Physostigmine, synthesis

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. 

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. 

Table 4.25 Summary of reaction metrics and synthesis tree parameters for physostigmine synthesis plans ranked according to overall kernel (maximum) RME. ...

Figure 4.57 Synthesis map showing starting materials used for the synthesis of physostigmine.

Scheme 4.19 Trost (—)-physostigmine synthesis plan (2006). (a) EtaN (72%) (b) (CH3)2SO (88%) (c) diallyl carbonate, LiOfBu, Mo, L (98%) (d) I/2OSO4, then Nal04 (92%) (e) recrystallization from iPrOH-cyclohexane (72%) (f) CH3NH2 HCI, then 1/2LiAlH4, 2H2O (88%) (g) BBra, 3H2O (79%) (h) Na, CH3N=C=0, then H2O (79%).

Figure 4.58 Synthesis tree for synthesis of physostigmine by the Yu method.

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. 

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. 

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. 

Kawahara, M., Nishida, A., Nakagawa, M. (2000) An Efficient Synthesis of Optically Active Physostigmine from Tryptophan Via Alkylative CycUzation. Organic Letters, 2, 675-678. 

Mukai, C., Yoshida, T., Sorimachi, M., Odani, A. (2006) Co2(CO)8-Catalyzed Intramolecular Hetero-Pauson-Khand Reaction of Alkynecarbodiimide Synthesis of ( )-Physostigmine. Organic Letters, 8, 83-86. 

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... 

Prioux-Guyonneau M, Mocaer-Cretet E, Cohen Y, Jacquot C. (1984). Evidence for an activating effect of tabernanthine on rat brain catecholamine synthesis and elimination. Experientia. 40(12) 1388-89. Prohovnik I, Arnold SE, Smith G, Lucas LR. (1997). Physostigmine reversal of scopolamine-induced hypofrontality. Cereb Blood Flow Metab. 17(2) 220-28. 

Shulgin s most significant accomplishment at Dow was to develop a pesticide known as physostigmine, a substance that was to become one of Dow s best-selling products. In appreciation of Shulgin s work, Dow provided him with a laboratory of his own where he was allowed to work on projects that were of special interest to him. One of those projects turned out to be the synthesis and study of psychedelic compounds. 

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). 

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

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... 

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. 

Organocatalytic asymmetric alkylation methodology has also been efficiently applied in a practical multi-gram synthesis of pharmaceutically interesting, optically active (—)-physostigmine analogs [7]. In the presence of 15 mol% of the catalyst 13 alkylation of the oxindole substrate 12 with chloroacetonitrile furnished the desired product 14 in 83% yield and 73% ee (Scheme 3.3, Eq. 2). The counter-ion of the... 

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. 

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. 

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