Chemical Science Blog

Strychnine, best known as a poison but also used medicinally as a stimulant, can now be synthesised in just six steps, say US scientists.

Christopher Vanderwal and his team from the University of California, Irvine created four new carbon-carbon bonds and a carbon-oxygen bond in four steps on the way to making strychnine.

‘Until recently, the fastest synthesis was completed by Viresh Rawal [from The Ohio State University, US] in 14 steps,’ says David MacMillan, an expert in organocatalysis from Princeton University in the US. ‘For a molecule of this complexity, 14 steps is an amazing accomplishment. To be able to complete this in just six steps is simply incredible and something I didn’t necessarily think would ever be possible.’

Defining the shortest route to complex, useful molecules is an important step in uncovering the most efficient way to produce these targets, says Vanderwal. ‘While the overall efficiency of our route isn’t any better than previous routes, the number of chemical operations needed is less than any predecessor,’ he says.

The synthesis began with a pyridinium ring opening reaction to form donor-acceptor dienes known as Zincke aldehydes

The team began with a century-old pyridinium ring opening reaction called the Zincke reaction – named after German chemist Theodor Zincke – in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitrochlorobenzene and a primary amine. This led to the formation of donor-acceptor dienes known as Zincke aldehydes. The next steps involved an intramolecular Diels-Alder reaction, a ruthenium catalysed hydrosilylation and a rearrangement-intramolecular conjugate addition leading to an aldehyde that was then converted to strychnine   

‘Strychnine is the oldest and perhaps most famous “celebrity molecule”,’ remarks MacMillan. ‘Total syntheses of this molecule are among the most famous of all completed to date. As such, the field of total synthesis uses strychnine synthesis as a molecular benchmark.’ 

‘Its first synthesis by Robert Burns Woodward, reported in 1954, stands as an absolute classic,’ adds Vanderwal. ‘Woodward’s pioneering achievement and the numerous syntheses since then have taught us about synthesis strategy, biosynthesis, reaction design, asymmetric catalysis, and more.’ 

Vanderwal sees the ability to build up complex molecular scaffolds in very few steps using their predictable reactivity pattern as the way forward. ‘It need not be a Zincke aldehyde, and the targets need not be indole alkaloids,’ he says. ‘The onus is on organic chemists to increase our ability to make molecules in the most efficient way possible.’   

Elinor Richards

Link to Chemical Science article:-

A synthesis of strychnine by a longest linear sequence of six steps
David B. C. Martin and Christopher D. Vanderwal, Chem. Sci., 2011
DOI: 10.1039/c1sc00009h

Graham Cooks	Zhong-Qun Tian	Christy Haynes
Duncan Graham	Jonathan Sweedler	Justin Gooding

I thought it would be nice to highlight some of the analytical content we have published over the last few months. From the latest developments in NMR, to advances in surface enhanced raman and mass spectroscopy, I’m sure you’ll agree its been a busy few months for analytical science in Chemical Science.

We are celebrating the Chinese New Year of the Rabbit by highlighting some of the articles across the general chemistry journals that have made us ‘hop’ with excitement.

These top articles by Chinese authors are FREE to access until the end of February. Download them today and leave your comments below.

Morphology control for high performance organic thin film transistors
Wei Shao, Huanli Dong, Lang Jiang and Wenping Hu 
Chem. Sci., 2011, DOI: 10.1039/C0SC00502A

Tailoring Au-core Pd-shell Pt-cluster nanoparticles for enhanced electrocatalytic activity
Ping-Ping Fang, Sai Duan, Xiao-Dong Lin, Jason R. Anema, Jian-Feng Li, Olivier Buriez, Yong Ding, Feng-Ru Fan, De-Yin Wu, Bin Ren, Zhong Lin Wang, Christian Amatore and Zhong-Qun Tian 
Chem. Sci., 2011, DOI: 10.1039/C0SC00489H

Ir-catalyzed highly selective addition of pyridyl C–H bonds to aldehydes promoted by triethylsilane
Bi-Jie Li and Zhang-Jie Shi 
Chem. Sci., 2011, DOI: 10.1039/C0SC00419G

Single microcrystals of organoplatinum(II) complexes with high charge-carrier mobility
Chi-Ming Che, Cheuk-Fai Chow, Mai-Yan Yuen, V. A. L. Roy, Wei Lu, Yong Chen, Stephen Sin-Yin Chui and Nianyong Zhu 
Chem. Sci., 2011, 2, 216-220

Artificial selenoenzymes: Designed and redesigned
Xin Huang, Xiaoman Liu, Quan Luo, Junqiu Liu and Jiacong Shen
Chem. Soc. Rev., 2011, DOI: 10.1039/C0CS00046A

