Catalytic Intramolecular Ketone Hydroacylation: Enantioselective Synthesis of Phthalides

Abstract

The development of a new transition-metal-catalyzed transformation can often allow a traditional reaction, perhaps one that employs stoichiometric amounts of reagents and harsh reaction conditions, to be replaced by a selective, atom economic process which proceeds under mild reaction conditions. This is certainly the case with the recent report from Dong and co-workers of a catalytic enantioselective synthesis of phthalide compounds. The disproportionation of aldehydes has traditionally been achieved under basic conditions and is known as the Cannizzaro reaction. A Lewis acid promoted variant—the Tishchenko reaction—is a related transformation that converts two carbonyl units into the corresponding ester. Both processes suffer from the formation of side products and have not been readily adapted to catalytic asymmetric reactions. As an alternative to these processes the Dong research group has developed catalytic enantioselective intramolecular ketone hydroacylation reactions. Transition-metal-catalyzed hydroacylation reactions usually proceed through initial formation of an acyl metal hydride species, and subsequent addition of this species across a multiple bond. Hydroacylation reactions of alkenes and alkynes are now well-studied processes, with a number of enantioselective variants already reported. However, the corresponding processes requiring addition of the acyl metal species across a ketone or an aldehyde—carbonyl hydroacylation—are much less studied. The key intermediates for both types of reaction, the acyl metal hydride species, are formed by the oxidative addition of the metal catalyst to the aldehyde C H bond; a process that can be considered as a type of C H activation. In common with a number of reactions that are based on C H functionalization, hydroacylation reactions offer advantages in terms of step and atom economy. Dong and co-workers originally developed a catalytic enantioselective intramolecular ketone hydroacylation reaction as a route to enantiomerically enriched seven-membered lactones (Scheme 1). To achieve efficient reactions the substrates employed in these transformations were required to feature a chelating ether group. Developing a ketone hydroacylation route to phthalide compounds presented a greater challenge, as the substrates needed to target the phthalide architecture would no longer allow the presence of a coordinating ether group. The reaction shown in Scheme 2 illustrates the basic process used to access enantiomerically enriched phthalide compounds. Ketobenzaldehydes such as 1 were the key substrates for the process, and delivered five-membered lactones 2, phthalides, through the proposed ketone hydroScheme 1. Synthesis of seven-membered lactone derivatives based on enantioselective ketone hydroacylation.