An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations

Abstract

The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.

Biocatalysed olefin reduction of 3-alkylidene oxindoles by baker's yeast

“…The preparation of enantioenriched 3-alkyl 2-oxindoles has been previously reported in the literature by means of different approaches. [29][30][31][32][33] In particular the reduction of 3-yliden-oxindoles catalysed by a chiral iridium complex was reported to proceed with ee up to 93%. 34 We reasoned that our results might be ascribable to an epimerisation of the newly formed stereogenic centre.…”

Enantioselective Arylation of Oxindoles Using Modified BI-DIME Ligands

“…The scope of the 3-arylation of oxindole 4 with respect to the aryl halide was examined next (Scheme 1). (4). Reagents and conditions: 1-2 mmol oxindole, 1.1 equiv LiHMDS (1 M in toluene), 1.1 equiv ArX, 2.5 mol% Pd 2 (dba) 3 , 5.0 mol% i-Pr-BI-DIME, 1-2 mL THF, 70 °C, 4-24 h. Yields are those of isolated products.…”

“…3-Substituted and 3,3-disubstituted oxindoles are common structural motifs found both in pharmaceuticals and natural products. 3 Oxindoles bearing a 3-aryl substituent have been found to exhibit diverse biological activity, such as p53 inhibition (1), 4 anticancer activity (2), 5 and neuroprotection (3) 6 (Figure 1). The methods reported for the synthesis of 3-aryloxindoles can roughly be divided into two categories: those which build the oxindole unit last after incorporation of the 3-aryl group in a precursor substrate, 6,7 and those which install the 3-aryl group onto an already assembled oxindole core.…”

A molecular electron density theory study of the [3 + 2] cycloaddition reaction of nitrones with ketenes

“…Accordingly, the nucleophilic P k − Parr functions of nitrone 1b and the electrophilic P k + Parr functions of ketenes 4b,c were analysed in order to characterise the most electrophilic and nucleophilic centers of the species involved in these 32CA reactions and, thus, to explain the regio-and chemoselectivity experimentally observed (see will take place between the most nucleophilic center of nitrone 1b, the O1 oxygen atom, and the most electrophilic center of ketenes 4b,c, the central C5 carbon, in clear agreement with the regioselectivity experimentally reported first by Taylor 42 and further by Houk. 13 On the other hand, analysis of the electrophilic P k + Parr functions of ketenes 4b,c also indicates that while the ketene O4 oxygen atom presents some electrophilic activation, P k + = 0.25 (4b) and 0.27 (4c), the terminal C6 carbon is slightly electrophilically deactivated, P k + = −0.03. This means that along the zw-type 32CA reaction of nitrone 1b with ketenes 4b,c, the terminal carbon does not participate in the reaction, and thereby, this zw-type 32CA reaction will present a complete CvO chemoselectivity.…”

“…12 Houk and co-coworkers studied the reaction between N-aryl nitrones and alkylarylketenes giving rise to a "pericyclic" cascade with chirality transfer. 13 However, their study only referred to a particular process in which it was suggested that the first cycloaddition step between the nitrone and the ketene is a one-step reaction but highly asynchronous.…”