Enantioselective direct α-alkylation of cyclic ketones by means of photo-organocatalysis

Abstract

We report here the first asymmetric catalytic alkylation of unmodified ketones with alkyl halides. This metalfree approach, which requires light in order to proceed, provides a rare example of highly enantioselective photochemical catalytic processes. An easily available cinchona-based primary amine catalyst guides both the stereoselectivity-defining event and, through the transient formation of photon-absorbing chiral electron donor-acceptor complexes, the photo-activation of the substrates.

Direct Asymmetric Alkylation of Ketones: Still Unconquered

“…[3e,f] More recently, a few examples have appeared involving the a- alkylation of ketones. Melchiorre’s group [50] extended theirA similar approach was reported by Luo and co-work- ers [52] for the alkylation of β-ketocarbonyls, accessing acyclic quaternary centers (Scheme 27). Again the combination of a chiral primary amine and Ru(bpy) 3 Cl 2 as photocatalyst achieved the corresponding alkylated products with good yields and excellent enantioselectivities.…”

Organocatalytic enantioselective desymmetrisation

“…The aziridine nitrogen atom is generally protected in desymmetrisation reactions and the nature of nitrogen protecting group adds an extra variable to reaction design. The reaction proceeded well using a range of cyclic substrates, with slightly lower enantioselectivities for simple alkyl substituted aziridines (142). 72 List and co-workers have developed a novel approach towards the nucleophilic ring opening of meso-aziridines.…”

“…140 Catalytic phthalic acid (37.5 mol%) encouraged the loss of water from the dibenzylic alcohol 308, forming the stabilised 4,4 0 -bis(dimethylaminophenyl)methane carbocation, which reacted with the transient enamine nucleophilic intermediate to give trans-2,4-disubstituted cyclohexanones in high yields, generally good drs and moderate to good ees. 142 Using cinchona alkaloid-based primary amine catalyst C-86, the cyclohexanone-derived enamine formed a donor-acceptor complex with the electron-poor aromatic ring; subsequent irradiation with visible light led to the formation of benzyl and iminium radicals, which could combine in a highly enantioselective manner. High catalyst loadings of 25 mol% were employed.…”

Enantioselektive Katalyse photochemischer Reaktionen

“…[89] Mechanistisch (68) in enantioselektiven a-Alkylierungen über-nehmen kçnnen. [92] In neueren Arbeiten haben Melchiorre und Mitarbeiter gezeigt, dass in vielen Fällen für die a-Alkylierung von Aldehyden [77] und Ketonen [93] kein zweiter Katalysator bençtigt wird. Vielmehr genügt eine direkte Anregung mit sichtbarem Licht, um derartige Alkylierungen durchzuführen.…”