Tricyclic Quinolizidine Alkaloids

The minor components (+)-kuraramine and isokuraramine were isolated from Sophora franchetiana (118,119), S. tomentosa (21), S. flavesens (22,120), S. mollis (121) along with the well-known alkaloid ( )-ammodendrine (74). 

A-Formylcytisine (81) and A-acetylcytisine (78) were isolated from the plants of Sophora 21,118,119,121,122) and Thermopsis 123), and A-ethylcytisine (82) and A-(3-oxobutyl)cytisine (83) from plants of Echinosophora koreensis 

Nakai 124-126). UV and IR spectra of 78 and 81-83 are characteristic of lupinine alkaloids of the cytisine series containing an a-pyridine ring. MS fragmentation patterns are similar to those of cytisine alkaloids. The structures of these alkaloids were confirmed by synthesis from cytisine by reaction with HCOOH (81), (CHjCO) (78), C2H5Br (82), or CH2=CH—COCH3 (83). 

The alkaloid isolated from Thermopsis alterniflora Bge. described as al-teramine (132,133), is, in our opinion, identical with tinctorine. 

Tsukushinamines A, B, and C, isolated from Sophora franchetiana (66,118,119), are considered to be isomeric compounds. Tsukushinamines A (21) and B (104) are epimers at C-14, and tsukushinamine C (105) differs from them in the position of the double bond and affords 21 on heating to 200°C in a 

---

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). 

The new alkaloid LC-2 was isolated fiom Lupinus cosentinii (87). It is considered to be a multiflorine derivative, probably an intermediate product in the biosynthesis of the latter alkaloid and occurring in plants together. There are absorption bands at 1580-1625 (——CH=CH—CO— ), 920, and 990 cm (—CH=CH2) in the IR spectrum of this alkaloid. In the H-NMR spectrum there are proton signals presented as doublets at 8 4.92 and 6.86, as in multiflorine (85). Alkaloid LC-2 is converted to desoxyhexahydrorhombifoline (86) by reduction with zinc in 2 N HCl (Scheme 4). Alkaloid LC-2 appears to be a tricyclic quinolizidine alkaloid, and its structure is given by formula 87. 

There has been considerable interest recently in tricyclic quinolizidine alkaloids containing side-chains, for example angustifoline (1). The conformations of angustifoline and of its dihydro- and desoxy-derivatives have been studied by i.r. and n.m.r. spectroscopy and by X-ray analysis,18 and rearrange-18 M. D. Bratek-Wiewiorowska, J. Mol. Struct., 1979, 55, 69. 

C14H22N2O, Mr 234.34, mp. 80.5-81 °C, [oId -7.5° (+5.2°) (C2H5OH). A tricyclic quinolizidine alkaloid of the sparteine type from 4 genera of the Fabaceae Cytisus, Diplotropis, Lupinus, Ormosia). A. exists as 2 optically active isomers The biosynthesis of A. in plants is assumed to involve ring opening and side chain degradation of lupanine as a precursor Ut. Waterman 8, 197-239. Planta Med. 59, 289 (1993). Pelletier 2, 105-148. 

Trichocarpine, 56-57 Tricyclic alkaloids, 129 Tricyclic cytisine, 143 Tricyclic gephyrotoxins, 71 Tricyclic quinolizidine alkaloids,... 

These tetracyclic and tricyclic quinolizidine alkaloids are commonly known as lupine alkaloids. The simple bicyclic alkaloids such as lupinine are produced from two lysine units via cadaverine. Tricyclic alkaloids such as cytisine are considered to be formed from tetracyclic alkaloids through anagyrine-type alkaloids (Fig. 5.2.7). 

Molecular mechanics (MM) calculations have been employed for determining dihedral angles and to establish a comparison with values calculated from coupling constants, during conformational studies of tricyclic and tetracyclic quinolizidine alkaloids. The MM results had to be treated with care, as they sometimes predicted ring conformations different to those supported by experimental data <1999JST215>. 

