Cembranolides synthesis

Paterson, I.. Gardner, M., and Banks. B.J.. Studies in marine cembranolide synthesis. A synthesis of 2,3,5-trisubstituted furan intermediates for lophotoxin and pukalide. Tetrahedron. 45. 5283. 1989. 

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. 

The reaction was also applied in a more complicated case during the total synthesis of the cembranolide ( )-anisomelic acid74. 

Intramolecular allylation has wide application in the synthesis of macrocycles [57]. Synthesis of humulene (107) by the cyclization of allyl acetate 105 to give 106 is an early example [58]. The 14-membered ring 109 was obtained from 108 and converted to cembranolide 110 [59]. 

Marshall and coworkers [107] sucessfully applied this reaction to the synthesis of some 14-membered isoprenoids. For example, cembranolide 181 (unnamed) was synthesized as shown in Scheme 59 [107b]. Thus, treatment of (a-alkoxyallyl)-stannane aldehyde 179 with BF3 EtjO at — 78 °C in dichloromethane at high dilution afforded a (Z) ( ) (88 12) mixture of macrocycle 180 in 88% yield. 

Other applications of this method include, e.g. the synthesis of the antibiotic A26771B (5i) [118] and the marine cembranolide isolobophytolide [119], Trost and Warner [120] reported that a-sulfonyl sulfones can also serve as the substrates of ir-allylpalladium complexes for macrocyclization. Furthermore, an a-hydroxy-carbonyl ketone was alkylated intramolecularly by a a-allylpalladium complex in the total synthesis of the macrocyclic sesquiterpene humulene [121]. 

The first synthesis of naturally occurring cembranolides has been reported by Kodama et al. in 1982 detailed below (Scheme 6-35). ... 

The homochiral hydroxyl enol ether 280, which was secured through BF3-promoted cyclization of alkoxy stannane 274, was elaborated to the cw-cembranohde 256. The synthesis confirmed the absolute stereochemistry of the natural cembranolide (Scheme 6-38). ... 

The first asymmetric total synthesis of ( )-trany-cembranolide (295) was reported by Taber and Song in 1997 (Scheme 6-39). The key step in the synthesis is the diastereoselective Rh-mediated cyclization of the enantiomerically pure diazo ester 288 to the tetrahydrofuran 289. 

The possible legioselecdvity and the preference for ( )>aUylic alcohol Hxxluction using the reoxida tive modification are demonstrated in a projected synthesis of cembranolides (equation 10). The substrate in this case contains two double bo and several allylic positions. This oxidation is reported to be even more selective than the aiudogous oxidation of geranyl acetate originally reported by Sh less. 

In synthetic studies directed toward the synthesis of the antileukemic cembranolide isolobophytolide (162), the photocycloaddition of 2,5-bis(hydroxymethyl)furan and p-r-butyldimethylsiloxybutanal... 

Other applications of carbanions a to a sulfone in total syntheses have recently been reported. Most of them used allylic sulfones or allylic halides. Two examples are reported here. In the synthesis of a precursor of cembranolides, a sulfone derived from geranyl bromide was coupled with an allylic alcohol epoxide (Scheme 65). An interesting point was that the coupling reaction gave high yields only when the lithiated sulfone was allowed to react with the epoxymagnesio alkoxide (the lithium salt of the epoxy alcohol did not react at all with the lithiated sulfone). 

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

Marshall, J.A., and DeHoff. B.S.. Cembranolide total synthesis. Anisomelic acid, Tetrahedron, 43, 4849, 1987. 

Various other functionalization procedures have been developed and all have been summarized in detail in a recent review10. Some representative examples should be mentioned synthesis of the antifungal metabolite ( )-avenaciolide (6)74, the mycotoxin asteltoxin (7)75,76 and the antileukemic cembranolide isolobophytolide (8)77. 

Ring-closing metathesis (RCM) has also been employed in the synthesis of substituted furans. Donohoe and co-workers used a ring-closing metathesis strategy to form the furan moiety of (-)-(Z)-deoxypukalide, a compound from the family cembranolides, which have been shown to exhibit neurotoxicity and anti-inflammatory properties. Treatment of a mixed acetal with Grubbs II catalyst, followed by in situ aromatization with PPTS, yielded the disubstituted furan in 85% yield over two steps. Seven additional steps were required to reach of (-)-(Z)-deoxypukalide. 

Nieto, M.I., Gonzalez, N Rodriguez, J Kerr, R.G., and Jimenez, C. (2006) New cytotoxic cembranolides isolation, biogenetic studies, and synthesis of analogues. Tetrahedron, 62,11747-11754. 

---