Pyrrolidine alkaloid

Pyrrolidine Alkaloids.—and tracer feeding results are in conflict for the biosynthesis of the pyrrolidine ring of nicotine. On the one hand ° [2- C]lysine afforded nicotine (138) with equal labelling of C-2 and C-3, whereas on the other the alkaloid obtained after exposing Nicotiana glutinosa plants to C02 was found to be more heavily labelled at C-4 and C-5 than C-2 and C-3 other workers have found uniform labelling of the pyrrolidine ring after application of 

Partially in an endeavour to define the stereochemical requirements for enzyme activity in nicotine biosynthesis, C-methyl derivatives of (141), namely (144), 

In addition to the unnatural nicotine precursors mentioned above, 5-fluoro-nicotinic acid has been administered, initially with fatal consequences, to Nicoti-ana N. tabacum). The plants were able to adapt to small doses of the substrate, however, and the fluoronicotine (147) was produced. 

The intriguing problem of the mechanism of hydroxylation of the tropine nucleus to give meteloidine (149) remains. The stereochemistry of the hydroxy-groups in (149) precludes an epoxide intermediate like scopolamine, and suggests the involvement of the dioxetan (154). 

Tritiated atropine was rapidly metabolized but not incorporated into hyoscyamine or other alkaloids in mature Datura innoxia  

On the other hand, the classical and spectacular synthesis of tropinone (6.65) by reaction of succindialdehyde, methylamine and 

It was found that [2- C]ornithine labelled only one of the bridgehead positions. It follows from this that the incorporation of the amino acid is unsymmetrical and cannot therefore involve the symmetrical base putrescine as an intermediate. As a result of corroborating tracer experiments obtained for tropane alkaloids and cuscohygrine 6.68), it is currently believed [44] that unsymmetrical ornithine incorporation is achieved through methylation to AT-methylornithine 6.61) followed by decarboxylation to give A-methylputrescine 6.62) this latter unsymmetrical base may also be formed from putrescine 6.63). It is to be noted that this pathway differs from that deduced for piperidine alkaloids, where non-symmetrical incorporation of the precursor amino acid (lysine) is more simply accounted for (Section 6.2.1). 

In the biosynthesis of nicotine 6.71) in Nicotiana species it has been found [45, 46] that both ornithine 6.60) and putrescine 6.63) are again involved in pyrrolidine-ring formation. For this alkaloid, however, incorporation of the amino acid is through at least one symmetrical intermediate, logically putrescine 6.63), because [2- C]ornithine gave nicotine 6.71) with label equally spread over C-2 and C-5 additional results were obtained with [ N]ornithines. This symmetrical pathway is supported by experiments with C02, although a few results indicate an unsymmetrical route [47, 48]. 

The intact incorporations into nicotine 6.71) of A -methylputrescine 6.62) and A -methyl-A -pyrroline 6.64) further define the pathway to this alkaloid [significantly label from C-2 of the precursor 6.64) appeared at C-2 of the alkaloid]. N-Methyl-A -pyrroline 6.64) was isolated in radioactive form after feeding, for example, radioactive ornithine to Nicotiana species, thus establishing its role as an intermediate in nicotine biosynthesis. Additional persuasive evidence comes from the isolation from Nicotiana of an enzyme which catalyses the conversion of putrescine 

The combined results for nicotine suggest the pathway ornithine [6.60) putrescine [6.63) [6.62) [6.64) which condenses with a 

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Pyrrolidine alkaloid transformations in insect organisms 98EJ013. 

The utility of strained disubstituted cycloheptenes in alkaloid syntheses is highlighted by Blechert s total syntheses of the bis-pyrrolidine alkaloid (+)-dihydrocuscohydrine (390) [161],thebis-piperidine alkaloid (-)-anaferin (in the form of its dihydrochloride 393) [162], and indolizine 167B (397) [163] (Scheme 77). 

In order to synthesise the pyrrolidine alkaloid, (-l-)-197B, bis-(i ,i )-tri-fluoromethanesulfonamide ligand was employed in the enantioselective addition of Zn( -Bu)2 to an allene-aldehyde, alfording the corresponding (i )-alcohol in 70% yield and 94% ee (Scheme 3.52). ... 

