Quinolizidin-2-one

Mannich reaction of the piperidine derivative (30) with 3-formylfuran gave a mixture of the four stereoisomeric quinolizidin-2-ones, cf. (31). The major product [as (31), but with a /3-furyl group] was isomerized with base to the most stable ftms-quinolizidinone (31), which on Wolff-Kishner reduction afforded a mixture of alkaloids (27) and (21). 

To trimethylsilylacetylene (20.4 mmol) dissolved in 80 ml THF at —5°C was added n-butyl lithium (20.4 mmol) followed by the dropwise addition of 3-isobutyl-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-benzo[a]quinolizidin-2-one dissolved in 30ml THF. The mixture was stirred at -5 °C one hour, slowly warmed to 20 °C, stirred 2 hours, and then quenched with NH4CI solution. THF was removed, the aqueous component extracted 3 times with 100 ml EtOAc, washed with water, brine, and concentrated. The residue was dissolved in 30 ml methyl alcohol containing 5 ml 5 M KOH, heated to 65 °C 30 minutes, then cooled and quenched with NH4CI solution. The solution was concentrated, extracted 3 times with 50 ml EtOAc, washed, dried, and the product isolated in 53.7% yield as a slightly brown solid. Elemental analysis data supplied. 

A novel rearrangement of suitably 2-substituted side-chain perhy-dro-isoxazolo[2,3-a]pyridines has been shown to afford indolizine and quinolizine derivatives (86TL1727). Thus, 2-spirocyclopropylperhydro-isoxazolo[2,3-a]pyridine (61), obtained as a mixture with the 3-spiro isomer from the reaction between 3,4,5,6-tetrahydropyridine-l-oxide and methylene cyclopropane, undergoes thermal rearrangement (400°C, 0.2 mmHg) to the quinolizidin-2-one (62). 

Benzo[a]quinolizidin-2-ones can be degraded in certain acidic media to 3,4-dihydroisoquinolines <83JOC1075>. For example, treatment of 2-iminobenzo[a]quinohzidines (146) with thioglycolic acid under a variety of experimental conditions led to the thiazolo[2,3-a]isoquinoline (149) instead of the expected spiro compound (148), and the same result was obtained starting from ketone (147) (Scheme 20) <90H(3l)2065>. These results were explained according to the mechanism, which is a... 

Ketone groups attached to quinolizidine systems also display the expected reactivity towards nucleophiles. This is illustrated in Scheme 23 with several reactions of benzo[a]quinolizidin-2-one systems (159). 

The use of imines as dienophilic components in [4 - - 2] cycloaddition reactions is well known <79H(12)949,82T3087). For example, a Diels-Alder reaction between the tetrahydropyridine (263) and ethyl 2,4-pentadienoate was the key step in Bohlmann s synthesis of lupinine (Scheme 54) <67CB2742>. Similar methodology has been applied to the preparation of a variety of areno[a]quinolizidin-2-ones (264) <85TL1277> (Equation (29)). 

The most widely used procedure for the preparation of benzo[a]quinolizidin-2-ones and their 3-alkyl derivatives (270) consists of the reaction between 3,4-dihydroisoquinolines and a,/3-unsaturated ketones, with iminium salt (269) as an intermediate <62CB2135>. 4-Dimethylamino-2-butanone derivatives can play the same role as unsaturated ketones, and have the advantage of allowing the reaction to be conducted in aqueous solutions, which facilitates the isolation of the product <69JCS(C)85> (Scheme 56). The yields obtained in the latter case are usually quantitative for 3-substituted benzo[a]quinolizidin-2-ones, but are considerably lower for the unsubstituted system because of the formation of a secondary product (271). Fortunately, this problem may be overcome by modifying the pH and temperature of the reaction medium <88TH822-0l>. 

Compound 183 undergoes B—N cyclodehydration to give the expected isoquinoline 184. Sodium borohydride as a reductive agent was ineffective. However, sodium cyanoborohydride reduction of 184 after prolonged interaction provides tetrahydroisoquinoline 185, which was transformed into an amido ester 186 with ethyl acrylate via Michael addition. The latter can be converted to the desired tricyclic system 187 via Dieckmann cycli-zation.As expected (i-kcto ester 187 is a mixture ofketo—enol tautomers, as proven by its spectroscopic data and a positive FeCls-MeOH test. It is likely that this is the first successful way for the syntheses of l,l-dimethylbenzo[a] quinolizidin-2-ones (Scheme 50) (83JOC1075). 

