Quinolizidine stereochemistry

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>. 

A similar procedure was applied to the synthesis of quinazolidine 189 from precursor 188 in the total synthesis of the natural product known as ( )-quinolizidine 2071 190, an alkaloid isolated from the skin of the Madagascar mantelline frog Mantella baroni, that shows an exceptional axial stereochemistry for the ethyl group at C-l. Quinolizidine 189 was transformed into 190 by oxidation and two consecutive Wittig methylenations (Scheme 34) <1999CC2281>. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

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 absolute configuration of 1 was established in 1967.4 Since then, l5 and 2a6 have been the subject of several syntheses. A challenge in both cases was the stereochemistry at the three stereogenic centers of the quinolizidine subunit. Tietze and co-workers have previously synthesized indole alkaloids of the corynanthe group,7 this problem is based on the recent enantioselective total synthesis of 1.2,8,12... 

Kametani and co-workers (43, 44) have used 13C NMR to study the effect of C-1 substituents on the stereochemistry of the quinolizidine system in this group of alkaloids. In O-methylcapaurine (73), which has a methoxy group at C-l, the quinolizidine system was considered to be in the cis form. This conclusion was based on the upheld shift of C-6. Comparison of 73 with 71 and 72 revealed some interesting differences. C-5, C-6, C-8, and C-l3 were all shielded in the cis form of the 13-methyltetrahydroprotoberberines relative to the trans form but only C-6 and C-l3 were affected in 73. Carbon-14 in 73 was shifted upheld relative to 72 in a manner analogous to that found for C-l in compound 72, and this steric shielding is probably greater than any chemical shift change associated with cis-trans interconversion. C-5 and C-8 of 73 did not show any upheld shift as they did in the 13-methyl compounds. These results indicated a difference in the cis conformation of the two types of compounds and it has been proposed that this was caused by different cis-trans equilibrium. constants (28, 48). 

The stereochemistry at C-5 is also reflected by relative rates of quarterniza-tion. The cis-fused bases react much faster than the trans stereomers. Inspection of models shows that the /ra/u-quinolizidine has four axial hydrogens blocking axial attack of the alkylating agent whereas the cis-quinolizidine shows only two 1,3-diaxial interactions (24, 37, 38). 

An X-ray study of vertaline hydrobromide established the structure and absolute stereochemistry of vertaline as shown in 51 (32, 43). The relative stereochemistry at C-l and C-3 in all alkaloids in the group is the same as in the biphenyl alkaloids for example, the biphenyl ether and lactone group are linked to the quinolizidine ring in axial and equatorial configurations, respectively. 

Demethoxyabresoline (67) was obtained as a noncrystalline solid. Spectroscopic investigation revealed the presence of a phenolic OH, a 1-phenyl-quinolizidine system, and a trans-cinnamyl group. The stereochemistry at C-l, C-3, and C-5 was the same as in abresoline. The molecular formula C25H29N05 was established by mass spectrometry. The presence of fragment ions at m/e 259 (M —164) and 258 was characteristic of p-hydroxy-cinnamyl esters of the phenylquinolizidol (63a). The assigned structure 68 was confirmed by basic hydrolysis to 63a and p-hydroxycinnamic acid as well as by catalytic hydrogenation to a known dihydro derivative (52). 

Analysis of all the above results led to only two possible structures, A and B, for lythrancines I-IV and lythrancepines I—III. Structure A is preferred because the molecular models show large interactions between the 10-methylene group and the aromatic hydrogen atoms in B and the 13-membered ring is highly strained. X-ray crystallographic studies of lythrancine 101 O-brosylate confirmed stereochemistry A. Thus, the absolute stereochemistry of seven quinolizidine alkaloids was established as 100-103 and 107-109 (104). 

Treatment of 17 with a Cd-Pb complex[l 1] in aqueous THF furnished the quinolizidine 18 in 92% yield as the only cyclized product. Stereochemistry of this quinolizidine was assigned by the NOE between Ha and Hb, in addition to the coupling constant of Hc. Finally, this assignment was confirmed by X-ray diffraction analysis. 

The 5,8-disubstituted indolizidines and 1,4-disubstituted quinolizidines are the more common structural patterns found in amphibian skin[21]. None of these alkaloids has so far been reported from any other source. In addition, the biological activity of only a few 5,8-disubstituted indolizidines has been investigated due to the isolation in minute quantities from the skin. Among them, the relative stereochemistry of quinolizidine 2071 was anticipated to be 75 by our chiral synthesis of 76[35] followed by stereocontrolled synthesis of 75[36]. A sample of synthetic racemate of 75 had produced the best separations on GC analysis with (3-dextrin chiral column[36]. 

We planned the enantioselective synthesis of 75 to determine the absolute stereochemistry of natural quinolizidine 2071. 

These changes of stereochemistry in C1S Nuphar methiodides are detectable in their l3C-NMR spectra when the fra/w-quinolizidine system is retained, para-... 

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. ... 

C-6 and one of the protons on C-17 and, on the other, creation of an H-H 1,3-diaxial interaction between protons on C-8 or C-8 and one of the protons on C-17. A new 8-syn-diaxial interaction between C-6 and C-8 (A B trans and A B cis) or between C-6 and C-8 (AB trans) was observed. As a stereochemical consequence of this interaction, the distance between the two quinolizidine rings decreases. The tetrahydrothiophene ring adopts a conformation between an envelope and a half-chair. Such stereochemistry in thiobinupharidine methiodide (34) was confirmed by X-ray single-crystal measurements (46). 

Protonation of compounds 16, 17, and 18 does not bring about any changes in the stereochemistry of their quinolizidine rings (40). 

The quatemization of nitrogen and/or sulfur seems to be more dependent on steric hindrance and stereochemistry around the sulfur atom different products are obtained in the series of alkaloids with equatorial sulfur as compared with those in which sulfur is axial. Thiobinupharidine (16) (sulfur equatorial) can be easily quatemized on nitrogen, resulting in only isomeric mono- or dimethiodides (57). In this reaction, partial trans-cis transformation of the quinolizidine ring was observed. This isomerization seems to be influenced by the presence of sulfur and does not follow the pattern observed for the C,5 Nuphar alkaloids (41) where direct dependence on the configuration of C-7 is controlling. No methyla-... 

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 diagnostic carbon for determination of the stereochemistry of methio-dides containing a double bond in the N-substituted quinolizidine ring is C-6, which is situated a to the quaternary nitrogen and a to the double bond. This... 

The stereochemistry of neothiobinupharidine S-oxides 72 and 73 and of thiobinupharidine S-oxides 23 and 74 was determined on the basis of the chemical shift values of C-6 and C-8 in the AB quinolizidine ring (35, 50). It was found that for one of the S-oxides of neothiobinupharidine and thiobinupharidine the difference in chemical shift values for C-6 is much larger relative to the sulfide than for the other S-oxide of neothiobinupharidine and thiobinupharidine. The... 

This is in fact a quinolizidine system, the stereochemistry of which has been reviewed by Bohlmann (42). The configuration of C-3 must be considered in its relation to that of Nb where the bond C-3 to Nb is defined as either cis or trans with reference to the bond C-3 to H and the free electronic doublet of Nb. 

Advances in the Study of the Stereochemistry of Quinolizidines, Indolizidines and Pyr-rolizidines I. M. Skvortsov, Russ. Chem. Rev. (Engl. Transl), 1949, 48, 262-281. 

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