cis-Dihydrocatechols as precursors to highly oxygenated troponoids. Part 2. Regiocontrolled syntheses of stipitatic and puberulic acids

Abstract

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

In vitro and in vivo antimalarial activity of puberulic acid and its new analogs, viticolins A–C, produced by Penicillium sp. FKI-4410

“…The NMR spectral data of 1 revealed a symmetrical hydroxytropolone, consisting of four resolved aromatic carbon and one carboxyl carbon signals (Table 2). In comparison with reported data, 1 was identified as puberulic acid 11 and 2 as stipitatic acid. 14 The structure elucidation of the other compounds was carried out by comparison of spectroscopic data obtained for 1.…”

“…FKI-4410. These compounds are puberulic acid (1) 9,10 and stipitatic acid (2), 11 along with three new analogs, designated viticolins A-C (3-5) (Figure 1). …”

The biology and synthesis of α-hydroxytropolones

“…This versatility is highlighted in the synthesis of both β thujaplicinol (Scheme 6) 47 and puberulic acid (Scheme 7). 48 …”

The Application of Dioxygenase‐Based Chemoenzymatic Processes to the Total Synthesis of Natural Products

“…An illustrative reaction sequence is shown in Scheme 13 and allows for concise syntheses of highly oxygenated troponoid compounds. [68] Specifically,c onversion of the parent cis-1,2-dihydrocatechol( 92), the product of the enzymatic cis-dihydroxylation of benzene, [21e] into the corresponding acetonide 93 and addition of dibromocarbene to this afforded am onoadduct that was readily converted into compound 94.O ver three steps norcarene 94 was transformed into the bicyclic enone 95 that on treatment with the non-nucleophilic base 1,8-diazabicyclo[5.4.0]undec-7-ene( DBU) was itself converted into the corresponding and extendede nolatea nd that, by virtue of being an orcaradiene, can undergo electrocyclic ringopeningt ot he corresponding cycloheptatriene. Loss of bro-mide ion from this last species then produced the fully conjugated and aromatic a-tropolone acetate and upon work up with sodium hydroxide this was cleaved to give the corresponding" free" tropolone 96.O ver af urther two and straightforward steps this was convertedi nto puberulic acid (97).…”