Asymmetric reduction of substituted indanes as scaffolds for the synthesis of potential drug candidates

The indanone core is ubiquitous to a host of isolated natural compounds that have shown significant biological activities against HIV, cancer, malaria, diabetes, respiratory disorders and many more.1 Isopaucifloral F and its isomer Paucifloral F have the indanone cores embedded in their structures. The former is found in grapes, nuts and other plants with medicinal properties and is a potential candidate for osteoporosis.2,3 It is reported to have interesting pharmacological and biological activities including antioxidant, anticancer, antifungal and antibacterial properties. The latter (Paucifloral F), is a promising anti-viral agent. Among the most privileged indanones, are the 3-substituted indanones which can be transformed into a variety of biologically active compounds. A new method for the synthesis of 3-aryl-2-phosphoryl indanones was developed for the first time using modified Heck cyclisation conditions.

The strategy was adopted after many unsuccessful Nazarov cyclisation attempts of phosphorylated chalcones that were obtained from Knoevenagel condensation of β-ketophosphonates previously synthesised by the phosphono-Claisen condensation of aryl esters and alkyl phosphonates.

Different types of 3-aryl indanones were also synthesized via classical Heck reaction of 2-bromo chalcones and kinetic resolution (KR) via asymmetric reduction of the prepared 3-aryl indanone cores using amino indanol catalysts was investigated for the first time on these types of systems. 50% ee was achieved on the major cis indanol while the minor had better enantioselectivity of 88%.

Reproducibility issues necessitated the use of an alternative reducing agent. Room temperature reaction of DPEN-based Ru(II) catalysts 10 mol% had a remarkable outcome at 50% conversion providing almost exclusively the cis isomer with dr > 95:5 (cis/trans), excellent ee of 94% and 82% ee on unreacted starting material on simple and substituted indanones.