Pyrido indole skeleton

The intramolecular cycloaddition of nitrones derived from iV-allyl-2-indolecarbaldehyde was used to an entry to pyrrolo- and pyrido[ 1,2-a]indole skeletons . For instance, the cinnamyl-substituted aldehyde 157 upon treatment with benzylhydroxylamine affords to the nitrone 158, which upon heating in refluxing toluene leads to mainly the cycloadduct 159. 

One of the rare examples, where the palladium catalyzed closure of a six membered ring leads to an aromatic heterocycle is presented in 4.18. Intramolecular transformation of the 2-bromoindole derivative in the presence of a palladium-BINAP catalyst led to the formation of the a-carboline (pyrido[2,3- ]indole) skeleton. The ring closure was accompanied by the oxidation of the intermediate dihydrocarboline derivative.21... 

The (i-carbolinc skeleton with its 9H-pyrido[ 3,4-fr ]indole (29) is frequently encountered in pharmacology due to its activity in the central nervous system at serotonin receptors. It also shows prominent biological properties at the benzodiazepine receptor (BzR) [45]. ZK 93423 (30) remarkably amplifies the agonist activity of such compounds towards BzR. 1,2,3>9-Telrahydro-(>-carbolines are common precursors of (i-carbolines [46]. 1,3.4,9-Tetrahydro-... 

The extension of the above regioselective 6-endo cyclization to appropriately substituted substrates provided a novel synthetic entry to the pyrido[4,3-b]carbazole skeleton of the indole alkaloid olivacine, which resulted in a concise total synthesis of its tetrahydro derivative ( )-guatambuine <6 IT 160 67CJC89>. 

Attention was centered on radical precursors in which the 3-pyridyl moiety was attached at the indole-3-position with the aim of directly producing the pyrido[4,3-b]carbazole skeleton of ellipticine by regioselective cyclization upon the 4-position of the pyridine ring. Satisfactorily, A-methyl and A-benzyl selenoesters 52a and 52b led to the ellipticine quinones 53a and 53b in acceptable yields (60 and 42% yield, respectively), after the radical cyclization and the in situ oxidation at the interannular methylene group. The cyclization was clearly less efficient from A-(methoxymethyl) selenoester 52c and no reaction was observed... 

Examples of migratory insertion to aromatic rings also include the total syntheses of anhydrolycorine-7-one (217) [102] and the f-azaebutnane series [103]. As illustrated in Scheme 38, an intramolecular Heck reaction of Af-acylindoline 216 installed the six-membered lactam in anhydrolycorine-7-one (217). In a similar process, the tetracyclic pyrido-[2 ,3 -prepared from bromopyridine 218 under phase-transfer catalysis conditions. Pyridyl indole 219 is a precursor of the pentacyclic skeleton of the E-azaeburnane series. 

Tsuda, Y., Ishiura, A., Hosoi, S., and Isobe, K., Studies toward total synthesis of non-aromatic Erythrina alkaloids. Part 2. A general method for synthesis of perhydro-6/7-pyrido[2,l-z]indole derivatives. Synthesis of isoerythroidine skeleton, Chem. Pharm. Bull., 40, 1697, 1992. 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

One representative example in enantioselective alkylation of benzylic C-H bond was disclosed by Gong and co-workers in 2010. Highly enantioselective alkylation of 3-arylmethylindoles with dibenzyl malonate was achieved in the presence of catalytic amounts of chiral copper complex L4 (Scheme 2.31) [169]. This protocol provides an excellent enantioselective route to natural product skeleton of 2,3,4,4a,9,9a-hexahydro-lH-pyrido[2,3-b]indoles. 

---