Cembranoids

Review of oxygenated 2,11-cyclized marine cembranoids, tri- and tetracyclic bioactive 0-heterocycles with cembrane skeleton 98H(49)531. 

Allylic bromides can also serve as progenitors for nucleophilic organochromium reagents. An elegant example is found in Still and Mobilio s synthesis of the 14-membered cembranoid asperdiol (4) (see Scheme 2).7 In the key step, reduction of the carbon-bromine bond in 2 with chromium(n) chloride in THF is attended by intramolecular carbonyl addition, affording a 4 1 mixture of cembranoid diastereoisomers in favor of the desired isomer 3. Reductive cleav-... 

An intramolecular Hiyama reaction was applied for macrocyclization in the synthesis of the racemic cyclic 14-membered cembranoid antitumor agent asperdiol10. 

In a variation of these reactions, Grieco and Masaki used p-toluenesulfonyl groups to direct alkylation reactions in the formation of carbon chains and then cleaved the sulphones with lithium in ethylamine. This type of synthetic construction involving the use of sulphur-containing molecules has become a typical sequence in organic syntheses. In this case, the reactions formed part of successful syntheses of squalene and sesquifenchene and were carried out without any migration or loss of stereochemical integrity of the double bonds. Similar sequences have been reported by Trost (prenylation reactions) and Marshall (synthesis of a cembranoid precursor). 

Phosphonate-based cyclization has been increasingly used in macrocyclic terpene synthesis. In a synthesis of the marine cembranoid (+)-desepoxyasperidiol the cyclization of the phosphonate (192) was attempted under a variety of conditions without success. 

Upon treatment with Me3SiOTf, the 2,5-dihydrofuran-containing 14-membered marine cembranoid sarcophytoxide was converted to a 10-membered ring product as shown below <06OL2957>. Presumably, the Lewis acid promoted the cleavage of the dihydrofuran ring to provide a transient allylic cation, leading to a transannular cyclization. 

Chang-Yih D, Rei-Sheu H, Cytotoxic cembranoids from the soft corals Sinularia gibberosa and Sarcophyton trocheliophorum, J Nat Prod 59 595—598, 1996. 

Hann, et al. Tobacco cembranoids block behavioral sensitization to nicotine and inhibit neuronal acetylcholine receptor function. J Neurosci Res... 

Wahlberg, 1., R. Arndt, T. Nishida, and C. R. Enzell. Tobacco chemistry. Syntheses and stereostructures of six tobacco seco-cembranoids. Acta Chem Scand Ser B 1986 40 123-134. Wahlberg, I., A. M. Eklund, C. Vogt, C. R. Enzell, and J. E. Berg. Tobacco chemistry. Two new 7,8-epoxycembranods from tobacco. Acta Chem Scand Ser B 1986 40(10) 855-860. 

Arndt, R, I. Wahilberg, C. R. Enzell, and J. E. Berg. Tobacco chemistry. Structure determination and biomimetic syntheses of two new tobacco cembranoids. Acta Chem Scand Ser B 1988 42(5) 294-302. 

Tobacco chemistry. Four new epoxy-cembranoids from tobacco. Acta Chem Scand 1992 46(8) 789-795. NT345 Eklund, A. M., ]. E. Berg, and 1. 

Eight new cembranoids from tobacco-structural elucidation and conformational studies. Tetrahedron 1993 49(22) 4975-4992. 

Zook, M., K. Johnson, T. Hohn, and R. Hammerschmidt. Structural characterization of 15-hydroxytrychodiene, a ses-quiterpenoid produced by tansformed tobacco cell suspension cultures expressing a trichodiene synthase gene from Fusarium sporotrichoid.es. Phytochemistry 1996 43(6) 1235-1237. Eklund, A.M., I. Eorsblom, ]. E. Berg, C. Damberg, and I. Wahlberg. Tobacco chemistry. Four new cyclized cembranoids from tobacco. Acta Chem Scand Ser A 1998 52(10) 1254-1262. 

