Adrenaline enantiomers

Figure 5.5. Molecular structures of adrenaline enantiomers Figure 5.6. Molecular structures of thalidomide enantiomers Figure 5.7. Molecular structures of ibuprofen enantiomers Figure 5.8. Molecular structures of fluoxetine enantiomers...

The term chiral recognition refers to a process m which some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule Very high levels of chiral recognition are common m biological processes (—) Nicotine for exam pie IS much more toxic than (+) nicotine and (+) adrenaline is more active than (—) adrenaline m constricting blood vessels (—) Thyroxine an ammo acid of the thyroid gland that speeds up metabolism is one of the most widely used of all prescription... 

Figure 24 shows the ternary phase diagram (solubility isotherm) of an unsolvated conglomerate that consists of physical mixtures of the two enantiomers that are capable of forming a racemic eutectic mixture. It corresponds to an isothermal (horizontal) cross section of the three-dimensional diagram shown in Fig. 21. Examples include A-acetyl-leucine in acetone, adrenaline in water, and methadone in water (each at 25°C) [141].

Higher differences for the interaction of both the biological and the synthetic receptors with the two enantiomers are found for the propanol-derivatives than for the ethanol-derivatives (Norephedrine, Metaraminol vs. Octopamime, Noradenaline Pseudoephedrine, Ephe-drine vs. Synephrine, Adrenaline). 

Adrenaline can exist as two enantiomers that are mirror images of each other (Fig. 2.3) and are thus non-superimposible. In Figure 2.3 the wedge-shaped bonds indicate bonds above the plane of the paper, the dotted bonds indicate bonds pointing... 

X-ray crystallography of the enantiomers of adrenaline has shown that the (-) form has the R configuration and the (+) form has S configuration. 

It should be noted that in older literature the terms d and I are used to denote (+) and (-) respectively and D and L are used to denote R and 5 respectively. A mixture containing equal amounts of (+) and (-) adrenaline or indeed enantiomers of any drug is known as a racemic mixture and of course will not rotate plane-polarised light. The physical separation of enantiomers in a racemic mixture into their pure (-t) and (-) forms is often technically difficult. 

Most often only one form shows correct physiological and pharmacological action. For example, only one enantiomer of morphine is active as an analgesic, only one enantiomer of glucose is metabolized in our body to give energy and only one enantiomeric form of adrenaline is a neurotransmitter. 

On-chip chiral separation of enantiomers of adrenaline, noradrenaline, and dopamine was achieved using a mixture of carboxymethyl-p-cyclodextrin (CMCD) and a polyamidoamine dendrimer (Starburst) [120], On-chip chiral separation of enantiomers of homovanillic acid, DOPA, cDOPA, methoxy-tyramine (MT), metanephrine, and normetanephrine was achieved using a mixture of 18-crown-6-ether and carboxymethyl-P-cyclodextrin [120],... 

Adrenaline (also known as epinephrine) has a chiral structure. In nature It Is a single enantiomer but it cannot have any diastereoisomers as It has only one stereogenic centre. 

Ropivacaine is an amide-type LA, a vasoconstrictor at less than 1% and a vasodilator at more than 1%. The fact that it is the pure S-enantiomer reduces its toxicity. Like phenol, it is metabolized by the liver and eliminated by the kidneys. When administered by dermal injection, it has a rapid onset of action (less than a minute) and the duration of action is longer than or equal to that of bupivacaine. Combining it with adrenaline does not prolong its duration of action, and a concentration of 0.75% provides longer anesthesia than a concentration of 1%. Neurological and cardiovascular tolerance to ropivacaine is much better than to bupivacaine. What is more, there is a considerable difference between the neurotoxic and cardiotoxic doses. The toxicity of ropivacaine is intermediate between that of lidocaine and bupivacaine. Direct intravascular injection of ropivacaine is still dangerous, however. 

Catechol is an intermediate for the synthesis of racemic adrenaline which, although quite medicinally active, can be resolved (ref. 36) in 71% yield to afford the more active R(-) enantiomer, the natural form, which can also be derived quantitatively by asymmetric reduction (ref. 37) of the synthetic precursor, adrenalone as the hydrochloride by catalytic hydrogenation in methanol containing the rhodium complex of (R)-o[(S)-1 ,2-bis(diphenylphosphine)ferrocenyl]ethyl alcohol. Adrenalone is obtained by the acylation of catechol with chloroacetyl chloride to afford 3,4-dihydroxy-w-chloroacetophenone followed by reaction with methylamine. 

Both ephedrine and pseudoephedrine are produced in enantiomerically pure form by plants, so, unlike the anti-asthma intermediates above, in this case we are talking about single enantiomers of single diastereoisomers. Adrenaline (also known as epinephrine) is also chiral. In nature it is a single enantiomer but it cannot exist as other diastereoisomers as it has only... 

The constitution of adrenaline was independently elucidated and published in 1901 by Thomas Bell Aldrich (1861-1938) at Parke-Davis. Friedrich Stolz (1860-1936), a chemist at Hoechst, was able to confirm the structure through synthesis in 1904. The enantiomers can be separated by crystallisation with tartaric acid. The natural (-)-adrenaline is 15 times more potent than the (+)-en-antiomer. 

FIGURE 7.9 The impact of chirality in (a) the biologically active adrenaline (epinephrine), (b) The two enantiomers of aspartame—only one of them is sweet, and it is sold under the name Nutrasweet. The other enantiomer of aspartame is bitter. All the molecules are shown also with 3D ball-and-stick representations. The arrows point to chiral centers of interest. 

Enantiomers differ in many types of biological activity. One enantiomer maybe a drug, whereas its enantiomer maybe ineffective. For example, only (—)-adrenaline is a cardiac stimulant (-l-)-adrenaline is ineffective. One enantiomer maybe toxic, another harmless. One may be an antibiotic, the other useless. One may be an insect sex attractant, the other without effect or perhaps a repellant. Chirality is of paramount importance in the biological world. 

Chirality plays a major role in the influence of many chemicals on receptor sites in the body. One enantiomer may prove a greater biological response than its enantiomer. A simple example is the hormone and neurotransmitter epinephrine, where it is known that (+)-(iS)-epinephrine (74) is less active than (-)-(i2)-epinephrine (75). The chirahty of (-)-epinephrine (also known as adrenaline) allows it to interact with the receptor site far better than the enantiomer. 

The difference in biological potency between enantiomers of compounds such as adrenaline, ephedrine and morphine is well-known. Manufacturers of more complex synthetic asymmetric drug molecules are now turning their attention to the merits of offering the patient only the biologically active enantiomer. Chapter 5 is an account of the progress that has been made in this expanding area of medicinal chemistry. 

For example, the albuterol drug (Proventil ), which mimes the effect of adrenaline helping at the bronchi dilatation in an asthmatic act, contains an equal measure of enantiomers, of which only L- is active, the other one can causing unpleasant secondary effects for this reason the levalb-uterol (Xopenex ) has been subsequently synthesized, towards isolating the levo-effect. 

The specific rotation of optically pure adrenaline in water (at 25°C) is —53. A chemist devised a synthetic route to prepare optically pure adrenaline, but it was suspected that the product was contaminated with a small amount of the undesirable enantiomer. The observed specific rotation was found to be —45°. Calculate the % ee of the product. 

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