Quinolizidine Systems Research Articles

The Chemistry of van de Moer Test for Cytisine

Cytisine is an alkaloid with biological activity that is used as medication for smoking cessation treatment. It is a quinolizidine derivative, one ring being 2-pyridinone, and there is a third cycle, a disubstituted piperidine. Thus, the analytical chemistry of this compound is relevant. In this communication we provide the chemistry involved in the spot test for cytisine identification by means of ferric chloride/hydrogen peroxide. The electron flow, step by step, is given from the alkaloid to the final colored products. The sequence is based on the chemical properties of the substrate and reagents, disclosing the series of reactions occurring in this assay. The process is in accordance with the experimental results. We also give the mechanism of cytisine degradation, from a quinolizidine system to 6,8-dimethyl quinoline, which involves an interesting rearrangement.

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli-Cushman protocol.

The Castagnoli–Cushman reaction of 3,4-dihydroisoquinolines with glutaric anhydride, its oxygen and sulfur analogues was investigated as a one-step approach to the benzo[a]quinolizidine system and its heterocyclic analogs. An extension towards the pyrrolo[2,1-a]isoquinoline system was achieved with the use of succinic anhydride. The results are evidence of an unexplored method for the access of the aforementioned tricyclic annelated systems incorporating a bridgehead nitrogen atom. The structures and relative configurations of the new compounds were established by means of 1D and 2D NMR techniques. The reactions between 1-methyldihydroisoquinoline and glutaric, diglycolic and succinic anhydrides yielded unexpected isoquinoline derivatives containing an exocyclic double bond. The compounds prepared bear the potential to become building blocks for future synthetic bioactive molecules.

Stereodirected synthesis of alkaloid-like quinolizidine systems

New stereoselective methods for the chemical modification of cytisine based on T-reactions are reported. A reaction of cytisine with 2-chloro-5-nitrobenzaldehyde and followed condensation with 1,3-dimethylbarbituric acid affords N-(5-nitro-2-{1,3-dimethylperhydropyrimidine-2,4,6-trione-5-methynyl})cytisine, which undergoes a cyclization with the tetrahydropyridine ring closure. The cyclization proceeds via two competing routes yielding 5,5-spirobarbituric acid derivatives with 11,19-diaza-pentacyclo[11.7.1.02,11.05,10.014,19]henicosane and 11,15-diazapentacyclo-[11.7.1.02,11.05,10.015,20]henicosane skeletons. The cyclization reaction in solutions afford either 24.25-trans and 15,16-trans isomers or trans and cis isomer mixtures, depending on the specific solvent. Meanwhile, 24,25-cis and 15,16-cis isomers are formed stereoselectively under heterogeneous conditions in water suspensions. Trans-5,5-spirobarbiturates under similar conditions undergo isomerization into more stable cis-analogs by the configuration inversion at the C7 atom. The synthesized 5,5-spirobarbituric acid derivatives were successfully converted into alkaloid-like quinolizidine systems (1R,2R,3R,13S)-7-nitro-18-oxo-11,19-diazapentacyclo[11.7.1.02,11.05,10.014,19]henicosa-5(10),6,8,14,16-pentaene-3-carboxylic acid and (1R,2S,3S,13S)-nitro-16-oxo-11,15-diazapentacyclo[11,7,1.02,11,05,10,015,20]henicosa-5,7,9,17,19-pentaene-3-carboxylic acid and their derivatives via the spiropyrimidine moiety removal by the stereoselective hydrolysis. The molecular and crystal structures of the target substances were elucidated by X-ray crystallography and NMR.

Chemical Modification of Plant Alkaloids. 8. Stereocontrolled T-Reactions of (1R,5S,12S)-Tetrahydrocytisine Derivatives

New heterocyclic quinolizidine systems were prepared from (1R,5S,12S)-tetrahydrocytisine. The synthetic scheme included arylation of tetrahydrocytisine by 2-fluoro-5-nitrobenzaldehyde and condensation of the resulting aldehyde with 1,3-dimethylbarbituric acid. The Knoevenagel intermediate obtained from the condensation was cyclized by a T-reaction to give two spirocyclic products as a derivative with the lupanine skeleton and its regioisomer with the 11,15-diazapentacyclo[11.7.1.02,11.05,10.015,20]heneicosane skeleton. The cyclization occurred highly stereoselectively. The structures of the products were proven using NMR and X-ray crystal structure analyses.

The Double-Bond Configuration of Corynanthean Alkaloids and Its Impact on Monoterpenoid Indole Alkaloid Biosynthesis.

