be harnessed to propel Danishefsky’s diene towards a new functionalisation manifold. It also reports the first stereocontrolled synthesis of the until-now elusive cis isomer of Danishefsky’s diene.”

Find out more in our interview with the authors

Decomplexation as a rate limitation in the thiol-Michael addition of N- acrylamides

Joseph S. Brown, Andrew W. Ruttinger, Akash J. Vaidya, Christopher A. Alabi and Paulette Clancy

Elizabeth’s comments: “In this thought-provoking contribution, Clancy and coworkers show that in Michael additions involving certain fluorous hydroxylated thiols, the rate-limiting step is not the addition itself, but the liberation of the product from the complex that it forms with other co-reactants. This work adds an intriguing new dimension to the mechanistic understanding of this important class of reactions.”

Find out more in our interview with the authors

Chemical methods for modification of proteins   

Neelesh C. Reddy, Mohan Kumar, Rajib Molla and Vishal Rai

Elizabeth’s comments: “In this review, Rai and coworkers survey key milestones in the field of protein chemical modification. With a special focus on the role of protein architecture in modulating innate reactivity, this work highlights the challenges and opportunities that chemists face when pursuing selective protein modification.”

Find out more in our interview with the authors

Tuning activation and self-immolative properties of the bioorthogonal alkene–azide click-and-release strategy

Jessica M. Fairhall, Madoka Murayasu, Sumit Dadhwal, Sarah Hook and Allan B. Gamble

Elizabeth’s comments: “Here, Gamble and coworkers push the boundaries of azide/alkyne cycloaddition kinetics with their development of a new series of click-and-release reactions. The work is a neat application of physical organic chemistry to expand the bioorthogonal chemist’s toolbox.”

Find out more in our interview with the authors

Meet the Editor:

Elizabeth Krenske is an Associate Editor for Organic & Biomolecular Chemistry since 2019. Elizabeth is an Associate Professor at the University of Queensland, Australia, where her research focuses on the computational study of organic reactions and modelling of drug molecules and interactions.

After starting out her career in chemistry as an undergraduate at the University of Queensland, Elizabeth undertook a PhD in the field of synthetic main-group chemistry at The Australian National University’s Research School of Chemistry, under the supervision of Professor S. Bruce Wild. She spent a further two years carrying out postdoctoral research at the Australian National University, before receiving a Fulbright Scholarship and commencing postdoctoral studies at UCLA with Ken Houk. Elizabeth returned to Australia in 2009 as an Australian Research Council (ARC) Australian Postdoctoral Fellow at the University of Melbourne, and moved to The University of Queensland in 2012 as an ARC Future Fellow. She is currently an Associate Professor and Strategic Research Fellow in the University of Queensland School of Chemistry and Molecular Biosciences. To find out more about Elizabeth and her research,  please visit her webpage.

From left to right: Brown, Ruttinger, Vaidya, Alabi and Clancy

Introducing the researchers: 

Joseph S Brown is currently a Postdoctoral Associate at the Massachusetts Institute of Technology in Professor Bradley Pentelute’s Lab in Chemistry. He received his B.Sc. in Chemical and Biomolecular Engineering from North Carolina State University in 2013 with Valedictorian Honors. At Cornell University, he earned his Ph.D. in Chemical and Biomolecular Engineering working with Professor Christopher Alabi on the structural and biophysical characterization of sequence-defined oligothioetheramides as a National Science Foundation (NSF) Graduate Research Fellow. He plans to apply his skills in synthetic chemistry, biophysical characterization, and biochemistry to aid the drug discovery of biologics focusing on the therapeutic disruption and modulation of protein-protein interactions.

Andrew W Ruttinger is currently a Ph.D. candidate in Chemical and Biomolecular Engineering at Cornell University, with Professor Paulette Clancy on the development of low-carbon and renewable energy technology. He earned his Bachelor of Engineering in Chemical Engineering from the University of Western Ontario, Canada. Upon graduation, Andrew plans to work in science policy, using his experience in developing green technology towards protecting Canada’s environment and climate.

Akash Vaidya received his B.S. in Chemical Engineering from Cornell University, where he was an undergraduate researcher for Professor Christopher Alabi. He spent two summers as a undergraduate research fellow with the Lyssiotis Research Group at the University of Michigan Medical School. Akash is currently pursuing his Ph.D. in Chemical and Biomolecular Engineering at the University of Delaware, where he plans to design (bio)polymeric materials for medical applications and lead outreach programs to promote diversity and inclusion in engineering.

