Indolo quinolizin-4-ones

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... 

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. 

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. 

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). 

A somewhat related two-step method for the synthesis of areno[a]quinolizines involves the preparation of a cyclic hemiacetal from a p-dicarbonyl compound and an a,p-unsaturated aldehyde. The subsequent reaction of this hemiacetal with tryptamine in the presence of a Brpnsted acid affords the target product, probably through a Pictet-Spengler reaction, and the use of chiral Brpnsted acids has been investigated and found to lead to good enantioselections in some cases [74]. The reaction between P-amidoesters derived from tryptamine and a,p-unsaturated aldehydes affords lactams derived from the indolo[2,3-fl]quinolizin-4-one system [75]. 

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