Reduction Indole

MK-677, an orally active spiroindoline-based growth hormone secretagogue (GHS) agonist, discovered by Merck and currently in Phase II clinical studies, was synthesized with a Fischer indolization as a key step. The synthesis of this agonist involved a Fischer indole/reduction process and was achieved in 48% overall yield from the relatively cheap starting material, isonipecotic acid 72. ... 

FIGURE 7.21 Enriched 13C-NMR spectrum of cyclopent[ ]indole reductive activation... 

Similar to the Fisher indole synthesis, reductive cyclization of nitro aromatics offers a powerful means of forming indoles. Reductive cyclization of ortho, 2 -dinitrostyrenes has occurred in many ways, by TiCl3, NaBH4-Pd/C, H2-Pcl/C, and other reductive methods.89 Corey and coworkers have used the Borchardt modification (Fe-AcOFI, sihca gel, toluene at reflux for the reductive cyclization of o-ji-dinitrostyrenes) to prepare 6,7-dimethoxyindole (Eq. 10.65) in a total synthesis of aspidophytine (see Schemes 3.3 and 3.4 in Section 3.2.l).89d... 

XLIII) the IR-spectrum of its iodide is also similar to that of sempervirine iodide and further shows the absence of a vinyl group. Catalytic hydrogenation of melinonine G over Adams catalyst in aqueous alkaline solution gives an indole which yields propionic and acetic acids on modified Kuhn-Roth oxidation and which, therefore, contains a C-ethyl group. All this evidence is accommodated in structure XLIV for melinonine G the indolic reduction product must then have structure... 

In addition to the general reviews on indole reduction that were cited above, several reviews and key papers on the dissolving metal reduction of indoles should be consulted for reference to the early work, ... 

The dissolving metal reduction of benzo[b]furans and dibenzofurans is a classical technique and, depending on the conditions, can give rise to a variety of products.Several examples are summarized in equations (104-108). " The cleavage of dibenzofurans to afford 2-hydroxy biphenyls (equation 107) is a particularly valuable route to these compounds. The reduction of 3-carbomethoxybenzofu-rans with Mg/MeOH (equation 108) is reminiscent of the indole reduction reported earlier (equation 51). 

Boger s synthesis commenced with the preparation of the left-hand fi agment 155. A sequence of phenol protection of 151, aldehyde oxidation, Curtius rearrangement, tosylation, nitro reduction, Boc protection, and Pb(OAc)4 mediated oxidation afforded quinodiimide 152. A key Diels-Alder reaction gave 153 in good yield. Treatment of 153 in a sequence of oxonolysis, aromatization, Boc deprotection, cyclization to the lactam, A-tosyl removal, indole reduction, and selective Boc protection afforded 154. Conversion of the lactam to the... 

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