Crassin acetate synthesis

An intramolecular cycloaddition of the tetradecatrienyl nitroethyl ether 263 was used in the synthesis of the 14-membered bicyclic precursor 265 of crassin acetate 266, a cembrane lactone possessing antibiotic and antineoplastic activity (332). Nitro compound 263 was obtained from farnesyl acetate (262) in several steps and was then treated with phenyl isocyanate and triethylamine to give the tricyclic isoxazoline 264 (Scheme 6.98). Conversion to ketone 265 was accomplished by hydrogenation of the cycloadduct with Raney Ni and boric acid followed by acetylation (332). In this case, the isoxazoline derived from a 3-butenyl nitroethyl ether moiety served to produce a 3-methylenetetrahydropyran moiety (332). 

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 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. 

Dauben, W. G., Wang, T. Z., Stephens, R. W. Total synthesis of ( )-crassin acetate methyl ether. Tetrahedron Lett. 1990, 31, 2393-2396. 

Selective reduction of allyl sulfides implies that no scrambling of the carbon-carbon double bond occurs during the process. Effectively this has proved to be the case especially when lithium in ethylamine is used, and the method has allowed the regio- and stereo-selective synthesis of a large variety of 1,5-dienes including squalene (Scheme 25, entry a), mukapolide (Scheme 25, entry b), dendrolasin (Scheme 25, entry c), the basic nucleus of crassin acetate (Scheme 25, entry d) from 7,7-dialkylallyl sulfides and allyl halides, and also of 1,5-enynes " from propargyl sulfides and allyl halides (Scheme 34, entry b). 

Dauben, W.G., Saugier. R.K.. and Fleischhauer, I., Synthetic studies directed toward cembranolides. Synthesis of the basic nucleus of crassin acetate, J. Org. Chem., 50, 3767, 1985. 

Ketone (27) and reagents related to it have been used in synthesis. In equation (50) is shown an application of the magnesium enolate in Still s synthesis of monensin the facial selectivity in this case is 5 1 and the reaction proceeds in 85% yield. The lithium enolate of (27) has been employed in a synthesis of the C-l.C-7 segment of eiythronolide A (equation 51) the facial selectivity in this case is 6 1. Ketone (31) was used in a synthesis of the basic nucleus of crassin acetate (equation 52). The aldol reaction of (31) with (32), derived from geraniol, occurs in 58% yield to give only one isomer. Four further... 

The McMurry reaction has also proved useful in the synthesis of a number of cembrenoid diterpenes, including crassin acetate methyl ether 119 [157], sar-... 

Marshall, J.A. and Royce, R.D. (1982) Synthetic studies on cembranolides stereoselective synthesis of a crassin acetate synthon. J. Org. Chem., 47, 693-698. 

Tius, M.A. and Reddy, N.K. (1991) Cembrane synthesis an advanced intermediate for crassin acetate. Tetrahedron Lett., 32, 3605-3608. 

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