Dibenzocyclooctadiene

A recent endeavor at the total synthesis of isopavines describes a promising novel route to these bases via functionalized dibenzocyclooctadienes (Scheme 27) 148). Dibenzocyclooctadienyl ether 132, formed from homoveratraldehyde (131) by a double Friedel-Crafts alkylation, is converted to dibenzocyclooc-tatrienol 133. Treatment with hydrazoic acid, followed by thermolysis and reduction, supplies ( )-isopavine (35) in good overall yield (53%). Subsequent attempts to prepare pavine bases by this approach have proved to be unsuccessful 148). 

The pharmaceutically very interesting dibenzocyclooctadiene lignans, such as steganacin, steganone and schizandrin8-10, constitute ideal synthetic substrates for this method since they have the required oxygenation pattern. 

In another series of related experiments Errede and coworkers prepared o-quinodimethane itself by the flash pyrolysis of o-methylbenzyltrimethylam-monium hydroxide 23 [72, 73], The conditions of this experiment were such that the o-quinodimethane was quenched soon after it was formed by cooling to - 78 °C. The product trapped out under these conditions was an approximately 25 75 mixture of 1,2,5,6-dibenzocyclooctadiene 20 and the spiro o-quinodimethane dimer 24 (Fig. 14). Dimer 24 can readily be seen to be the result of the Diels-Alder reaction of one o-quinodimethane bis-exo-methylene diene unit across one of the exo-methylene groups of another o-quinodimethane. The spirodimer... 

Fig. 16. Proposed linear polymerization of a hisbenzocyclobutene to give a poly(l,2,5,6-dibenzocyclooctadiene 29)...

Even though the reagent usually cleaves methyl ethers, the corresponding ether 2b cun be obtained from lb in high yield. The ether is stable to acids, but an F.2 elimination to give the alcohol 3b is possible with base. The alcohol is an obvious precursor to a dibenzocyclooctadiene by dehydration, best effected by thermolysis... 

The biogenetic relevance of spirodienone intermediate A is supported by the isolation of other spirodienones from Eupomatia laurina, namely the eupodienones [85], which were found to rearrange under acid conditions to give dibenzocyclooctadiene-type lignans [86]. 

Vanadium(V)-mediated intramolecular coupling of 90 furnished the dibenzocyclooctadiene diester 91 (45% yield), which underwent sequential oxidations at the benzylic C-8 position (via the bromide and the alcohol) to install the requisite keto group. Saponification of both esters in 92 followed by decarboxylation at 200°C furnished keto-acid 89, which was treated with formaldehyde as described above to give racemic steganone 12 and eventually steganacin 2. From a later report [109] and the work of Raphael, it seems obvious that under the decarboxylation conditions 89 was produced in an equimolar mixture with its atropisomer... 

The application of the Ullmann coupling to the synthesis of dibenzocyclooctadiene lignans was described in the late 1970 s by the groups of Ziegler and of Brown and Robin. 

Natural products 130-140 are dibenzocyclooctadiene lignans (Figure 9-8). Structurally, they contain a linked biphenyl or phenyl/ketocyclohexadiene system, which can have either an S- (130-136) or R-configuration (137-140). Each ring is substimted at positions 1, 2, 3 and 12, 13, 14 with combinations of methoxy, methylenedioxy, or hydroxy groups. Four carbons C-6 C-9 and the biphenyl link-... 

TABLE 9-7. Anti-HIV Activities of Potent Dibenzocyclooctadiene Lignans and Biphenyl Derivatives ... 

Dibromination of Dibenzocyclooctadiene Lignans Five dibrominated derivatives (142-146, Figure 9-8) were synthesized from compounds 132 and 137-140, and evaluated for anti-HIV activity. Only 143 had an ECso lower than 10 pM (EC50 = 7.2 pM and TI = 5) however, it was still less potent than its parent compound 137 (EC50 = 2.0 pM and TI = 56, Table 9-7). 

Building on their earlier research into S-endo cyclisations of Sml2-generated ketyl-type radicals, Molander and co-workers [107,108] developed this process as a key step in the syntheses of several naturally occurring lignans of the dibenzocyclooctadiene type. For example, they prepared the biaryl-chromium tricarbonyl complex 128 containing orffio-formyl and butenolide... 

The stoichiometric reaction of proparene 113 and the carbene complex 114 at 25 °C gave rise to trace amounts of styrene, dibenzocyclooctadiene 117, and other polymeric products (Scheme 4.43) [89]. Dibenzocyclooctadiene 117 was considered to be formed from the mthenacyde 115 via a quinodimethane intermediate, while styrene was formed by the decomposition of the isomeric ruthenacycle 116. The qui-... 

SCHEME 93. Synthesis of dibenzocyclooctadiene-type neolignans and spirodienones... 

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