Christopher Alabi is the Nancy and Peter Meinig Family Investigator in the Life Sciences at the Robert Frederick Smith School of Chemical and Biomolecular Engineering at Cornell University. Research in the Alabi lab seeks to utilize synthetic and analytical tools to understand how the composition and sequence of a macromolecular chain affects its chemical, structural and biological properties with an eye towards engineering sustainable materials and biomolecular therapeutics.

Paulette Clancy is a Professor and inaugural Head of the Department of Chemical and Biomolecular Engineering at the Johns Hopkins University. She is also the Samuel and Diane Bodman Professor Emerita of Chemical Engineering at Cornell. Her group develops new algorithms to advance our ability to make accurate models of materials, especially electronic materials and sustainable energy systems.  More recently, her group is developing new machine learning techniques to accelerate the search for optimal materials processing protocols and new materials.

What inspired your research in this area?

We were inspired to pursue this work because it promised to unlock new and exciting chemical reaction schemes including automated, robotic, and/or combinatorial syntheses using the thiol-Michael addition. While we chose to study oligothioetheramides (oligoTEAs) in this work, we expect that the new mechanistic understanding of the thiol-Michael addition reaction that we have uncovered will be broadly applicable, allowing us to create designer monomers for other types of materials and polymer science applications.

What do you personally feel is the most interesting outcome of your study?

While surprising at first, our most interesting finding was that physical associations could be strong enough to dictate rate-limiting steps within the reaction mechanism. Other groups have observed this for acrylates (Desmet et al., Polymer Chemistry (2017)), but the addition of this work has clarified our understanding of the exact mechanism, including product decomplexation. It was also exciting to see the nearly quantitative agreement between experiments and accurate DFT calculations coupled to a method of finding energy barriers (Nudged Elastic Band) that give exquisitely detailed insight into the mechanism that underlies this popular Michael addition reaction.

What are you going to be working on next?

We believe that sequence-defined materials like oligoTEAs could offer a promising new approach to controlling the design of new biomaterials. Precision biomaterials are still finding their niche, but are well-positioned to contribute as therapeutics, diagnostics, catalysts, and others. Many of these applications rely on selective and high-affinity molecular recognition events, which is our focus at this time. Computationally, we are working on a new approach that deploys machine learning to accelerate discovery of sequence-controlled oligoTEAs to match a given objective. Even with just 12-15 “beads” on the oligoTEA backbone, the size of the combinatorial problem precludes a trial-and-error search, whether computationally or experimentally.  Machine learning can help us tame this otherwise overwhelming design space.

Read the full article: Decomplexation as a rate limitation in the thiol-Michael addition of N- acrylamides

See the other articles showcased in this month’s Editor’s Collection

See all the full articles on our publishing platform

From left to right: Dian Agung Pangaribowo and Manabu Abe

Introducing the researchers:

Manabu Abe was born in Sakai City, Osaka Prefecture, Japan. He received his Ph.D. from the Kyoto Institute of Technology (KIT), Professor Akira Oku, in 1995, studying the oxidative ring-opening reaction of cyclopropanone acetals and its application to organic synthesis. After 12 years in Osaka University as an assistant professor and associate professor, he moved to Hiroshima and became a full professor in Organic Chemistry at the Department of Chemistry, Graduate School of Science, Hiroshima University (HIRODAI) in 2007. His research focuses on reactive intermediates chemistry, especially on diradicals, organic photochemistry and unusual molecules.

Dian Agung Pangaribowo received his Master’s degree in 2013 from Airlangga University, Surabaya, Indonesia. He is currently a doctoral program student at the department of chemistry, graduate school of science, Hiroshima University, under the supervision of professor Manabu Abe. His current research focuses on photochemical [2+2] cycloaddition reaction of Danishefsky-Kitahara diene with a carbonyl compound.

What inspired your research in this area?

Electronically excited-state molecules, which are generated by photolysis and have different electronic characteristics from their ground-state molecules, possess strong potentials to produce unexpected reactions and products that are not expected in the thermolysis of the same combination of compounds. In this study, as a case study, we are very much interested in exploring regio-, stereo-, and chemo-selectivities in the photolysis of Danishefsky-Kitahara diene with carbonyl compounds, whose selectivities should be different from those in the thermolysis.

