1- quinolizidines from

Plant-derived neurotoxic psychodysleptics affect peripheral neural functions and motor coordination, sometimes accompanied by delirium, stupor, trance states, and vomiting. Prominent among these toxins are the pyrollizidines from peyote. Also included are erythrionones from the coral tree and quinolizidines from the mescal bean (see Figure 19.2). 

The occurrence of quinolizidines in skin extracts from dendrobatid frogs has been suspected for some time (5), but only recently have sufficient mass and FTIR spectral data been obtained to permit assignment of structures to quinolizidines from dendrobatid and ranid frogs and bufonid toads. As yet, none of these quinolizidines has been isolated in quantities sufficient for nuclear magnetic resonance spectral characterization. 

Fig. 14. Structures of 1,4-disubstituted quinolizidines from amphibians. All have been characterized only by mass and FTIR spectral properties 73,81)- All have the 4, lOZ configuration. The configuration at the 1 position is as yet unknown.

The absolute stereochemistry of ipecoside was determined by correlation studies with dihydroprotoemetine. Because the yield of the product in each step was low and a complex mixture of compounds was formed during the reaction, recourse was taken to the use of radioactive material. Vigorous acid hydrolysis of [0-methyl-3H]0,0-dimethyldihydroipecoside furnished 15 or 16 in equilibrium with 17 or 18, and also several isomeric benzo-quinolizidines. From this, after sodium borohydride reduction, (— )-[0-methyl-3H]dihydroprotoemetine (19) of known absolute configuration... 

It appears that Winterfeld and Holschneider (132) were responsible for the first reported synthesis of authentic norlupinane (quinolizidine) from non-alkaloid starting materials. The first step in their synthetic... 

Stereospecific reductive ring closure to N-condensed beterocyelics Quinolizidines from y-(2-pyridyl)ketones... 

Rauh MF, Cardelhna JH, Choudhary MI, Ni CZ, Clardy J, Alley MC. Clavepictines A and B c3dotoxic quinolizidines from the tunicate Clavelina picta. J. Am. Chem. Soc. 

Jain P, Garraffo HM, Yeh HJC, Spande TF, Daly JW, Andria-maharavo NR, Andriantsiferana M. A 1,3-disuhstituted quinolizidine from a madagazcan mantelhne frog (manteUa). J. Nat. Prod. 1996 59(12) 1174 1178. 

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). 

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. 

Molecular mechanics (MM) calculations have been employed for determining dihedral angles and to establish a comparison with values calculated from coupling constants, during conformational studies of tricyclic and tetracyclic quinolizidine alkaloids. The MM results had to be treated with care, as they sometimes predicted ring conformations different to those supported by experimental data <1999JST215>. 

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>. 

Two-dimensional thin-layer chromatography (TLC) with adsorbent gradient has allowed the separation of quinolizidine alkaloids in the herb and in several alkaloids from Genista sp. <2004MI89>. 

As shown in Scheme 14, a sulfuric acid-catalyzed dehydration-cyclization-elimination domino sequence starting from protonation of the secondary hydroxy group of the indolo[2,3- ]quinolizidine 112 led to the isolation of the pentacyclic compound 113 in good yield <1999EJ03429>. 

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 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>. 

Many polyhydroxylated quinolizidines <1995CRV1677>, frequently designed as azasugars, are powerful glycosidase inhibitors and therefore have potential therapeutic application. The 7-oxa-l-azabicyclo[2.2.1]heptane derivative 191, obtained from 3-0-benzyl-l,2-0-isopropylidene-l,5-pentadialdo-a-D-xylofuranose with... 

Clavepictines A and B (210 and 211, respectively) were obtained from the allenic ester 227. The reduction of its ester group to aldehyde, followed of addition to the latter of hexylmagnesium bromide, OH protection, and N-deprotection gave compound 228. A silver(i)-mediated cyclization of this compound afforded quinolizidine 229 and its C-6 epimer in a 7 1 ratio (Scheme 44). The former compound was readily converted into the target alkaloids <1997JOC4550>. 

---