Physostigmine alkaloids

Carbamate Insecticides. These are stmcturaUy optimi2ed derivatives of the unique plant alkaloid physostigmine [57-47-6] a cholinergic dmg isolated in 1864 from Phjsostigma venenosum (see Alkaloids) (17,24,35—39). The carbamates maybe considered synthetic derivatives of the synaptic neurotransmitter acetylcholine, with very low turnover numbers. The A/,A/-dimethylcarbamates of heterocycHc enols (36) and the Ai-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 A/-methylcatbamates of oximes have subsequentiy been found to be effective systemic insecticides. 

The alkaloid physostigmine found in the calabar bean is another classic milestone molecule in total synthesis. Metrics for thirteen plans to this molecule are summarized in Table 4.25. 

Matsuura, T, Overman, L.E., Poon, D.J. (1998) Catalytic Asymmetric Synthesis of Either Enantiomer of the Calabar Alkaloids Physostigmine and Physovenine. Journal of the American Chemical Society, 120, 6500-6503. 

Materials required The cholinesterase preparation (biotests or simple extracts from biological tissues), the reagents for a reaction medium choosen (see section 3.2.), alkaloid physostigmine salycilate and its derivative neostigmine ("Sigma"). 

The anticholinesterase alkaloid physostigmine (250) was photodegraded at 300 nm to deoxyeseroline (251) in 10% yield, along with a not readily purified... 

The classic cholinesterase inhibitor is the alkaloid physostigmine (6)/ eserine (7). It was first isolated from the calabar bean, the seeds of Physostigma venenosum. Many novel natural products with AchE-inhibifing properties have shown promise as therapeutics for AD. Some examples of such products (pure compounds/plant extracts or formulations) are briefly reviewed here. 

The classic cholinesterase inhibitor is the alkaloid physostigmine (33), also called eserine. Investigations carried out in the nineteenth century on the ordeal poison esere, which consisted of an extract of the Calabar Bean, the seeds of Physostigma venenosum Balf, resulted in the isolation of (33)... 

Carbamates are sold at a lesser volume than are organophosphorus compounds. The first carbamate (urethane) insecticides were developed in the late 1940s at Geigy Chemical Co. in Switzerland. Research on carbamates was inspired by the known toxicity of the alkaloid physostigmine, which occurs naturally in a West African bean. 

A series of tricyclic indole alkaloids (physostigmine alkaloids) has been obtained from the cheilostome bryozoan Flustrafoliacea (90). In addition, flustramide B (83) and flustrarine B (84) were isolated from this bryozoan (91). Flustrarine B (84) was prepared from previously known fiustramine B (85) (92) via oxidation with hydrogen peroxide. Five fiustramine derivatives, dihydroflustramine C (86) and its N-oxide (87), fiustramine D (88) and its N-oxide (89), and isoflustramine D (90), were isolated from the methylene chloride fraction of the aqueous methanol extract of a Canadian F. foliacea, and these alkaloids were found to be responsible for the antimicrobial activity of the extract (93). Oxidation of dihydroflustramine C (86) and fiustramine D (88) with m-chloroperbenzoic acid afforded the corresponding A-oxides (87 and 88, respectively). 

The development of Sevin and related insecticides resulted from studies on the alkaloid physostigmine, which has a methyl carbamate portion. These studies also led to the development of potent nerve gases such as Sarin . 

Subsequently, Overman and co-workers reported an application of their method in an en-antioselective total synthesis of the alkaloid (-)-physostigmine (50), which as an effective acetylcholine esterase inhibitor is of interest for... 

This lactonization was later extended to indole derivatives [123], and the influence of different groups on sulfur on the process was explored within an application to the total synthesis of the alkaloid physostigmine [124] (Scheme 14). Thus methyl indolyl sulfoxides rendered practically racemic... 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

Complete n.m.r. assignments for the alkaloids physostigmine, norphysostig-mine, eseramine, and physovenine have been added to the rapidly growing list of available data. 

The organophosphates and the carbamates differ typically in speed or ease of reversibility of cholinesterase inhibition (Ol). As a rule, reversibility is much greater with the carbamates, which include such drugs as neostigmine, pyridostigmine, and the alkaloid physostigmine or such in-... 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

The alkaloid physostigmin (1) and its analogues bearing pyrrolo[2.3-b]pyrrolidine structural units have attracted attention because of their activity as cholinesterase inhibitors. A short synthesis of compound 2 possessing a pyrrolopyrrolidine skeleton includes the following reactions, in which 4-hydroxycoumarine (X, cf problem 76) is used as starting material ... 

Let us resume the account of enzymes as bearers of drug receptors. The alkaloid physostigmine (2.8), although without effect on leech muscle, was... 

Many alkaloids contain an indole nucleus as a part of their structure. Monoterpene-derived indole alkaloids see Chapter 34) are the most important of these compounds, but several other significant types of indole alkaloids exist. Ergot alkaloids formed from tryptamine and a mevalonate-derived hemiterpene unit are of medical importance. Others, such as harmane alkaloids, physostigmine and a series of structurally similar alkaloids, Calycanthus alkaloids (Calycanthaceae) and related compounds (principally from the Rubiaceae), and relatively minor types of alkaloids from the Ascelpiada-... 

Perez-Castells and colleagues used Co fCOlj to transform N-(2-ethynylphenyl)-N-(prop-l-enyl) acetamide to a cyclopenta[(t]indol-2-one (Scheme 2, equation 1) [7]. Saito and colleagues adapted a Pauson-Khand reaction, using either COj(CO)g or Mo(CO), to the syntheses of IH-pyrrolo[2,3-fc]indol-2-ones and 2//-thieno[2,3-( ]indol-2-ones (equation 2) [8, 9]. Molybdenum is actually superior to cobalt in these Pauson-Khand reactions vide infra). Mukai and coworkers used a cobalt Pauson-Khand reaction to synthesize pyrrolo[2,3-b]indoles including the alkaloid physostigmine (equation 3) [10,11]. 

The calabar bean, seeds from Physostigma venenosum Balf. (Leguminosae), was used traditionally in Africa, particularly southeast Nigeria, for ritual deaths associated with the funeral of a chief and as an ordeal poison to determine the guilt or innocence of persons accused of a crime [1]. The pyrroloindole alkaloid physostigmine (12) (also referred to as eserine) was first isolated from the seeds of P. venenosum in the nineteenth century [75]. It is a short-acting and reversible inhibitor of AChE [12]. 

SCHEME 13.8. Catalytic asymmetric Heck processes in the enantioselective total synthesis of the Calabar alkaloids (—)-physostigmine 27 and (—)-physovenine 28. 

---