Synthesis of Lignans Utilising the Acyl-Claisen Rearrangement: Total Syntheses of (+)-Ovafolinin A, B, (–)-Bicubebin A, B and (+)-Bicubebin C

Abstract

Lignans are a diverse class of natural plant products which continue to provide new chemical structures as potential biologically active compounds. The recent syntheses of lignans has allowed for the development of new synthetic methods, confirmed or corrected proposed structures for these natural products and allowed for the synthesis of analogues for the optimisation in biological activity. Selectively functionalised 1,4-diarylbutane-1,4-diols have been shown to undergo a number of different reactions upon treatment with methanesulfonyl chloride and trimethylamine leading to three different sub-classes of lignans, depending on the nature of the aryl groups. Rearrangement leading to 4,4- diarylbutanals was the most common transformation and these butanals were reduced to give analogues of seco-lignans. Due to their linear, freely rotatable, structure many of these natural secolignans are reported without any stereochemical assignment. Analysis of the synthetic seco-lignans and analogues revealed significant differences between the NMR data of syn- and anti-isomers. This information was then used to determine the relative stereochemistry of previously undefined natural products. The mechanism of these novel rearrangements to form the 7,7-diaryl-8,8′-dimethylbutan-7′-ol lignans were then analysed using deuterium labelling studies. This revealed that an unexpect OTBS migration takes place in competition with cyclisation to form a spirocyclic intermediate which rearranges to give 4,4-diarylbutanals, whereas the OTBS migration gives rise to the observed aryl tetralin products. A range of dibenzyl butyrolactone lignans were then synthesised utilising the acyl-Claisen rearrangement of phenyl propionyl chlorides and 4-phenylbut-2-en-1-yl morpholines to give 2,3- dibenzyl morpholine pentenamides. Upon dihydroxylation, these compounds cyclise to give 5- hydroxymethyl analogues of dibenzyl butyrolactone lignans. Reduction of these compounds followed by oxidative cleavage and subsequent oxidation completed a novel short synthetic route to a number of biologically active dibenzyl butyrolactone lignans. Next, the first total synthesis of (-)-bicubebin A was achieved through the dimerization of 3,4-dibenzyltetrahydrofuran lactol lignan, (-)-cubebin, under mild conditions. Alongside the synthesis of (-)- bicubebin A were synthesised two previously unreported dilignans, (-)-bicubebin B and (+)-bicubebin C. Analysis of the data for (-)-bicubebin B showed it matched those of reported (-)-cis-cubebin. Subsequent synthesis of the proposed structure of cis-cubebin confirmed it did not match the reported data. This work therefore confirmed the structure and absolute stereochemistry of (-)-bicubebin A, and permitted the structural reassignment of cis-cubebin as (-)-bicubebin B. Following this the first total synthesis of ovafolinin A and B, lignans that consist of a unique bridged structure containing a penta- and tetracyclic benzoxepin and an aryl tetralin, was achieved with an acylClaisen rearrangement initially being utilised to construct the lignan backbone with correct relative stereochemistry. It was found that judicious use of a bulky protecting group placed the reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective ii synthesis of (+)-ovafolinin A and B, which confirmed the absolute stereochemistry of the natural products. Comparison of optical rotation data suggests that these compounds are found as scalemic mixtures in nature.