Experimental evidence is provided for the coherence of the double-bond geometry and the occurrence of "secondary cyclizations" in the biosynthesis of monoterpenoid indole alkaloids. Biosynthetically, akuammiline, C-mavacurine, and Strychnos alkaloids are proposed to be derived from the corynanthean alkaloid geissoschizine, a key intermediate in the biosynthetic pathway of these monoterpenoid indole alkaloids. This process occurs by so-called "secondary cyclizations" from geissoschizine or its derivatives. Although corynanthean alkaloids like geissoschizine incorporate E or Z double bonds located at C19-C20, the alkaloids downstream in the biosynthesis exclusively exhibit the E double bond. This study shows that secondary cyclizations preferentially occur with the E isomer of geissoschizine or its derivatives. This is attributed to the flexibility of the quinolizidine system of the corynanthean alkaloids, which can adopt a cis or trans conformation. For the secondary cyclization to take place, the cis-quinolizidine conformation is required. Experimental evidence supports the hypothesis that the E double bond of geissoschizine induces the cis conformation, whereas the Z double bond induces the trans conformation, which prohibits secondary cyclization of the Z compounds.

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis.

Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile. In particular, the main biological effects described for indoloquinolizidines include analgesic, anti-inflammatory, antihypertensive, and antiarrhythmic activities, as well as inhibition of multiple ion channels, affinity for opioid receptors, and activity against Leishmania. For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders.

Synthesis and Conformational Analysis of Disubstituted Sparteine Derivatives

Synthesis of disubstituted sparteine derivatives and their diperchlorate salts was performed. Their IR and NMR spectra were analysed to determine the structure of these compounds, as well as the substituent and the protonation effects. It was shown that both unsaturated (2,17β-dimethyl-2,3-didehydrosparteine (12), 17β-isopropyl-2-methyl-2,3-didehydrosparteine (13)) and saturated (2,17β-dimethylsparteine (14), 17β-isopropyl-2-methylsparteine (15)) newly obtained sparteine derivatives have the same configurational-conformational system: trans A/B chair/chair, trans C/D boat/chair. The methyl and the isopropyl (both equatorial) groups at C-17 appear the elements stabilizing the boat-chair system of the C/D rings, which does not change either on the introduction of the second substituent to the opposite quinolizidine system (the A/B rings) or on protonation. The protonation of the free bases obtained gives only disalts. The atoms undergoing the protonation are either C-3 and N-16 in 12 and 13 or both nitrogen atoms (N-1 and N-16) in 14 and 15. The methyl group introduced on the carbon atom C-2 takes equatorial position, as in 2-methylsparteine (2).

Concise, Divergent β-Lactam-based Route to Indolizidine and Quinolizidine Derivatives via Sequential Regio- and Stereocontrolled Intramolecular Nitrone-alkene Cycloadditions

A novel, concise, divergent methodology to both indolizidine and quinolizidine systems based on the sequential regio- and stereocontrolled intramolecular nitrone-alkene cycloaddition (INAC) reactions of 2-azetidinone-tethered alkenylaldehydes is reported.

Rearrangement of ammonium ylides produced by intramolecular reaction of catalytically generated metal carbenoids. Part 2. Stereoselective synthesis of bicyclic amines

Ammonium ylides produced by intramolecular reaction of copper carbenoids tethered to cyclic allylic amines undergo [2,3]-rearrangement to deliver bicyclic amines. The reaction can be performed using a cyclic N-allylamine in which the diazo group is tethered adjacent to nitrogen, or a vinyl-substituted cyclic amine in which the diazo group is N-tethered to the ring. In the former type of reaction, stereoselective ylide formation and rearrangement usually delivers high levels of diastereocontrol. In the latter case, efficient ‘chirality transfer’ can be accomplished when the reaction is performed using an enantiomerically pure substrate. The reactions have been used to construct pyrrolizidine, indolizidine and quinolizidine systems, and the CE sub-unit found in the manzamine and ircinal alkaloids.

Highly stereoselective construction of trans(2,3)-cis(2,6)-trisubstituted piperidines: An application to the chiral synthesis of Dendrobates alkaloids

Abstract A general and flexible route to the 5,8-disubstituted indolizidine and 1,4-disubstituted quinolizidine system found in Dendrobates alkaloids has been developed. The key step for this synthesis is the highly stereoselective Michael reaction of a didehydropiperidinecarboxylate ( 1 ) to afford a trans (2,3)- cis (2,6)-trisubstituted piperidine. In this manner, the chiral formal synthesis of indolizidines 207A and 209B and the total synthesis of indolizidines 223J, 235B' and Cl-epimer of quinolizidine 207I have been achieved.

Palladium(0)-Catalyzed Heteroarylation of 2- and 3-Indolylzinc Derivatives. An Efficient General Method for the Preparation of (2-Pyridyl)indoles and Their Application to Indole Alkaloid Synthesis.

