& Natural Products Biomimetic Synthesis of (+)-Ledene, (+)-Viridiflorol, (À)-Palustrol, (+)-Spathulenol, and Psiguadial A, C, and D via the Platform Terpene (+)-Bicyclogermacrene Duc N. Tran and Nicolai Cramer* [a] Abstract: (+)-Bicyclogermacrene is a strained bicyclic and common sesquiterpene found in several essential oils. A short and good yielding synthesis of bicyclogermacrene pro- ceeding in seven steps is reported. This terpene is used as key platform intermediate for a biomimetic access to several aromadendrene sesquiterpenoids, such as ledene, viridiflorol, palestrol, and spathulenol. Furthermore, bicyclogermacrene is shown to be the terpene component in the synthesis of the meroterpenoids psiguadial A, C, and D. Introduction Terpenoids constitute one of the largest natural product fami- lies, [1] with an important economic value, for example, as fla- vours, fragrances, spices, and drugs. [2] The biosynthesis of ter- penoids is commonly divided into two phases: the cyclase and the oxidase phase. [3] The cyclase phase converts a linear pre- cursor into the particular cyclic scaffold. During the oxidase phase, sequential C =C and C ÀH bond oxidations transform the hydrocarbon into the individual terpenoid accounting for the functional group diversity within a terpenoid family. Meroter- penoids belong to a large subgroup of natural products with a mixed polyketide terpenoid origin. [4] Recently, a family of meroterpenoids, the psiguadials A (1), C (2), and D (3) were isolated from psidium guajava, an important food crop (fruits) and medicinal plant (leaves and bark) in the tropical and sub- tropical regions (Figure 1). [5] The psiguadials are structurally re- lated to the macrocarpals that were isolated from eucalyptus globulus, [6] pointing towards a similar biosynthetic origin. Sev- eral members of these meroterpenoids are associated with in- teresting biological properties, such anti-HIV [6b] and antibac- terial activity, [6a,c] as well as inhibition of aldol reductase [6e,f] and glucosyl transferase. [6h] However, their mode of action and potential molecular targets so far have remained elusive. Biosynthetically, they are hypothesized to derive from phloro- glucinol derivatives and the terpene bicyclogermacrene (4) (Scheme 1). [6b, 7] Moreover, a wide range of terpenoids are postulated to orig- inate biosynthetically from bicyclogermacrene. [7–9] The aroma- dendranes are a family of hydroazulene compounds that occur at different oxidation levels (Figure 2). These compounds are found in plants and show cytotoxic, [10a] antiviral, [10b,c] antibacter- ial, [10d,e] and antifungal [10f] properties. A point to note is that ar- omadendrenes with opposite absolute configurations have been isolated from corals. [11] We reasoned that an access to substantial amounts of bicy- clogermacrene would constitute an ideal platform to initiate synthetic efforts based on biomimetic strategies. Such bioin- spired synthesis would not only constitute an efficient access to individual natural products but would also allow us to con- firm their proposed biosynthetic pathway for this terpenoid family. Herein, we report a concise synthesis of (+)-bicycloger- macrene and its use as a platform intermediate to access a range of terpenoids and meroterpenoids. Synthesis of (+)-bicyclogermacrene Although bicyclogermacrene (4) is a rather frequently occur- ring constituent of essential oils from various plants, [8] it is nei- ther commercially available nor has received significant atten- tion in the synthetic community. So far, there is only a single Figure 1. Selected meroterpenoids built from a phloroglucine and a sesqui- terpene unit. [a] D. N. Tran, Prof. Dr. N. Cramer Laboratory of Asymmetric Catalysis and Synthesis EPFL SB ISIC LCSA, BCH 4305 1015 Lausanne (Switzerland) Fax: (+ 41) 21-693-9700 E-mail : Nicolai.cramer@epfl.ch Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201403082. Chem. Eur. J. 2014, 20,1–7 # 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 && These are not the final page numbers! ÞÞ Full Paper DOI: 10.1002/chem.201403082