The Half Decent Pharmaceutical Chemistry Blog

This is it: the end of Laboratoire Organique, which also coincides with the last post which deals with organic chemistry on this blog. Actually this is not completely true, since I'll keep talking about pharmaceutical chemistry,  syntheses of drugs and other things which have undoubtedly something to do with organic chemistry.

This post also doubles as the first one of the Camptothecin Week, a series of articles about this drug and its properties. On this occasion, molecular biology will appear for the first time: oddly, I've covered a lot of different subjects, but never spent a word on what's likely to be centre of my entire life, as I said a few months ago.

To kick off the Camptothecin Week and give a proper send off to organic chemistry, it's time to put on your black, leather coat and dark sunglasses. Oh, and don't forget to take that pill (no, I don't mean Viagra: I was just trying to mock the film!). It's time to tackle the mind-blowing, outrageously long, total synthesis of camptothecin!


Our first reagent is a derivative of furan, which will provide the base for two of the five rings this molecule is composed of (namely, D and E). This procedure, though, requires the use of several protecting groups: right after the esterification of a carboxyl (where triethylamine is needed to neutralize the HCl the reaction produces), the other acidic function is reduced to alcohol (using borane in THF) and protected by dihydropyran. This step takes place in the presence of a very weak acid (p-toluenesulfonic acid), so that neither the already formed protecting groups nor the esters are altered at all.


The ester is finally reduced as well and subsequently oxidized to ketone: this is a perfect target for a Grignard which introduces a precious ethyl group. Then the ketone is synthesized again, this time utilizing Collins reagent.

Molecules with terribly complicated names (but, fortunately, clear structures) appear as the ketone is turned into a pretty weird compound, a cyano silyl ether, which is chromatographically isolated and treated in such a way that an amide is obtained. Apparently, quenching has to be performed as soon as the hydrolysis is over: this is, in my opinion, the sole step in the whole preparation where you have to be quick. The rest of the time, you generally wait days before you could go on.


A couple of time-consuming steps lead to an unprotected, chiral derivative of furan: this mixture has to be resolved through (3) fractional crystallization(s) (benzene:heptane 1:1) using 5 equivalents of natural quinine (very environmentally friendly, eh?).

A lactone is yielded adding a lot of either triethylamine and methyl chloroformate. Quinine is removed and the product purified. A photooxidation of the lactone, in the presence of eosin, with 2,6-lutidine results in a mixture of products: both undergo halogenation of their newly synthesized hydroxyl with thionyl chloride and Vilsmeier reagent (which, if you remember, appeared in one of the best Saturday Night Synthesis I've ever posted). That hydroxyl, in fact, doesn't look like the easiest to be substituted, does it?

To complete the synthesis, you now need to synthesize the remaining three cycles: acridine nicely provide them, by simply getting its ozonide, reducing it with sodium borohydride and, finally, converting it to a secondary tricyclic diamine.


Both pseudo-acid chlorides react with the amine yielding, after a worryingly long series of chromatographic separations, a close derivative of camptothecin.


The final product is obtained by adding lithium mercaptide in a polar solvent such as HMPA, resulting in an impressive 90% yield.

Sadly, this synthesis used to be performed by (undergraduate) students of industrial pharmacy, many years ago, but, nowadays, as either the number of students and exams (hence, lectures) increased, we simply study it. As a result I can't report the many incidents that might have occurred during such a complex synthesis.

This job is supposed to be done by those who opt for a career as organic chemist, but, as I told you, I chose something rather different. And that means it's time to say goodbye (not farewell) to organic chemistry.

Stay tuned, pharmacologists, because our time has come again, at last!