This article is part of ChemTalk’s Organic Synthesis Series. These longer articles are designed to show how ideas and reactions from organic chemistry are put into practice in the synthesis of pharmaceuticals and other useful compounds.
Why make quinine?
Quinine is an antimalarial compound that was first extracted from the bark of a cinchona tree in 1820. During World War II, organic chemists in the United States worked to try and synthesize quinine, to develop a more secure supply of the drug for soldiers fighting abroad. Numerous synthetic routes to quinine exist, and it remains an important target compound for modern organic chemists to test their new tools against. Quinine is also the compound that gives tonic water its tonic!
Quinine is a naturally occurring alkaloid compound. It is comprised of a quinoline ring, two benzene rings fused together with a nitrogen atom, and a quinuclidine group, a bicyclic tertiary amine. The structure of quinine is shown below, with the quinoline ring shown in blue, and the quinuclidine group shown in red.
This article will cover two different synthetic routes to quinine, the original Woodward-Doering route, and the Stork route. Note that these two routes use completely different starting materials, and every step is different. Organic chemistry gives us myriads of reactions to utilize when trying to synthesize a target compound, and part of the skill of being an organic chemist is knowing when to strategically employ a specific reaction in a larger synthesis.
Reactions Used
- Nucleophilic Substitution
- Aromatic Substitution
- Oxidation of alcohols
- Alkylation
- Claisen Condensation
- Wittig Reaction
The Woodward-Doering Route (1944)
The first synthesis we’ll discuss is now regarded as the first total synthesis of quinine. It was first published in 1944 by Bob Woodward and William Doering.
We are going to pick up the Woodward route around the third step, where our aromatic ‘starting material’ (not quite the starting material Woodward and Doering started from) undergoes a Betti reaction to make a new C-C bond between the phenol adjacent carbon and a carbon with a piperidine substituent.
Next, this bulky extended piperidine substituent is replaced with a methyl group in an aromatic substitution reaction. Why start with such a confusing group only to immediately switch to a methyl group? Placement and protection are important factors to consider when building up a complicated synthetic target. The Betti reaction gave us a substituent right next to the phenol, whereas methylation may have given us methyl groups all over the place.
After methylation, hydrogen gas and a platinum oxide catalyst are used to reduce the double bonds in the upper ring, then an acetyl group is added to the nitrogen. More hydrogen gas, this time with a nickel catalyst, is used to reduce the aromatic bonds in the lower ring. The use of this nickel catalyst means we get selective stereoisomers for the two hydrogens shown, but the alcohol (formerly a phenol) and methyl groups could be any stereochemistry.
Next, the secondary alcohol is oxidized to a ketone with chromate. This ketone then reacts with nitroethane in a ring opening reaction that leaves us with an ester and an oxime (imine with an OH group).
The next few steps are focused on making the terminal alkene that appears in the (almost) final product. We do another hydrogen/platinum oxide hydrogenation to convert the oximine (imine with an alcohol) to a secondary amine, then this amine is exhaustively alkylated with potassium carbonate and methyl iodide. We get our alkene by way of a Hofmann elimination reaction.
A few substitution reactions give us the benzoyl and ester groups we are looking for.
Finally, we couple this complicated cyclohexane with a substituted quinoline and use HCl to get rid of the extra ester group. We now have the final Woodward product.
Unfortunately, the original synthesis published by Woodward and Doering stops here. Based on prior work, they thought that conversion of their final product to quinine was a done deal, but this assumption would bring controversy.
The Stork Route (2001)
In 2001, Gilbert Stork published what he called the “First Total Synthesis of Quinine”, claiming that the final few steps Woodward and Doering didn’t include wouldn’t work out.
The starting point for the Stork route is a gamma-lactone ring with an alkene. This alkene will appear in the final quinine structure and is a big difference between the Woodward route and the Stork route. A few steps were dedicated to making this alkene in the Woodward route, so the Stork starting point might appear to be a simplification, but remember that alkenes can undergo all kinds of reactions, so we will have to be more careful about the kinds of reagents we use to preserve this functional group.
The first reaction opens the lactone ring and adds a tertiary amine. In the opening the lactone ring, one of the oxygen atoms becomes an alcohol, which is then protected with a tert-butyldimethylsilyl (TBS) protecting group, a common choice for alcohols. Enolate alkylation then attaches a two carbon chain with another protected alcohol. This time the protecting group is a tert-butyldiphenylsilyl group (TBDPS), similar to the TBS group, but with slightly different reactivity. If the same protecting groups were used, it would be more difficult to deprotect each alcohol independently. In this synthesis, deprotecting each alcohol at different points is important, but in other syntheses, it may not matter. This alkylation step helped build up the skeleton of quinine, and also gave us an important group that will be used later to close the final quinuclidine ring.
After the alkylation step, the first OH group is deprotected, then the lactone ring is closed back up again, and the lactone ketone is reduced to an alcohol.
Next, a Wittig reaction opens the tetrahydrofuran ring.
A Mitsunobu reaction converts the deprotected alcohol group to an azide, then the vinyl methoxy group created by the Wittig reaction is converted to an aldehyde.
Now we add in the quinoline piece, and prepare to make the final few transformations.
The last few steps deal with closing the two rings necessary to form the quinuclidine group. First the alcohol group (that was just an adehyde) is oxidized to a ketone, then another Wittig reaction occurs, closing the first ring.
However, we don’t want any double bonds to appear in the final quinuclidine group, so NaBH4 reduces the carbon-nitrogen double bond to a single bond, while leaving our terminal alkene group untouched.
To prepare for the second ring closure, the TBDPS protecting group is first removed with HF, then is converted to a methanesulfonate group (OMs), which is an excellent leaving group.
Another ring closure reaction leaves us with our final product minus an alcohol group. Reaction with sodium hydride and oxygen get us to quinine.
Why such complicated steps?
Both of these synthetic routes are fairly lengthy, at around 18 steps each. They also both employ harsh reaction conditions and sometimes obscure reagents. Sometimes, there is only one option for a synthetic transformation. This may be because of other functional groups that have to be preserved, or maybe because only one way to do that transformation is known. When synthesizing medicines like quinine, which will go on to interact with proteins or other biomolecules, a specific stereochemistry is required to fit the 3D geometry of a protein binding pocket. Synthesis of quinine, and not one of its other 16 stereoisomers, means that a very careful set of stereoselective reactions needs to be devised. Both the complexity and the stringent stereochemistry requirement contribute to the lengthy and complicated syntheses of quinine. Organic chemists continue to discover new reactions and occasional revisit classic synthetic targets like quinine to test their new tools, and possibly improve upon their biological activity.
Revisiting Quinine
One example of a new synthetic tool being applied to the synthesis of quinine is described in a paper from 2018 from the University of Vienna. In this work, the authors used new C-H bond activation techniques to develop a simpler synthetic route to quinine. This new route also afforded the ability to synthesize analogues of quinine, with improved antimalarial activity.