Quinolizidine structure

The quinolizidine structure is sometimes found in molecules of complex alkaloids belonging to the indole, isoquinoline, or other families of alkaloids that... 

The 13C NMR spectrum of geissoschizine is given in [382]. (231) It has been known for some time that geissoschizine [382] possesses the 3absorption between 5 3-8 and 4-6). Confirmation of this is... 

Two lactonic arylquinolizidine alkaloids, vertaline (61) and decaline (62), which possess a diphenyl ether moiety have been synthesized (20-22). The former alkaloid has a m-quinolizidine ring, while the latter possesses a trans-quinolizidine structure. Unnatural 17-O-methyllythridine (63), a derivative of lythridine (64), was synthesized utilizing a new strategy for macrolide cycliza-tion (23). 

Corydaline, in contrast wdth mesocorydaline, shows Bohlmann bands in the region of 2800 cm i in its IR-spectrum. This w as interpreted to indicate a raws-quinolizidine structure for corydaline and a B C cis configuration for mesocorydaline. 

Lupanine is comparatively easily dehydrogenated with mercuric acetate 62, 69), a property not usual for cis-quinolizidine structures. The conformation, with ring C in boat form, appears to be the favored conformation equilibrium (5, 35, 70). 

The cascade sequence was also used to synthesize indolizidine, pyrrolizidine, and quinolizidine structures. Thus, heating oximes 52 at 180 °C in a sealed tube provided cycloadducts 53 or 54 in 60-76% yields (equation (1)) (89TL2289). Each of the products were isolated as single diastereomers. When five-membered rings were obtained from the cycloaddition, cis-anti isomers (i.e. 53a,b) were formed, whereas formation of a six-membered ring led only to the cis-syn isomer (i.e. 54a,b). 

When the unconjugated amino lactone 12a, previously obtained as a degradation product of securinine (Scheme 1), was heated under reduced pressure the isoquinuclidine 53 was obtained in low yield (Scheme 9) (29). This rearrangement appears not to have had any significance in the structural elucidation of securinine but it has intrinsic chemical interest and thus will be discussed separately here. The IR spectrum of 53 shows bands at 2821, 2721, and 2681 cm , representative of a m is-quinolizidine structure and at 1794, 1735, and 1644... 

The saturated system, i.e. quinolizidine (4), is far more important due to the bewildering profusion of quinolizidine alkaloids in nature it has been estimated that 25-30% of all known alkaloids belong to the quinolizidine-indolizidine group. Some examples of alkaloids containing the quinolizidine structure are given below in structures (5)-(10) the simple quinolizidine alkaloids lupinine (5) and nupharidine (6) the Lycopodium alkaloid lycopodine (7) with a hydrojulolidine... 

In contrast to the reductive cyclization, the indolo[2,3-a]quinolizidine structure can also be formed from 7V-)8-(3-indolyl)ethylpiperidine derivatives by oxidizing the piperidine moiety to an immonium ion followed by spontaneous cyclization. Unfortunately, chemical yields obtained from this oxidative cyclization tactic were extremely low in most cases <62JOC2283, 62JA4914). An alternative was to form the piperidine A-oxide and then to cyclize it into indolo[2,3-a]quinolizidine using trifluoroacetic anhydride <72CC930> or ferrous sulfate <72JOC1083>. 

These are also referred to as lupin alkaloids since they were first discovered in Lupinus spp. They occur primarily in the Papilionaceae family. The quinolizidine structure consists of two carbon rings with a shared nitrogen atom. Their precursor is lysine. 

While for developing of simple piperidine alkaloids, e.g., pelletierine (Punica granatum), piperine (Piper nigrum et longum), and lobeline (Lobelia inflata), only one molecule of lysine is necessary, for quinolizidine alkaloids - e.g., lupinine (Lupinus luteus), sparteine of antiarrhythmic activity (Sarothamnus scoparius), and cytisine of respiratory stimulant effect (Laburnum species) - two molecules of lysines are indispensable. It was also proved that lycopodine (Lycopodium tristachyum, clubmoss) of quinolizidine structure has no polyketide origin, but it is a modified dimer of pelletierine, which, in turn, is derivable from lysine and acetate. 

