Biomimetic total synthesis of litseaverticillols A, C, D, F, and G: singlet-oxygen-initiated cascades.

Abstract

chloroform extracts from the leaves and twigs of a perennial shrub, Litsea verticillata Hance, found in Cuc Phuong National Park, Vietnam. The eight new sesquiterpenes (1– 8) were fully characterized because of their potent anti-HIV activity. More advanced biological studies revealed that compounds 1–8 inhibit HIV-1 replication in HOG.R5 cells (a reporter cell line) with IC50 values (the concentration required for 50% inhibition) ranging from 2 to 15 mgmL 1 (8– 85 mm). Furthermore, this viral inhibition was shown to be selective; HOG.R5 cell growth was only significantly affected at concentrations twoto threefold higher than the IC50 values. The demonstrated anti-HIVactivity in the absence of any apparent toxicity to host cells shows these molecules to have an impressive selectivity and makes them attractive candidates for further study. Of equal interest is the puzzle of how the racemic litseaverticillols (1–8) are derived in the natural environment. Racemic mixtures are highly atypical of natural products, whose syntheses are usually templated by homochiral enzymes. Herein, we provide a potential answer to this dichotomy in the form of a proposed biomimetic synthesis that delivers litseaverticillols A (1) and C (3) as the products of a one-pot, five-operation cascade sequence beginning with an achiral precursor and initiated by a cycloaddition reaction involving singlet oxygen (O2). [3] Further support for the biogenetic hypothesis is garnered from the subsequent elaboration of litseaverticillol A through singlet-oxygenmediated transformations to afford three additional family members. Careful examination of these structurally related sesquiterpenes revealed that litseaverticillols D–H (4–8) could arise from direct oxidation of the first-generation litseaverticillols A–C (1–3). For example, litseaverticillols D, F, and G are the three possible products that can be derived from an ene reaction with O2 [4] at the side-chain double bond most distal to the cyclopentenone ring in litseaverticillol A (Scheme 2). In a similar manner, litseaverticillol B could be expected to be the precursor to litseaverticillol E, while litseaverticillol H may represent the oxidation product of both litseaverticillols F and G. This proposed biogenetic origin of the litseaverticillols D–H is in full accord with the high natural abundance of the three components necessary for the photochemical formation of highly reactive singlet oxygen, which are: a) molecular dioxygen (ca. 20% in atmospheric air),