Palladium(0)-catalyzed coupling of (1-(benzenesulfonyl)-2-indolyl)zinc chloride (1) and (1-(tert-butyldimethylsilyl)-3-indolyl)zinc chloride (6) with diversely substituted (alkyl, methoxy, methoxycarbonyl, nitro, hydroxy) 2-halopyridines gives the corresponding 2- and 3-(2-pyridyl)indoles [4 and 7 (or 8), respectively] in excellent yields. A series of other 3-(heteroaryl)indoles (pyrazinyl, furyl, thienyl, indolyl) have been similarly prepared from 6. The potential of some of these (2-pyridyl)indoles in alkaloid synthesis is demonstrated. Thus, from 2-(2-pyridyl)indole 4b, a new synthetic entry to the indolo[2,3-a]quinolizidine system, involving stereoselective hydrogenation of the pyridine ring with subsequent electrophilic cyclization upon the indole 3-position from an appropriately N(b)-substituted 2-(2-piperidyl)indole, is reported. For this purpose, Pummerer cyclizations have been extensively studied. Whereas the indole-unprotected sulfoxide 17 gives the corresponding indoloquinolizidine 19 in low yield and mainly undergoes an abnormal Pummerer cyclization that ultimately leads to sulfide 18, the N(a)-protected sulfoxides 24a and 24b afford the respective indoloquinolizidines 25a,b in 70% yield. On the other hand, the conversion of 3-(2-pyridyl)indole 8k into tetracyclic ketone 35 by stereoselective hydrogenation, followed by cyclization of the resulting all-cis-3-(2-piperidyl)indole 34, represents a formal synthesis of Strychnos alkaloids with the strychnan skeletal type (tubifoline, tubifolidine, 19,20-dihydroakuammicine). A similar conversion of 8j into nordasycarpidone constitutes a formal synthesis of the alkaloids of the uleine group. Reduction of nordasycarpidone leads to tetracycle 37, an advanced intermediate in a previous synthesis of tubotaiwine, a Strychnos alkaloid with the aspidospermatan skeletal type. Finally, piperidylindole 34 was transformed into tetracycle 41, an ABDE substructure of akuammiline alkaloids, by a sequence involving the skeletal rearrangement of an intermediate spiroindolenine as the crucial step.

A new synthetic entry to the indolo[2,3-a]quinolizidine system. Electrophilic cyclizations on the indole ring from 2-(2-piperidyl)indoles

A new synthetic route to the indolo[2,3-a]quinolizidine system, involving the Pd(0)-catalyzed cross-coupling of a 2-indolylzinc derivative with a 2-halopyridine, stereoselective hydrogenation of the pyridine ring, and electrophilic cyclization upon the indole 3-position from the resulting 2-(2-piperidyl)indole, is reported.

Stereochemical studies by mass spectrometry: C15Nuphar alkaloids

AbstractRepresentative C15 Nuphar alkaloids, containing the quinolizidine system, were studied by high‐resolution mass spectrometry and metastable‐ion decomposition analysis. The appearance with N‐oxide species of ions at m/z 168, useful in ascertaining the stereochemistry of the quinolizidinic ring junction, are also discussed.

Crystal and molecular structure of 15-oxosparteine-N(1)-oxide perchlorate

[C15H25N2O2 +·ClO 4 − ,M r =364.83, is monoclinic:P21,a=7.885(1),b=10.685(1),c=10.658(1) A,β=105.63(1)°,V c =864.8(2) A3,Z=2,D x =1.39(1)g cm−3, λ(CuKα)=1.54178 A,μ(CuKα)=21.4 cm−1,F(000)=388 e,T=292K,R=0.066 for 1205 unique reflections. The piperidine ringsA, B, C, andD have chair, chair, boat, and half-chair conformations, respectively. The quinolizidine system (ringsA/B) has atrans configuration. The cations are interconnected by a hydrogen bond O(N1)⋯O(C15) of 2.552(10) A into chains along [010]. Atoms C(12) and C(13) from ringD of the cation are disordered. Very high thermal parameters of the oxygen atoms of the perchlorate anion may indicate its orientational disorder.

Sarains: A New Class of Alkaloids from the Marine Sponge Reniera Sarai

AbstractReniera sarai, a marine sponge of the Ceractinomorpha subclass easily collectable in the Bay of Naples, is characterized by a series of cyclic nitrogenous compounds, which for many years have resisted all attempts of structural investigation.Complex separation steps have now led to three new compounds, named sarain‐1, sarain‐2 and sarain‐3. Their structures have been partially determined mainly by a 500 MHz NMR study, utilizing the 1H‐1H homonuclear and 1H‐13c heteronuclear NMR Chemical shift correlation techniques. Sarains belong to a new class of pentacyclic alkaloids, containing in their skeletons a quinolizidine system linked to a tetrahydropyridine moiety. Two linear alkyl chains, placed between the two heterocyclic systems, supply the two remaining cycles. Recently a series of biologically active bis‐quinolizidine and 1‐oxa‐quinolizidine alkaloids have been isolated from the sponges Petrosia seriata and Xestospongia exigua, respectively. A common biogenetic origin should connect these alkaloids to sarains. Sarains show phase transfer catalytic properties.

