Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are lipids that are mainly found in the membranes of archaea and acidobacteria. Geochemists use these lipids to determine the temperature of a sediment sample of a certain age. ‘It is difficult to make unambiguous measurements of these types of lipids because there is no good calibration worldwide’, says Adri Minnaard, professor of organic chemistry at the University of Groningen. ‘You need reference compounds, and these are not really available yet. We see this as an incentive to produce such substances.’

Optical rotation

Minnaard and his group started the total synthesis of this substance. ‘In many cases – like this one – the stereochemistry is unknown, so of course we wanted to find out.’ In this case it was particularly challenging, explains the Groningen professor. ‘For known chiral compounds, such as lactic acid, the optical rotations are known. All you have to do is measure the substance and then look up whether it rotates to the left or to the right.’

‘With a new substance from nature, this is not known, because the fact that something has an optical rotation does not tell you what form it is’, Minnaard continues. ‘Two important ways of finding out are either to convert your molecule into a structure whose rotation we know, or to determine the crystal structure using X-rays. But you have to have enough product to do that, and it has to be crystalline.’

This was not the case with the brGDGT Ia studied by the Groningen researchers. However, a third option has been available for about twenty years: vibrational circular dichroism (VCD). ‘This is based on the fact that chiral molecules react differently to circularly polarised light’, explains Minnaard. ‘This vibrational method allows you to look into the infrared range. A VCD spectrum alone does not allow you to deduce which stereochemistry you are dealing with, but when combined with DFT calculations, you can make simulations that show which variant you are dealing with.’

Black and white

Although the method is constantly improving, the problem in this project was that the compound is cryptochiral. ‘This means that the groups around the chiral centre show virtually no difference’, explains Minnaard. ‘Chirality is black and white, but I would almost say that this molecule is only “slightly” chiral, although you can’t really say that.’

The Groningen researchers therefore had to push the VCD method to its limits in the IR range, in collaboration with their German colleagues, ‘because the spectrum you see in the paper was quite poor’, says Minnaard. ‘But we did it!’ In a follow-up study, the researchers hope to obtain cleaner spectra for this and similar compounds.

Mahapatra, S. et al. (2025) Chem. Eur. J. e202500702, DOI: 10.1002/chem.202500702