The first synthesis of atropine was achieved by Richard Willstätter in 1901 [7]. Before continuing the discussion of his work it is perhaps useful to remind ourselves of the situation which faced organic chemists at this time. Recent innovations such as mass spectrometry, infrared spectroscopy and nuclear magnetic resonance spectroscopy which are taken for granted today, were simply not available to assist in the determination of structure. Instead chemists had to rely on hard won information based upon simple chemical tests. This information was often inadequate and incomplete and the determination of structure was a process of detective work which often required great intuition and creativity. At this time structure determination was not always equivocal and final proof could only be established by unambiguous synthesis of the compound with the suspected structure followed by comparison with an authentic sample of the natural product. Thus synthesis was often a matter of utilitarian necessity rather than the creative, elegant art form illustrated by the work of many of the great synthetic chemists such as Woodward and Corey.

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Richard Willstätter was a giant in the field of plant natural products and this was recognised when he was awarded the Nobel Prize for Chemistry in 1915 [8, click on image to link to Nobel site]. He was interested in many alkaloids including atropine (1) and the structurally similar cocaine (3) molecule. Both of these compounds yielded tropinone (2) as a degradation product and so his synthesis targeted this molecule initially.



It was relatively straightforward to reduce tropinone to tropine and hence form its ester atropine.


His preparation of tropinone is a competent but long synthesis which demonstrates one of the fundamental difficulties involved in the preparation of complex organic molecules. Although the individual steps in the synthesis generally give good to excellent yields, there are many of them which means that the overall yield becomes diminishingly small, of the order of 1%.  As a result the early steps in the synthesis have to be carried out on inconveniently large quantities of material,  and despite this, usually have to be repeated several times in order to obtain sufficient material to carry out the later stages on an acceptable scale.

In 1917 Robinson [9] approached the synthesis in a totally radical way.  In his own words:

© The Nobel Foundation

"By imaginary hydrolysis at the points indicated by the dotted lines,  the substance may be resolved into succinaldehyde methylamine and acetone.   ...It was proved that tropinone is obtained in small yield by condensation of succinaldehyde with acetone and methylamine in aqueous solution.  An improvement followed by the replacement of acetone by a salt [calcium] of acetone dicarboxylic acid.  

The initial product is a salt of tropinone dicarboxylic acid,  and this loses two molecules of carbon dioxide with the formation of tropinone when the solution is acidified and heated" [10, click on image to link to Nobel site].

This resulted in the formation of  tropinone in one step.   More recent work by Schöpf has allowed the yield for this reaction to be raised to about 90%,  mainly by carrying out the processed under buffered conditions.

For a more detailed account of these syntheses it is worth reading the account by Ian Fleming in  his book Selected Organic Syntheses, A Guidebook for Organic Chemists [11].

Tropinone may then be converted into tropine by metal in acid reduction, the best yields being obtained  using zinc in HI.   It may be noticed that the final precursor in the Willstätter synthesis appears to be tropine.  This is not the case as the material is its geometric isomer,   j -tropine,  and thus tropine is formed by oxidation of j -tropine to tropinone followed by stereoselective reduction of the carbonyl group.


Tropic acid

Mackenzie and Ward [12] proved the structure of tropic acid by synthesis from acetophenone in 1919:

Note that the addition of HCl in step 4 contravenes Markownikoff's rule.  This is presumably due to the electron withdrawing effect of the carboxyl group which destabilises the tertiary carbonium ion intermediate relative to the primary carbonium ion.  It is tropic acid which introduces the stereocentre into the atropine molecule.  The racemic mixture formed from this reaction sequence may be resolved by reaction with quinine followed by fractional crystallisation of the diastereoisomers..


More recently Blicke et al have prepared tropic acid from phenylacetic acid via a Grignard reagent and formaldehyde:



The final problem in the synthesis,  the combination of tropine and tropic acid,  was overcome by a Fischer-Speier esterification [13].  The acid and alcohol were heated together in the presence of HCl to yield atropine

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