Synthesis starting from natural resourcesÂ
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- Quinic Acid
- Quinuclidines: Quincorine (QCI) and Quincoridine (QCD)
The synthesis of many pharmaceuticals and agrochemicals relies on the availability of chiral intermediates serving as building blocks for further structural and stereochemical elaboration. Chiral Pool Synthesis uses nature`s „ready made“ chiral centers, usually amino acids, carbohydrates, terpenes or sometimes alkaloids from which pieces containing the required chiral centers can be taken and incorporated into the product.
For instance the natural compound quinic acid has been used as a chiral starting material in the synthesis of the antiviral medicine Tamiflu® for the treatment of influenza. Quinuclidines are well-known starting materials for several Active Pharmaceutical Ingredients.
Quinic Acid is a well-known member of the chiral pool. It occurs in various plants, fruits as well as vegetables. Quinic acid is the biosynthetic precursor of shikimic acid and thus part of the shikimate pathway. Important branchpoints of this pathway are phenolic acids such as gallic aicd and also chorismic acid and a wide variety of medicinal natural products containing amino groups. A pharmaceutical application of quinic acid is the synthesis of Tamiflu® (oseltamivir, GS4104) which is a neuraminidase inhibitor of influenza viruses (J. Am. Chem. Soc. 1997, 119, 681) and used for the oral treatment of all common influenza viruses (type A and B).
Quinuclidine compounds are known to have a high affinity towards various receptors (5-HT3, 5-HT4, NK1…).
For this reason they have high potential in the treatment of different diseases such as alzheimer, arteriosclerosis, inflammatory diseases / allergies (hay fever, eczema), bronchitis, high cholesterol levels, urinary incontinence, cancer etc..
For instance the top-selling drug Solifenacin is a competitive muscarinic receptor agonist, which is used in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Other API´s / pharmocological active compounds are stated in the following scheme.
Newly developed QCI- and QCD-compounds provide access to chiral and more complex therapeutic agents.
The additional hydroxymethyl functionality of QCI and QCD compared to 3-Quinuclidinone allows attachment of further pharmacophoric groups and prodrugs.
Combinatorial techniques and high throughput screening will facilitate further developments in pharmacology and catalysis. Apart from their biological activity the class of substances has been used increasingly in other molecular recognition processes, especially for developing efficient phase transfer catalysts and transition metal mediated reactions.
A broad variety of new Cinchona alkaloid analogues, piperidines and homoquinuclidines are easily accessible.
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