Pyrrolidine alkaloids synthesis

Pyroglutamic acid is a useful starting material for the synthesis of several natural products, such as pyrrolidine alkaloids, kainoids, and other unnatural amino acids. Interesting chemose-lective Michael additions of anions derived from pyroglutamates have been reported (see Eqs. 4.54 and 4.55).69... 

Whereas the Annonaceae are characterized primarily by benzylisoquinoline alkaloids, two pyrrolidine alkaloids have recently been found in species belonging to this family. Squamolone (29) was isolated from Annona squamosa L. by Chinese workers in 1962 (68). Despite careful spectroscopic investigation and a total synthesis (Eq. 1), squamolone was assigned the incorrect diazepine formula 30. The correct structural formula (29) was later established by an unambiguous synthesis of 30 (Eq. 2). Compounds 29 and 30 proved to have very similar spectroscopic properties, which could justify the early confusion (69). 

Last but not least, a very intriguing terpenoid pyrrolidine alkaloid, poly-zonimine was milked from the millipede Polyzonium rosalbum (148). The structural formula of polyzonimine (118) is based on an X-ray crystallographic analysis of its perchlorate and by a total synthesis. 

Curiously, the synthesis of shihunine via a phenylcyclopropylimine (187) is the sole example of a simple pyrrolidine alkaloid obtained according to this general pyrroline synthesis (188) (Scheme 40). 

The chemistry of pepper has long been studied and the pungent principle of black pepper—a piperidine alkaloid, piperine 134—was isolated as early as 1877 (201). Its synthesis from the acid and piperidine was accomplished in 1882. (202). The corresponding pyrrolidine alkaloid trichostachyne (135) was isolated some 100 years later from several Piper species (see below). The cooccurence of piperidine and pyrrolidine alkaloids is a common feature of the chemistry of pepper. In many cases, the crude alkaloid extract is first cleaved with acids or bases and then each alkaloid is reconstituted by selective amidation. For the sake of unity, this chapter will be limited to comments on pyrrolidines, even in cases where they are minor alkaloids. 

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

The plethora of piperidine (242) and pyrrolidine alkaloids in Nature have made attractive targets for total synthesis, particularly since many contain a hydroxyl moiety adjacent to the amino group. This functionality is the case with the pseudodisto-mins-piperidines with antitumor activity isolated from the Okinawan tunicate Pseudodistoma kanaka. The limited availability of the natural material has prompted... 

Most cyclizations to form five-membered rings involve the 5-exo mode of cyclization. An exception has been reported in the intramolecular sulfenoamination of 3-alkenylamines used in the synthesis of pyrrolidine alkaloids (equation 102).215 229 Other examples include the aminomercurations of Af-sub-stituted-l-amino-3-butenes162,23° and the methylsulfenilium ion-initiated cyclization of 0-(2-propenyl)-/V-tosylaniline 231... 

A review entitled General Methods of Alkaloid Synthesis includes pyrrolidine, pyridine, and Sceletium alkaloids.1 Another summarizes nitrogen-containing compounds in tobacco and tobacco smoke, and includes some pyrroles, pyrrolidines, pyridines, and alkaloids related to nicotine.2... 

A review of recent chemistry of Indian Piper spp. has appeared it includes some pyrrolidine alkaloids.8 The synthesis of tricholeine (6), an alkaloid of P. trichostachyon, has been reported the pathway is summarized in Scheme 2.9... 

Catalytic palladium-ene cyclizations may also open new perspectives in alkaloid synthesis, considering the smooth formation of pyrrolidines and piperidines. Scheme 46 and Table 14 illustrate the cyclizations of palladium-ene precursors (I) (221 entries 1-4) and (J) (223 entries 5, 6) containing a nitrogen atom as part of the bridge. The leaving group in (223) can even be a simple hydroxy group (entry 6). ... 

Denmark and Marcin showed that 2,2-disubstituted 1-nitroalkenes undergo facile MAD-promoted [4 -r 2] cycloaddition with n-butyl vinyl ether in toluene at 0 °C to give cyclic nitronates as anomeric mixtures in good yield [173]. This method is a promising route to the stereoselective synthesis of disubstituted pyrrolidines and can thus be applied to the synthesis of the biologically active pyrrolidine alkaloid, mesembrine (Sch. 134). 

The enantioselective total syntheses of several piperidine and pyrrolidine alkaloids of tobacco were accomplished in the laboratory of J. Lebreton. ° In the final stage of the total synthesis of (S)-A/-methylanabasine, a one-pot Cbz-deprotection-hydrogenation-Eschweiler-Clarke methylation was carried out using a HCHO/MeOH/Pd(C)/H2 system at room temperature with an overall 88% yield. 

Also the hydroamination/cyclization of chiral aminoallenes has been utilized in the synthesis of various alkaloid skeletons [120]. The pyrrolidine alkaloid ( + ) 197B (Scheme 11.25), as well as the indolizidine alkaloid (+) xenovenine (Scheme 11.26),... 

This section summarises recent work on alkaloids containing the pyrrolidine nucleus. A short review concerning the synthesis of this group has appeared. A variety of Labiatae plants have been screened and some of them have been shown to contain pyrrolidine alkaloids. Cuskhygrine has been found in the roots of three Datura species and stachydrine has been obtained from Capparis spinosa3 The structure of trichostachine (1) Piper trichostachyon) has been elucidated by spectral means and confirmed by synthesis. Ficine (5), an interesting flavonoid alkaloid, has been synthesised. Friedel-Crafts reaction between... 

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