Indolo quinolizin

The reduction of l-(j8-3-indolylethyl)pyridinium ions (58) with lithium aluminum hydride was investigated as a means of causing cyelization to indolo-quinolizines (58a). These reactions gave as the... 

A further application of the Dieckmann cyclization is that leading to the synthesis of 3,4,6,12-tetrahydro-l(2jE )-indolo[2,3-6]quinolizin-l-one (398). ... 

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... 

Oxoquinolizine-3-carboxylates (e.g., 466) are excellent fluorophores that show a strong fluorescent response to Mg2+ but not to Ca2+, avoiding the very frequent interference between both cations <2001BCC203>. The fluorescence of indolo[2,3-tf]quinolizines has also been used for the design of fluorescent histamine H2 receptor antagonists as probes of this receptor <2003BML1717>. 

The simplest member of the indolo[2,3-a]quinolizine alkaloid group has been found in Dracontomelum magniferum Bl. (II) it possesses structure (—)-l. No name has as yet been given for this levorotatory alkaloid. 

Utilizing Wenkert s cyclization process, a number of new approaches have been elaborated for the synthesis of simple indolo[2,3-a]quinolizine derivatives. For example, treatment of JV-[2-(indol-3-yl)ethyl]piperidine (V-oxide (134) with trifluoroacetic anhydride gave piperideinium intermediate 135 in a Polonovski-type reaction, which could be cyclized in acidic medium to ( )-l (101). 

A new route has been developed for the efficient formation of the variably substituted indolo[2,3-a]quinolizine ring system, starting from a properly substituted 2-piperidone (103, 104). For the preparation of octahydroindolo-quinolizine (1), the unsubstituted 2-piperidone 139 was treated with triethox-onium tetrafluoroborate. Then the corresponding lactim ether 140 was alkylated with 3-chloroacetylindole followed by a subsequent two-step reduction process and Bischler-Napieralski ring closure. Finally, reduction of the C=N bond afforded ( )-l (104). 

Didehydrogeissoschizine (147) has been proposed to be the biogenetic precursor of simple indolo[2,3-a]quinolizine alkaloids such as flavopereirine (148)... 

Danieli et al. 116), both of which utilize an alkylation process of 1-methyl-3,4-dihydro-(3-carboline (150) in the key ring-forming step. In the first one, treatment of 150 with a-methylene- y-butyrolactone gave enamide 172, which, when reduced with lithium aluminum hydride, afforded indolo[2,3-a]quinolizine derivative 173. The desired ethylidene substituent at C-20 has been developed from the hydroxyethyl side chain in a four-step sequence as shown below. 

Dihydrocorynantheol (21), first isolated from Aspidosperma marcgravianum (147), is the simplest corynanthe alkaloid. The members of this type of alkaloid have three stereo centers in the D ring of the indolo[2,3-a]quinolizine skeleton. This substitution pattern allows four possible relative arrangements for the C-3, C-15, and C-20 stereo centers, the names of which are normal, pseudo, alio, and epiallo, respectively. 

Corynantheidol (255) has been prepared by Hanaoka et al. (155), who started from piperideine derivative 268 and tryptophyl bromide (197). The key cyclization step, resulting in indolo[2,3-a]quinolizine 270 as the major product besides 271, was carried out by mercuric acetate oxidation in the presence of the disodium salt of ethylenediaminetetraacetic acid (EDTA), followed by sodium borohydride reduction. Finally, lithium aluminum hydride reduction of 270 provided ( )-corynantheidol in good yield (155). 

Lactam 299 was prepared from tryptamine and cyano diester 298 by reductive alkylation in about 12% yield. Phosphorus oxychloride cyclization of 299, followed by catalytic reduction, resulted in the corresponding trans disubstituted indolo[2,3-a]quinolizine 300. After transesterification, formylation and methyla-tion were carried out in two subsequent steps with ethyl formate in the presence of triphenylmethylsodium and with an excess of diazomethane to supply ( )-dihydrocorynantheine (163). 

On the other hand, ( )-corynantheine was achieved from key intermediate 301, used previously in the synthesis of ajmaline (167). The fra/u-tosylhydrazone derivative 302 afforded the desired vinyl-substituted indolo[2,3-o]quinolizine 304 in moderate yield along with the corresponding ethylidene-substituted isomer. Formylation and methylation of 304 afforded finally ( )-corynantheine (164). 

The natural antipode of corynantheine (35, 155, 20/ ) has elegantly been prepared by Autrey and Scullard (168), starting from yohimbone (305), synthesized and resolved previously by Swan (169). Yohimbone (305) was converted to 18-formylyohimbone (306) and then through 307 to oxime 308. On reaction with thionyl chloride, 308 underwent a Beckmann fragmentation to the trans-substituted indolo[2,3-a]quinolizine 310, which after desulfurization and esterification resulted in the levorotatory methyl corynantheate (304). This product... 

A stereoselective total synthesis of ( )-hirsutine has been developed by Brown et al. (179). Catalytic hydrogenation of hydroxycyclopentenone 327, prepared previously (180), afforded a mixture of isomeric diols 328, which were quantitatively cleaved by sodium periodate to supply 329. Reductive amination of 329 with tryptamine resulted in tetrahydropyridine 330, which upon treatment with aqueous methanol in the presence of hydrochloric acid gave indolo-[2,3-a]quinolizine 321 with pseudo stereochemistry. Conversion of 321 to ( )-hirsutine was accomplished in a similar manner by Wenkert et al. (161) via selective reduction with diisobutylaluminum hydride and methylation with methanol (179). 

The addition product of ethyl acetoacetate and methyl a-methoxyacrylate was hydrolyzed, and the resulting dicarboxylic acid was treated with dimethylamine hydrochloride and aqueous formaldehyde. The product of the Mannich reaction was decarboxylated, reesterifed, and finally treated with methyl iodide to supply quaternary salt 469 as the main product. During the above one-pot process, elimination also took place, yielding unsaturated ketone 470, which was later utilized as its hydrogen bromide adduct 471. Reaction of 3,4-dihydro- 3-car-boline either with 469 or 471 furnished the desired indolo[2,3-a]quinolizine derivative 467 as a mixture of two diastereomeric racemates. 

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). 

Treatment of 4-chlorobutanoyl Reissert compounds 219 and 220 with sodium hydride in dimethylformamide afforded indolo[2,3-a]quinolizine derivatives 221 and 222, respectively, in an intramolecular alkylation process (Scheme 28). 

One application of lactone 140 as a chiral synthon may be found in the asymmetric synthesis of (+)-12b-epidevinylantirhine (143), a cleaved product of geissoschizol (Scheme 28) [62-63]. Treatment of 140 with tryptamine in hot toluene afforded 142, which cyclized to lactam 142 by mesylation and an Sn2 displacement. Hie Bischler-Napieralski reaction of 142, followed by reduction of the resulting iminium salt with NaBH4, produced stereoselectively, the indolo[2,3-a]quinolizine as a single isomer, which was further reduced with DIBAL to give (+)-12b-epidevinylantirhine (143). 

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