Angewandte Chemie International Edition ,
The Beaver as Chemist
Total synthesis of enantiomerically pure nupharamine alkaloids from castoreum
Contact: Horst Kunz, Universität Mainz (Germany)
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Stereoselective Synthesis of Enantiomerically Pure Nupharamine Alkaloids from Castoreum
the dried scent glands of the Canadian beaver, was once one of the most
valuable scent components derived from animals. Castoreum contains a
complex mixture of substances, including a number of compounds known as
nupharamine alkaloids. Many of these have been structurally
characterized. Researchers working with Horst Kunz at the University of
Mainz (Germany) have now, as they report in the journal Angewandte Chemie,
determined the stereochemistry (precise spatial structure) of another
castoreum component by using a total synthesis. A total synthesis is the
complete chemical synthesis of a complex organic natural substance from
simple, easily attainable starting materials.
use their fat- and pheromone-containing gland secretions to groom their
fur and to mark their territory. In the past, the resin-like content of
the dried glands was used as medicine to treat various complaints, such
as cramps, “hysteria”, and nervousness. In antiquity it was even used to
treat epilepsy. Castoreum’s effectiveness can be explained by the
salicylic acid it contains—aspirin is also based on this substance.
Castoreum was once in such demand that the beaver was threatened with
extinction. Today, there are special beaver farms where the beavers rub
their secretions off onto special collection containers. In addition,
castoreum is now only used for homeopathic remedies and in some perfumes.
team from Mainz undertook the synthesis of a minor component
(5-(3’-furyl)-8-methylindolizidine), which makes up less than 0.0002% of
castoreum. In principle, the structure of this nupharamine is known. It
has an indolizidine skeleton (a special ring system made of one
six-membered and two five-membered rings). However, one detail has
remained unknown: the stereochemistry at one of the carbon atoms of the
six-membered ring. The four bonds of a carbon atom point toward the
corners of a tetrahedron. If there are four different bonding partners,
there are two possible spatial arrangements possible, which are mirror
images of each other. This type of carbon center is called “chiral”.
of the two possible versions of the nupharamine, the cis-trans
form, has previously been produced enantioselectively. The German team
has now achieved the enantioselective total synthesis of both versions—the all cis form for the first time. To do this they used a
carbohydrate as a chiral auxiliary. This is a molecule that is attached
to a starting material in order to shield one side of the molecule in
subsequent reaction steps so that only the desired stereochemical form
of the product is formed.
and mass-spectrometric analyses of both synthetic products and the
nupharamine isolated from natural castoreum showed that the all-cis
form is identical to the natural product.