The recent synthesis and application of silicon-stereogenic silanes: A renewed and significant challenge in asymmetric synthesis
Li-Wen Xu, Li Li, Guo-Qiao Lai and Jian-Xiong Jiang
Chem. Soc. Rev., 2011, DOI: 10.1039/C0CS00037J

Supramolecular amphiphiles
Xi Zhang and Chao Wang  
Chem. Soc. Rev., 2011, 40, 94-101

Ordered mesoporous materials as adsorbents
Zhangxiong Wu and Dongyuan Zhao
Chem. Commun., 2011, DOI: 10.1039/C0CC04909C

Semiconductor quantum dots photosensitizing release of anticancer drug
Zhenzhen Liu, Qiuning Lin, Qi Huang, Hui Liu, Chunyan Bao, Wenjin Zhang, Xinhua Zhong and Linyong Zhu 
Chem. Commun., 2011, 47, 1482-1484

Novel triptycene-derived hosts: synthesis and their applications in supramolecular chemistry
Chuan-Feng Chen 
Chem. Commun., 2011, 47, 1674-1688

This month sees the following articles in Chemical Science that are in the top ten most accessed:-

Total synthesis of diazonamide A 
Robert R. Knowles, Joseph Carpenter, Simon B. Blakey, Akio Kayano, Ian K. Mangion, Christopher J. Sinz and David W. C. MacMillan 
Chem. Sci., 2011, 2, 308-311, DOI: 10.1039/C0SC00577K, Edge Article 

Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide 
David S. Surry and Stephen L. Buchwald 
Chem. Sci., 2011, 2, 27-50, DOI: 10.1039/C0SC00331J, Perspective 

Nitrogen-directed ketone hydroacylation: Enantioselective synthesis of benzoxazecinones 
Hasan A. Khan, Kevin G. M. Kou and Vy M. Dong 
Chem. Sci., 2011, Advance Article, DOI: 10.1039/C0SC00469C, Edge Article 

Ru-catalyzed activation of sp3 C–O bonds: O- to N-alkyl migratory rearrangement in pyridines and related heterocycles  
Charles S. Yeung, Tom H. H. Hsieh and Vy M. Dong 
Chem. Sci., 2011, Advance Article, DOI: 10.1039/C0SC00498G, Edge Article 

Ir-catalyzed highly selective addition of pyridyl C-H bonds to aldehydes promoted by triethylsilane 
Bi-Jie Li and Zhang-Jie Shi 
Chem. Sci., 2011, Advance Article, DOI: 10.1039/C0SC00419G, Edge Article 

Palladium-catalyzed amination reactions in flow: overcoming the challenges of clogging via acoustic irradiation 
Timothy Noël, John R. Naber, Ryan L. Hartman, Jonathan P. McMullen, Klavs F. Jensen and Stephen L. Buchwald 
Chem. Sci., 2011, 2, 287-290, DOI: 10.1039/C0SC00524J, Edge Article 

Palladium-catalyzed coupling of functionalized primary and secondary amines with aryl and heteroaryl halides: two ligands suffice in most cases 
Debabrata Maiti, Brett P. Fors, Jaclyn L. Henderson, Yoshinori Nakamura and Stephen L. Buchwald 
Chem. Sci., 2011, 2, 57-68, DOI: 10.1039/C0SC00330A, Edge Article 

Sulfonated graphene as water-tolerant solid acid catalyst
Junyi Ji, Guanghui Zhang, Hongyu Chen, Shulan Wang, Guoliang Zhang, Fengbao Zhang and Xiaobin Fan 
Chem. Sci., 2011, Advance Article, DOI: 10.1039/C0SC00484G, Edge Article 

Mechanised materials 
Megan M. Boyle, Ronald A. Smaldone, Adam C. Whalley, Michael W. Ambrogio, Youssry Y. Botros and J. Fraser Stoddart 
Chem. Sci., 2011, 2, 204-210, DOI: 10.1039/C0SC00453G, Minireview 

Synthesis of boron doped polymeric carbon nitride solids and their use as metal-free catalysts for aliphatic C-H bond oxidation 
Yong Wang, Haoran Li, Jia Yao, Xinchen Wang and Markus Antonietti 
Chem. Sci., 2011, Advance Article, DOI: 10.1039/C0SC00475H, Edge Article 

Why not take a look at the articles today and blog your thoughts and comments below.

Fancy submitting an article to Chemical Science? Then why not submit to us today or alternatively email us your suggestions.

