Saturday Night Synthesis: Atropine
Good evening and welcome! This week, one of the posts outlined an important feature of physostigmine, so, I've decided to complete the cycle by making of atropine, an important antidote of the aforementioned AChE inhibitor, the protagonist of tonight's SNS.
Atropine is one of the first drugs in the history: a great cosmetic for women, a reliable poison for men and women who had enemies (mm, sounds interesting...). It still has to be considered the leading compound in the design of most of muscarinic antagonists.
Moreover, the drug can be used as a mydriatic or to treat bradycardia, poisoning with AChE inhibitors (including some of those you can find in chemical weapons) and muscarine-producing mushrooms.
Although we are about to start synthesizing it, it has to be said that atropine can be found in fascinating Atropa Belladonna (one of the best-looking plants I've ever seen). Only the levo enantiomer, which is the active one, but the base used for the extraction deprotonates the chiral carbon and, due to the position of the ester, you'll certainly understand while you always get the chiral mixture.
Let's take a look at this (total) synthesis.
The first part of the synthesis begins with phenylacetic acid: two equivalents of a Grignard reagents, basically, are used in a quite uncommon acid-base reaction. We complete the synthesis of tropic acid with formaldehyde and hydrochloric acid. The product will obviously have to undergo chiral resolution, since we need L-hyoscyamine only.
Now let's start to discuss the cool stuff.
An acetal of succinic aldehyde is opened and treated with methylamine and acetone dicarboxylic acid. I must say, I like the proposed mechanism very much and it's, to be honest, the reason why I chose this very synthesis, this week.
I mean, one of my professors of organic chemistry used to say he didn't believe in most of proposed mechanisms (especially when it comes to name reactions). Here I find it extremely plausible, considering that water and CO2 are released.
By the way, after this superb mechanism, we end up with tropinone: hydrogenation will yield two geometric isomers, pseudotropine (which isn't needed) and tropine, we must separate.
Finally, tropine reacts with the tropic acid and we yield atropine, or, to be precise, L-hyoscyamine.
The mechasnism may indeed be beautiful, but not as you have drawn it. Hemi-aminals do not react in the fashion you have drawn - rather you should generate an iminium ion by protonation-elimination of water. Secondly - you should have the enolate of the beta-keto acid as the nucleophile - it shouldn't need to involve the acid group.
Have a look see here
http://holivo.pharmacy.uiowa.edu/reaction/robinson.pdf
Yup, my fault: I wanted to summarize the mechanism, in order to have a decent final size,so badly, that I didn't check the arrows after some copy'n'paste.
Now it should be OK. BTW, thank you SO much!
The synthesis of tropinone is fantastic. Robinson was a genious. I think that particular synthesis is a real landmark in synthetic chemistry, ushering in the era of increasing complexity. Some might scoff at it now because it is a one-step total synthesis of an achiral molecule, but come on, it's a one step total synthesis! I highly suggest the original paper on tropinone, well worth the read:
Robinson, J. Chem. Soc. 1917, 762.