The Half Decent Pharmaceutical Chemistry Blog

Tonight is the night...

Hello and welcome to the last episode of Saturday Night Synthesis of this series. Simply looking at tonight’s protagonist you might wonder what makes this antiviral drug so special to be in our grand finale. Well, quite a lot to be honest as this synthesis is basically the only reason why, last year, I thought of  describing a synthesis of a drug on any given Saturday night, despite the fact that I hate this sort of weekly, compulsory posting, that forces you to write something on a certain day, turning a great hobby in a work-like duty.

There is no particular reason, I’ll admit, to like this synthesis so much. But, you know, love is always irrational and illogic. The moment I started to study the chemistry of Vidarabine it was love at first sight. Actually, I doubt love is right expression: it’s more a sort of Sturm und Drang, an explosion inside of me, an erupting ensemble of primeval, hidden passions that all comes out at the same time, a cathartic burst of feelings.

All of sudden I feel like I’m in a Caspar David Friedrich painting and my ears are filled with Felix Mendelssohn’s “Fingal’s Cave”.
So, I don’t care too much how drug works (as many other antiviral drugs it’s a fake nucleotide which, after a cycle of phosphorylations, targets the viral DNA polymerase both inhibiting it or yielding an incorrect DNA strand because Vidarabine is basically an adenine bound to D-Arabinose instead of D-Ribose)  or what its clinical applications are (herpes simplex and varicella Zoster). I just want to see this wonderful, touching, enantioselective synthesis, hoping you’ll like it.

The concerto opens with pentose carbohydrate D-Xylofuranose, whose hydroxyls are not only all protected with benzoyl groups, but also with a spatial orientation which is exactly the opposite of that of D-Arabinose. However, changing the orientations of those substituents is easier than what it may seem. First, bromide is added, in acetic acid, and this yields a mono-brominated intermediate, which reacts with chloro-mercuric adenine in what is, by a large margin, my favourite name reaction: the enantioselective Koenigs-Knorr reaction.
Apparently, the reaction begins carbonyl from the protecting benzoyl group in 2’ promoting the formation of a five-term cyclic ketal through the displacement of bromide from the 1’-position. This is also helped by the HgX-group, which tends to evolve into a stable bi-halogenated derivative compound, leaving a negative charge on the purine, therefore, quickly binding to the sugar.  However, all this amazing orchestration gave us a useless intermediate where the sugar is bound to the wrong part of the purine.
Luckily, the benzoyl group breaks the bond with the nitrogenous base twice, so, we end up, once again, with an alpha-oriented ketal, with a delocalised positive charge. The purine undergoes a rearrangement and, now with the negative charge where it ought to be, stereoselectively (with a beta-oriented linkage) binds to the sugar.
At this stage, the structure has reached a decently nucleotide-like shape. So, it’s time to turn Xylose into Arabinose, by epimerising both 2’ and 3’ hydroxyls. First, the protecting group are removed with gaseous ammonia and methanol.
An alpha-oriented cyclic ketal encompassing the 5’ and 3’ position is yielded by adding acetone and, with this protection in place, methanesulfonyl chloride is added, giving a lovely leaving group to the 2’-OH.
Acetic acid and 100°C will do the job of opening the ketal and sodium methoxide yields a beta-oriented epoxide between 2’ and 3’.
This last structure is finally opened, featuring correctly-oriented products, with sodium benzoate in a mixture of DMF and water, so that, at last, Vidarabine is yielded.