This group of alkaloids has a pyridone nucleus and generally takes the tetracyclic or tricyclic form. The a for pyridone alkaloids is L-lysine, while the j8, q> and X the same as for other quinolizidine alkaloids. Quinolizidine alkaloids containing the pyridone nucleus are the P from the (—/-sparteine by cleavage of the C4 unit. The first quinolizidine alkaloid with the pyridone nucleus is tricyclic cytisine, which converts to four cyclic alkaloids. In this synthesis the anagyrine, the most poisonous quinolizidine alkaloid with a pyridone nucleus, has its own synthesis pathway. 

Although the detection and isolation of bicyclic, tricyclic, and tetracyclic quinolizidine alkaloids and stereochemical studies, increasingly aided by X-ray analysis, proceeds apace, the main emphasis this year is on synthesis of the Nuphar, azaphenalene, and phenanthroquinolizidine alkaloids. 

For the above mentioned tricyclic quinolizidines, a comparison of the HCCH dihedral angles determined by H NMR J analysis and those predicted by molecular modelling or established by X-ray structures, when available, was also performed, which corroborates the previous stereochemical analysis [200]. The reason indicated for the similarity of conformations of these alkaloids in the solid state and in solution is the partial flattening of ring B, caused by the presence of a flat system in ring A, that diminishes the steric hindrance of ring C in an all chair conformation. 

Porantherilidine (415), the only bicyclic member of a group of quinolizidine alkaloids from the Australian shrub Poranthera corymbosa, was described in the previous chapter on simple indolizidine and quinolizidine alkaloids in Volume 28 of this series (/). The related tricyclic alkaloid porantheiidine (416) is included here as an obvious carbinolamine derivative of the simple bicyclic system. 

C. Tricyclic and Tetracyclic Alkaloids.—The chemical ionisation (C.I.) mass spectra of several quinolizidine alkaloids in the presence of methane as reactant gas have been studied the alkaloids concerned include a-isosparteine, lupanine,... 

Quinohzidine alkaloids, hypothetically derived from quinolizidine (10-18), are a special group of bicyclic, tricyclic and tetracyclic secondary metabolites of some legumes, especially legumes of the genera Lupinus, Baptisia, Thermopsis, Genista, Cytisus, Chamae-cytisus. Laburnum and Sophora (Fabaceae), which occur as a complex mixture of several compounds. Quinolizidine alkaloids are... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

The utility of the [2 + 2]-photocydoaddition to 4-aza-2-cyclohexenones has been explored by Comins et at. in synthetic approaches to different alkaloids [71, 72]. As originally reported by Neier et al. the corresponding acyl- and alkoxycarbonyl-substituted 2,3-dihydropyridin-4(lH)-ones are particularly useful substrates [73], In a recent study, the intramolecular reaction of dihydropyridone 61 was found to lead to the tricyclic product 62, which was further converted into the quinolizidine 63... 

Thiazolidines. formation, 168-169 Tricyclic alkaloids, 242-251 coccinellines, 245, 246-247 cyclopenta[b]quinolizidines. 247-249 gephyrotoxins, 242-245 pynolizidine oximes, 249-251 Trypargine, 262-263... 

The most common group of alkaloids possessing a quinolizidine nucleus is that of the lupine alkaloids which can simply be classified as bicyclic (lupinine/epilupinine type), tricyclic (cytisine type) or tetracyclic, (sparteine/lupanine or matrine type). Fig. (23). This grouping is made according to structure complexity and without considering biosynthesis, as the detailed biosynthetic pathways are still not completely understood. 

Simple bicyclic compounds form a rather small subset of the lupine (or lupin) alkaloids, the overwhelming majority of which have tricyclic or tetracyclic structures based on the quinolizidine motif. These alkaloids are characteristic metabolites of the Papilionoideae, a sub-family of the Leguminosae (Fabaceae), although representative examples have also been isolated from several other plant families. The simple lupine quinolizidines were surveyed in Volume 28 of this treatise (7), while later reviews in Volumes 31 (5) and 47 (9) comprehensively covered all classes of lupine alkaloids, including those containing indolizidine components. Much relevant material is also to be found in the review on the biosynthesis of pyrrolizidine and... 

---