Quinolizidine, quaternization

With starting materials containing a bridgehead-nitrogen, e.g. quinolizidine 11, a third quaternization/elimination sequence is necessary for complete elimination of the nitrogen as final product a triene is then obtained ... 

The nitrogen atom in quinolizidine derivatives behaves as a tertiary amine and hence it can undergo quaternization by reaction with alkyl halides. For instance, berberine derivative 101 was transformed into 102 by treatment with 3-iodopropanol followed by anion exchange. Compound 102 was then transformed into intermediate 103, which was employed as a precursor for the the preparation of bis-ammonium salt 104 (Scheme 10). This compound showed ultrashort curare-like activity in rhesus monkeys <2001JOC3495>. 

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 quaternization of simple quinolizidine and related alkaloids has attracted much attention, directed primarily at the stereochemistry of the reaction. Methylation of trans-quinolizidine (545) affords the ra-fused 5-methylquinolizidinium salt (546) its isomer (548) is available only by the cyclization of piperidine derivative (547) (51JA3681). 

The quinolizidine system in monomeric C15 alkaloids in some cases is susceptible to inversion of the ring junction, which is accompanied by inversion of the relative configuration of C-7. Protonation of the nitrogen atom, quaternization, or V-oxide formation are the conditions which cause such transformations. 

In analogy to the transformations observed for other compounds, a similar process was proposed for the interconversion of thiaspirane sulfoxides and to explain the dependence of the thermolytic process on sulfoxide stereochemistry. Scheme 1 shows the probable mechanism of the transformation. Stereochemical transformations of the C30 Nuphar thiaspiranes have been observed on quarter-nization of thiobinupharidine (16) (equatorial sulfur atom). The quaternized quinolizidine system is transformed from the trans to the cis form with inversion of the relative configuration of the corresponding C-7 or C-7. ... 

Different changes are observed when quaternization causes inversion of the quinolizidine ring from trans to cis, as is observed in the case of nupharidine (which is an N-oxide) (32) and deoxynupharidine methiodide (71) (41, 69). In such cases the tertiary carbon atoms in the 3 position (C-4, C-10) with respect to the new N+—O" or N+—C bonds exhibit a paramagnetic shift, and the secondary carbon atom (C-6) exhibits a diamagnetic shift in comparison with similar carbon atoms in the free base. 

The change of conformation of the N-substituted quinolizidine ring from trans to cis (as a result of quaternization of nitrogen) causes a change of stereochemistry of C-7 or C-7. In consequence, C-17 changes from a diaxial relationship in thiobinupharidine (16) to an axial-equatorial one or, in the case of cis-AB, cis-A B thiobinupharidine dimethiodide (41), to an equatorial-equatorial relationship. This causes a signal shift for C-17 downfield by 5 and 10 ppm, respectively (43). 

The quaternization of simple quinolizidines and related alkaloids has attracted much attention, directed primarily at the stereochemistry of the reaction. Methylation of rro/u-quinolizidine affords... 

Quaternization of the nitrogen atom is the first step of the classical Hofmann degradation of quinolizidines, a reaction that is still widely practised <82JOC5i4l, 82AP(315)273, 84TL5169>. As an example, the degradation of deoxynupharidine methiodide (140) and its 7-epi derivative (141) <83H(20)1773,84JST(ll6)l> is summarized in Scheme 19. 

The detection of the conformation of the quinolizidine system of the tetrahydroprotoberberines has been approached from several angles including IR Bohlmann bands, rates of quaternization, circular dichroism, PMR... 

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