What do you personally feel is the most interesting outcome of your study?

Two important findings emerged in the photolysis of the trans-configured Danishefsky-Kitahara diene with benzophenone; (1) a clean isomerization from the trans-form to the cis-form of the diene, which has not been achieved so far in thermal reactions. (2) Potentially bioactive compounds, oxetanes, are formed in high yields. The chemo-selectivity of the photochemical reaction is totally different from the Lewis acid-promoted thermal reaction.

What are you going to be working on next?

Since the Danishefsky-Kitahara diene is synthetically useful compound and considered as an “electron-rich” compound, we are interested in investigating the possibility of the photoinduced electron transfer reactions of the diene to find new types of synthetically useful chemical reactions.

Read the full article: Photochemical [2+2] Cycloaddition Reaction of Carbonyl Compounds with Danishefsky Diene

See the other articles showcased in this month’s Editor’s Collection

See all the full articles on our publishing platform

From left to right: Fairhall, Murayasu, Dadhwal, Hook and Gamble

Introducing the researchers: 

Dr Jessica Fairhall received her PhD in 2020 from the University of Otago, under the supervision of Dr Allan Gamble and Prof. Sarah Hook. Her PhD focused on the bioorthogonal reaction between aryl azides and trans-cyclooctenes as a technique for cancer-specific prodrug activation. During her PhD she also received a 4 month fellowship to conduct research at Novartis Institutes for BioMedical Research in Emeryville California. She is currently working as a Clinical Editor for the New Zealand Medicines Formulary, and is starting a new role at the University of Otago as a Research Fellow in October.

Madoka Murayasu graduated with a BPharm (Hons) First Class in 2016 from the University of Otago. Her Honours project focused on bioorthogonal prodrug activation strategies. Madoka is currently working as a community pharmacist in New Zealand.

Dr Sumit Dadhwal completed his PhD at the University of Otago in 2018 with Dr. Allan Gamble and Prof Sarah Hook. His PhD research focused on the development of stimuli-responsive biomaterials for drug delivery applications. Currently he is working as a Research Fellow at the University of Otago.

Professor Sarah Hook is Chair of Biopharmaceutics at the School of Pharmacy, University of Otago in Dunedin, New Zealand. She received her PhD in 1996 from the Department of Microbiology and Immunology at the University of Otago. She joined the faculty of the School of Pharmacy in 2001. Research interests include the development of one-shot sustained release, particulate and responsive formulations for the delivery of small and large molecule therapeutics. Her research in the field is aided by her knowledge and experience in the fields of immunology and pharmaceutical formulation science. She has published more than 100 papers since joining the School of Pharmacy.

Dr Allan Gamble received his PhD in organic chemistry in 2008 from the University of Wollongong in Australia with Prof Paul Keller. He then moved to Canberra to take up a postdoctoral position at the Australian National University with Prof Chris Easton. Here he worked on peptide hormone regulation until late 2010. In 2011, he was awarded a Sir Keith Murdoch Postdoctoral Fellowship through the American Australian Association to work with Prof Paul Wender at Stanford University on developing new drug delivery strategies. In May 2012 he took up the position of Lecturer in the School of Pharmacy at the University of Otago and was promoted to Senior Lecturer in 2016. His research interests are in the areas of bioorganic and physical organic chemistry and drug delivery.

What inspired your research in this area?

Our research group has a strong focus in bioorganic and physical organic chemistry, and applying our skills to the development of new drug delivery strategies (prodrugs, hydrogels, nanoparticles). Over the past 8 years we have been influenced and motivated by the chemistry of Professors Carolyn Bertozzi, Joseph Fox and Marc Robillard. The initial inspiration stems from Dr Gamble’s research experience as a postdoc in the Wender group. Here he developed a passion for drug delivery and bioorthogonal chemistry. While preparing applications for an independent career in academia, Dr Gamble formulated an idea that would use the strain-promoted alkene-azide cycloaddition coupled with self-immolative linker chemistry to deliver cytotoxic drugs for cancer therapy. The alkene-azide cycloaddition appeared to have been left-out of the bioorthogonal reaction toolkit due to the formation of unstable adducts (e.g., 1,2,3-triazoline and imine), therefore providing an opportunity to establish a research group with a primary focus of developing this chemistry.

