Nature is asymmetric

How would you like to live in Looking-glass House, Kitty? I wonder if they’d give you milk in there? Perhaps looking-glass milk isn’t good to drink...’ Lewis Carroll, Through the looking-glass and what Alice found there, Macmillan, 1872. You are chiral, and so are Alice, Kitty, and all living organisms. You may think you look fairly symmetrical in a looking-glass, but as you read this book you are probably turning the pages with your right hand and processing the information with the left side of your brain. Some organisms are rather more obviously chiral: snails, for example, carry shells that could spiral to the left or to the right. Not only is nature chiral, but by and large it exists as just one enantiomer—although some snail shells spiral to the left, the vast majority of marine snail shells spiral to the right; humans have their stomach on their left and their liver on their right; honeysuckle (Lonicera) climbs by spiralling to the left and all bindweed (Convolvulus) spirals to the right. Nature has a left and a right, and it can tell the difference between them. You may think that human beings are sadly lacking in this respect, since as children we all had to learn, rather laboriously, which is which. Yet at an even earlier age, you could no doubt distinguish the smell of oranges from the smell of lemons, even though this is an achievement at least as remarkable as getting the right shoe on the right foot. The smells of orange and lemon differ in being the left- and right-handed versions of the same molecule, limonene. (R)-(+) Limonene smells rounded and orangey; (S)-(–)-limonene is sharp and lemony. Similarly, spearmint and caraway seeds smell quite different, although again this pair of aromas differs only in being the enantiomeric forms of the ketone carvone. Evolution has left many of us regrettably sensitive to (+)-androstenone, the smell of stale human urine. (–)-Androstenone is essentially odourless.

Even bacteria know their right from their left: Pseudomonas putida can use aromatic hydro carbons as a foodstuff, degrading them to diols. The diol produced from bromobenzene is formed as one enantiomer only. How can this be? We said in Chapter 14 that enantiomers are chemically identical, so how is it that we can distinguish them with our noses and bacteria can produce them selectively? Well, the answer lies in a proviso to our assumption about the identity of enantiomers: they are identical until they are placed in a chiral environment. This concept will underlie all we say in this chapter about how to make single enantiomers in the laboratory. We take our lead from nature: all life is chiral, so all living systems are chiral environments. The sheer complexity of life means that nature has to build its living structures from molecules that are chiral, principally amino acids and sugars. For all of those chiral molecules, evolution has forced the use of a single enantiomeric form, for example every amino acid in your body has the same configuration (usually labelled S). From this fact derives the larger-scale chirality of all living structures, from the right-handed double helix of DNA to the location of a blue whale’s internal organs. The answer to the question posed by Alice at the start of the chapter is most certainly no—her kitten’s digestive system will be able to hydrolyse the achiral fats in the looking-glass milk quite easily (achiral compounds are superimposable on their mirror image), but looking-glass proteins (which will be made of D-amino acids) and L-lactose will be quite indigestible. For a perfumer or flavour and fragrance manufacturer, the distinction between the differently scented enantiomers of the same molecule is clearly of great importance. Nonetheless, we could all get by with caraway-flavoured toothpaste. Yet when it comes to drug molecules, making the right enantiomer can be a matter of life and death. Parkinson’s disease sufferers are treated with the non-proteinogenic amino acid dopa (3-(3,4-dihydroxyphenyl)alanine). Dopa is chiral, and only (S)-dopa (known as L-dopa) is effective in restoring nerve function. (R)-Dopa is not only ineffective, it is quite toxic, so the drug must be marketed as a single enantiomer.

In other cases, only one of the two enantiomers of a drug molecule possesses activity: the antidepressant citalopram and the painkiller naproxen are both marketed only as their S enantiomer because the R enantiomers are essentially inactive. In a few cases, the enantio mers both have activity, but in different ways: (+)-Darvon and (–)-Novrad are a painkiller and a cough suppressant, respectively. It is not only drugs that have to be manufactured enantiomerically pure. This simple lactone is the pheromone released by the Japanese beetle Popilia japonica as a means of communication. The beetles, whose larvae are serious crop pests, are attracted by the pheromone, and synthetic pheromone is marketed as ‘Japonilure’ to bait beetle traps. Provided the synthetic pheromone is the stereoisomer shown, with the Z double bond and the R configuration at the stereogenic centre, only 25 μg per trap catches thousands of beetles. You met this compound in Chapter 27, where we pointed out that double bond stereocontrol is important since the E isomer of the pheromone is virtually useless as a bait (it retains only about 10% of the activity). Even more important is control over the configuration at the chiral centre because the S enantiomer of the pheromone is not only inactive in attracting the beetles, but acts as a powerful inhibitor of the R enantiomer—even 1% of S enantiomer in a sample of pheromone destroys the activity. So you see why chemists need to be able to make compounds as single enantiomers. we looked at relative stereochemistry and how to control it; this chapter is about how to control absolute stereochemistry. We call this asymmetric synthesis. In the last 25 years or so, this subject has occupied more organic chemists than possibly any other, and we are now at a point where it is not only possible (and in fact essential because of strict regulatory rules) to make many drug molecules as single enantiomers, but it is also even possible to make many chiral molecules that are indigenous to nature more cheaply in the laboratory. By 2007.

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مواضيع ذات صلة

Catalytic asymmetric reduction of ketones

Chiral reagents

Enantiomeric excess

Alkylation of enolates

Resolution can be used to separate enantiomers

Palladium catalysis in the total synthesis of a natural alkaloid

Alcohols and amines as intramolecular nucleophiles

Oxypalladation and the Wacker oxidation

Alkenes coordinated to palladium (II) are attacked by nucleophiles

Palladium-catalysed amination of aromatic rings

Intramolecular alkylations make rings

Vinyl epoxides provide their own alkoxide base