Indolo- quinolizidine

CiqHi Nj, Mr 272.35, mp. 258-260 C, an indolo-quinolizidine alkaloid from the Gelsemium species G. sempervirens and G. elegans (Loganiaceae). For synthesis, see Lit.. S. has antitumor activity and shows a tendency for DNA intercalation (cytotoxicity). 

Conformational study of geissoschizine isomers and their model compounds (geissoschizine is the indolo[2,3-fl]quinolizidine derivative considered to be an important participant of indole alkaloids biogenesis) 99H(51)649. 

Racemic and chiral syntheses of some indolo[2,3-<2]quinolizidine alkaloids through a lactim ether route 98H(47)525. 

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... 

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>. 

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>. 

Tryptophan (and also tryptophanol) undergoes a stereoselective cyclocondensation with racemic compound 249, in a very interesting process involving a kinetic resolution with epimerization of the tryptophan stereocenter and simultaneous desymmetrization of the two diastereotopic acetate chains <2005CC1327>, affording the enantiomeri-cally pure lactam 250. A subsequent treatment of the latter compound with trifluoroacetic acid led to the indolo[2,3- ]quinolizidine 251 through an intermediate acyliminium cation (Scheme 50) <20050L2817>. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

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>. 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

When pyridinium salt 187 was transformed to an indolo[2,3-a]quinolizidine compound in a similar way and the unsaturated lactone 188 was hydrogenated over platina catalyst, a mixture of vallesiachotamine-type compounds (189 di-astereomers) epimeric at C-20 was formed (134). These compounds have also been prepared in optically active form from vallesiachotamine (9), thus producing the first chemical correlation between synthetic and natural vallesiachotamine derivatives (134). 

A review has appeared regarding the infrared and nuclear magnetic resonance spectroscopic investigations of quinolizidine alkaloids (303). The connection between the C/D ring junction and the existence of Bohlmann bands in the IR spectra of indolo[2,3-a]quinolizidines has been reinvestigated and interpreted (304). 

In comparison with other spectroscopic methods, 13C-NMR spectroscopy affords the most valuable information for the stereochemical and conformational analysis of quinolizidine compounds. On the basis of the results, summarized in a review by Tourwe and van Binst (313) as well as in a series of publications (314-318), the steric structure elucidation of indolo[2,3-a]quinolizidine alkaloids has been facilitated. 

Results and data gathered on mass spectroscopy of various indole alkaloids have been summarized by Hesse (320). The derivation of the characteristic fragments of indolo[2,3-a]quinolizidines has been interpreted by Gribble and Nelson (321), who investigated C-3, C-5, C-6, C-20, and C-21 deuterated derivatives of octahydroindolo[2,3-a]quinolizine (1). Kametani et al. have observed and proved, with labeled compounds, a methyl transfer from the ester function of reserpine derivatives to the basic nitrogen atom during mass-spectroscopic measurement (322). 

Results of a study of acid-catalysed epimerization of indolo [2,3-a]quinolizidine derivatives support a mechanism involving nitrogen lone pairs in an eliminative ring opening-ring closure. ... 

Padwa and co-workers (232,233) adapted their thioisomiinchnone generation-cycloaddition strategy to the synthesis of several tetrahydroisoquinoline alkaloids and the indolo[2,3-a]quinolizidine alkaloid alloyohimbane 333 (Scheme 10.44). 

The nature of the ring fusion in quinolizidine derivatives may be determined from the 15N chemical shifts, which are to lower field in the transfused derivatives. This is shown for the indolo[a]quinolizidines 73 and 74 (chemical shifts to low field of external anhydrous liquid ammonia)115 and by the perhydropyrido[l,2-c][l,3]thiazines 8 66.9 trans conformer 312, 8 43.9 S-inside cis conformer 313.ll5a... 

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... 

To test the necessity of aromatic n electrons in the epimerization reaction, indolo[2,3-a]quinolizidines with different substituents at C-10 were prepared [14]. Subjecting these compounds to epimerization conditions (TFA, 90°C, 60 min) gave the following results, Table 1. 

Table 1. Epimerization experiments with 10-substituted indolo[2,3-a]quinolizidines.

Another way to test the operation of Mechanism 1 is to subject C-l2b alkyl substituted indolo[2,3-a]quinolizidines to epimerization conditions. Should Mechanism 1 be operative, these compounds could not epimerize. Thus, C-l2b methyl substituted indoloquinolizidines 20 - 25 with different structural features were prepared by Lounasmaa and co-workers [22], Fig. (3). As well as testing Mechanism 1, they investigated the effect of different structural features on the epimerization reaction in general. 

Preparation of the dodecahydro benz[/]indolo[2,3-a]quinolizidine ring structure relied on the Fry reaction [39] of salt 52, which, after subsequent acid-induced cyclization, yielded three compounds, 53 - 55, Scheme (13). 

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]. 

The stability of indolo[2,3-a]quinolizidine epimers can be determined by conformational analysis, bearing in mind three important factors ... 

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]. 

Demuynck, L. et al., Rearrangement of Indolo[2,3-a] Quinolizidines to Derivatives with E-Azaaspidospermane Skeleton, Tetrahedron Letters, 30 (6) 719-722 (1989). (English Abstract). 

Interestingly, Barzai-Beke et al. (84) found that LTA oxidation of indolo[2,3-a]quinolizidine cyanoacetate 260 gives a mixture of the corresponding iminium salts 261 and enamine 262. When the mixture in CH2CI2 solution is allowed to stand at room temperature, iminium salt 263, epimeric with 261, is produced (Scheme 31). 

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. 

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