Chemical Science Blog

Computation experiments by researchers from the University of Geneva have illuminated their understanding of chemistry they previously reported and, importantly, have led to an improvement of the original methodology.

Alexandre Alexakis’  group developed a copper-catalysed asymmetric allylic alkylation, which transforms a racemic starting material into an enantioenriched product.

Computational modelling led to a revision of the original mechanistic explanation for the reaction outcome. The researchers propose that each enantiomer of the starting material undergoes divergent reactivity, where (R)-1 reacts through anti-S_N2’ oxidative addition whilst its antipode (S)-1 reacts through anti-S_N2. The regiodivergent oxidative addition leads to the formation of a common Cu(III) intermediate 2, which undergoes rapid reductive elimination to give the product (R)-3.

This work clearly demonstrates the importance of acertaining mechanistic insight in order to improve the practical application of organic chemistry.

Download Alexakis’ Edge article to find out more.

The anticancer drug cisplatin has revolutionised cancer chemotherapy. Its ability to effectively treat a wide range of cancers has made this drug a popular therapeutic choice but the side effects can be severe, including possible damage to the kidneys and nervous system. Researchers have been trying to avoid these side effects by designing systems to deliver the cisplatin to the target area, where it can be released to selectively destroy the cancer tissue.

Promising delivery vehicles for platinum-based drugs include liposomes, polymers and dendrimers, organic macrocycles, nanoparticles, viruses and carbon nanotubes. Now, James Crowley’s group at the University of Otago, New Zealand, have reported the first example of cisplatin inclusion in a metallosupramolecular cage.

Two cisplatin molecules are bound within the cage and can be released on demand by introducing Cl^– or 4-dimethylaminopyridine (DMAP). These ligands compete for binding with the cage Pd^II centres and induce dissociation of the cage structure. If the cage is deconstructed using Cl^–, it can be reassembled by adding Ag⁺ ions, which precipitate the Cl^– out of the system and allow the cage to re-form. This is particularly impressive since there are few reported examples of stimulus-induced cage assembly and disassembly. This controllable uptake and release of a drug molecule shows that similar systems may have real application for drug delivery in the future.

To find out more about Crowley’s metallosupramolecular cage, read the full article.

Posted on behalf of Cally Haynes, Chemical Science web writer.

A strategy for regiochemical reversal of reductive macrocyclisations of aldehydes and terminal alkynes has been developed by US researchers. Using an advanced synthetic intermediate directed towards the methymycin/neomethymycin class of macrolides, selective endocyclisation provides the natural twelve-membered ring series, whereas ligand alteration enables selective exocyclisation to provide access to the  unnatural eleven-membered ring series. The twelve-membered ring adduct was converted to 10- deoxymethynolide, completing an efficient total synthesis of this natural product.

Reference:
Nickel-Catalyzed Regiodivergent Approach to Macrolide Motifs
A-R Shareef, D H Sherman and J Montgomery, Chem. Sci., 2012
DOI: 10.1039/c2sc00866a

A mild and efficient procedure for the oxidative alkynylation of N- and P-based nucleophiles has been devised by scientists in France to make ynamides and alkynylphosphonates. These versatile alkynes add functionality to organic molecules and are used in medicinal chemistry and materials science. The heteroatom polarises the triple bond, allowing for highly regio- and stereoselective transformations. An advantage of the method is that it does not require a base, thermal activation, an inert atmosphere or expensive chemicals.

Reference:
Click-Alkynylation of N- and P- Nucleophiles by Oxidative Cross-Coupling with Alkynylcopper Reagents: A General Synthesis of Ynamides and Alkynylphosphonates.
K Jouvin, J Heimburger and G Evano, Chem. Sci., 2012
DOI: 10.1039/c2sc00842d

High nucleophilic reactivity and functional group tolerance are opposing properties of organometallic compounds. While organolithium compounds are highly nucleophilic so react with most electrophiles, organosilicon compounds are on the low reactivity end of the nucleophilicity scale. They tolerate numerous electrophilic functional groups and often require (Lewis) base activation to react.

Organoboron compounds, which are key intermediates in organic synthesis, are positioned in between. While some of them undergo non-catalysed C–C bond forming reactions with various electrophiles, others tolerate a variety of functional groups and are most valuable substrates for Pd-catalysed cross couplings (Suzuki–Miyaura reactions).

As it is difficult for the preparative chemist to decide which functional groups are tolerated and which do react with organoboron reagents in the absence of a catalyst, scientists in Germany have established a quantitative reactivity scale for representatives of the most important classes of organoboron reagents and they have applied these data for predicting the feasibility of transition metal free C–C bond forming reactions.

Reference:
Nucleophilicity parameters for designing transition metal-free C-C bond forming reactions of organoboron compounds
G Berionni, B Maji, P Knochel and H Mayr, Chem. Sci., 2012
DOI: 10.1039/c2sc00883a

Scientists in Germany have synthesised the core part of a sugar compound produced by the pathogenic bacteria responsible for meningitis – Neisseria meningitides – which could be used in a vaccine for meningococcal diseases, in particular meningitis B.

Pathogenic bacteria produce a polysaccharide layer, forming a capsule to cloak antigenic proteins on their surface that would otherwise provoke an immune response to destroy the bacteria. Currently available vaccines are based on capsular polysaccharides and provide protection against four major forms of meningitis, but not meningitis B. This is because the capsular polysaccharide for meningitis B resembles carbohydrates present in the central nervous system, so using it in a vaccine risks triggering an immune response against them as well.

Now, Peter Seeberger from the Max Planck Institute of Colloids and Interfaces, Potsdam, and colleagues have made the inner core of the lipopolysaccharide produced by N. meningitides as a safer alternative. The resulting tetrasaccharide consists of Hep (heptose) and Kdo (octulosonic acid) building blocks.

Synthesis of the core tetrasaccharide of Neisseria meningitidis lipopolysaccharide
Total synthesis of the core tetrasaccharide of Neisseria meningitidis lipopolysaccharide, a potential vaccine candidate for meningococcal diseases
You Yang, Christopher E. Martin and Peter H. Seeberger
Chem. Sci., 2012, Advance Article
DOI: 10.1039/C1SC00804H

Read the full story in Chemistry World

Link to journal article

Scientists from the UK have used a molecular capsule to control the reactivity of an organic compound.

A molecule’s reactivity is commonly controlled using protecting group chemistry, in which a certain functional group is blocked to avoid unwanted reactions at that site. However, this can be costly in terms of time and reagents.

Now, Maarten Smulders and Jonathan Nitschke from the University of Cambridge have used a supramolecular cage as a whole-molecule protecting group. An organic molecule can be encapsulated within the cage, preventing its reaction, and addition of a competing guest can then release the molecule and initiate the reaction when required.

The team constructed the cage from four iron units in a tetrahedral arrangement. External sulfonate groups confer water solubility, while the interior of the cage provides a hydrophobic environment to encapsulate organic molecules. Unlike traditional protecting group chemistry, this method relies not on the functionality of the molecule but on its size and shape, providing a complementary protection strategy to those commonly used.

Encapsulation of furan prevents its reaction, but upon addition of benzene as a competing guest, furan is released from the cage and undergoes a Diels-Alder reaction with maleimide

Read the full story in Chemistry World

Link to journal article
Supramolecular control over Diels–Alder reactivity by encapsulation and competitive displacement
Maarten M. J. Smulders and Jonathan R. Nitschke
Chem. Sci., 2012, Advance Article
DOI: 10.1039/C1SC00847A