Synthesis of cis- and trans-Davanoids: Artemone, Hydroxydavanone, Isodavanone, and Nordavanone

Abstract

A concise and versatile synthesis of both cis and trans diastereomers of the natural products artemone, hydroxydavanone, isodavanone, and nordavanone has been accomplished. The preparation of trans-davanone is also described. Each synthesis is six to eight steps from geranyl acetate, with differentiation between cis and trans products occurring through a diastereoselective cyclization prior to derivatization. Many of these compounds are minor components of davana oil and have now been synthesized for the first time.Davana oil, the essential oil of the Indian sage Artemisia pallens, contains over 30 terpenoid natural products (Figure 1). 1 The most abundant of these is cis-davanone, 2 which is reported to have antifungal, 3 antispasmodic, 4 and antibacterial 5 properties. Indeed, cis-davanone has been the target of several synthetic studies. 6 Other davanoids (compounds with structures related to davanone) have received much less attention in synthetic and bioactivity studies, perhaps due to their relative scarcity in davana oil. 1 Among the davanoids that have never before been prepared stereoselectively (if at all) are trans-davanone, trans-nordavanone, trans-artemone, cis-and trans-hydroxydavanone, and cis-and trans-isodavanone. The most compelling target among these is cis-hydroxydavanone, whose antifungal activity is four-fold greater than that of davanone against a range of fungi. 3 Driven by the possibility of discovering more potent antifungal agents and the lack of stereoselective syntheses of many of these compounds, we adapted our enantioselective seven-step synthesis of cis-davanone 6g to these other davanoids. We previously reported five-step syntheses of cis-and trans-davana acid ethyl esters (1 and 2) using Pd 2 dba 3 and either C 3 -(S)-TunePhos or C 3 -(R)-TunePhos, respectively. 6g These esters were treated with prenylmagnesium chloride to produce cis-and trans-artemone directly (3 and 4, see Scheme 1). The γ-prenylated products 3 and 4 did not undergo a second Grignard addition to the ketone, as Baran et al. observed for a similar reaction. 7 Our sixstep synthesis of cis-artemone (3) is significantly shorter than the only previous stereoselective route, a 20-step achievement by Honda et al. 6e A nonstereoselective preparation of artemones has been reported by Naegeli et al. 8 Scheme 1 Preparation of cis-and trans-artemoneIn order to prepare other davanoids, cis and trans esters 1 and 2 were converted into the corresponding Weinreb amides 5 6g and 6, respectively (Scheme 2). From these Weinreb amides, cis-and trans-nordavanone (7 and 8) were readily generated with methylmagnesium chloride. Likewise, trans-davanone (9) was obtained after reaction of 6 with prenylmagnesium chloride.