Some plants accumulate alkaloids with very different chemical structures which are nevertheless related biosynthetically. In some cases the biosynthetic route may be branched, but in some it is rather clear that the more complicated structures arise from the simpler molecules. The latter condition is encountered in lupines. While the majority of alkaloids are of a coupled quinolizidine structure, two uncommon alkaloids, lupinine and epilupinine, are of a simple quinolizidine structure. The idea that lupinine is a precursor of sparteine, i.e., a bisquinolizidine, was first proven by experiments in which radioactive lupinine was fed to the plants and radioactive sparteine and its derivatives were isolated (Schuette, 1960 Nowacki et al.y 1961). In this study, varieties of Lupinus luteus from Palestine, Portugal, and central Europe were tested. There were plants that produced only one major alkaloid, either sparteine or lupinine however, the hybrid plants which produced sparteine also produced a small amount of lupinine. Consequently, it was a typical example of intermediate inheritance. The F2... 

Researchers at GlaxoSmithKline have numerous recent patent applications describing several series of H3 antagonists including the benzazapines (41) [115] and (42) [116], quinolizidines (43) [117], isoindolines (44) [118], and the piperidine amides (45) [119] and (46) [120]. All of these structures were disclosed as functional H3 antagonists. 

Cytisine is a tricyclic quinolizidine alkaloid that binds with high affinity and specificity to nicotinic acetylcholine receptors. In principle, this compound can exist in several conformations, but semi-empirical calculations at the AM 1 and PM3 levels have shown that stmctures 19 and 20 are more stable than other possible conformers by more than 50 kcalmol-1. Both structures differ by 3.7 kcalmol 1 at the AMI level and 2.0 kcalmol 1 at the PM3 level, although this difference is much smaller when ab initio calculations are employed <2001PJC1483>. This conclusion is in agreement with infrared (IR) studies and with H NMR data obtained in CDCI3 solution, which are compatible with an exo-endo equilibrium < 1987JP21159>, although in the solid state cytisine has an exo NH proton (stmcture 19) (see Section 12.01.3.4.2). 

Structural characterization of many quinolizidine derivatives has been established by X-ray diffraction. For example, this technique, in combination with spectroscopic methods, showed that (+)-2-thionosparteine 21 and (+)-2,17-dithionospartine 22 are conformationally rigid and have their lactam and thiolactam groups close to planarity, with the exception of the lactam group in 21, and that rings A and C adopt distorted sofa conformations <2005JST75>. 

Nuclear Overhauser enhancement spectroscopy (NOESY) experiments play a very important role in structural studies in quinolizidine derivatives. For instance, the endo-type structure of compound 28 was proven by the steric proximity of the H-3a and H-12a protons according to the NOESY cross peak, while the spatial proximity of the H-6f3 and H-8/3 protons reveals that tha A/B ring junction has a /ra t-stereochemistry. Similarly, compound 28 could be distinguished from its regioisomer 29 on the basis of the NOESY behavior of its H-13 atom <1999JST153>. 

The combination of H NMR, 13C NMR data and H- H and H- C correlations has been widely employed for the structural assignment of quinolizidine natural products. One example is the alkaloid senepodine A 30,... 

Similar conformational equilibria occur in arenoquinolizidines (e.g., structures 43-45 for benzo[ ]quinolizidines and 46-48 for dibenzo[ g]quinolizidines). 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

In comparison with other spectroscopic methods, 13C-NMR spectroscopy affords the most valuable information for the stereochemical and conformational analysis of quinolizidine compounds. On the basis of the results, summarized in a review by Tourwe and van Binst (313) as well as in a series of publications (314-318), the steric structure elucidation of indolo[2,3-a]quinolizidine alkaloids has been facilitated. 

The common structural feature of quinolizidine alkaloids is a decalin ring system with a nitrogen at one vertex. Often a second or third nitrogen atom is... 

Kinghom, A.D. and Balandrin, M.F. (1984). Quinolizidine alkaloids of the Leguminosae Structural types, analysis, chemotaxonomy and biological activities, in Pelletier, S.W., Ed., Alkaloids chemical and biological perspectives, John Wiley and Sons, New York, pp. 105-148. 

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