Philippos Knutákēs,A Sigma Aldronikki,B Zorba I. Elliniki,C Carona LaagerbeardA and Günther SchlonkC*
Abstract
We, the chemists of Twitter, here set forth our syntheses, that time may not decompose what our hands have brought into being. We report great and wonderful deeds, manifested by both theoretical and experimental chemists, and together with all this, we discuss the reasons why we sought to make labyrinthamine.
Introduction
Traditional or “folk” medicines have long been recognised as a valuable source of useful biomolecules for the modern chemist. This is best demonstrated by Tu Youyou’s discovery of the antimalarial drug artemisinin in a Chinese herbal remedy, which earned her a share of the 2015 Nobel Prize in medicine.1 Chinese, African and Indian folk medicines are the primary focus of current research, but the traditional remedies of Europe have been largely ignored, on the assumption that if any interesting chemistry existed there, we would have found it by now.
In 2019, Jack Day and Edith Dallas from the Hellenic School of Theological Chemistry upended this presumption.2 They were conducting a review on the efficacy of Pliny the Elder’s ancient Roman remedies, when they came across the following passage in the Naturalis Historia:
“If the vision fades or grows blurry, take the nut of the coleus tree, and grind it with saltpetre, sand and the urine of an irate badger. Apply this paste to the eyes during a full moon, then burn the top half a fox, and toss the ashes over the left shoulder. This will cure the blindness, though if the lower half of the fox is used, or if the badger is only surly, death will instead result.”
Pliny the Elder, IX 404, Naturalis HistoriaTranslated by Vin Diesel
References to the “Coleus tree” are sprinkled throughout the classical texts, in which it is characterised as broad-leafed tree of medium height, growing around the coast of the Aegean and bearing an unpalatable, bitter-tasting nutty fruit. The oldest such reference is an alternative account of Theseus’s battle with the minotaur, by Outis of Sicily.3 In the traditional tale, Ariadne, daughter of King Minos, gives the hero Theseus a ball of thread, which he uses to retrace his steps through the labyrinth. Outis, however, insists that it was the court alchemist, Bophades, who aided Theseus. Vexed by King Minos’s decision to cease funding his research, the disgruntled alchemist gave Theseus an extract of coleus nuts, which allowed him to see clearly in the dark confines of the labyrinth. Thus prepared, Theseus slew the minotaur and humiliated king Minos (Figure 1).
Figure 1: A photograph of a Cretan black-figure amphora (c. 650 BC). It depicts the alchemist Bophades handing Theseus an extract of coleus nuts. A coleus tree stands behind Bophades, while the Minotaur is visible behind Theseus. Photo courtesy of the British Museum of Purloined Antiquities, Croydon.
Day and Dallas believed that these two stories were too similar to be explained by coincidence and concluded that the nuts of the coleus tree must harbour a natural product with optical activity (in the ocular, as opposed to chiral sense). They hypothesised that such a molecule could be a potent curative for glaucoma and cataracts,3.5 if it could be isolated. The only problem with this plan was that the coleus plant had been extinct for the better part of 1500 years.
In an act of almost unbelievable good fortune, however, a living specimen was found growing out the back of a Goody’s Burger House in Heraklion later that year.4 When word reached Day and Dallas that the coleus tree (now classified as Coleus tavroskata) had been rediscovered, they immediately obtained a sample of the tree’s nuts. From these, they extracted and characterised the family of molecules which are now known as the helleneamines: labyrinthamine, minotaurine and gordiane (Figure 2).
These supernatural products possess some of the most fiendish carbon architectures in all chemisdom, to say nothing of their rampant hypervalency. This alone is more than enough motivation for their synthesis, even without their potential biological activity. Indeed, gordiane has already been synthesised in one step by Alex McEdon at the Phrygian University. His crucial disconnection was to bisect the molecule completely, and construct all six bonds simultaneously with an ingenious sextuple-cuprate addition (Scheme 1).
Despite attempts by many of the world’s greatest synthetic chemists, no successful syntheses of minotaurine or labyrinthamine have been reported to date. We were confident that we would succeed where others had failed, however, and armoured in our ambition, we set out to make labyrinthamine.
Retrosynthesis We decided that the best way to navigate this carboniferous maze was to pick one end, and follow a chain of carbons until we reached the other (Scheme 2). We started with the butenolide at the top, envisioning that condensations with theucydidiene (4) and platone (5) might establish the foundations of intermediate g. A subsequent reduction with tantalus chloride (TaCl2) and 6, followed by coupling reactions with galene 7 and allene 8 was anticipated to deliver intermediate V. Finally, we proposed that a sigmatropic rearrangement and confabulation with a Cretan bullvalene would complete the carbon skeleton, and that some simple functional group interconversions and cross-linking would complete the molecule.
Synthesis
So that all worked fine (Scheme 3). We experienced no major issues with the first 120 steps of the synthesis. When the time came to instal the final isonitrile, however, we encountered some complications. We had selected the Kolokithokeftedes isonitrilation for this purpose, but we observed a complete lack of reactivity under standard conditions. The ligands used in this reaction, cis-EPhos (L1) and O-EdoPhos (L2), are highly active and cis-selective, and typically deliver excellent yields. That being said, O-EdoPhos is very challenging to purify, as its dodecyl groups give it a strong affinity for the mother liquor during crystallisation. As such, we selected cis-EPhos for a suite of mechanistic and kinetic experiments.
Spectroscopic analysis of the wine-dark reaction mixture indicated no catalyst decomposition, and isotope-labelling studies showed 100% conversion of starting material into starting material, with catalyst turn-over numbers approaching infinity.
We used computational chemistry to probe the underlying causes of this baffling reactivity, for two main reasons. First, because of the precious nature of our starting material, and second, because computational chemistry is an adjacent discipline to mythology anyway.5 Our calculations indicated that in the cis-EPhos-catalysed reaction with our substrate, a lower-energy pathway existed from the penultimate intermediate back to the starting materials (Scheme 4).
As such, the catalytic cycle spins continuously, without getting anywhere. Thus it pains us to report that our synthesis of labyrinthamine has stalled at the final hurdle.
Conclusion
“Every art and every investigation, and likewise every practical pursuit or undertaking, seems to aim at some good. In some cases the activity of practising the art is itself the end, whereas in others the end is some product over and above the mere exercise of the art.” 6 Such was aristotle’s commentary on the art and science of total synthesis, and these words consoled us in our failure to make labyrinthamine. We are confident, however, that extensive optimisation of the final reaction will reward us with success. Further experiments are currently underway in our laboratory, and we expect to report a complete synthesis any day now.
Notes and References
1. https://www.nobelprize.org/prizes/medicine/2015/summary/
2. “On the phytochemistry of C. tavroskata and the helleneamines” J. Day, E. Dallas, 2019, Hellenic J. Chem., 300, 480–481.
3. “Crazy Rich Minoans” Outis of Sicily, 590 BC.
3.5 Not to be confused with the pike, which is a cure for cataphracts.
4. “These nuts are back from the dead!” Heraklion Times, 2019.
5. Note: one is a series of stories we tell ourselves to make sense of the world, even if they have no real foundation in reality, and the other is mythology.
6. “Nicomachean Ethics” Aristotle, 340 BC, Book 1, near the start.