Quinolizidines, trans

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>. 

The Hg(ll) cation was used to activate the double bond in lactam 178, which was obtained by detosylation of 177 using the Parsons method. This strategy allowed the synthesis of quinolizidine derivative 179, which was obtained as a single /raar-diastereoisomer (Scheme 31). Besides its higher thermodynamic stability with respect to that of the m-isomer, formation of the trans-isomer must involve a lower activation energy since its intermediate precursor, in which the lone pair of electrons of nitrogen must attack from the back side of the mercuronium ion, is sterically less hindered than the precursor of the m-isomer <2003TL4653>. 

A functionalized piperidine system 204, on deprotection of the BOC group followed by treatment of the resulting amine with Me3Al, afforded a 4 1 mixture of trans- and cis- 4,6-disubstituted quinolizidines 205 and 206 (Scheme 39) <1999T15209>. 

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. 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

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). 

The bisquinolizidine alkaloid petrosine, C30H50N2O2, was isolated from Pe-trosia seriata 112). IR absorption bands occur at 1712 (—CO—), 2770, and 2810 cm (trans-quinolizidine) protons of a secondary methyl group are at 8 0.94 J = 6.4 Hz) in the H-NMR spectrum. Examination of C-NMR and H-NMR spectra as well as X-ray structural analysis revealed the presence of two quinolizidine fragments in the petrosine molecule (65). They are joined by pen-... 

Albertidine, isolated from Leontice Albertii Rgl. (196,197), is a crystalline, optically active tribase. There are IR absorption bands for a trani-quinolizidine system at 2750 and 2793 cm and a six-membered lactam carbonyl at 1640 cm The absorption in the fingerprint region is similar to that of matrine. The mass spectrum of albertidine is characterized by ion peaks at miz 247 (M -1), 219, 205, 192, 177, 150, 137, 98, and 96 which are typical for matrine alkaloids (209). On the basis of spectroscopic data and taking into account the tranj-quinolizidine band in the IR spectrum, the probable structure 182, with rings A/B-trans, was proposed. 

Albertamine, (-)-leontalbamine, and (+)-leontismidine were isolated from Leontice albertii and L. Smirnovii (228,229). They have the same composition, C,5H24N202. The IR spectra of these alkaloids are characterized by the absorption bands giving evidence for the presence of hydroxyl and amide carbonyl groups. There is also absorption (except in the albertamine spectrum) in the region of 2700-2800 cm attributed to trans-quinolizidine systems. The UV spectra show absorption maxima at 220 nm. 

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... 

This effect is also shown by comparison of the coupling constants in the perhydropyrido[l,2-c]pyrimidines 35 and 36,65 trans-fused dibenzo-[a,/]quinolizidine (29) (J6ai,6eq — 12.7 Hz),51 and quinolizidine (Jgem — 11.3 Hz).66 The similar coupling constants of the C-l and C-3 methylenes in the... 

The nature of the ring fusion in quinolizidine derivatives may be determined from the 15N chemical shifts, which are to lower field in the transfused derivatives. This is shown for the indolo[a]quinolizidines 73 and 74 (chemical shifts to low field of external anhydrous liquid ammonia)115 and by the perhydropyrido[l,2-c][l,3]thiazines 8 66.9 trans conformer 312, 8 43.9 S-inside cis conformer 313.ll5a... 

A study of isomeric monomethylquinolizidines revealed an apparent exception to the Bohlmann-bands criterion.133 1348 All the compounds adopted trans-fused conformations and all except the trans- 4-H,lO-H)-4-methyl derivative 86 showed pronounced Bohlmann bands in their IR spectra. The 4-methyl derivative 86 gave rise to only one Bohlmann band at 2805 cm"1. Thus the Bohlmann criterion should be applied to 4-substituted quinolizidines with care. 

A value of AG° for the quinolizidine equilibrium was obtained by IR spectroscopic techniques. Dilute solution measurements (0.006 M CC14) in 10-cm cells on trans-(l-H,9a-H)-l-hydroxyquinolizidine (99 100 101) showed a small band at 3250 cm-1 corresponding to the H-bonded ds-fused con-former 101. The epimeric cis-(l-H,9a-H) compound was taken as a 100% H-bonded model, and the concentration of the cis-fused conformer 101 was then deduced. A correction must be made for the presence of 100, which was estimated by studies on the conformational equilibrium in l-methyl-3-... 

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... 

All the monomethyl- and monohydroxyquinolizidines exist predominantly in the trans-fused conformation and the early IR and H-NMR studies on which these assignments were based (cf. especially Ref. 134) have been reviewed.14 The predominance of the trans-fused conformation for many quinolizidine derivatives has also been demonstrated by 13C-NMR spectroscopy.79,86 The trans-fused conformation for 182, the only transfused monomethylquinolizidine to show anomalous Bohlmann IR absorption (Section II,E,1), has been confirmed by 13C-NMR spectroscopy.214... 

These results show AG° (trans cis) for the benzo[a]quinolizidine to be less than that (2.6 kcal mol 2) for the quinolizidine equilibrium. 

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