Sarcophytols

Sarcophytols A (46) and B (47) are simple cembranoids isolated from the Okinawan soft coral S. glaucum and have been reported to possess potent inhibitory activities against various classes of tumor promoters.70 71 Sarcophytol A (46) mediated dose-dependent diminution of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transformation of JB6 cells.72 When evaluated for potential to inhibit TPA-induced JB6 cell transformation, several of the sarcophine metabolites (48 to 58) mediated inhibitory responses greater than sarcophytol A (46) or sarcophine (45), most notably 7a-hydroxy-y8(19) deepoxysarcophine (50), which was comparable to 13-cz s-retinoic acid. These studies provide a basis for further development of novel furanocembranoids as anticancer agents. 

Di51 Sarcophytol A Marine soft coral EBV, Colon-2, Liver-2, Lung-1, Mam-3, Pancr, [97-100,204,205]... 

This cyclization was used to obtain the 14-membered sesquiterpene sarcophytol B (1) (last step, 46% yield).2... 

Scheme 6.3 illustrates a few of the main structural classes of soft coral compounds. Included in this list are the tubulin interactive agents, eleutherobin 41 and sarcodictyin A 42, which show nanomolar potency against cancer cell lines. Also of interest are the pseudopterosin A 44 terpenoids which reduce inflammation. Two other terpenoids, sarcophytol A 43 and sinulodurin A 45, have shown micromolar activity against BALB/3T3 and mammary epithelial cells respectively. 

The Stork-Takahashi method has been applied to the synthesis of a number of macrocyclic natural products including Muscone,217 Sarcophytol-A2H and Peri-planone B.220... 

Up to 20 sarcophytols were isolated from the Sarcophyton genus with the name of sarcophytol from A to T (except sarcophytol L, including two sarcophytol T) (Figure 6-2). 

Chemical examination of Sarcophyton glaucum collected at Ishigaki island, Okinawa Prefecture, resulted in the isolation of seven cembranoid diterpenes, namely sarcophytol A (3), sarcophytol A acetate (4), sarcophytol B (5), sarcophy-tonin A (6), and minor constituents sarcophytol C (7), D (8), and E (9). These compounds were found to be susceptible to autooxidation while being purified. The structural determination of these compounds was made mainly based on proton and carbon nuclear magnetic resonance (NMR) spectral evidence and degradative studies by ozonolysis. X-ray crystallographic analysis for the two crystalline compounds, sarcophytol B (5) and D (8), has been reported. The total lipid extracts of S. glaucum comprise about 40% sarcophytol A (3), 5% each of sarcophytol A acetate (4) and sarcophytonin A (6), about 1% sarcophytol B (5), and minor amounts of sarcophytol C (7), D (8), and E (9). 

A new cembranoid derivative sarcophytol T (25) in addition to sarcophytol A (3), sarcophytol N (19), and sarcophytol F (10) were reported from the same species. Sarcophytol T (25) as well as its isomers sarcophytol N (19) and sarcophytol F (10) were converted by autooxidation to bicyclo [9.3.0] tetradecane derivatives, when they were kept in CHCI3 solution at room temperature. Interestingly, Konig and Wright reported a second sarcophytol T (26) isolated from an Australian sample of S. ehrenbergi von Marenzeller (Alcyoniidae, OctocoraUia) in 1998 its structure was determined by spectroscopic data and confirmed by chemical correlation (Figure 6-2). 

The wide-ranging biological activities exhibited by members of the cembranoid family of marine diterpenes, for example, deoxysarcophine, lophotoxin, sinularin, aseperdiol, and sarcophytol A, in combination with their diversity of structure and the lack of flexible synthetic methodology for the elaboration of 14-ring carbo-cycles, have made this family of natural products a particularly challenging area for the synthetic chemist. Methods that have been developed for macrocyclization in the cembranoid field include... 

The first total synthesis of sarcophytol A (3), which was reported by Takayanagi et al. in 1990, ° was achieved in a highly stereo- and enantioselective manner starting from , -famesol (91) it included (1) a newly developed Z-selective (Z > 35 1) Horner-Emmons reaction with a phosphonate nitrile, (2) modified cyanohydrin macrocyclization, and (3) enantioselective (93% ee) reduction of macrocyclic ketone 100 as its key steps (Scheme 6-1). 

Then Li et al. reported on a concise total synthesis of ( )-sarcophytol A (3) from the derivative of , -farnesol (91) by a low-valent titanium-mediated intramolecular McMurry olefination strategy (Scheme 6-4). ... 

The first total synthesis of ( )-sarcophytol B (5) from S./i-famesal (92), which was reported by McMurry et al. in 1989, used a low-temperature titanium-induced pinacol coupling reaction of 1,14-dialdehyde as the key step. They concluded that the natural sarcophytol B has the stereochemistry of a trans diol (Scheme 6-5). Li et al. reported on a concise total synthesis of ( )-sarcophytol B (5) from /i./i-famesol (91) by a low-valent titanium-mediated intramolecular McMurry... 

The closure of the macrocyclic ring by means of an intramolecular 8 2 reaction is a straightforward approach, and sulfur-stabilized carbanion alkylation has been successfully applied in the synthesis of 14-membered cembranoids. The synthesis of nephthenol (40) and cembrene A (59) is an example of this methodology. In Li and Yue s report, the total synthesis of ( )-sarcophytol M (17) was achieved from ger-aniol (137) through 12 steps and in 8.9% overall yield with an intramolecular nucleophilic addition of a sulfur-stabilized carbanion to a ketone as a key step. This example is the first of the closure of a macrocyclic ring with the intramolecular nucleophihc addition of a sulfur-stabilized carbanion to a ketone (Scheme 6-7). 

Characteristic to some important cembrane diterpenoids, such as isocembrene, cembrene, cembrene C, and sarcophytol A, is a 1,3-diene unit in the macrocyclic skeleton. In continuation of our ongoing project on the total synthesis of cembrane-type diterpenoids, we intended to explore a novel macrocyclization method to... 

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