A Short and Facile [2 + 2] Photocycloaddition Protocol Toward Construction of a Levuglandin Skeleton

Abstract

The γ-ketoaldehyde functionality of levuglandins (LGs) has a great propensity for various diseases such as Alzheimer's, atherosclerosis, and renal diseases. The synthesis of LGs constitutes a challenge for synthetic organic chemists due to their complex structures and low abundance in nature which has prompted us to develop its quick synthesis. This study aimed to explore a novel route for the construction of a levuglandin skeleton. We envisaged that the photocycloaddition of an appropriate alkene with equivalent propyne would give the cyclobutene adduct. The oxidative cleavage of the photocycloadduct can lead to the formation of the keto-aldehyde functionality. In this study, the readily available isopropenyl acetate (5) and methyl oleate (6) were used as starting materials to synthesize the target compound 13. The key step involves photocycloaddition of compounds 5 and 6, a regio-controlled elimination of the hydroxy group of compound 10, forming a cyclobutene derivative, as well as an oxidative cleavage of the cyclobutene derivative gives the framework of levuglandin. The intriguing chemistry of elimination resulting in the inseparable mixture of regioisomeric cyclobutenes has also been discussed. The route was simple and economical and helped for the creation of γ-ketoaldehyde functionality which is vital for the activity of levuglandins and can be extended for the construction of prostanoid skeleton through aldol condensation of the γ-ketoaldehydes.