Bicyclic indoles

Similarly, tryptophol 27 was obtained in 60-70% yield with other amines. Each by-product related to the corresponding amine was also observed (Scheme 4.20). For example, using triethylamine as base forms indole impurity 75 while using dicyclohexyl amine leads to the formation of bicyclic indole impurity 76. 

Thereafter, molecules have been synthesised with a bicyclic ring, such as a quinoleine or an indole, inserted. Many of these compounds like zoniporide and BMS-284640 are selective NHE1 inhibitors, but some inhibit also other isoforms. Most recently, an additional group of compounds with 4-substituted (benzo[b]thiophene-2-carbonyl) guanidines has been synthesised and these are potent NHE1 inhibitors. A structurally distinct compound, S-3226, was found to be the first selective NHE3 inhibitor. 

Indole-2,3-quinodimethanes [44] 44 are bicyclic outer-ring dienes that are widely used to prepare a variety of heterocyclic polycyclic compounds. These dienes, generated by extrusion of CO2 from lactones, are then trapped by dienophiles. Some examples of Diels Alder reactions of the dienes 44 are reported in Scheme 2.19. 

This suite of BVMOs is available via whole-cell expression systems and represents a complementary platform of biocatalysts for diverse applications in chiral synthesis. Representatives of this collection were utilized in the enantiodivergent synthesis of the indole alkaloids alloyohimbane and antirhine from a fused bicyclic precursor (Scheme 9.19) [151]. 

One last word on heterocycles. Very small couplings (< 1 Hz) have been found to exist between some protons on different rings of bicyclic heterocycles. For example, in indole, there is a 3-7 coupling of about 0.7 Hz. In practise however, these very small couplings may only manifest themselves as a broadening of the signals concerned. 

Variation of the ring portion of acyclovir has been achieved. Compounds include monocyclic (isocytosine, triazole, imidazole), bicyclic (adenine, 8-azapurine, pyrrolo[2,3-c/]-pyrimidine, pyrazolo[3,4-[Pg.131]

The Fischer indolization of bicycloketones of the morphane series often has been used for the synthesis of the corresponding azocinoindoles (89TL3841, 90TL2449, 92LA461). Thus, bicyclic ketone 44, under Fischer conditions, has been transformed into azocinoindole 45 in moderate yields (94JOC3939 Scheme 11). 

Similarly, mono- and bicyclic 1,2-diazines tethered to indole dienophiles by only one alkylene chain 14 afford tetra-and pentacyclic condensed carbazoles 15. Unactivated pyridazines undergo these thermally induced [4+2] cycloaddition reactions only very sluggishly. However, the examples with the more activated electron-deficient pyridazines, especially pyridazine diesters and pyridazino[4,5-, pyridazindiones, demonstrate the synthetic usefulness of this strategy for the construction of polycyclic carbazoles (Equation 3) <2004T6495>. 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

Indok. This is a bicyclic (one five-membered ring plus one six-membered ring) aromatic heterocycle. Since most indole-containing drugs are substituted with the remainder of the drug being positioned at the 3 position, the aromatic hydroxylation tends to occur at the 4-7 position. 

The relative abundance of indole-based therapeutic agents is attributable only in part to the fact that this nucleus forms part of a pharmacophore for selected CNS agents. The indole moiety, however, likely simply serves as a rigid bicyclic support in the majority of the agents discussed below. 

Indole derivatives might also be prepared by the palladium catalysed reductive heteroannulation of o-nitrostyrene derivatives. The bicyclic olefin, shown in 3.75. was converted to the indole derivative in good yield.94 The reaction, which was run under forcing conditions utilises carbon monoxide as the reducing agent. 

The reaction of pyrrole with dichlorocarbene, generated from chloroform and strong base, gives a bicyclic intermediate which can be transformed to either 3-chloropyridine (155) or pyrrole-2-carbaldehyde (156). Indole gives a mixture of 3-chloroquinoline (157) and indole-3-carbaldehyde (158). The optimum conditions involve phase transfer (76S249, 76S798). Benzofuran reacts with dichlorocarbene in hexane solution to give the benzopyran (159), whereas benzothiophene fails to react. 

The poisonous components of the most deadly mushroom Amanita phalloides (the Death Cap) are bicyclic heptapeptides which have an additional covalent bond that connects the ( -sulfur atom of an l-cysteine residue with the carbon atom in position 2 of the indole ring of the L-tryptophan. Phalloidin (or phalloidine) is the most abundant member of a whole family of related cyclic heptapeptides called phallotoxins (for a review, see Wieland1 1). These poisonous peptides, therefore, contain a cross-linking moiety consisting of L-tryptophan coupled to L-cysteine, designated tryptathionine (1), alternatively called 5-(trypto-phan-2-yl)cysteine or 2-(L-3-alanylsulfenyl)-L-tryptophan (Scheme 1). 

In addition to acyclic and monocyclic enamines, bicyclic and tricyclic enamines also undergo cycloaddition with dihalocarbenes. Endocyclic enamines , such as pyrrole and indole, add dichforocarbene and the adducts rapidly undergo ring cleavage to afford 3-chloropyridine and 3-chloroquinoline, respectively, in moderate yields (c/. Section 4.7.3.9).75-77... 

One of the first examples of radical cydization reactions in the total syntheses of indole alkaloids was Stork s approach towards ( )-gelsemine (55) [58] featuring a mixed acetal 6-exo radical cydization as the pivotal step (Scheme 23). Thus, exposure of cyclopentene bromide 117 to standard radical cydization conditions led to the cii-fiised bicyclic ester 118. A relatively dilute concentration (0.02 M) was needed to minimize possible intermolecular reactions although the intramolecular reaction was kinetically more favored. Diastereomeric phenylselenides were easily obtained by treating 118 with LDA and quenching the enolate with diphenyl diselenide. The a,P-unsaturated ester 119 was secured when the selenide underwent... 

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