Hydroxylated quinolizidines

In the laboratory of F.G. West, the stereoselective silyl-directed [1,2]-Stevens rearrangement of ammonium ylides was investigated as a potential key step toward the enantioselective synthesis of various hydroxylated quinolizidines. The dimethylphenylsilyl group served as a surrogate for one of the hydroxyl groups in the product. The Fleming-Tamao oxidation was performed under Denmark s conditions to avoid oxidation of the tertiary amine to the corresponding A/-oxide, and the desired quinolizidine did was obtained in 81% yield. 

The dehydrogenation of 4-aryl quinolizidines is very interesting, too. The double bond of the salts is formed in the position and not in the expected position (127). In several cases, hydroxylation takes place in the dehydrogenation of 1-methylquinolizidine (115), especially of cis-and rfl/i5-l-methyldecahydroquinolines (128,129) (Scheme 5). 

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>. 

Thermopsamine was isolated from Thermopsis lanceolata R. Br. (137). There are two absorption bands of an axial hydroxyl group at 3370 and 1023 cm and bands representative of rrans-quinolizidine at 2680-2800 cm Mn the IR spectrum. Heating of thermopsamine with hydrogen iodide over red phosphorus... 

Albertine, isolated from Leontice Albertii Rgl. (216,226,227), is an optically active monoacidic tribase. There are the absorption bands at 1655 (lactam carbonyl), 1675 (double bond), 2795-2760 (tra i-quinolizidine), and 3300 cm (hydroxyl group) in the IR spectrum. The UV spectrum shows an absorption maximum at 224 nm (log e = 4.2) for a —C=C——C=0 group. Albertine... 

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. 

Completion of the total synthesis of clavepictines A and B is shown in Scheme 10. Conversion of 18 to the alcohol 19 via 4 steps and reduction of the hydroxyl group in 19 via iodide gave the quinolizidine 20. Finally, the dienyl moiety was constructed by Julia coupling, and deprotection furnished clavepictine B. Acetylation of the hydroxyl group of clavepictine B gave clavepictine A. 

Nupharolidine (9) was isolated from Nuphar lutea (28). Its structure was determined by IR, 1H-NMR, and mass spectroscopy. Compound 9 was the first example of a Nuphar alkaloid with a hydroxyl group in the quinolizidine system. This alkaloid is isomeric with castoramine (59), nuphamine, and isocastora-mine (10). 

Isocastoramine (10) was isolated from Castor fiber L. (26) and represents an alkaloid with a hydroxyl group in the B ring (C-8) of the quinolizidine system. The structure of 10 was determined by spectroscopic methods and by transformation of 10 into a mixture of (-)-deoxynupharidine (14) and (—)-7-epideoxynupharidine (15). 

The Structural identification of (-)-6a-hydroxylupanine was based on the analysis of its spectral data and is in full agreement with the C15H24N2O4 molecular formula determined by HRMS [219]. The mass fragments at m/z 247 [M-OH] and m/z 246 [M-H20] suggested the presence of a hydroxyl substituent, further confirmed by an IR absorption band at 3400 cm". Further analysis of the IR spectrum also provided evidence for the quinolizidine nucleus (2860, 2810 and 2750 cm, tram Bohlmann absorption bands) and the oxo substituent (1640 cm, lactam group). 

Subsequent manipulation (including reduction of the ketone, selenoxide elimination, hydroxylation, Baeyer-Villiger oxidation, and a ring contraction of the product) gave 185, which gave the quinolizidine 186 on reduction and hydrolysis. Two stereoisomers of 186 were made similarly from stereoisomers of 184. ... 

The biochemistry and molecular biology of quinolizidine alkaloid biosynthesis have not been fully characterized. Quinolizidine alkaloids are formed from lysine via lysine decarboxylase (LDC), where cadaverine is the first detectable intermediate (Scheme 6). Biosynthesis of the quinolizidine ring is thought to arise from the cyclization of cadaverine units via an enzyme-bound intermediate 176). LDC and the quinolizidine skeleton-forming enzyme have been detected in chlorop-lasts of L. polyphyllus 177). Once the quinolizidine skeleton has been formed, it is modified by dehydrogenation, hydroxylation, or esterification to generate the diverse array of alkaloid products. 

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