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... 

Several eco-friendly approaches to vinyl-/i-lactams (219-221) bearing a vinyl substituent at various positions on the ring (Scheme 9.71) have recently been described by Manhas [122]. Vinyl-/i-lactams are efficient synthons for a variety of compounds of biomedical interest, e. g. isocephalosporins, carbapenem intermediates and pyrrolidine alkaloids. MORE chemistry techniques allow highly accelerated syntheses using limited amounts of solvent and with efficient stereocontrol, thus achieving high atom economy . 

IX. Addendum Pyrrolidine Alkaloids from Black Pepper. 312... 

Two reviews on pyrrolidine alkaloids have appeared in volumes I (7) and VI (2) of this series. At that time, the only alkaloids mentioned were hygrine (1), hygroline (2), cuscohygrine (3), stachydrine (4), and betonicine (5). Carpaine,... 

Hygrine (1) and hygroline (2) were known compounds when the first reviews on pyrrolidine alkaloids in this series were written. Since 1950, the configurations of 1 and 2 have been determined and new sources of the alkaloids have been found. 

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. 

Although no experiment has yet been reported to support the idea, it seems clear that a majority of the pyrrolidine alkaloids arise from the ornithine, pu-trescine, and proline pool. This could be the case for ficine (61) and isoficine (62), vochysine (63), and phyllospadine (64) but also of the Darlingia alkaloids, which share common features with hygrine this assertion probably also holds for the ruspolinone (25) and odorine-roxburghlin (59) families. Peripentadenine, isolated from a plant of the family Elaeocarpaceae, bears resemblance to other alkaloids of the elaeocarpus type such as isoelaeocarpicine (124) (161). It cannot be excluded, however, that spermidine may be a biosynthetic intermediate instead of putrescine. The question of the origin of ant alkaloid substances remains so far without an obvious answer. 

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 chemical diversity of pyrrolidine alkaloids indicates a broad spectrum of biological activities, which, however, does not allow, at the present time, structure-activity relationship studies. The available data are inhomogeneous, ranging from investigations of pure compounds to reports of use in folk medecine. 

Finally, the report by Angenot et al. of an exceptional increase of antimitotic activity in strychnopentamine (104) caused by the presence of a supplementary pyrrolidine ring, is worth noting (199). Chemists might use this fact as an reason to promote interesting new syntheses of pyrrolidine alkaloids or creation of unnatural molecules containing pyrrolidine. 

The preparation of a special chapter in this series on the constituents of pepper (6) led us to ignore pepper alkaloids. After publication of the chapter, we discovered that it dealt with the alkaloids of red pepper species (Capsicum, So-lanaceae), which are not pyrrolidines, and the purpose of this addendum is to provide a survey of the pyrrolidine alkaloids contained in black pepper species Piper, Piperaceae. 

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. 

Piper trichostachyon C.DC. from India contains a variety of pyrrolidine alkaloids in its stem and leaves. Among these one finds trichostachyne (135) (210), its C2 homolog 1-piperettylpyrrolidine (141) (211), tricholein (142) (212), and a long-chain dienamide trichonine or l-pyrrolidinyl-(E, )-eicosa-2,4-di-enamide (143) (213). 

Two new pyrrolidine alkaloids, radicamines A (16) and B (17) [characterized as (2,5,35,45,55)-2-hydroxymethyl-3,4-dihydroxy-5-(3-hydroxy-4-methoxyphenyl)-pyrrolidine and (25,35,45,55)-2-hydrox-ymethyl-3,4-dihydroxy-5-(4-hydroxyphenyl)-pyrrolidine, respectively] were isolated from Lobelia chinensis Lour, (family Campanulaceae) by Shibano et al. the present investigators also demonstrated both the... 

ShibanoM, TsukamotoD, Masuda A, Tanaka Y,KusanoG. (2001) Two new pyrrolidine alkaloids, radicamines A and B, as inhibitors of a-glucosidase from Lobelia chinensis Lour. Chem Pharm Bull 49 1362-1365. 

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