10//- quinolizidine

Sparteine and its enantiomer pachycarpine are both employed as oxytocics in childbirth to initiate uterine contractions and to decrease post-partum hemorrhage. They are often employed as substitutes for the ergot alkaloids and oxytocin. 

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The first compound studied (56) was quinolizidine (41), which can be readily converted to J >-dehydroquinolizidine (42) in 60% yield by the action of 4 moles of mercuric acetate in 5% aqueous acetic acid on 1 mole of the amine. Mercurous acetate precipitates as the reaction progresses at... 

The mechanistic sequence as outlined for quinolizidine-10-c/has metallic mercury as the reduced species. Mercurous acetate is the form in which the mercury eventually appears. It has been shown (76) that under the standard operating conditions, mercuric acetate will oxidize metallic mercury to the... 

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... 

Bohlmann et al. (118-121) observed that an infrared absorption band between 2700-2800 cm is characteristic of a piperidine derivative possessing at least two axial carbon-hydrogen bonds in antiperiplanar position to the free-electron pair on the nitrogen atom. The possibility of forming an enamine by dehydrogenation can be determined by this test. Compounds which do not fulfill this condition cannot usually be dehydrogenated (50, 122,123). Thus, for example, yohimbine can be dehydrogenated by mercuric acetate,whereas reserpine or pseudoyohimbine do not react (124). The quinolizidine (125) enamines (Scheme 4), l-azabicyclo(4,3,0)-nonane, l-azabicyclo(5,3,0)decane, l-azabicyclo(5,4,0)undecane, and l-azabicyclo(5,5,0)dodecane have been prepared in this manner (112,126). 

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). 

Upon methylation of /) -dehydroindolizidine (55), dialkylated compounds 115 and 116 are formed in addition to C-monomethylated product 114. Compound 115 is accessible also by methylation of 8-methyl-zJ -dehydro-quinolizidine (//i). 

Reactions of Enamine Salts with OrganometalUc Compounds Organolithium and organomagnesium compounds react with enamine salts to give amines substituted on the ix-carbon atoms. The treatment of. -dehydroquinolizidinium perchlorate (163) with alkylmagnesium halides gives 9-alkylated quinolizidines (164) (252,256). Formation of... 

The reaction of 2-(a-pyridyl)alkylmalonic acid with J -piperideine leading to formation of 3-((x-pyridyl)quinolizidine-l-carboxylic acid on decarboxylation, has been used by Van Tamelen and Foltz (316) for the syntheis of the alkaloid lupanine (Scheme 20). A very elegant synthesis of matrine has been accomplished by Bohlmann et al. (317). 

An interesting synthesis of quinolizidines was achieved using a vinylogous variation of the Bischler-Napieralski reaction. Angelastro and coworkers reported that treatment of amide 26 with PPSE (polyphosphoric acid trimethylsilyl ester) followed by reductive... 

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

The intramolecular cyclization of l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5, 6-tetrahydropyridine (140) and l-(3-bromopropyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (143) (89T5269) resulted in the synthesis of quinolizidine ring system 141 and indolizidine ring system 144 in 43% and 72% yields along with the reduced tetrahydropyridines 142 and 145 in 21% and 8% yields, respectively. All the cyclized products appeared to be (ran.s-fused indolizidines or quinolizidines. The (ran.s -fused simple indolizidines are known to be some 2.4 kcal mol more stable than the d.s-fused isomers (68TL6191). In the and-isomer the methoxycarbonyl substituent occupies an equatorial position. 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

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. 

Racemic and chiral syntheses of some indolo[2,3-<2]quinolizidine alkaloids through a lactim ether route 98H(47)525. 

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 ... 

Quinolizidine synthesis via intramolecular immonium ion based Diels-Alder reactions total synthesis of ( )-lupinine, ( )-epilupinine, ( )-criptopleurine and ( )-julandine [97]... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

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