Simple Pyrrolidine Alkaloids

Simple Pyrrolidine Alkaloids.—It is well established that ornithine (1) is a key precursor in the biosynthesis of pyrrolidine alkaloids. Notably, the amino-acid (1) is utilized for the biosynthesis of nicotine (5) via the symmetrical intermediate putrescine (3), whereas the biosynthesis of tropane alkaloids, e.g. scopolamine (6), avoids any symmetrical intermediate1,2 (cf. Vol. 11. p. 1). 

The first intermediate beyond ornithine in the biosynthesis of tropane alkaloids has been deduced to be (S-A-methylornithine (2). Recently, (2) was identified as a natural constituent for the first time in a plant, namely Atropa belladonna, which produces tropane bases.5 The (2) was labelled by radioactive ornithine (1), but, unfortunately, the alkaloids were not, so correlation between the formation of (2) and the biosynthesis of alkaloids has not yet been achieved. 

The biosynthetic pathway to both nicotine (5) and the tropane alkaloids includes A-methylputrescine (4) as a probable intermediate. New results6 obtained for nicotine (5) and scopolamine (6) with 1 l-13C,14C wef/zy/awmo-15Nl-A-methyl putrescine 1(4) labels as shown nicely confirm this. The specific incorporation of both stable isotopes was closely similar to that of the 14C label in both alkaloids, indicating intact incorporation of the precursor. The labelling patterns deduced are illustrated ( = 13C, = 15N), and they are in accord with earlier results that were 

3 The Biosynthesis of Mycotoxins , ed. P. S. Steyn, Academic Press, New York, 1980. 

Herbert, The Biosynthesis of Secondary Metabolites, Chapman and Hall, London, 1981. 

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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). 

Quantitative information concerning simple pyrrolidine alkaloids is rather rare. The roots of Nicandra physalodes contained 0.1% hygrine whereas five Physalis spp. contained considerably less (Romeike 1965a,b). The content of the epigeal parts of N. physalodes was even extremely low. Surprisingly, cuscohygrine turned out to be the main alkaloid of Datura discolor roots with a concentration of 0.06% which amounts to 20% of the total alkaloid content (0.31%). This is in contrast with other Datura spp. where tropanes (hyoscyamine/scopolamine) represent the principal alkaloids (Evans and Somanabandhu 1974a). 

The most recent example of pyrrolidine synthesis by C-H functionalization was illustrated in 2014, when Che and coworkers demonstrated the synthesis of pseu-doheliotridane, a simple pyrrolidine alkaloid, by employing a ruthenium-catalyzed C-H insertion reaction (Scheme 16.44) [89]. Although diazocarbonyl compounds are generally required as the precursor of the metal carbenoid intermediate, they utilized an alkyl diazomethane as the carbene source. To this end, tosylhydrazone 192 was reacted with [Ru(TTP)(CO)] (TTP tetra(p-tolyl)porphyrin) (1 mol%) and KjCOj, which generated ruthenium carbene 193 in situ, followed by C-H insertion to produce pseudohehotridane in 95% yield with high diastereoselectivity. 

Besides piperidine alkaloids, a total of 19 pyrrolidines have been found in the secretions of thief ants and fire ants of the genera Solenopsis and Monomorium. Among these, compounds 80-84 are simple pyrrolidines with two saturated linear all-carbon side chains only in Solenopsis latinode is there a secondary amine (82) and its methylated analog (85). One or two terminal unsaturations are present in compounds 86-91, which all possess a (hex-l-en)-6-yl chain and a 5-, 7-, or 9-carbon saturated chain. Compounds 93, 94, 96, 97, and 98 are the A-l-pyrrolines corresponding to pyrrolidines 80, 82, 90 (93 and 96 corresponding to 80, 94 to 82, and 97 and 98 to 90). 

Pyrrolidine is the simple five-membered cyclic amine and pyrrolidine alkaloids contain this ring somewhere in their structure. Both nicotine and atropine contain a pyrrolidine ring as do hygrine and tropinone. All are made in nature from ornithine. Ornithine is an amino acid not usually found in proteins but most organisms use it, often in the excretion of toxic substances. If birds are fed benzoic acid (PI1CO2H) they excrete dibenzoyl ornithine. When dead animals decay, the decarboxylation of ornithine leads to putrescine which, as its name suggest, smells revolting. It is the smell of death . 

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],... 

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). 

Pyrrolidine alkaloids a group of Alkaloids (see) with simple structmes. P.a. are either derivatives of proline (e.g. stachydrin and its diastereoisomer, beto-nicin), or they are derived from a Af-methyl-2-alkyl-pyrrolidine (e.g. hygrin and cuskhydrin). The latter occur together with the tropane alkaloid with which they share the same biogenetic precursors, ornithine and acetate. 

The term simple pyrrolidines is chosen here for those alkaloids whose structure is characterized by one or two isolated pyrrolidine rings without any other heterocycUc moiety. This restriction separates them from the biogenetically closely related nicotinoids and tropanes, respectively. Shortly after the discovery of the famous tropane alkaloid cocaine (Niemann 1860) a second alkaloid, hygrine , was discovered in the leaves of Erythroxylum coca Lam., Erythroxylaceae (Wohler and... 

The method of Bella is a supreme example of how the organocatalytic asymmetric Mannich reaction can facilitate the synthesis of simple pyrrolidine or piperidine alkaloids starting from achiral starting materials. Therefore, in the snbsequent paragraphs, we wish to review recent efforts made by various research groups to implement an organocatalytic asymmetric Mannich reaction as key step in the total synthesis of alkaloids, predominately derived from L-Om and n-Lys. 

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