Direct Coupling of Indoles with Carbonyl Compounds:  Short, Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and Fischerindole Alkaloid Families

Abstract

The invention of a method for the direct union of indoles and carbonyl compounds (ketones, amides, esters) is described. Using this new method, a short, enantioselective, gram-scale and protecting group-free synthetic entry to the fischerindole and hapalindole indole alkaloid family has been achieved from carvone and indole. Total syntheses of (+)-hapalindole Q and (-)-12-epi-fischerindole U isothiocyanate are reported. The absolute stereochemistry of the latter natural product has also been determined.

C-2/C-3 Annulation and C-2 Alkylation of Indoles with 2-Alkoxycyclopropanoate Esters

“…Recent examples of indole functionalization include asymmetric C-3 Friedel-Craft reactions, 1,2,3 allylations, 4,5 radical couplings, 6 arylations, 7,8,9 Michael-additions, 10 C-H activation, 11 and N-arylations. 12 Indoles containing a fused 5-membered ring at the C-2 and C-3 positions are well represented in nature, and include the penitrems 13 and kopsane 14 alkaloids.…”

Oxidative C–C bond formation in heterocyclic chemistry

“…To our delight, when the reaction was attempted, it furnished the desired indole-carvone hybrid 7 as a single diastereomer, albeit in low yield. 12 This initial result was encouraging and we set out to optimize the yield of this remarkable transformation to synthetically useful levels. It should be noted that this first skirmish was not clean and generated at least ten to fifteen compounds, from which 7 was obtained.…”

“…By employing the same conditions which were successful for the union of carvone and indole we were able to expediently access a number of indoles which were previously unobtainable by direct means as shown in Table 2. Simple ketones, esters, and amides work well, and the reaction can be used to form quaternary centers with complete diastereocontrol (12). Compounds with unprotected functionality (13) can also be coupled, requiring only an extra equivalent of LiHMDS.…”

Palladium-Catalyzed Regioselective 2-Carbethoxyethylation of 1H– Indoles By C-H Activation: One-Step Synthesis of Ethyl 2-(1H-Indol-2-Yl) Acetates

“…Owing to the development of the transition-metal catalyzed C-H activation chemistry, methods for regioselective direct C2/C3-alkenylation [27][28][29][30][31][32][33], alkynylation [34][35][36][37][38][39][40][41], cyano [42,43] and arylation [44][45][46][47][48][49][50][51][52] of indole nucleus have been well developed to date. However, regioselective C2-alkylation of indole is more challenging.…”