Methiodides of nuphar alkaloids: Part I. Studies on stereochemistry by carbon-13 nuclear magnetic resonance spectra of some thiospirane C 30 and C 15 methiodides

The 13C NMR spectra of deoxynupharidine, 7-epideoxynupharidine and thiobinupharidine methiodides have been studied and the correlations between the stereochemistry of these compounds and corresponding chemical shifts are described. Quaternization of the nitrogen causes no steric changes in the trans-quinolizidine system of 7-epideoxynupharidine, whereas deoxynupharidine methiodide has a transformed quinolizidine system with cis ring fusion. Quaternization of thiobinupharidine with methyl iodide results in two isomeric monomethiodides which have been characterized as A′-B′- trans and AB- trans isomers of quaternary salts.

Crystal and molecular structure of 17-?-methyl-?-isolupanine perehlorate

The formula of the title compound is C16H27ClN2O5,P21/a = 8.348(1),b = 10.127(1),c = 11.264(2) A, β = 116.42(1) °,Z = 2,D x = 1.41 g cm−3,V c = 852.8(2) A3,MW = 362.9, μ (CuKα) = 2.25 mm−1. The structure was solved by direct methods and refined by full-matrix least squares to anR value of 0.055 for 1197 reflections. The cation consists of twotrans quinolizidine systems. RingA is a distorted half-chair, and the remaining rings are chairs. The CH3 group attached to C(17) is in the axial position. There is a weak hydrogen bond between N(16) and O(2) of the ClO 4 − group with N(16) ... O(2) distance 2.968(7) A.

Action of N‐bromosuccinimide on some indolizidine and quinolizidine systems

AbstractOxidation of the alkaloids (‐)tylocrebrine, (‐)septicine and (±)canadine by N‐bromosuccinimide gave the corresponding tetradehydroiminium salts in which the six‐membered heterocyclic rings were aromatized. Evidence was provided for the preferred path of the two available alternatives. Reduction of these salts with sodium borohydride regenerated the starting bases but without the optical activity. In contrast to the simpler 1,2,3,4‐tetrahydroisoquinolines, hydrastine gave a brominated isoquinolinium salt with the loss of dimethoxy phthalide anion. A discussion of the stoichiometry and a probable mechanism is presented.

The solvent‐induced shift in the proton NMR of some quinolizidine substituents

AbstractThe proton chemical shift values for the methyl groups in the nine monomethylquinolizidines are determined in deuterochloroform and benzene solutions. This solvent change results in the shielding of all the methyl groups except those in 1(a)‐and 3(a)‐methylquinolizidine which become deshielded. These results are compared with those obtained earlier for equatoral and axial methyl and methylene groups attached to the quinolizidine systems in Nuphar alkaloids and related compounds.

Quinolizidines. I. Quaternization of the quinolizidine system: effect of .BETA.,.GAMMA.-unsaturation on stereoselectivity in methiodide formation.

Quaternization of benzo [a] quinolizidine (Ib) with methyl iodide gave a 3.6 : 1 mixture of the cis- (IIb : X=I) and the trans-methiodide (IIIb : X=I). The 9, 10-dimethoxy derivative (Ia) also gave the corresponding cis- (IIa : X=I) and trans-methiodide (IIIa : X=I) in a ratio of 3.3 to 1. Treatment of enamines Va, b with methyl iodide furnished the N-methylated product (VIa, b) and the C-methylated product (VIIa, b) in a ratio of 1.2 : 1. Catalytic hydrogenation of VIa, b produced a mixture of the cis- (IIa, b) and the trans-methosalt (IIIa, b) in a rough ratio of 2.8 : 1, whereas that of VIIa, b gave the 1-methylated benzo [a] quinolizidine (VIIIa, b). Compound VIIIa was alternatively prepared from piperidone IX by the Bischler-Napieralski cyclization and subsequent hydrogenation. In the case of the simple quinolizidine system with the simplest β, γ-unsaturation (XV), the quaternization with methyl iodide produced the cis- (XVI) and the trans-methiodide (XVII) almost equally. Repetition of the known methiodide formation of XXVI and hydrogenation of enamine methiodide XIX confirmed their reported high stereoselectivity, and factors responsible for the difference in stereoselectivity between these reactions of the β, γ-unsaturated system and the saturated system have been discussed. At 250° the cis-methiodides (IIa, b, XX) isomerized to the corresponding trans-fused salts (IIIa, b, XXI) to some extent and one may roughly compare the susceptibilities of IIa, IIb, and XX, which decrease in that order.