Dr Cornelius von Riesen describes how a new process converts the Cinchona alkaloid extracted from the bark of a tree selectively into the new chiral quinuclidines Quincorine and Quincoridine.
The Cinchona alkaloids quinine, quinidine, cinchonine and cinchonidine the most produced alkaloids for commercial use are extracted from the bark of the Cinchona tree, which is cultivated in the climatic zones of the equator from 1400 m onwards on an agricultural scale. The major cultivation areas are central Africa, South America and Indonesia. From sowing to harvesting it takes about 12 to 13 years.
Thanks to a new and patented transformation Buchler can convert the Cinchona alkaloid selectively into aromatic quinoline and an enantiomerically pure quinuclidine derivative (Quincorine and Quincoridine). This multiple oxidation-reduction transformation has been invented in the group of Professor H M R Hoffmann at the University of Hannover. Earlier attempts to transform Cinchona alkaloids described in the literature led to inevitable destruction of the azabicyclic cage.
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 diseases such as Alzheimer, arteriosclerosis, allergies (hay fever, eczema) and also high cholesterol levels. For example, quinuclidine compound AF 102 B is in phase III of clinical trials against Alzheimer. Previously, highly functionalised quinuclidines had only been accessible by multistep syntheses. Usually, such routes are circuitous and costly. The simple 3-quinuclidinone is commercially available and has been elaborated into a variety of biologically active derivatives. Newly developed QCI- and QCD-derivatives provide access to more complex and selective therapeutic agents which are also enantiomerically pure. The additional hydroxymethyl functionality of QCI and QCD and their derivatives allows attachment of further pharmacophoric groups and prodrugs.
Combinatorial techniques and high throughput screening will aid 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.
The asymmetric dihydroxylation and enolate alkylation reflect the remarkable versatility of these substances (K B Sharpless and E J Corey). QCI- and QCD-derivatives open a path to a wide variety of non-natural and semi-natural Cinchona alkaloids. Similarly, a series of new chiral building blocks has been developed expanding the chiral pool of fine chemicals (Org. Lett. 1999, 1, 1607; J.Org. Chem. 2000, 65, 3982; Org. Lett. 2000, 2, 1661).
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 recent application 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). The drug targets one of the two important surface structures of the virus, ie the neuraminidase protein. The enzyme is practically identical for all common influenza viruses. Enzymic activity of viral neuraminidase is essential for liberating newly formed virus particles and hence for spreading infection viruses in the organism. If the neuraminidase is inhibited, the virus cannot infect new cells.
In summary, Cinchona alkaloids, quinic acid and the new derivatives Quincorine and Quincoridine are valuable chiral building blocks. Both QCI and QCD have a high chirality content. Being (2.2.2) bicyclics they contain three overlapping boat-like segments and have a higher energy content than isomeric (3.2.1) bicyclics. Soon these building blocks will be accessible in kilogram quantities.
Since the tragic experience with thalidomide some 40 years ago, the quest for enantiomerically pure instead of racemic drug has been pervasive and the FDA now requires biological activity profiles for individual stereoisomers. Natural products and modified natural products which occur in one enantiomeric form only, are attractive starting materials and continue to be developed.
Buchler GmbH produces and supplies enantiomeric pure compounds for the pharmaceutical, chemical and soft drinks industry. The alkaloids quinine (for the treatment of malaria and muscle cramp), quinidine (for the therapy of arrythmics), cinchonine, cinchonidine (separation of racemic mixtures via diastereomeric salts) and quinic acid are as much part of the portfolio as speciality chemicals for industry and universities.
ENQUIRY No 72
Dr Cornelius von Riesen is with Buchler GmbH, Braunschweig, Germany. www.quinine-buchler.com
