Physostigmine alkaloids, synthesis

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. 

Node and Fuji have developed a new chiral synthesis of various alkaloids using chiral nitroalkene, (S)-(-)-2-methyl-2-(2 -nitrovinyl)-S-valerolactone. Scheme 8.11 shows a total synthesis of (-)-physostigmine, a principal alkaloid of the Calabar bean.53 The key nitroalkene is prepared by asymmetric nitroolefination of a-methyl-8-lactone using a chiral enamine (see... 

Eserine (physostigmine) has a pyrroloindole skeleton. This alkaloid is used as an anticholinesterase drug, which is fairly important in the treatment of Alzheimer s disease. Eserine is synthesized in Physostigma venenosum and stored in the seeds of this leguminous plant. The synthesis pathway starts with tryptamine, which is transformed into eserine (Eigure 45). 

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. 

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). 

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... 

Reductive intramolecular cyclizations constitute a powerful tool for the synthesis of various indoles. The tricyclic indole derivative 118, a key intermediate in a previous synthesis of the alkaloid r//-physostigmine, was prepared by reductive cyclization of the precursor 119, for which an interesting synthetic route was developed <03JOC6133>. 

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]. 

Of the five alkaloids with known structures, physostigmine (1), esera-mine (3), and physovenine (4) have been synthesized 1-4). Since the conversion of physostigmine (1), a principal alkaloid, to physovenine (4) (6) and geneserine (S) 7,8) has also been established, synthesis of the former implies acquisition of the latter two alkaloids in a formal sense. Up to 1970, the synthesis of geneserine (5) was not reported because its structure had been considered to be the /V-oxide of physostigmine (1) until 1969 9-II) since its first isolation in 1915 (72), The four approaches to the synthesis of physostigmine (1) may be classified into four types based on the key step employed (i) the Fischer indolization route, (ii) the indole alkylation route, (iii) the oxindole alkylation route [including synthesis of physovenine (4)], and (iv) the oxidative indolization route 1-4) (Scheme I). 

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 ... 

Electrophilic N-prenylation of indole has, for instance, been employed in the synthesis of N-prenylindolactam-V (3, Scheme 1) [18], where the yield is only moderate, probably due to the simultaneous presence of the amide moiety. The natural product (—)-indolactam V (1) is a potent inhibitor of protein kinase C isozymes [28]. Other examples include the total syntheses of deformylflustrabromine B [11], of derivatives of physostigmine and debromoflustramine B [22], or of vulcanine and borrerine [24]. The key step of the synthesis of N-prenyltryprostatin B features N-prenylation with concomitant 3-prenylation (see Sect. 3.1) [29]. As a side reaction, prenylation of diketopiperazines, a frequent stmctural motif in prenylated indole alkaloids, was observed. 

The main poisonous substance of Calabar beans was isolated in 1864, and was named physostigmine [IJ.The plane structure of this alkaloid was determined in 1925, and the absolute stereochemistry of (—)-physostigmine was clarified by degradation studies in 1969 [2,3]. Subsequently, the total synthesis of DL-physostigmine was achieved [4]. Calabar beans were known as Esere by the indigenous people, and so physostigmine is also known as eserine. 

Very recently, an enantioselective version of this transformation and its application towards the synthesis of alkaloids esermethole (217) and physostigmine (218) has been described by Zhn and coworkers [115]. In the new protocol, KCN is replaced by the less toxic K4[Fe(CN)6], Pd(OAc)2 is nsed as catalyst and (S)-DIFLUORPHOS (221) as ligand, leading to oxindole 220 in np to 78% yield and 77% ee (Scheme 8.55). Lautens and coworkers [116] also made use of this general concept by combining a Mizoroki-Heck/C—H activation/cyanation step for the preparation of polycyclic benzonitriles under microwave irradiation. 

Michael adducts from p-aryl- and P-alkyl substituted nitroolefins in high yields (68-97%), good diastereoselectivities (dr 3/1 to >20/1), and excellent enantioselec-tivities (88-99% ee). This novel organocatalytic approach has been used in the formal synthesis of the alkaloid (-H)-physostigmine (Scheme 2.92). Catalyst 168 was... 

Physostigmine (Y) belongs to the class of indole alkaloids (cf p. 147). A recent synthesis of Y starts from 2-iodo-4-methoxyaniline (X) and performs the following sequence of reactions key step is a Pd-catalyzed domino cyanation process (c). 

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

Nakagawa and Kawahara deployed a [3+2] annulation during their concise synthesis of (it)-desoxyeseroline 96 and ( )-physostigmine 97 (Scheme 41.21). This alkaloid was isolated from Calabar beans and Streptomyces and presents anticholinesterase properties. After an extensive screening of Lewis acid, it was found that 1 equivalent of... 

Overman effected an enantioselective Heck cyclization of aryl iodide 132 to furnish 133 in 95 % ee in the synthesis of the alkaloid physostigmine (134), a constituent of the seeds of the African calabar bean (Scheme 13.18) [77]. 

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