Alkaloids pyrrolidine family

The Pyrrolidine Family. The alkaloid hygrine (3.7) isolated from leaves of plants from the Coca group is an example of a simple pyrrolidine derivative. It and other members of this family have been found to originate from the amino acid ornithine (Scheme 3.6). 

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). 

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. 

Several species pertaining to the sub-family Myrmicinae (e.g., Solenopsis spp., Monomorium spp.) are characterized by a venom rich in dialkylated saturated nitrogen heterocycles (e.g., piperidine, pyrrolidine, indolizidine, pyrrolizidine). Exhaustive lists of these alkaloids have already been published [114-116]. Since then, only a few more of these alkaloids have been reported from a few further species. 

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... 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

There are many pyrrolidine alkaloids derived from ornithine and another large family of piperidine alkaloids derived from lysine by similar pathways involving... 

In addition to benzylisoquinolines, the family Lauraceae furnishes phenanthro-quinolizidine alkaloids such as the previously mentioned cryptopleurine (31) [77], a highly cytotoxic and vesicant substance first isolated from Cryptocarya pleurosperma [78]. These alkaloids are closely related structurally to the phenanthroindolizidines, a group of bases found in the families Asclepidaceae and Moraceae that are likewise vesicant. An example is tylocrebrine (56), which is elaborated by a Queensland plant from each family, Tylophora crebriflora [79] and Ficus septica [80], respectively. In the latter it occurs along with the seco analogue septicine (57), its presumed biosynthetic precursor. Apart from phenanthroindolizidines, certain Ficus spp. produce some simple pyrrolidine bases such as ficine (58) that are noteworthy because of their flavonoid substituents [81],... 

Hyoscyamine.—Hyoscyamine (103) is a member of a large family of alkaloids in which a pyrrolidine ring is derived from ornithine. The biosynthetic pathway to hyoscyamine shown in Scheme 22 is supported by a wealth of evidence from past work.68 It is noteworthy that the route from ornithine to (102) parallels exactly the corresponding sequence (path b, Scheme 16) by which lysine is converted to A -piperideine in the currently favoured route to sedamine. Further support69 for this sequence has come from the administration of ATa-methyl-ornithine (101) to Datura stramonium plants. The precursor was multiply labelled with 14C as indicated and the activity was incorporated specifically into the corresponding positions of the alkaloid, without change in isotopic ratio. In contrast, the JV -methyl isomer of ornithine was biologically inert. 

The Indole Family. Tryptophan is also the precursor of another large alkaloid family based on the indole system. Usually, indole is found fused to other rings, as in physostigmine (3.22). Here, a pyrrolidine ting is fused to the b-face of indole. This alkaloid occurs in calabar beans. It is a potent inhibitor of cholinesterase, and like other such chemicals, it causes contraction of the pupil of the eye. In harmine (3.23), a pyridine ring is fused to the b-face. 

Because they exhibit various fascinating biological activities [1], polyhydroxylated alkaloids that mimic sugar structure arouse a growing interest in the last few years. Naturally occurring iminosugars are classified in five structural families polyhydroxylated pyrrolidines, piperidines, indolizidines, nor-tropanes, and pyrrolizidines (fused pyrrolidines with N at the bridgehead) alkaloids [2]. The pyrrolizidine skeleton with a hydroxyl substituent at C-3 is relatively rare in Nature and appears to be restricted to specific families, while piperidine and pyrrolidine skeleton are conunon in many species. 

As these alkaloids are derived by a short biosynthetic sequence involving reactions that appear to be widespread in plants, it is not surprising that pyrrolidine alkaloids are commonly encountered. Many of the families in which pyrrolidine alkaloids are found are not particularly closely related. Monocotyledenous and dicotyledenous angiosperms and ferns are represented (Massiot and Delaude, 1986). In most cases, these alkaloids are found only sporadically among the various members of these families. 

An unusual type of pyrrolidine alkaloids involving flavo-noid structures (8-11) has been reported from the Combreta-ceae, Moraceae, Vochysiaceae, and Zosteraceae (Fig. 29.3) (Houghton, 1987 Leete, 198 Massiot and Delaude, 1986). Similar alkaloids are found in the Rubiaceae and Meliaceae (Houghton, 1987) none of these families are particularly related. The NMR spectra of these compounds have been reviewed (Houghton, 1987). 

The tropane alkaloids comprise a large well-defined structurally group of natural products, occurred mainly in family Solanaceae but also are found in the families Convolvulaceae, Erythroxylaceae, Proteaceae, Rhizophoraceae, etc. [1], Common structural element of these alkaloids is the tropane skeleton, crnisisting of a pyrrolidine and piperidine ring sharing the nitrogen atom and two carbon atoms. The systematic name of the tropane skeleton is 8-methyl-8-azabicyclo[3.2.1.]octane (Fig. 12.1). Currently, the number of these alkaloids is more than 200 [2-4]. 

Nicotine is also accumulated in considerable proportions in other Nicotiana species and in a few species of some other solanaceous genera, e.g., Duboisia (for details see below). Moreover, it was detected in extremely small amounts in species of several other genera of this family. Furthermore, it is also a common minor component in the Convolvulaceae beside pyrrolidine and tropane alkaloids (for details see below). 

Table 3.7 Occurrence of pyrrolidine, tobacco, and tropane alkaloids in both large Solanales families compared with the occurrence out of the Solanales. Data on tropanes based on Lounasmaa and Tamminen (1993), Griffin and Lin (2000) and references therein data concerning the Convolvulaceae based on the literature given in Table 3.2... 

---