Abstract:

A convenient approach toward the indoloquinolines neocryptolepine and 6-methylquinindoline from a common intermediate, is reported. Both sequences, designed for maximum use of accessible reagents and robust conditions, are straightforward and efficient. They involved the amidation of 2- aminobenzaldehyde (prepared by iron-mediated reduction of 2-nitrobenzaldehyde) with 2- nitrophenylacetic acid, followed by a K2CO3-assisted cyclization to form a 3-(2-nitrophenyl)quinolin-2- one as the common precursor. Me2CO3-mediated N-methylation of the lactam, reduction of the nitro moiety and final cyclization resulted in 55% overall yield of neocryptolepine, whereas cyclocondensation and N-methylation afforded 79% overall yield of 6-methyl quinindoline. Thus, the sequences toward the targets entailed two POCl3-promoted C–N bond forming reactions, two Fe-mediated nitro group reductions and two base-promoted transformations.

Author affiliation: Kaufman, Teodoro Saúl. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario. CONICET; Argentina

Author affiliation: Larghi, Enrique Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario. CONICET; Argentina

Author affiliation: Bracca, Andrea Beatriz Juana. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario. CONICET; Argentina

Author affiliation: Heredia, Daniel Alejandro. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario. CONICET; Argentina.

Author affiliation: Mendez, María Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario. CONICET; Argentina.

Abstract:

A straightforward approach toward 6-bromo-2-isopropylidenecoumaranone, a potential intermediate toward alkaloid TMC 120-B, pseudodeflectusin, and other natural products, was reported. The synthetic sequence involved the reaction of 3-bromosalicylaldehyde with chloroacetone and cyclization of the resulting ether to a 2-acetylcoumaranol intermediate. This was followed by sequential methyl Grignard addition and Jones’ oxidation to the corresponding coumaranone, which was dehydrated to the final product with the methanesulfonyl chloride/pyridine reagent. The protection of the coumaranol as the corresponding THP-ether resulted in improved product yields.

Author affiliation: Pergomet, Jorgelina Leonor. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.

Author affiliation: Kaufman, Teodoro Saúl. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.

Author affiliation: Bracca, Andrea Beatriz Juana. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.

Abstract:

The first total synthesis of 5-(1-hydroxy-1-ethyl)-2-isopropyliden-2H-benzofuran-3-one, is reported in its racemic and in one of its optically active [(S)-( )] forms. This heterocycle, isolated from Verbesina luetzelburgii, is the only known 2-isopropyliden-2H-benzofuran-3-one produced by species of Verbesina. The sequence took place in eight steps and 19% overall yield (up to 33% for the chiral form), from 40-hydroxyacetophenone. It entailed carbonyl group protection as the 1,3-dioxolane and a phenol ortho formylation, followed by a Williamson etherification with chloroacetone and an organocatalytic cross-aldolization, to afford a 2-acetyl-2,3-dihydrobenzofuran-3-ol intermediate. The latter underwent a methyl Grignard addition to the carbonyl moiety, followed by selective oxidation of the benzylic alcohol and deprotection, resulting in a b-hydroxy diketone derivative. A MsCl-assisted dehydration of the tertiary alcohol, established the isopropylidene motif, whereas the syntheses culminated by chemical or enzymatic (carrot, celeriac) selective reductions of the exocyclic carbonyl group.

Author affiliation: Kaufman, Teodoro Saúl. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina.

Author affiliation: Bracca, Andrea Beatriz Juana. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina.

Author affiliation: Larghi, Enrique Leandro. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina.

Author affiliation: Pergomet, Jorgelina Leonor. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina.