ChemistGPT

There was lots of talk of ChatGPT apparently deciding to teach itself organic chemistry…now…ChatGPT is language model, it’s not really an artificial intelligence (AI) in the strict sense, all it really is is a sophisticated autocomplete that analyses your prompts and weighs up the most likely combination of words with which to reply. I wondered whether the only chemistry in all that hype was the chemistry between olfactory receptor and odourant molecules in bovine ordure. So, I set it a challenge, giving it the following prompt:

You are to act as an expert organic chemist. You need to devise a reaction scheme using retrosynthetic analysis for the drug molecule Taxol.

This is how it responded:

Taxol is a complex natural product that has antitumor activity and is used in the treatment of various cancers. The molecule contains a complex array of functional groups, including multiple stereocenters, which make its synthesis a significant challenge.

Here is a possible retrosynthetic analysis of taxol:

Step 1: The first step involves disconnection of the C13 side chain from the taxane core. This can be achieved using a standard acid-catalyzed esterification reaction between a carboxylic acid and an alcohol. This disconnection leads to the formation of the intermediate 10-deacetylbaccatin III.

Step 2: The second step involves disconnection of the A and B rings from the taxane core. This can be achieved using a retro-Diels-Alder reaction. The retro-Diels-Alder reaction involves breaking the six-membered ring formed in the Diels-Alder reaction between the A and B rings. This leads to the formation of the intermediate 9-dihydro-13-acetylbaccatin III.

Step 3: The third step involves disconnection of the C ring from the taxane core. This can be achieved using a ring-opening reaction. The ring-opening reaction involves breaking the bond between C9 and C10, leading to the formation of the intermediate 7,8-didehydro-10-deacetylbaccatin III.

Step 4: The fourth step involves disconnection of the D ring from the taxane core. This can be achieved using a ring-closing reaction. The ring-closing reaction involves forming a new bond between C1 and C14, leading to the formation of the intermediate 5-deoxy-4-O-methyltaxol.

Step 5: The final step involves disconnection of the C2 side chain from the taxane core. This can be achieved using a standard nucleophilic substitution reaction. This leads to the formation of the final product, taxol.

Overall, the retrosynthetic analysis of taxol involves a series of complex reactions, including esterification, retro-Diels-Alder reaction, ring-opening reaction, ring-closing reaction, and nucleophilic substitution reaction. These reactions can be challenging to carry out in practice, and developing efficient and practical synthetic routes to taxol remains an active area of research in organic chemistry.

Now, it’s a long time since I did any retrosynthetic analyses for organic chemistry and I was never any good at them when I was meant to be. So, I’ll put this to social media and see what some proper chemists think.

First comment in was from ChemJobber, who said “the first disconnection to start with 10-deacetylbaccatin is reasonable”

I wrote about the first total synthesis of Taxol back in the 90s, and recall that the overall reaction scheme had well over 20 steps…

Nessa Carson dissected it and found the ChatGPT scheme rather lacking – here. She also pointed out that in Step 5 it completes the retrosynthesis of Taxol by disconnecting it all the way back to… Taxol (lol)