The enantioselective construction of tetracyclic diterpene skeletons with Friedel–Crafts alkylation and palladium-catalyzed cycloalkenylation reactions

Abstract

Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product.

Applications of Friedel–Crafts reactions in total synthesis of natural products

“…Malachowski and co-workers in 2015 developed an approach for the formation of tricarbocyclic scaffold via an extension of the asymmetric Birch–Cope sequence along with intramolecular FC alkylation reaction. 216 An asymmetric method for the synthesis of the tetracarbocyclic framework of the gibberellins 197a or the ent -kauranes 197b was demonstrated by the same group. 216 There is a tetracarbocyclic ring system in the unit of both the gibberellins and the ent -kauranes 197b.…”

“… 216 An asymmetric method for the synthesis of the tetracarbocyclic framework of the gibberellins 197a or the ent -kauranes 197b was demonstrated by the same group. 216 There is a tetracarbocyclic ring system in the unit of both the gibberellins and the ent -kauranes 197b. The asymmetric formation of tetracyclic diterpene frameworks began from the 5-iodo-salicylate derivative 198.…”

“…Finally, the tetracarbocyclic framework of the gibberellins 197a or ent -kauranes 197b was obtained from 200a and 200b upon several steps ( Scheme 43 ). 216 …”

Insight into the shift and rearrangement of carbocation in Friedel-Crafts alkylation of unsaturated fatty acids revealed by GC–MS

“…Alkylation of cyclohexene and 1-pentyl chloroformate in the presence of triethylsilane yielded mixtures of 2-and 3-cyclohexylpentane in a ratio of 1.3:1, due to the Wagner-Meerwein rearrangement [5]. The isomeric compounds of alkyl chain might be generated through rearrangement of carbocation in Friedel-Crafts alkylation [17][18][19]. The cyclobutene skeleton was formed from cyclopropyl group by rearrangement of carbocation under Lewis acid conditions [20].…”