Physostigmine, total synthesis

Brossi A, Pei X-F and Greig NH (1996) Phenserine, a novel anticholinesterase related to physostigmine total synthesis and biological properties. AustJ Chem 49, 171-181. 

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. 

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. 

Wunberg, J.B.P.A. Speckamp, W.N. (1978) New Total Synthesis of dl-Physostigmine (dl-Eserine) Via Regioselective NaBH4-reduction of Imides. Tetrahedron, 34, 2399-2404. 

Trost, B.M. Zhang, Y. (2006) Molybdenum-Catalyzed Asymmetric AUylation of 3-Alkyloxindoles Application to the Formal Total Synthesis of (—)-Physostigmine. Journal of the American Chemical Society, 128,4590M591. 

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

Rege, P.D. Johnson, F. (2003) Application of Vicarious Nucleophilic Substitution to the Total Synthesis of dl-Physostigmine. Journal of Organic Chemistry, 68, 6133-6139. 

A total synthesis of (-)-physostigmine is accomplished from a chiral nitroolefin of Eq. 4.101 (Scheme 4.17).128... 

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... 

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 versatile oxindole nucleus has been stitched into designs for the total synthesis of other heterocyclic systems including the hexahydropyrroloindoles esermethole and physostigmine <07CEJ961> as well as pyrrolidinoindoline natural products <07TL1805>. ... 

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... 

Scheme 13 Total synthesis of (-)-physostigmin according to L. E. Overman.

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... 

Scheme 3-53 A total synthesis of physostigmine employing a Heck reaction with ligand-induced asymmetry [23a],...

Scheme 6-40 Asymmetric Heck reaction to form a quaternary center from a total synthesis of (—)-physostigmine.

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 treaunent) from a total synthesis of ( )-physostigmine 203 (Scheme The reaction occurs in 84% yield with 95% ee,... 

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

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. 

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

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. 

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. 

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