Benzo quinolizidine

Similar conformational equilibria occur in arenoquinolizidines (e.g., structures 43-45 for benzo[ ]quinolizidines and 46-48 for dibenzo[ g]quinolizidines). 

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 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... 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

Hetero-Diels-Alder reactions have been succesfully employed for the synthesis of arenoquinolizine systems. For example, as shown in Equation 10, treatment of tetrahydroquinoline 319 with Danishefsky s diene 320 in the presence of a Lewis acid gave the benzo[c]quinolizidine derivative 321 <2000JME3718>. 

The reaction of compound 364 with a radical initiator gave a mixture of diastereomeric benzo[tf]quinolizidines 365 and 366 through the radical cascade process summarized in Scheme 83 <1999TL1149>. 

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

As suggested by the title the principal emphasis in this chapter will be on the quinolizinium ion and its benzo analogs, with quinolizine and quinolizidine derivatives being mentioned only if they are obtained from, or transformed to, the aromatic species. For a more comprehensive treatment of these non-cationic species, the earlier reviews by Thyagarajan <65AHC(5)291> and by Mosby <61HC(15-2)1001> should be consulted. 

The chemical shift of the angular proton in benzo[c]quinolizidines will differ from that in quinolizidine itself as a result of delocalization of the lone pair electrons over the aromatic ring in certain conformations. Examples are provided by 29 and 30. In trans-fused 29, the nitrogen lone pair is delocalized over the aromatic ring and thus the anti-coplanar shielding mechanism is lost and the angular proton absorbs to low field of that in the cis conformation 30.51... 

These results show AG° (trans cis) for the benzo[a]quinolizidine to be less than that (2.6 kcal mol 2) for the quinolizidine equilibrium. 

Three isomers of the benzo[a]quinolizidine 210 adopt the frans-quinoliz-idine conformations 211,212, and 213, as shown by the Jgcm values (Section II,B,2), Aae values of the C-6 methylene protons, and the chemical shift of the angular proton (Section II,B,I). Both Aae and the chemical shift of the... 

Indolo or benzo fusion at the 5,6-position in perhydropyrido[l,2-c]pyrim-idine (335-340) (Fig. 13), as in 360 and 361 shifts the equilibrium in favor of the cis-fused conformer 364 and the axial JV-methyl trans-fused con-former 362, with 54% of the equatorial iV-methyl trans-fused conformer 363 present at room temperature (CDC13 solution).284 285 The shift in equilibrium (compare corresponding shift for 192-194 compared to quinolizidine 179-181, Section III,B,3) is presumably a result of a destabilization of 362 and 363 by the peri-type interaction involving the C-l-H and either the... 

Intramolecular cyclization of a, -enamide esters Reaction of the a,(3-en-amide (1) with either trimethylsilyl triflate (1 equiv.) or t-butyldimethylsilyl triflate (1 equiv.) and N(C2H5)3 at 15° results in the benzo[a]quinolizidine 2 in high yield. 

The l3C-NMR spectral data of benzo[a]quinolizidine compounds have been reported (154,282,283), and many examples from the isoquinoline alkaloids have been reviewed by Hughes and MacLean (284) (Volume XVIII, Chapter 3, in this treatise). As described in Section III, B, l3C-NMR spectroscopy, together with H-NMR and UV spectroscopy, has also played the leading role in the confirmation of the endocyclic double-bond structure in the dihydroisoquinoline moiety of 0-methylpsychotrine (7)... 

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. 

Tri-n-butyl)stannylethenyl)-2-hydroxy-3-(2-methylpropyl)-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-benzo[a]quinolizidine... 

The preparation of benzo-[a]quinolizidines (1) and hexahydro-llbH-benzo[a] quino-lizidines Step 1 reagents is described (2)... 

Chiral syntheses of benzo[a]quinolizidine-type Alangium alkaloids 88H(27)1009. 

Pyrrolizidine alkaloids, chemistry and toxicology of 86MI9. Quaternary benzo[c]phenanthridine alkaloids 90CCC2840. Quinolizidine alkaloids 87WCH393. 

No systematic study of catalytic hydrogenation of quinolizinium salts is available. In most cases reduction has been by palladium or platinum with hydrogen at atmospheric pressure to yield the decahydro derivative (the quinolizidine). The first example is provided by Boekelheide and Gall,125 who produced quinolizidine (104). Benzo[b]quinolizinium salts are cata-lytically reduced first in the central ring to give 6,11-dihydro derivatives (105).126 Benzo[c]quinolizinium salts (cf. 4) can be reduced in two stages.120... 

This chapter is organized in much the same manner as its predecessor, with some subsections expanded whenever warranted. Unless otherwise noted, the structural formulas of optically active compounds in this chapter represent their absolute configurations, and the numbering system employed for the benzo[n]quinolizidine alkaloids is identical with that used previously 1,12). 

As regards the 21 benzo[a]quinolizidine-type Alangium alkaloids, they can be structurally classified into four types according to their substitution patterns in the aromatic ring A (i) 9,10-dimethoxy type (72), (ii) 8-hydroxy-9,10-dimethoxy type (73), (iii) 9-hydroxy-lO-methoxy type (74), and (iv) 10-hydroxy-9-methoxy type (75) 7,10,16). Thus, type 72 includes 10 alkaloids... 

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 stereoselective radical cascade approach to benzo[a]quinolizidines using Et3B was highly effective [18]. When 14 was treated with "Bu3SnH in the presence of... 

Scheme 11. Stereoselective radical cascade approach to benzo[a]quinolizidines...

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