The bromotropolones (4), (5) and (10) undergo palladium-mediated cross coupling with a wide range of organostannanes to produce alkenyl -, alkyl- and aryl-substituted tropolones . The methodology has been applied to the synthesis of the monoterpenes β- dolabrin (11),β- thujaplicin (12), 4-isopropyl-7-methoxytropolone (13) and β- thujaplicinol (14). Cross coupling of bromotropolones (4), (5) and (10) with various aryltrimethylstannanes or arylboronic acids has permitted the preparation of the bicyclic colchicine analogues (30)-(43) which have been tested for tubulin -binding activity. The X-ray crystal structure of the most active of these systems, compound (38), is reported.
Stipitatic and puberulic acids, 1 and 2 respectively, have both been prepared in a fully regiocontrolled manner using commercially available cis-1.2-dihydrocatechol 3 as the common starting material. In the case of the former acid, compound 3 was converted over six simple steps into the ester 12. Oxidation of this latter compound produced the o-homo-o-benzoquinone 13 which acted as a Michael acceptor when treated with methoxide ion and the resulting conjugate could be trapped with acetic anhydride to give the acetoxy enone 14. Base-promoted ring-expansion of 14 then afforded the troponoid 15, the acquisition of which constitutes a formal total synthesis of stipitatic acid. Attempts to develop an analogous synthesis of puberulic acid failed. However, a successful synthesis of this natural product was achieved by elaborating the tetra-oxygenated compound 25, which is readily prepared from the diol3, to the bromotropolone 28. Palladium-catalysed methoxycarbonylation of this latter compound, followed by hydrolysis of the intermediate ester afforded the acid 29, the structure of which was established by X-ray methods. Two-fold demethylation of compound 29 then delivered puberulic acid 2.The mould metabolites stipitatic acid 1 2t and puberulic acid 2 3t were first isolated in 1942 and 1932 respectively but it was not until 1945 that Dewar made the then dramatic proposal4 that the former compound contained the 'aromatic' a-tropolone OH HO PoH 'OH 0 0 " 2 , ' ' OH '"OH HO&' 1 HOzd 2 3 V Reference 15 3 * H02C 15 Br 8 X=Br 9 x=u 10 X = C02H J ii ic iii I 11 X=C02Me 14
Reaction of various a-homo-o-benzoquinones, e.g. 42, with BF,*Et20 results in the formation of the tropolonoboron difluoride derivatives, e.g. 43, of the isomeric a-tropolones, e.g. isopygmaein 33.
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