Asymmetric phase-transfer-catalyzed intramolecular N-alkylation of indoles and pyrroles: A combined experimental and theoretical investigation

摘要

Asymmetric phase-transfer catalysis (PTC) has risen to prominence over the last decade as a straightforward synthetic methodology for the preparation of pharmacologically active compounds in enantiomerically pure form. However, the complex interplay of weak nonbonded interactions (between catalyst and substrate) that could account for the stereoselection in these processes is still unclear, with tentative pictorial mechanistic representations usually proposed. Here we present a full account dealing with the enantioselective phase-transfer-catalyzed intramolecular aza-Michael reaction (IMAMR) of indolyl esters, as a valuable synthetic tool to obtain added-value compounds, such as dihydro-pyrazinoindolinones. A combined computational and experimental investigation has been carried out to elucidate the key mechanistic aspects of this process. La catalisi asimmetrica per trasferimento di fase è, a tutt'oggi, una fra i metodi di sintesi stereoselettivi pi efficaci per la preparazione di intermedi chiave dell′indotto farmaceutico. Tuttavia, i complessi network di legami deboli che generalmente si instaurano fra catalizzatore e substrato in queste trasformazioni non consentono di comprendere appieno gli aspetti alla base delle elevate stereoselezioni ottenute. In questo studio, con un approccio combinato sperimentale/computazionale, vengono esplicitati gli aspetti meccanicistici chiave nella sintesi enantioselettiva di composti ad elevato valore aggiunto come i diidro-pirazinoindoloni, tramite addizione tipo aza-Michael intramolecolare per trasferimento di fase (IMAMR). Union is strength: A combined computational and experimental investigation has shed light on a network of weak interactions responsible for the high stereochemical translation in the phase-transfer-catalyzed intramolecular N-alkylation of indoles (see figure).