Miltirone

Salvia miltiorhiza Bunge. Tan Seng (Red-rooted sage) (root) Tanshinone, cryptotanshinone, isocryptotanshinone, miltirone, tanshinol, salviol, acetylsalicylic acid 33.226.235,428,429 Treat angina pectoris, cerebral atherosclerosis, diffusive intravascular clotting, thrombophlebitis, antioxidant. 

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. 

The three-step sequence used to convert enone 65 to miltirone (56) is shown in Scheme 5.7 and consists of, first, a Wolff-Kishner reduction to convert the C(5) carbonyl moiety into a methylene, followed by deprotection of the aryl methyl ethers and oxidation to an ortho-quinone using ceric ammonium nitrate. The physical and spectroscopic data of our synthetic miltirone are identical with those reported for the natural material. 

From the Diterpene Carnosol to the Benzodiazepine Agonist Miltirone... 

Attempts to hydrolyse the ester 2 with either KOH/IfyO/MeOH at 50°C or LiOH/THF/IfyO at reflux or AcOH in quinoline at 120°C were unsuccessful, and the starting material was recovered unchanged. Use of KO Bu/DMSO at 40-60°C for 4 hours, however, followed by aqueous acid gave a mixture of four products, the major of which (80%) was shown to be the acid 3. Ether cleavage of 3 with BBr3/CH2Cl2 at room temperature proceeded rapidly (5 min), and while the catechol derivative could be isolated and characterised spectroscopically, it was rapidly oxidised in air to 4, the potent benzodiazepine agonist miltirone. 

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. 

Tanshen (Salvia miltiorrhiza Bung), a medicinal plant, has been used in traditional Chinese medicine for its tranquilizing, sedative, circulation-promoting and bacteriocidal effects. [73], It has proven to be a rich source of abietane o-quinone diterpenoids. Miltirone (197) is a tricyclic diterpenoid quinone which has been isolated from the roots of salvia miltiorrhiza Bung. The isolation of miltirone constitutes a new addition to naturally occurring quinines related to tanshinones [74,75] isolated from the same source. 

Dry clean tanshen rhizomes were powdered and extracted with hexane for three days at room temperature. The hexane solution was kept overnight and then filtered. After removal of the solvent a residue was obtained which was separated into seven colored fractions by column chromatography with silica gel. Miltirone was isolated by preparative tic from fraction 1 (light red) using hexane ethyl acetate (4 1) followed by benzene-acetone (20 1). The product obtained was recrystallized from ethylacetate, m.p. 100-101°C. Its structure was confirmed by mass spectrum, NMR, IR and UV spectra which agree quite closely with those of Ho et al [76], Miltirone showed antioxidant behavior comparable to that of the commonly used phenolics BHT and BEA [77], The antioxidant activity of miltirone in lard at 100°C was determined with a Rancimat. Miltirone and other related compounds may have the potential of being used as natural antioxidants in food and cosmetics. 

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

Fig (23) Acid (193) prepared from bromoanisole (190) by standard organic reactions, undergoes cyclization with polyphosphoric acid leading the formation of tetralone (194). A Reformatsky reaction on compound (194) with methyl g-bromocrotonate followed by aromatization produces compound (195). It is converted to compound (196) by treatment with methylmagnesium and cyclization. The corresponding phenol was oxidized to miltirone (197). 

The transformation of ester (195) to phenanthrene (196) was carried out in two steps (i) treatment with excess of methylmagnesium bromide and (ii) heating the resulting alcohol with polyphosphoric acid at 170°C. Demethylation of (196) followed by oxidation provided miltirone (197). 

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 (24) Oxidation of (198) gives o-quinone (199) which on heating with vinylcyclohexene (200) gives miltirone (197). 

O-quinone (199) prepared from catechol (198) was heated with vinylcyclohexene (200) in refluxing ethanol. Miltirone (197) was isolated by column chromatography in 28-30% yield. About 5% of (200) could be recovered Lower temperatures or longer reaction times damaged the reaction. 

Snyder observed the o-quinone dienophile reported by Knapp et. al. Sharma [79] was very unstable and thus the yield of miltirone was poor. In order to improve the yield of miltirone, it was planned to prepare o-quinone dienophile in situ. This plan was carried out by heating a mixture of 3-isopropyl-1,2-dihydroxybenzene (201), 6,6-methyl-l-... 

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. 

Cyclohexanone (202) was converted to compound (203) whose transformation to cyclohexanone (204) was accomplished in three steps. It underwent cyclialkylation with boron trifluoride etherate affording the cyclized product (205) (R=R,=OMe) in 64% yield along with naphthalene (206) (R=Ri= H,H). Compound (205) on heating under reflux with DDQ in benzene produced ketone (207) whose tosylhydrazone on treatment with sodium cyanoborohydride afforded reduced product (208). Deprotection of the aryl methyl ethers and oxidation with ceric ammonium nitrate led to the formation of miltirone (197). 

Dehydrogenation of (205) produces ketone (207) whose transformation to miltirone (197) was achieved by deoxygenation, demethylation and oxidation respectively. 

Miltirone (diterpene quinone, tanshinone) Salvia miltiorrhiza (Lamiaceae) [root]... 

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