Cembranoids synthesis

Tius, M.A. and Cullingham, J.M. (1989) Marine cembranoid synthesis. Tetrahedron Lett., 30, 3749-3752. 

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. 

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. 

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). 

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],... 

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). 

The total synthesis of the cembranoid diterpene (+)-crassin acetate methyl ether was accomplished by W.G. Dauben et al. In the final stages of the total synthesis, the sensitive a-methylene group was introduced onto the six-membered lactone by using the Eschenmoser methenylation procedure. The lactone was deprotonated with LDA and then treated with Eschenmoser s salt. In the second step, the dimethylamino group was exhaustively methylated and the quaternary ammonium salt underwent a smooth Hofmann elimination upon deprotonation with DBU. 

Thus, for example, the cyclic propargylic allylic ether (242 equation 49) rearranges completely within 30 min upon treatment with Bu"Li in THF-hexane at -20 C, whereas the acyclic analog (244 equation SO) requires 12 h under comparable conditions. Alcohol (243) serves as a useful intermediate for the synthesis of cembranoid diterpenes. ... 

Paquette, L.A., Wang, T.-Z., Philippo, C.M.G., and Wang, S., Total synthesis of the cembranoid diterpene lactone (-i-)-cleomeolide. Some remarkable conformational features of nine-membered belts linked in a 2,6-fashion to a methylenecyclohexanc core, J. Am. Chem. Soc., 116, 3367, 1994. Moskva, V.V., and Razumov, A.I., Phosphinic and phosphinous acids. Part 34. Phosphorylated 1,3-dioxolanes, Trans. Kazan. Khim.-Tekhnol. Inst., 34, 273, 1965 Chem. Abstr, 68, 39729y, 1968. Razumov, A.L, and Gurevich, P.A., Synthesis of phosphorylated 1,3-dioxoles, Zh. Obshch. Khim., 38, 944, 1968 J. Gen. Chem. USSR (Engl. Transl.), 38, 909, 1968. 

Paquette, L.A., Wang, T.-Z., Philippo, C.M. G., and Wang, S., Ibtal synthesis of the cembranoid diterpene lactone (-r)-cleomeolide. Some remarkable conformational features of nine-membered belts linked in a 2,6-fashion to a methylenecyclohcxane core, J. Am. Chem. Soc., 116, 3367, 1994. 

Myers also found that the HS model provided accurate predictions of the regio-and stereochemical outcomes of ring closures aimed at the synthesis of cembranoid natural products [15]. Calculations for the cyclization of macrocyclic radicals 35... 

This type of coupling was routinely used by Marshall (allyl chlorides or phosphates) in the synthesis of cembranoids, employing a cuprate made from the bromomagnesium analog TIPS-C=C-CH2MgBr (2), which is prepared from TIPS-C= C-CH2Br. As a rule, with these allylic electrophiles, Sn2 ... 

In 2003, Deslongchamps and coworkers reported an elegant synthesis of (+)-chatancin (112) in 17 steps involving a biomimetic transannular cycloaddition (Scheme 8.18) [48]. Although there are no evidences of in vivo transannular Diels-Alder (TADA) reaction in cembranoids, Deslongchamps hypothesized that 112 could be obtained from a macrocyclic pyranophane such as 116a. To verify... 

Tang B, Bray CD, Pattenden G, Rogers J. Total synthesis of (+)-Z-deoxypukalide, a furanobutenolide-based cembranoid isolated from the pacific octocoral Leptotgorgia spp. Tetrahedron 2010 66 2492-2500. 

Ellis JM, Crimmins MT. Strategies for the total synthesis of C2-C11 cyclized cembranoids. Chem. Rev. 2008 108 5278-5298. 

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