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Scientific bad luck

and being honest about it - 8 july 2008

In 1933 a mister Copenhagen was stationed in Cape Town doing a bit of crawfish research. Naturally he wanted to have some of his life specimen shipped back to London but alas, the weather was bad, the ship's engine broke down, the weather was bad again, damaging the holding tank, washing overboard some of the crawfish and injuring the remaining ones causing their premature death. In a letter to the journal Nature (DOI) Copenhagen laments that is was highly probable that the specimens would have survived a considerably longer period if it had not been for misadventure .

Also see part 1 of bad luck in science (and being honest about it).

(-)-cyanthiwigin F total synthesis

6 July 2008 - Organic chemistry

The (-)-cyanthiwigin F total synthesis (Enquist, Stoltz 2008 DOI) featuring a double catalytic enantioselective transformation made headlines this month. What is this process all about and what makes it so special?
The molecular target in any case did not warrant urgent synthetic synthesis: it is one of many known cyanthiwigins and part of an even larger class of cyathins. Millions of compounds display some kind of biological property that can potentially be used in medicine. The molecule is a fused tricyclic system with 4 stereocenters, two of which are quaternary which makes synthesis tricky.

Here is how it was done. Step one is a Claisen-Dieckman condensation (first inter- then intracondensation) of the di-allyl ester of succinic acid. The acidic protons in the 1,3-diketone groups can be replaced by a methyl group with iodomethane and a base. These reactions are not very stereospecific and intermediate 3 is a diastereomeric mixture of racemic (R,R) and (S,S) and meso (R,S).

In a traditional approach this reaction is a failure because the desired enantiomer (R,R) is contaminated by an equal part of (S,S) (the meso contamination can be dealt with). In this approach the researchers decided to forge ahead with the next step, a decarboxylative allylation on the mixture itself.

Surprisingly the reaction product 4 is a mixture of desired (R,R) and meso (R,S). What happens is that twice in this reaction a carboxylic ester group is replaced by an enolate ion, destroying a stereocenter (process called stereoablation). The outcome of the reaction (16 possible pathways) is then governed by the stereochemistry of the BOX ligand and the stereochemistry of the remaining stereocenter.

In the remainder of the reaction an olefinic side group is attached via a Negishi coupling to tetraene 5, the second generation Hoveyda-Grubbs Catalyst closes a 7-membered ring in 6 and at the same time functionalises the remaining alkene with a vinyl boronic ester. This product is then oxidized to aldehyde 7 with sodium perborate. The final steps are a radical addition (of recent 2005 invention DOI) joining the acyl group with the internal alkene, and a palladium catalyzed organocopper addition that almost fails due to excessive reduction.

So are double enantioselective reactions are viable strategy in organic synthesis? It seems the stereochemical outcome of this particular reaction was one governed by chance rather than by design, so no need to get al excited.

Another aspect this reaction is new: it does away with protective groups. The authors note that PG-free reactions are still rare in total synthesis and interestingly cite Robinson's classic tropinone synthesis of 1917 and Barans Hapaindole work of 2007 (fast becoming a classic although you might think otherwise if you believe the commentators at Wikipedia's protective group talk page).

The message clearly is not to dispair when faced with ugly reaction mixtures or destroyed functional groups but simply go ahead and repair the damage along the way (also see previous post on Prostratin total synthesis).

Bent phenyls

3 July 2008 - Organic chemistry

Bending benzene rings is nothing new. The record bend in basket shaped cyclophanes stands at 21°. The molecule depicted below (Strohmann et al. 2008 DOI) is not a cyclophane but nevertheless odd.

It is the silicon analogue of a benzyl anion with two additional methyl groups on silicon and a lithium counterion which is coordinated to PMDTA.

Whereas a benzyllithium is planar with the lone pair in a p-orbital, silyllithiums have increased s-character with corresponding pyramidalization.

X-ray crystallography for this compound reveals a longer than usual Si-C bond length, a smaller than usual Si-C-C angle attributed to Bent's rule and surprisingly a Silicon dihedral angle of 172 ° which makes the benzene ring bent. As an interesting generalization this bending is found to take place with all higher elements in the carbon group and the nitrogen group.

The researchers explain this bending by Pauli repulsion between thefrontier orbital on silicon and the one on the arene. This repulsion is loosely related to the Pauli exclusion principle in which electrons in two filled orbitals tend to repulse each other at short range because they cannot occupy the same state. The frontier orbital of silicon can avoid alignment and overlap by this bending mode.

Only problem with this explanation is that the phenyl group flips towards the silicon lone pair. Simply flipping away would also put an end to steric concerns

Aromatic - not so antiaromatic redox pair

01 July 2008 - Aromaticity

Acenes and in particular heteroacenes are in the picture as organic electron-carrier materials. The pyrazine compound on the left recently described by Shaobin Miao et al. (DOI) is a promising candidate. In the solid state the intrastack distance is only 330 picometer compared to 380 pm for the same acene without the alkyne side groups and better pi stacking means better electron mobility.

As a sort of side show the researchers compared the diazine with its dihydroazine cousin which can be obtained by hydrogenation using Wilkinson's catalyst. This compound is unstable and easily converts back to the diazine by oxydation with air.

This redox pair is theoretically also an aromatic (4n+2) - antiaromatic 4n pair (both planar) but it turns out both systems are aromatic with aromaticity reduced in the dihydrodiazine. In fact the HOMO-LUMO band gap for the dihydrodiazene (in silico and based on fluorescence) is actually the higher of the two reflecting higher stability.

This system and the main conclusion (there are limits to antiaromaticity) is comparable to one described in 2007 by the same group (DOI).

CAS number crunching

29 June 2008 - cheminformatics

A cheminformatics session recently applied to the CAS registry by CAS people reveals some interesting figures (Lipkus et al. DOI). 98% of over 24 million frameworks (cyclic molecules, side chains or stereochemistry ignored) contain a heteroatom, 18% of atoms in a framework are heteroatoms with nitrogen in the lead (66%) followed by oxygen (23%) and sulfur (9%). 50% of frameworks have between 20 and 30 atoms and even-numbered frameworks outnumber odd-numbered frameworks, an effect attributed to dimerization.

A collection of 143 structures is sufficient to describe half the compounds. The distribution of frameworks in fact obeys a power law: a small number of frameworks make up a lot of molecules while many frameworks occur infrequently. This power law is comparable to Zipf's law for word counts or the rich get richer principle and confirms that chemists are more likely to use a particular framework to make a compound the more often that framework has been used in the past.

Angewandte chemie VS JACS

27 June 2008 - Publishing

The Angewandte chemie recently announced they beat the Journal of the Chemical Society (JACS) in the annual Journal Citation Reports impact factor competition (Link). This presents a problem because JACS on their website also announce victory (link), so what to do.

The Angewandte lists an IF of 10 in the category chemistry, multidisciplinary while JACS claims the title the most cited journal in chemistry based on an IF of 7.9.

Could be a category issue but be also beware that 18 out of the top-25 Angewandte articles are in fact reviews, minireviews or highlights. JACS on the other hand doesn't do reviews. Reviews easily accumulate citations but are not exactly the original research it should be about.

And what is the point of indexing citations anyway. Three points of criticism. Firstly, the most recent 2007 index is based on citations for the years 2005 and 2006 only. A citation in a 2007 journal for a 2004 article is irrelevant. Secondly, in a lot of journals citations are often just reading suggestions or a list of examples of similar work rather than references to relevant work. And lastly, referencing to reviews draws away the attention to the original breakthrough work.