Physostigmine structure

Physostigmine, an alkaloid obtained from a West African plant, is used in the treatment of glaucoma. Treatment of physostigmine with methyl iodide gives a quaternary ammonium salt. What is the structure of this salt ... 

Physostigmine (eserine) is a carbamate found in the calabar bean (Physostigma benenosum), which acts as an anticholinesterase. It was used in West Africa in witchcraft trials by ordeal. It has also been used in human medicine. Insecticidal carbamates are structurally related to it and also act as anticholinesterases (Ballantyne and Marrs 1992). 

Julian, P.L., PM, J., Boggess, D. (1934) Studies in the Indole Series. II. The Alkylation of 1-Methyl-3-formyloxindole and a Synthesis ofthe Basic Ring Structure of Physostigmine. Journal of the American Chemical Society, 56, 1797-1801. 

Figure 4. Structure of Physostigmine, an Insecticidal Alkaloid Isolated from Physostigma venenosum as a Model Compound for the Synthetic Carbamate Insecticides...

Carbamate Insecticides. These are structurally optimized derivatives of the unique plant alkaloid physostigmine [57-47-6], a cholinergic drug isolated in 1864 from Physostigma venenosum (see Alkaloids) (17,24,35—39). The carbamates maybe considered synthetic derivatives of the synaptic neurotransmitter acetylcholine, with very low turnover numbers. The N,N-dimethylcarbamates of heterocyclic enols (36) and the N-methylcarbamates of a variety of substituted phenols (35) with a wide range of insecticidal activity were described in 1954 (35). The latter are the most widely used carbamate insecticides, and the N-methylcarbamates of oximes have subsequently been found to be effective systemic insecticides. 

FIGURE 27.3 Chemical structures of physostigmine, galanthamine, and codeine. 

Upon Julian s return to the United States, DePauw University offered him a faculty position and research support. His first project was the total synthesis of physostigmine, an indole alkaloid extracted from the Calabar bean, used in the treatment of glaucoma. Sir Robert Robinson at Oxford University in England was also working on this synthesis. Julian achieved the synthesis of physostigmine, and showed that Robinson s hypotheses about its structure were wrong. 

Contrary to the need for periphery-selective drugs that avoid the brain for the treatment of myasthenia gravis, AD treatment demands carbamates which easily penetrate the blood-brain barrier. Moreover, since any activity in the periphery will cause undesirable side effects , it is preferable to develop and use a CNS-selective drug. Since physostigmine had already been shown to be of value in AD patients, it is only natural that the new carbamates were modeled on its structure. 

Further evidence for this structure for physostigmine was obtained from other reactions on eserethole. It was found that eserethole (IV R = C2H5) could be reduced (13, 14), one mole of hydrogen being absorbed. The reduction product, dihydroeserethole (V), was a secondary amine, indicating that a ring had been opened next to the nitrogen atom. When eserethole methiodide was treated with base, eseretholemethine was formed, a reaction which was reversible with hydriodic acid (15). 

The proof of structure of dehydroesermetholemethine gave considerable further support to the 3a-methylpyrrolo[2,3-6]indole structure for physostigmine proposed by Robinson. The Robinson structure for the alkaloid also was derived easily from tryptophan, thus offering an obvious biogenetic route of synthesis by the plant (this will be discussed in more detail later). 

The reactions of physostigmine also show some similarities (e.g., facile reduction cleavage of the pyrrolo ring) to those of folicanthine, calycan-thidine, and chimonanthine, which are now known to possess the structures of bis(pyrrolo[2,3,-6]indoles) (27, 28, 29, 30, 31, 32a, 32b see also Chapter 16 of this volume). 

The first satisfactory approach to the synthesis of the physostigmine ring system was devised by King et al. (33). Their method is illustrated in structures XII to XIV. Synthesis of the indolenine XII was achieved... 

The physostigmine ring system has also been synthesized by methylation of the Grignard compound prepared from suitably substituted tryptamines. This method, illustrated in structures XVIII and... 

In connection with a postulated route of biosynthesis of physo-stigmine (q.v.), Witkop and Hill (20) devised a new method of synthesis of the physostigmine ring system, outlined in structures XXXa toXXXIV. 

An attempt was made to extend this procedure to the synthesis of the physostigmine ring system, using the approach outlined in structures XL to XLIII (46). However, all attempts to cyclize the phenylhydrazone... 

In the original paper which presented Robinson s structure for physostigmine Stedman and Barger (13) suggested a possible biosynthetic route to the physostigmine ring system (see accompanying scheme). Tryptamine, produced by decarboxylation of tryptophan, was... 

Further evidence for structure X was spught in comparing NMR-spectra of calycanthine and physostigmine. This comparison indicated that five-membered N rings are not present in calycanthine. 

The typical physostigmine fragmentation pattern permitted the structural elucidation of noreserine06 (Fig. 8) and eseramine.121... 

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