Pyrrolidine alkaloids with

The Pearson syntheses of (—)-augustamine and (—)-amabiline by a common strategy are very noteworthy. They brilliantly show how the awesome power of intramolecular 2-azaallyl anion-olefin cycloadditions can be marshalled for the rapid assembly of complex pyrrolidine alkaloids with excellent efficiency and atom economy. 

Natural Products. Four new broussonetines, M, O, P and Q (106-109), pyrrolidine alkaloids with p-glycosidase inhibitory properties, have been isolated from branches of Broussoneta kazinokiP... 

Scalusamides A-C, isolated from the culture of Penicil-lium citrinum taken from the parrotfish Scalus ovifrons, are new pyrrolidine alkaloids with antifungal and antibacterial properties (Tsuda et al, 2005). 

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 . 

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. 

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. 

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... 

Numerous UCNMR investigations on alkaloids have been reported in the literature [598, 599]. In Table 5.13 the 13C chemical shifts and structures of representative alkaloids of different types are collected Pyrrolidine, piperidine and pyridine [600-602], tropane [600, 603-605], izidine [606-612], indole [600, 603, 613-633], isoquinoline [599, 630, 634-647], quinolinic [648-656], imidazole [657], yuzurimine alkaloids [658], alkaloids with exocyclic nitrogen [659, 660], diterpenoid [661-663], steroid [664-666] and peptide alkaloids [667-671], The complete signal assignment for the alkaloids given in Table 5.13 was achieved using the correlations between 13C NMR spectral parameters and structural properties and the 13C chemical shift values of model compounds described in Chapters 3 and 4 of this monograph. 

Alkaloids with Condensed Pyrrolidine and Piperidine Rings... 

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

Pyridoxal-media ted decarboxylation of dopa gives dopamine and this reacts with the keto-acid to form an imine salt. This is an open-chain inline salt unlike the cyclic ones we saw in the pyrrolidine alkaloids, but it will prove to have similar reactivity. 

The imine salt is perfectly placed for an intramolecular electrophilic aromatic substitution by the electron-rich dihydroxyphenyl ring. This closes the isoquinoline ring in a Mannich-like process (Chapter 27) with the phenol replacing the enol in the pyrrolidine alkaloid biosynthesis. 

Heteroatom-assisted metaUation reactions are very common and especially useful for the selective o-functionalisation of aromatic compounds. More recently, activation of non-aromatic substrates has attracted attention but only a few examples pertinent to protecting groups will be cited here. Kerrick and Beak90 [Scheme 1.53] showed that pyrrolidine protected with a /erf-butoxycarbonyl (Boc) group 53.1 is enantioselectively deprotonated by rcc-BuLi activated by the alkaloid (-)-Sparteine (533).91 Enantioselective deprotonations mediated by (-)-Sparteine were first exploited by Hoppe and co-workers for the retaliation of saturated92 and allylic9394 carbamates. 

Cuscohygrine, l,3-bis(l-methyl-2-pyrrolidinyl)propan-2-one, one of the best known pyrrolidine alkaloids found in Erythroxylon coca, was synthesized by condensation of acetonedicarboxylic acid with two molecules of jV-methyl-2-hydroxypyrrolidine.163 Arcamore et al.l6i have obtained an antibiotic substance called distamycin A (131) from... 

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 piperidine alkaloids were mentioned in the chapter (p. 1418) where the pathway was described as similar to that of the pyrrolidine alkaloids . We can follow the same reactions starting from lysine instead of ornithine. The first stage produces the cyclic iminium salt fi om lysine by decarboxylation with pyridoxal. 

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