Quinolizidines, conformations

An attempt was made to extend this result to an estimation of K for the quinolizidine equilibrium. For the 2-methyl compound 116 discussed above, there is a difference of one gauche-butane (gb) interaction between the cis- and trans-fused conformers 116 and 117 compared with a difference of three such interactions between the quinolizidine conformers 118 and 119. This gives AG° at 25°C for quinolizidine as 2.8 + 2gb = 2.8 + 1.6 = 4.4 kcal mol-This value is uncertain because even groups remote from... 

The tetrahydroprotoberberine alkaloids have a tetracyclic ring structure which is based on the dibenzo[a,g]quinolizidine system (Fig. 12). Carbon-13 NMR has been used extensively to study the quinolizidine conformation... 

The 13C spectrum of emetine (112) (Fig. 23 and Table XXII) was examined by Wenkert and co-workers (69). The chemical shift assignments were made by comparison with the shifts recorded for the simple isoquinolines and pro-toberberine alkaloids such as tetrahydropalmatine (69) (6, 14), and with indolic analogues of emetine (69). The shifts of C-4 and C-6 are characteristic of a trans-quinolizidine conformation for this ring system by analogy... 

A second group of workers has concurred that the preferred conformation of geissoschizine (106) in solution is one in which the C/D ring junction is cis and the substituent at C-15 is axially disposed to a boat-shaped ring D in contrast, geissoschizine adopts a trans C/D quinolizidine conformation in the crystal. 

Conformational effects appear to be important in determining which tertiary a-hydrogen is removed. For example, 4-phenyl-, 4-p-nitrophenyl-, and 4-/)-methoxyphenylquinolizidine (83) all are oxidized to the corresponding /j < -iminium salts (84) and not to the conjugated zJ -iminium salts (85) (86). The authors Judged that steric hindrance was responsible or that the conformation of the 4-sabstituted quinolizidines did not contain ideal... 

Conformational study of geissoschizine isomers and their model compounds (geissoschizine is the indolo[2,3-fl]quinolizidine derivative considered to be an important participant of indole alkaloids biogenesis) 99H(51)649. 

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>. 

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>. 

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

Substituents may play a crucial role in the conformation of quinolizidine systems. Thus, compound 49 shows a trans-conformation 50 with all three hydroxyl groups in equatorial positions. For its diastereomer 51, a -conformation 52 was initially proposed, but the H NMR data point at the /raor-conformation 53, with axial orientation of the hydroxy substituents and presumably stabilized by an intramolecular hydrogen bond <2004T3009>. 

Antirhine (11) was isolated first from Antirhea putaminosa (F. Muell.) Bail, in 1967 (79). Final determination of the stereostructure of antirhine, including conformational analysis, has been reported by Bisset and Phillipson (20). They established that the thermodynamically more stable conformer possesses a cis-quinolizidine ring junction as shown in formula 11 however, some of the conformer with a trans junction (11") is also present. 

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 X-ray data available suggest that some alkaloids have a different conformation in solution than in crystal form (41). The presence of a nitrogen atom, capable of inversion, ensures certain conformational mobility of quinolizidine molecules, and the reaction conditions should be considered in establishing their... 

Among quinolizidine alkaloids, sparteine and its stereoisomers have been studied in detail by X-ray analysis (42-50). It was demonstrated that proper conformation was not reorganized in monohydrates (42), diperchlorates (43), or methyliodides of a-isosparteine (11) (53). Unlike in the case of a-isosparteine, in spareteine diperchlorate rings C/D appear to have a boat-chair conformation (44-46). On the basis of spectroscopy data a cis conformation for sparteine methyliodide (12) was proposed (57,52). However, radiographic examination (53) of this compound showed it to have the trans conformation (13). 

Emphasis is placed on simply substituted free bases. The problems of conformational equilibria in /V-alkylpiperidinium salts and N-quaternization reactions and the relationships of these to conformational equilibria in the free bases are not covered, since this area is a large one requiring separate treatment. In other relevant previous reviews, the topics include heterocyclic conformational analysis,3-7 interactions in azacyclic systems,8 the conformational analysis of piperidine,9 hexahydropyrimidines,10,11 hexahydropyri-dazines,12 quinolizidines,13 the conformational analysis of bi- and polycyclic... 

The Aae criterion was applied to the problem of the piperidine equilibrium (10 11) by examining the H-NMR spectrum of the deutero derivatives 12, 13, and 14 at — 85°C when ring inversion is slow on the NMR time scale.37 The Aae values are recorded in Table I. The preferred conformation for the N-substituted piperidines 13 and 14 was assigned as lone-pair axial because for these compounds Aae values were similar to those in quinolizidine. However, in piperidine (12), where the Aae value is similar to that in cyclohexane, the lone pair was assumed to occupy the equatorial position in the preferred conformation. In support of this contention, protonation of... 

Although the magnitudes of Aae for the C-8 methylene protons in dibenzo-[a,g]quinolizidines differ from those in quinolizidines, use may be made of Aae in conformational assignments.48 For example, in tetrahydropalmatine (trans-fused) (24) Aae is 0.70 ppm, whereas in O-methylcapaurine (cis-fused) (25) Aae is 0.38 ppm. 

The chemical shift of the angular proton in benzo[c]quinolizidines will differ from that in quinolizidine itself as a result of delocalization of the lone pair electrons over the aromatic ring in certain conformations. Examples are provided by 29 and 30. In trans-fused 29, the nitrogen lone pair is delocalized over the aromatic ring and thus the anti-coplanar shielding mechanism is lost and the angular proton absorbs to low field of that in the cis conformation 30.51... 

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