Miltirone synthesis

We have found that intramolecular Friedel-Crafts alkylations of conjugated dienones permit the efficient preparation of functionalized hydrophenanthrenes (Equation 5.1).21 Since this represents a new strategy for the synthesis of 6,6,6-fused tricycles, we sought to demonstrate its utility through the total syntheses of miltirone (56) and two closely related diterpenoids sageone (57), which possesses significant antiviral activity,22 and arucadiol (58), 23... 

Since arucadiol and miltirone both have an aromatic "B" ring, enone 64 served as a common intermediate for both of these quinone pigments. The aromatization of 64 was readily achieved using 2,3-dicyano-5,6-dichloro-l,4-quinone (DDQ) (Equation 5.2). With substrate 65 in hand, only demethylation of the ethers was required to complete a synthesis of arucadiol (58). This transformation was accomplished in nearly quantitative yield using boron tribromide. Our synthetic arcudiol was spectrally identical with the natural material. 

ABSTRACT This article reviews the literature published dealing with the synthesis of some bioactive diterpenes. It describes the biological activity and synthesis of only four diterpenes pisiferic acid, camosic acid, triptolide and miltirone. This review excludes the discussions of Taxodione, a bioactive diterpene, because it has already been reviewed [85], The utility of several reagents in the total synthesis of terpenoid compounds has been documented. It can be observed that several routes have been developed for the synthesis of a single diterpene. 

Nasipuri and Mitra [63] reported the first total synthesis of miltirone (197) and this is described in Fig. (23). 

The synthesis of miltirone (197) by Nasipuri follows the route similar to Thomson s [74] and Kasikawa s [78] approach to tanshinones bearing the benzofuran unit. 

Fig (25) Catechol (201) on oxidation with silver oxide generates 3-isopropyl-o-benzoquinone (199) which undergoes ultrasound-promoted cycloaddition with 6,6-dimethyl-1 -vinylcyclohexene (200) yielding the synthesis of miltirone (197). 

Thus it can be observed that ultrasound-promoted cycloaddition has proven to be an expedient route for the synthesis of miltirone. We believe this approach would prove very valuable for the synthesis of related abietane natural products. 

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