In a typical chemical reaction, the goal is to find the best conditions to get the highest yield. Combinations of reagents, catalysts, temperatures and times are tested to find the optimal conditions. Finding the best combinations should require testing the majority of the possible combinations, but typically only 5–10 combinations are tested to avoid the ‘curse of dimensionality’ –  where the number of possible experiments grows exponentially with the number of variables. 

Now, US scientists reporting in Chemical Science say that, contrary to this reasoning, experience shows that synthesis and property optimisations are far easier to achieve than the curse of dimensionality suggests. They put forward the ‘OptiChem’ theory, concluding that the most efficient method is to change all important variables, performed with automated high-throughput synthesis.

Intrigued? Download the Edge article by Herschel Rabitz and colleagues to learn more.

Photocatalysis of organic molecules in fatty acid membranes offers a plausible method for energy transfer and storage in prebiotic systems. We don’t know how early cells were formed – one suggestion is that the initial cell like structures were made through the self-assembly of fatty acids to form vesicles. However, this hypothesis still leaves many questions, including how these vesicles could harness energy for chemical reactions – an essential step for creating more complex systems. 

In an Edge article published in Chemical Science, James Boncella and colleagues have reported that they developed a primitive energy transduction mechanism. Their research demonstrates that photocatalytic reactions involving polycyclic aromatic hydrocarbons (PAH) trapped in the vesicle membrane are capable of capturing and storing energy. 

The vesicles are made from a hydrophobic membrane of fatty acids and polycyclic aromatic hydrocarbons surrounding an interior void containing metal anions. This membrane acts as barrier that prevents charged molecules from entering and leaving the vesicle. In a series of chemical reactions electrons are transferred across the membrane and trapped in charged molecules contained in the interior void. The cycle uses the PAH in the membrane as a photocatalyst to reduce Fe(CN)₆^3- inside the vesicle. The PAH is then regenerated by oxidising EDTA molecules outside the cell which act as the electron source. Boncella explains that the cycle is a single electron process for harvesting energy. The next question is: “Can we use this energy to do useful chemistry?” 

Unlike conventional methods to create vesicles the team used a complex mixture of short chain fatty acids and polycyclic aromatic hydrocarbons based on the composition of carbonaceous meteorites. The team hopes that these conditions mimic the environment found on earth thousands of years ago.

James Boncella reveals more about his work in a Chemical Science audio file, which accompanies his Edge article. Download it for free and let us know what you think of his research.

A powerful strategy for selectively modifying the side-chains of proteins has been developed, which is hoped will enable the creation of new tools to investigate protein interactions involved in human diseases.

Modifying the side-chains of the amino acids that make up proteins is simple, but because a particular type of side-chain may appear many times in a given protein, modifying just one of them is a tough challenge. Brian Popp and Zachary Ball at Rice University, Houston, have been using chemical reactivity ideas and reaction design to try and solve this problem. 

In their solution, they decided to dispense with the standard approach of designing a highly selective reagent. Instead, they used a reagent that is hardly selective at all, but one that only works in the presence of a rhodium catalyst. The trick is to place the catalyst exactly where it’s needed by attaching it to a coiled peptide that binds to the right bit of the target protein. This brings the catalyst and the side-chain into close proximity, allowing them to react as soon as the reagent – a diazo derivative of styrene ­– is added.

Ball thinks that this approach is ‘a big step forward’. The main benefit is that the high reactivity of the diazo compound allows it to react with the side-chains of over half the naturally occurring amino acids, a broader range than any established method. The method is also highly specific, as any catalytic units that start to react where they are not wanted are quickly destroyed by reaction with water, which is the solvent for the reaction. 

 As well as looking to establish the robustness of their new method, future work may involve investigating how it could be used to tag, image, or modify the structure or function of natural proteins. “We believe this work will create powerful tools to investigate transient protein interactions, such as those along signalling pathways that lead to human disease,” says Ball.

Download the Edge article from Chemical Science for free to read more about this exciting work.

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A greener, non-toxic method for brominating aromatic hydrocarbons has been developed by Japanese scientists. Using 9-mesityl-10-methylacridinium ion as the photocatalyst, Shunichi Fukuzumi‘s team at Osaka University selectively brominated a range of aromatic hydrocarbons and thiophenes under visible light irradiation, using aqueous hydrogen bromide as the Br source and oxygen as the oxidant.

 A number of bromination protocols use elemental bromine and N-bromosuccinimide as the Br sources, but these are toxic, hazardous and can over-brominate, producing mixtures. The photocatalytic reaction will enable scientists to synthesise brominated compounds on a large scale without the cost of isolation and purification.

Find out more by downloading Fukuzumi’s Chemical Science Edge article for free.

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