Synthesis of -physostigmine and

Azomethine ylids derived from amidines undergo internal [3 + 2]cyclization reactions with a styrenic double bond present in the starting amidine. This strategy has been applied to the synthesis of physostigmine and erythramine. 

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. 

Morales-Rios, M.S., Santos-Sanchez, N.F., and Joseph-Nathan, P. (2002) Efficient formal total synthesis of physostigmine and physovenine conformational analysis of key intermediates. J. Nat. Prod., 65, 136-141. 

XXXVIII), m.p. 128°, identical with the product obtained from physostigmine (XXXIX), and, as the latter had already been synthesised from 1-eseroline by Polonovski and Nitzberg,i the work of the American authors constituted the first complete synthesis of physostigmine. 

Takano, S., Meriya, M., Ogasawara, K. (1991) EnantiocontroUed Total Synthesis of (—)-Physovenine and (—)-Physostigmine. Journal of Organic Chemistry, 56, 5982-5984. 

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... 

Asymmetric induction has also been evaluated in the reaction of a-aryl substituted ketones, esters, and lactones (43). The potential of the method is demonstrated by the synthesis of some naturally occurring or nonnaturally occuring chiral compounds (Scheme 15). Similarly, asymmetric synthesis of ( — )-physostigmine, a clinically useful anticholinesterase agent, is accomplished by using phase-transfer alkylation of... 

Once the medicinal properties of I and II were appreciated, the inevitable synthesis of carbamate analogs followed. The anticholinesterase activity of physostigmine- and eserine-related synthetics suggested their possible use as Insecticides but tests of early compounds failed, due to the quaternary ammonium barrier to penetration of the insect cuticle present in them. 

For large-scale synthesis of physostigmine, Julian and Pikl (38) devised a simpler route to the key intermediate XXII. Condensation of the sodium salt of 5-ethoxy-1,3-dimethyloxindole with 1,2-dibromo-ethane yielded 3- -bromoethyl-5-ethoxy-l,3-dimethyloxindole, which on heating with methylamine in methanol at 100° gave the V-methyl-amine XXII directly. 

Since it had already been shown by Polonovski and Nitzberg (11) that eseroline could be converted into physostigmine by the action of methyl-isocyanate, Julian and Pikl s synthesis of /-eseroline constituted the first complete synthesis of physostigmine. 

An entirely different approach to the synthesis of physostigmine was recently described by Harley-Mason and Jackson (41). This procedure was based on the earlier observation (42) that the ferricyanide oxidation of /3-aminoethylhydroquinones (XXVIIa) led directly to the... 

Asymmetric Alkylation. 7Y-[4-(Trifluoromethyl)benzyl]-cinchoninium bromide (1) has been used as chiral phase-transfer catalyst in the alkylation of indanones (eq 1). For the alkylation of a-aryl-substituted carbonyl compounds the diastere-omeric 7Y-[4-(trifluoromethyl)benzyl]cinchonidinium bromide (2) was used to obtain the opposite stereochemistry (eqs 2 and 3). The asymmetric alkylation of oxindoles was used as the key step in an asymmetric synthesis of (—)-physostigmine (eq 4). ... 

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). 

This method, however, is still not practical from a synthetic point of view, because a much more efficient synthesis of 29 and an equivalent oxindole 12 of the Jones synthesis had already been established in 1935 by Julian and Pikl starting from p-ethoxyacetanilide (131) and employing the intramolecular Friedel-Crafts reaction in the synthesis of physostigmine (1) 38,44) (Scheme 20). 

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. 

Oxindoles with defined stereochemistry at C3 have served as valuable precursors for entry into tetrahydro- or hexahydropyrroloindole natural product scaffolds. As illustrated in Table 1, a variety of approaches to asymmetric oxindole synthesis have been applied for introduction of the key C3 stereocenters embodied within (+)-aUine [84, 85], CPC-1 [86], ( )-esermethole (a formal synthesis of ( )-physostigmine) [87-90], (+)-gliocladin C [91], and (-l-)-asperazine [92]. 

Scheme 4.15 Enantioselective Michael addition of racemic 3-alkyl oxindoles to nitroalkenes and application to the total synthesis of ( + )-physostigmine.

Pinto, A., Jia, Y, Neuville, L. andZhu, J. (2007) Palladium-catalyzed enantioselective domino Heck-cyanation sequence development and application to the total synthesis of esermethole and physostigmine. Chem. Eur. J., 13, 961-7. 

Using a related strategy, Zhu and coworkers [65] recently described a formal enantioselective total synthesis of (—)-physostigmine (110) that featured a novel asymmetric Mizoroki-Heck cyclization/cyanation sequence. Oxindole 114, an intermediate in an earlier synthesis of physostigmine [66], was prepared from anilide 113 by carrying out the cyclization under cationic Mizoroki-Heck conditions with (,S)-DIFLUORPHOS as the hgand and potassium ferricyanide as the source of cyanide. Using these conditions, (5)-oxindole 114 was formed in 78% yield and 61% ee (Scheme 16.28). 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treatment) from a total synthesis of ( )-physostigmine 203 (Scheme 31).The reaction occurs in 84% yield with 95% ee, which is remarkably efficient for the construction of a quaternary center. Reaction conditions that favor the neutral manifold of the Heck reaction are employed. Examination of the scope of the oxindole synthesis and mechanistic analysis have appeared. " Group selective reactions are also powerful reactions in carbopalladation asymmetric synthesis.From a synthesis of (+)-vemolepin 206, alkenyl triflate 204 is... 

SCHEME 27.6. Synthesis of (+)-esermenthol 37 and formal synthesis of (+)-physostigmine 38. 

Asakawa K, Noguchi N, Takashima S, Nakada M. Preparation of a new chiral building block containing a benzylic quaternary stereogenic center and a formal total synthesis of (—)-physostigmine. Tetrahedron Asymm. 2008 19 2304— 2309. 

Yu, Q.S. Lu, B.Y (1994) Total Synthesis of Racemic Physostigmine, Physovenine and its Sulfur Analog by the Oxindole-5-O-tetrahydropyranyl Ether Route. Heterocycles, 39, 519-525. 

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. 

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. 

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