Making sugars from cyanide: an alternative to the formose reaction
In the previous post, we explored the formose reaction and its potential role in ribose production (as well as other sugars) on the early Earth. However, its low yield and selectivity, not to mention decomposition after the yellowing point, would seem to constrain its potential for ribonucleotide synthesis. While CO2 is quite stable and hence unreactive, an unobvious carbon source for carbohydrate synthesis can be found in a deadly compound known as hydrogen cyanide (HCN).
Grab a cup of coffee (or a drink of your choice) and let us explore how to make sugars from cyanide, UV-light, and metal complexes
Briefly on hydrogen cyanide
Hydrogen cyanide (HCN) is a 1-carbon feedstock that was likely present in early Earth's atmosphere, potentially forming in the atmosphere during violent events such as meteoritic impacts and spark-discharge (such as lightning). Unlike the triple bond between carbon and nitrogen, which is very strong, the hydrogen-carbon bond is very weak. In fact, HCN is a weak acid, and the loss of hydrogen leaves a negatively charged CN– group. Due to its high reactivity, HCN has been among the most widely studied carbon feedstocks in prebiotic chemistry. The toxic compound has been shown to be involved in the production of amino acids (the building blocks of proteins), nucleobases, (the component of DNA and RNA that allows for base-pairing), and the topic of this post– sugars.
Synthesis of sugars via Kiliani-Fischer synthesis
The Kiliani-Fischer synthesis/homologation was first developed by Heinrich Kiliani and Hermann Emil Fischer as a method for synthesising sugars in the late 1800s. However, its utilisation in origins of life research was pioneered quite recently by Dougal Ritson and John D. Sutherland (1) at the MRC Laboratory of Molecular Biology in 2012. The reaction involves a sequence of 3 steps which repeats itself to lengthen the carbon chain.
The first step is the nucleophilic attack of CN– to the carbonyl (C=O), leading to the reversible formation of a cyanohydrin*. The equilibrium favours the cyanohydrin, which is relatively stable. Hence, it has been proposed as a possible mechanism to protect carbohydrates from degradation.
*A cyanohydrin is a functional group that contains a nitrile group (C≡N) and a hydroxyl group (OH) attaching to the same carbon.
The second step involves the reduction of the nitrile group (C≡N) which involves two electrons and two protons, leading to the formation of an imine (C=N) group.
The last step is the hydrolysis of the imine group, forming an aldehyde or ketone, after which the sequence can repeat to extend the length of the sugar.
The conventional Kiliani-Fischer synthesis requires very specific catalytic conditions not likely found on early Earth. In order to fit prebiotic conditions, Ritson and Sutherland used complexes formed from abundant metals (such as copper and iron) and cyanide which, under ultraviolet light, released the electrons necessary for reduction. The electrons are then sourced from hydrogen cyanide (1) or hydrogen sulfide (2) in the solution to replenish the ones lost during the reduction process.
Advantages of the UV-driven Kiliani-Fischer synthesis
Unlike the formose reaction, which unselectively produces a plethora of sugars in minute quantities, the products of the Kiliani-Fischer synthesis adapted by Ritson and Sutherland are the cyanohydrins of formaldehyde, glycolaldehyde, and glyceraldehyde. "Isn't the point to make ribose to make ribonucleotides?", I hear you ask. Actually, prior to their 2012 article, the Sutherland group had previously demonstrated a ribonucleotide synthesis (3) based on earlier works by Orgel and coworkers (4). This synthesis, commonly called the Powner-Sutherland pathway, relies on smaller sugars, namely glycolaldehyde and glyceraldehyde, instead of the structurally complex ribose, which possesses 7 stereoisomers.
In addition, the reactive carbonyl group (C=O) is attacked immediately after formation by cyanide (CN–) which is already present in the mixture. The formation of the cyanohydrin prevents the aldehyde/ketone from unwanted side reactions and decomposition. In order to get back the aldehyde/ketone, we only need to heat up the mixture. Because HCN is a volatile gas, it will be continuously removed from the solution. This shifts the equilibrium, reverting the cyanohydrins back to their aldehyde/ketone counterparts and cyanide according to Le Chatelier's principle.
Having said that, the proposed reaction is not without criticism, some of which are highlighted below.
Compared to N2 and CO2, HCN concentrations according to simulations were significantly lower (5). How much HCN is necessary to drive the Kiliani-Fischer synthesis is an open discussion. Due to its reactivity, HCN can react with other molecules present on the early Earth including itself, further diminishing its concentration.
In addition, the Powner-Sutherland pathway (3) is very specific sequence of reaction. In other words, if the starting materials are introduced in the wrong order or all included in one pot, it is unlikely to result in ribonucleotides or very small amounts.
The UV-driven Kiliani-Fischer synthesis proposed by Ritson and Sutherland provides a relatively efficient method to convert HCN to 2 and 3-carbon sugars. While its impact on sugars and ribonucleotide availability on early Earth is debatable, the reaction is no doubt a powerful asset in the prebiotic chemist’s toolkit.
1 D. Ritson and J. D. Sutherland, Nat Chem, 2012, 4, 895–899.
2 D. J. Ritson and J. D. Sutherland, Angew. Chemie Int. Ed., 2013, 52, 5845- 5847.
3 M. W. Powner, B. Gerland and J. D. Sutherland, Nature, 2009, 459, 239–242.
4 R. A. Sanchez and L. E. Orgel, J. Mol. Biol., 1970, 47, 531–543.
5 D. C. Catling and K. J. Zahnle, Sci. Adv, 2020, 6.
Hey there, Cogito here. Thanks for reading, hope you learnt something. Apologies this one has taken so long, I'm still working on managing my time between doing PhD and making content. The next post will be a breath of fresh air as I re-read Dr. Stone and have a think about how science engagement can incorporate some of its elements.
For more about the complexity of sugar synthesis, see Sugars & Origins of Life Research
For more about the formose reaction and carbonyl chemistry, see What is the Formose Reaction?