Hedges SH, Herbert RB, Wormald PC (1983) Biosynthesis of lythraceae alkaloids Incorporation of DL-[4,5- C2,6- C] lysine and ds- and trans-4-(3,4-dihydroxyphenyl)-quinolizidin-2-one into vertine and lythrine. J Chem Soc Chem Commun 145-147... 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

The common intermediate in two published biomimetic routes to Lythraceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach based on a biogenetic hypothesis of Ferris et al. (62), Wrobel and Gol biewski condensed pelletierine (126) with isovanillin (128) and obtained a transfused quinolizidine derivative (130, jS H-5) (64) in 75% yield. A model condensation of pelletierine (126) with benzaldehyde which resulted in a mixture of quinolizidones was reported earlier by Matsunaga et al. (65). In another approach Rosazza et al. (52) condensed A -pjperideine (132) with /J-ketoester 133 to get 134. The next stage in both approaches was reduction of the ketone and esterification or transesterification with derivatives of p-hydroxycinna-mic acid (135 or 136). Investigations into the oxidative coupling of 137 were unsuccessful. 

As shown in Section I, Clemmensen reduction of quinolizidin-1 -one (1) gave perhydroazaazulene (3) instead of the expected quinolizidine (2). The mechanism of this rearrangement has been studied and the reaction has been used for a synthesis of azaazulene derivatives (61 Mil). 

The synthesis of isosophoramine (26) employs as crucial stages the partial hydrogenation of iV-alkyl salts of ) -acyl (or cyano) pyridines, and acid-catalysed cyclization of the resulting l-alkyl-3-acyl (or cyano)-2-piperideines. Alkylation of nicotinonitrile with 6-bromohexan-2-one ethylene ketal afforded the salt (27), which on palladium-catalysed hydrogenation yielded the piperideine (28). Anhydrous acid-catalysed (TsOH) cyclization of (28) gave the three quinolizidine stereoisomers (29)—(31), which were separated and analysed by n.m.r. spectroscopy and equilibration studies in acid (TsOH-CgH ) and alkaline (KOBu -Bu OH)... 

Yamashita S, Kurono N, Senhoku H, Tokuda M, Onto K. Synthesis of phenanthro[9,i0-6]indohzidin-9-ones, phenan-thro[9,f 0-Z)]quinolizidin-9-one, and related benzolactams by Pd(OAc)2-catalyzed direct aromatic carhonylation. Eur. J. Org. Chem. 2009 2009(8) 1173-1180. 

The C/C double bonds in the quinolizine system can be reduced by catalytic hydrogenation. One example, involving the transformation of an indolo[2,3- ]quinolizidine substrate 76 into compound 77, can be found in... 

An intramolecular Mannich reaction of carboline derivative 352 afforded a complex bridged system containing an indolo[2,3-tf]quinolizidine moiety, as a mixture of two diastereomers. One of them, 353, was transformed into the alkaloid tacamonine 15 (Scheme 79) <2002T4969>. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

One of the most important tetracyclic quinolizidine alkaloids with a quinolizidine nucleus is lupanine, which is in fact 2-oxo-lla-sparteine. In absolute configuration, lupanine is (-I-)-lupanine with a molecular weight of 248 and melting point of 127 Lupanine occurs in L. polyphyllus, L. albus and... 

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

An attempt was made to extend this result to an estimation of K for the quinolizidine equilibrium. For the 2-methyl compound 116 discussed above, there is a difference of one gauche-butane (gb) interaction between the cis- and trans-fused conformers 116 and 117 compared with a difference of three such interactions between the quinolizidine conformers 118 and 119. This gives AG° at 25°C for quinolizidine as 2.8 + 2gb = 2.8 + 1.6 = 4.4 kcal mol-This value is uncertain because even groups remote from... 

The different conformations of indolo[2,3-a]quinolizidines play an important role in predicting the thermodynamically more stable epimer (see below). The indolo[2,3-a]quinolizidine system can exist in three main conformations one C/D trans ring juncture (conformation a) and two C/D cis ring junctures (conformations b and c). These are in equilibrium by nitrogen inversion and cw-decalin type ring interconversion. Ring C is considered to be in a half chair conformation and ring D in a chair conformation, Scheme (16) [40]. 

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