What do you personally feel is the most important outcome of your study?

Our initial work in this area (Chem. Sci. 2015, 6, 1212-1218; Bioconjugate Chem. 2018, 29, 324-334) provided proof-of-principle for the click-to-release activation of a prodrug in vitro using the alkene-azide cycloaddition. However, the physical organic chemistry components of the reaction, namely the kinetics for the click and release steps were not ideal for bioorthogonal applications in vivo. In the current study (Org. Biomol. Chem., 2020, 18, 4754-4762), we have been able to establish the fastest-to-date strain-promoted alkene-azide cycloaddition that also maintains a rapid drug release profile. The rate constants for the click and subsequent release steps pave the way for in vivo studies that will benefit from using this chemistry.

What are you going to be working on next?

We continue to work towards improving the physical organic chemistry components of the alkene-azide cycloaddition so that we can further extend its click-to-release bioorthogonal chemistry applications. Using the results of this recent study we are investigating in vivo prodrug activation in mice, and applying the alkene-azide click-to-release strategy to drug delivery systems (e.g. hydrogels and nanoparticles).

Read the full article: Tuning activation and self-immolative properties of the bioorthogonal alkene–azide click-and-release strategy

See the other articles showcased in this month’s Editor’s Collection

See all the full articles on our publishing platform

From left to right: Reddy, Molla, Kumar and Rai

Introducing the researchers: 

Neelesh C. Reddy obtained his B.Sc. from Deogiri College and M. Sc. from Dr. Babasaheb Ambedkar Marathwada University Aurangabad, Maharashtra, India. For his Ph.D., he joined the research group of Dr. Vishal Rai at the Indian Institute of Science Education and Research Bhopal, India. Neelesh is developing modular chemical technologies for precision engineering of native proteins. Further, he is using the platform for the synthesis of homogeneous antibody-drug conjugates for directed cancer chemotherapeutics.

Rajib Molla obtained his B. Sc. (2016) from West Bengal State University and M. Sc. (2018) from West Bengal State University. At present, he is pursuing his Ph.D. under the supervision of Dr. Vishal Rai at the Indian Institute of Science Education and Research Bhopal. He is applying his experience in organic and organometallic chemistry to develop new chemical methodologies for protein bioconjugation.

Mohan Kumar obtained his B.Sc. (2016) from Lucknow University and M.Sc. (2018) from the National Institute of Technology Manipur, India. In 2019, he joined the research group of Dr. Vishal Rai at the Indian Institute of Science Education and Research Bhopal, India. In his Ph.D., he is developing chemical technologies for the modification of proteins in live cells.

Vishal Rai received his Ph.D. in 2008, working in the area of asymmetric synthesis from the Department of Chemistry, Indian Institute of Technology Bombay (India), under the supervision of Prof. I. N. N. Namboothiri. In 2008, he joined the group of Prof. Andrei Yudin in the Department of Chemistry, University of Toronto (Canada), to work on chemoselective methodologies and peptide macrocycles. Vishal started his independent career in the Department of Chemistry, Indian Institute of Science Education and Research Bhopal (India) as Assistant Professor in 2011 and became Associate Professor in 2017. He is the recipient of Swarnajayanti fellowship, Ramanujan fellowship, and DAE Young Scientist Award. In 2018, he established Plabeltech Private Limited, a company strengthened by the protein labelling technologies developed by his team. His research group is developing chemical technologies for precision engineering of native proteins. Further, they are translating these platforms to enable directed and precision therapeutics.

What inspired your research interests in chemical protein modification?

The knowledge to enable selective modification of native proteins could provide a tremendous boost to the biotechnology and healthcare sectors.

What primary research are you carrying out in the area?

Our group is developing chemical technologies for precision engineering of proteins. We are excited about its potential to empower directed therapeutics and believe that it can enable precision therapeutics with small molecules one day.

How do you hope this review will help and inspire future research in the area?

This review intends to provide a chemist’s perspective of “what, why, and how” in the field of protein bioconjugation.

Read the full article: Chemical methods for modification of proteins

See the other articles showcased in this month’s Editor’s Collection

See all the full articles on our publishing platform