NT451 Ollson, E., A. Holth, E. Kumlin, L. NT462 Bohlin, and I. Wahlberg. Structure-related inhibiting activity of some tobacco cembranoids on the prostaglandin synthesis in vitro. Planta Med 1993 59(4) 293-295. 

The Mediterranean has also given peculiar triterpenes of squalene origin and an unusual cyclized cembranoid, coralloidolide C (Chart 7.5.A/I/PO). The latter resembles diterpenoids from tropical octocorals, indicating that these cnidarians, on migration to temperate waters, have conserved genes for secondary metabolites. 

D Ambrosio, M. GuoriCTo, A. Fabbri, D. Pietra, F. (1987) Coralloidolide A and coralloidolide B, the first cembranoids from a Mediterranean organisms, the alcyonacean Alcyonitm coralloides. Helv. Chim. Acta, 70, 63-70. 

Metabolism studies are essential for approval of any clinically useful drug. Microorganisms have been successfully used as in vitro models for prediction of mammalian drug metabolism due to the significant similarity of certain microbial enzyme systems, specifically fungi, with mammalian liver enzyme systems.66 The following metabolism study represents the first for a cembranoid diterpene and may aid future development of other cembranoids as clinically useful drugs. 

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. 

Figure 3. Carbon-carbon bonds introduced from synthetic building blocks by Nicolaou et al. (A) and Danishefsky et al. (B, C2-C9 broken after ketene cycloaddition). In the putative biosynthesis of the diterpenoid 4,7-oxaeunicellanes from cembranoid precursors, only one additional carbon-carbon bond (Cl-CIO) would have to be formed (C). (1 R1 = (E)-N(6 )-methyluroca-nyl, R2 = beta-D-0(2)-acetylarabinopyranosyl stereochemistry has been omitted for clarity).

In conclusion, three independent syntheses of marine eunicellane diterpenoids have been developed, which will be the basis of the future development of this exciting natural product class. The biosynthesis of the eunicellanes probably involves the oxidative cyclization of a cembranoid precursor lacking solely the bond between Cl and CIO (C, Fig. 3). Considering the number of carbon - carbon bonds formed in the course of... 

Diastereoselective macrocycUzation. A ke> step in a synthesis of the 14-membered cembranoid asperdiol (4) involves intramolecular ( yclization of the aldehydo allylic bromide (1) with chromium(II) chloride. The intermolccular version of this reaction is known to be anf/-selective (8,112). Treatment of racemic 1 with CrCl, (5 equiv., THF) results in a 4 1 mixture of the two anti-diastereomers 2 and 3 in 64% combined yield. The stereochemistry of this cyclization is evidently controlled by the remote epoxide group. The natural product was obtained by deprotection of 2 (Na/NH, 51% yield). 

Marshall and Cleary [115] synthesized 7 (8)-desoxyasperdiol 198), a precursor of the cembranoid asperdiol by using sulfonyl stabilized anion displacement of... 

Pattenden and coworkers [133] have described the use of allylic radical intermediates in macrocyclizations leading to several natural products. For example, the cembranoid mukulol 220) [133 a] was synthesized as shown in Scheme 72. lodotetraenone 217 was heated under reflux for 3 h in the presence of Bu3SnH and AIBN in benzene. A 1 4 mixture of 218 and 219 was obtained together in 40% yield and 219 was converted into mukulol (220). 

Dauben et al. [153] successfully applied this procedure to the total synthesis of the cembranoid crassin acetate methyl ether (258). As shown in Scheme 86, the keto aldehyde 256 was treated with TiClj/Zn-Cu in refluxing DME to give the cyclic olefin 257 in 65% yield (E Z = 4 3). The germacrane sesquiterpenes have also been synthesized using this method [154],... 

In the synthetic studies on cembranoid natural products by Marshall et al. [155], an alcohol-halide coupUng was used to construct the macrocycles. As shown in Scheme 87, the linear precursor 259 was cyclized to 260 in 71 /o yield by addition of 1 equiv of EtMgBr to a solution of the chloro alcohol 259 in HMPA-THF and stirring at reflux for 4 h. There are also other examples of this macrocyclization method [156]. 

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