Atropine: Chemistry

No study of poisonous plants would be complete without examining atropine, the quintessential toxin of Solanaceae. Before we begin, please appreciate the following fact: atropine (tropane alkaloid) is not just a deadly toxin, it is vital to all medical settings across the world. Atropine has saved more lives than it has ended, a concrete testament to dose makes poison (or medicine). 

Atropine contains a characteristic tropane ring. In chemistry, ring means that atoms join to form a cycle, imagine a snake biting its own tail. The tropane ring is unique because it is a ring within a ring, we call that a bicyclic system. It incorporates a five-member carbon-nitrogen ring (pyrrolidine) into a six-member ring (piperidine). Examine Figure 1 carefully, both rings are numbered and coloured in red.

Tropane arises naturally from an amino acid called L-ornithine, which on chemical modifications gives rise to a bicyclic ring (Figure 1). Tropane is represented by four equivalent chemical structures. The bolded wedge bonds depict parts which are pointing out of the plane (coming out of screen towards you). Here, I chose the form which looks like a 'chair', because it ideally represents tropane ring in 3D (Figure 2). Valence electrons repel one another in space, this causes tropane ring to adopt a 'chair' appearance.

Alkaloids like atropine (tropane) must contain at least one nitrogen atom. It is the nitrogen which confers alkalinity to alkaloids. Hence, atropine can be neutralised by acid to produce salt, such as atropine sulfate (atropine + sulfuric acid). The acid-base chemistry of atropine has great implications in pharmacy, we will examine those in subsequent post.

Figure 1: Chemical structure of tropane alkaloids.

The chemistry of atropine was pioneered by German chemists in the 19th century. Atropine was first isolated by Mein in 1831 from the roots of Datura, and subsequently the deadly nightshade (Atropa belladona), which lent atropine its name. All alkaloids end in the suffix '-ine', the prefix infers Latin name of the alkaloid bearing organism. Atropa (Atropos) is the Greek deity of Fate who cuts the thread of life, alluding to potent toxicity.

Back in the 19th century, chemists did not have the privilege of cutting-age analytical (spectroscopic) techniques. They had to break down atropine into smaller fragments by reacting it with various reagents, then decude the partial structures by observing associated chemical reactions. Finally, atropine would be pieced back together (synthesised) from the proposed fragments. It's an extremely tedious but remarkable feat!

That said, we will follow the footsteps of early chemists and break down atropine by boiling it with a strong acid. That produces two principal components, namely, an alcohol (like whiskey) and an organic acid (like vinegar). The alcohol contains a tropane skeleton,  it's called tropanol. The organic acid is called 'tropic acid' since it was produced from atropine. Recall that alcohol and organic acid contain the functional groups hydroxyl (-OH) and carboxyl (-COOH), respectively. Tropanol is designated as 3-alpha, because the -OH group at carbon number-3 points downwards. If it is to point upwards (3-beta), that's gives the chemistry of cocaine-type tropane alkaloid. Examine the numbering of tropane ring, it starts at the back of the chair, moves clockwise, and ends with carbon 8 at the nitrogen atom.

When German chemists Liebig, Kraut, Lossen and Ladenburg (ca. 1879) combined 3-alpha tropanol and tropic acid, voila! they made atropine. That means, atropine is an ester, the condensation product of alcohol with organic acid (one molecule of water is released as side product). The basic structure of an ester is shown in Figure 1, it contains a carboxylate functional group (R–COO–R). Most tropane alkaloids are ester of tropanol with different organic acid.  Scopolamine is almost identical to atropine, but has an additional 3 member ring called epoxide, which is incorporated at carbon 6 and 7 of its tropane ring. This alone makes scopolamine 30 – 50 times more potent than atropine on the human brain!

Speaking of potency, atropine is only about 70% biologically active. 30% of which does literally nothing to human body. This is because atropine is a racemic mixture, it comprises two molecules which are mirror images of one another in equal proportion (1:1). Look at your left and right hand, they are mirror images which when overlapped, the thumb and pinky won’t match. If we separate a racemic mixture, the individual component (solution in solvent) each rotates polarised light to the "right-hand side/ (+)-angle" or "left-hand side/ (–)-angle", respectively. This phenomenon is called stereoisomerism, i.e., molecules of the same structure have different spatial arrangement. The point of difference is called a stereocenter, it usually comprises carbon atom with four different attachments (sometimes called chiral carbon). In the case of atropine, the stereocenter is carbon 2' of tropic acid.  Stereoisomerism is prevalent in almost all natural products and 70% of human drugs, it confers therapeutic, inactive, or toxic effects. Thus, atropine (racemate) has zero light-rotation property; its light-rotating mirror images are called enantiomers, specifically, (–)-hyoscyamine and (+)-hyoscyamine (Figure 2).

 

Figure2: 3D structure of atropine and its individual enantiomers.

Examine Figure 2 carefully, here's your homework. Chemists differentiate enantiomers by devising a system that labels stereocenter as S (left) or R (right). This is not done by measuring light rotation, it is a standardised system chemists all around the world agreed upon. Light rotation is only used to describe individual stereoisomers, which may contain one or more stereocenters. For example, laevorotary hyoscyamine rotates polarised light to the left, so we call it (–)-hyoscyamine. The symbol  dextro, D- or (+)- is used for its optical antipode. Now look at (–)-hyoscyamine, I have labelled stereocenter carbon-2' in red, it is bonded to four non-identical components. We assign priorities to all four starting with the ester carbon (1st priority),  alcoholic carbon (2nd priority), phenyl ring (3rd priority), and hydrogen atom (4th priority). Then, we move the 4th priority (hydrogen atom) downwards into paper plane, and examine whether priorities 1, 2 and 3 are arranged clockwise or anti-clockwise. If they go anti-clockwise, we denote the stereocenter as S; if they go clockwise, we denote R. (–)-hyoscyamine has an S-configuration at carbon 2', can you assign the configuration at (+)-hyoscyamine? If so, congratulations! You have completed the first phytochemistry course here! See you in the next one.