Quinolizidine ring systems

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 stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to Aj, bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum at 410 nm presufiaably due to the conjugated enone system present in 29. 

There has been considerable development during the year in the chemistry of lythraceae alkaloids containing quinolizidine ring systems, especially in synthesis. 

Two related procedures for the synthesis of the quinolizidine ring system have been reported by Comins et al. which utilize, as the key step, regiospecific attack of a functionalized carbanion at the 2-position of a 4-substituted 1-acylpyridinium salt (Scheme... 

Three compounds containing a quinolizidine ring system have recently been isolated from beetles belonging to the family Coccinellidae. The first of these is coccinellin, C13H23NO, which appears to be an effective constituent of the defensive secretion of the common ladybird, Coccinella septempunctata L. Coccinellin is an N-oxide which can be reduced to the parent tertiary base, pre-coccinellin the latter is also present in the haemolymph of the insect. 

Quinollzldlne alkaloids. General term for alkaloids containing at least one quinolizidine ring system (per-hydroquinolizine) (figure). 

Sparteine 115 and lupanine 116, containing a tetracyclic bis-quinolizidine ring system, are alkaloids of the legumes (Fabaceae) species of lupin (Gems Lupinus) and broom (genus Cytisus, Sarothamnus, Genista). Sparteine 115 has been used in the management of cardiac arrhythmias [61]. 

Certain other groups of alkaloids that coincidentally have a quinolizidine ring system are discussed in other chapters. For example, the alkaloids of the Lythraceae are discussed in Chapter 37 and those of the genus Nuphar are discussed in Chapter 36. Yet other quinolizidine alkaloids (18 and 19) are known from the Ericaceae (Vaccinium myrtillus) and the Euphorbiaceae (Poranthera corymbosa) (see Piperidine... 

Nuphara alkaloids a group of alkaloids possessing a piperidine or quinolizidine ring system, which are found in various species of water lily (Nuphar spp.). All N.a. contain a sesquiterpene skeleton, which is cyclized by the inclusion of nitrogen, oxygen or sulfur. The chief N.a. are nupharidine, nuphara-mine and thiobinupharidine. Castoreum or castor, the secretion from the preputial follicles of the beaver, contains castoramine (iW, 247, m.p. 65-66 °C) which is related to the N.a. it is not known whether it is synthesized by the animal, or derived from water... 

In addition to demonstrating the feasibility of intermolecular iminium-ion-based [4+2] cycloadditions in aqueous media for entry into the monocyclic and fused bicyclic piperidine backbones, a few intramolecular variants are also detailed, which allow for the construction of azabicyclo [4.3.0] and [4.4.0] systems. For example, cyclization of dienylamine hydrochlorides, 4 and 5, in the presence of aqueous formaldehyde at 50°C for 48 h gives rise to the bicyclic 5,6 (indolizidine) and 6,6 (quinolizidine) ring systems in 95% and 65% yields, respectively ... 

Figure 1 Alternative numbering systems for the indolizidine and quinolizidine ring systems.

The application of the RCM reaction to the construction of nitrogen-containing ring systems, including quinolizidine derivatives, has been reviewed <1999EJ0959>. From that date, this strategy has become more and more common in quinolizidine synthesis, especially in cases where the cyclization takes place by formation of a bond 7 to the heteroatom. Some examples are given below. 

The common structural feature of quinolizidine alkaloids is a decalin ring system with a nitrogen at one vertex. Often a second or third nitrogen atom is... 

Alkaloids are basic plant natural products that typically have a nitrogen atom as part of a heterocyclic ring system and indeed are classified on this basis. Thus major classes of alkaloids are based on indole, isoquinoline, pyrrolidine, piperidine, pyrrolizidine, quinoline, tropane, quinolizidine or other heterocyclic ring systems. Other alkaloids are basic monoterpenoid, sesquiterpenoid, diterpenoid, steroid, purine, pyrimidine or peptide entities. Some of these compounds are exceptionally toxic [1,6, 7-12]. 

The reaction of 92 with sodium carbonate in MeOH affords the ester 93, while the reduction of 92 with LAH leads to ring cleavage, affording the bridged ring system 94 (Scheme 19). Then 94 was converted to the quinolizidines 97 and 98 via 95 and 96, respectively, in a two-step reaction in 62% and 58% yields <2002SL85>. 

The 13C spectrum of emetine (112) (Fig. 23 and Table XXII) was examined by Wenkert and co-workers (69). The chemical shift assignments were made by comparison with the shifts recorded for the simple isoquinolines and pro-toberberine alkaloids such as tetrahydropalmatine (69) (6, 14), and with indolic analogues of emetine (69). The shifts of C-4 and C-6 are characteristic of a trans-quinolizidine conformation for this ring system by analogy... 

The Lythraceae alkaloids have four centers of chirality—three chiral carbon atoms at the quinolizidine ring C-l, C-3, and C-5, and the dissy-metric biphenyl or biphenyl ether link. The chirality of the biphenyl system in all alkaloids of the group is the same. The chirality of the biphenyl ether link is also the same for all alkaloids in this class (22, 23, 32). 

Finally, it might be noted that several brominated tetrahydro- and dihydro-p-carbolines are known, for example woodinine (64) [52,53] and 19-bromoisoeudisto-min U (65) [54], both from Eudistoma spp. The tunicate Pseudodistoma arborescens has yielded arboresddine A (66) a brominated derivative of the well-known indolo[2,3-a]quinolizidine alkaloid ring system [55]. 

Many other synthetic benzo a]quinolizidine derivatives, structurally more or less related to the alkaloids of types 72-75, have been available a number of indole alkaloids carrying the indolo[2, 3 3,4]pyrido[l,2-b][2,7]-naphthyridine ring system, structurally analogous to the A. lamarckii alkaloids 56-64, have been isolated from other plants and/or synthesized. However, this section is not intended to cover them because of the limited space. 

A review dealing with the stereochemistry of bridgehead nitrogen compounds, which discusses quinolizidine derivatives, may be useful in studies on alkaloids which exhibit this ring system.50... 

Captodative dienes, such as the 2-cyano-l-aza-1,3-butadienes 128 and 129, also undergo hetero Diels-Alder reactions, both inter- and intramolecularly (Scheme 23). Reactivity and regio- and stereo-selectivity in these processes have been accounted for in terms of a concerted asynchronous mechanism involving a diradicaloid transition state [69]. The intramolecular cases illustrated here have been shown to be successful for the preparation of indolizidine 130 and quinolizidine 131 ring systems. 

In quinolizidines, carbons a to the nitrogen are deshielded by its inductive effect (38). Their chemical shifts are higher for the /ranj-fused ring systems, and the value of A<5 = — ds is similar... 

---