Novel synthetic approaches to the palmarumycin skeleton

Article abstract of DOI:10.1016/S0040-4039(00)01625-7

Oxidation of readily available aminonaphthols 7a and 7b with activated manganese dioxide gives palmarumycin analogues 8a and 8b in good yield. The related benzoquinone monoacetals 10a-c undergo cycloaddition with 3-methoxy-2-pyrone at high pressure to giv

Full text of DOI:10.1016/S0040-4039(00)01625-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9105–9107
Novel synthetic approaches to the palmarumycin skeleton
Ian G. C. Coutts,a,* Robert W. Allcocka and Hans W. Scheerenb
aDepartment of Chemistry and Physics, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK
bDepartment of Organic Chemistry, University of Nijmegen, Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received 24 July 2000; revised 14 September 2000; accepted 20 September 2000
Abstract
Oxidation of readily available aminonaphthols 7a and 7b with activated manganese dioxide gives
palmarumycin analogues 8a and 8b in good yield. The related benzoquinone monoacetals 10a–c undergo
cycloaddition with 3-methoxy-2-pyrone at high pressure to give adducts 12a–c, also possessing the
palmarumycin framework. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: quinones; acetals; Diels–Alder reactions.
The palmarumycins are a group of fungal metabolites isolated1 from Coniothyrium sp.
Compound 1, palmarumycin CP1, may be regarded as the parent member of the series, with
others displaying a range of hydroxylation, unsaturation or epoxidation. Several of the series
exhibit antibacterial, anti-fungal, or potentially anti-cancer activity.
Palmarumycin CP1 is a 5-hydroxy-1,4-naphthoquinone in which the 1-carbonyl has formed a
spiro-acetal with naphthalene-1,8-diol, and represents a rare example of a naturally-occurring
quinone monoacetal in which the acetal is derived from phenolic hydroxyls, a class of compound
in which we have long been interested.2 Adding to this our current involvement with antifungal
compounds,3 we have initiated a programme of evaluating palmarumycin analogues as anti-
infective agents.
The combination of biological activity and unusual structure of this family of compounds has
attracted the attention of several groups. Published syntheses have used two routes for
constructing the key acetal linkage. In the first,4,5 5-methoxytetralone undergoes slow acid-
catalysed reaction with naphthalene-1,8-diol to give ketal 2, which is converted to 1 by judicious
oxidation and demethylation. An alternative, biomimetic approach6 involves the multi-stage
synthesis of diphenol 3, which, on treatment with phenyliodonium diacetate, undergoes oxida-
tive coupling to 4; this is then further oxidised to CP1.
* Corresponding author. Fax: +44 115 8486636; e-mail: ian.coutts@ntu.ac.uk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01625-7

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Our approach to the palmarumycin skeleton (Scheme 1) exploits the synthesis of quinone
ketals by the oxidation of aryloxyanilines.7 Reaction of naphthalene-1,8-diol with benzyl
chloride/K2CO3/butanone gives in high yield 1-benzyloxy-8-hydroxynaphthalene 5a which, on
treatment with 1-fluoro-4-nitronaphthalene in DMSO, affords dinaphthyl ether 6a. This is
converted quantitatively by hydrogenation to aminophenol 7a, which, on immediate oxidation
with activated manganese dioxide, gives deoxy-CP1 8 in 80% yield. The same sequence, starting
with the known8 1-benzyloxy-5-methoxy-8-naphthol 5b, allows ready access to 8b, a regioisomer
of O-methyl-CPI, in comparable yield.
Scheme 1. (i) NaH/THF; (ii) DMSO; (iii) H2/Pd/C; (iv) MnO2/benzene
Scheme 1 provides an efficient synthesis of 8a,b, useful substrates for modifications such as
reduction or epoxidation. It does not, however, allow for the introduction of a hydroxyl group
peri to the quinone carbonyl, as the requisite 5-alkoxy-1-fluoro-4-nitronaphthalene would be
difficult to prepare. An alternative strategy, shown in Scheme 2, is to attempt to incorporate the
hydroxyl by a Diels–Alder approach. Here, 3-methoxy-2-pyrone 11 is used as a synthon for
1-hydroxybutadiene (adducts formed using 3-hydroxy-2-pyrone9 proved to be unstable). It was
hoped that subsequent decarboxylation and oxidation of adducts 12 would lead to compounds
13, substituted analogues of O-methyl CP1, which could be demethylated if required.
Reaction of 5a with appropriately substituted 4-fluoronitrobenzenes gave virtually quantita-
tive yields of ethers 9a–c, which were efficiently converted as before to the benzoquinone acetals
10a–c.
Mono-acetals of quinones10 or quinoneimines11 are much less reactive dienophiles than their
parent quinones, but undergo cycloaddition more readily at high pressure.12 When equimolar

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Scheme 2. (i) H2/Pd/C; (ii) MnO2/benzene; (iii) 12–15 kbar
mixtures of acetals 10a, 10b or 10c and pyrone 11 were maintained at 12–15 kbar, adducts 12a–c
were formed quantitatively, and as single regio- and stereoisomers. Although not entirely
1
13
unambiguous, the H and C NMR spectra of the adducts suggest that they are endo products,
with the substituent orientation as shown in the Scheme.
Thermal cycloaddition was less efficient. Prolonged reaction of acetal 10a with 11 in refluxing
benzene resulted in an equilibrium mixture, from which adduct 12a could be isolated in 55%
yield. In higher boiling solvents there was evidence of extensive decomposition.
Attempts to eliminate carbon dioxide from the adducts thermally, or with acid or base
catalysis, led to retro-Diels–Alder reaction or to decomposition, although aromatisation of 12a
and 12b occurred cleanly in the mass spectrometer. These results, however, illustrate the
potential of this approach to palmarumycin analogues for structure–activity studies, and the
reaction of 12 and related acetals with a variety of dienes is under current investigation.
The significant anti-microbial activity of several of the acetals and derived adducts will be
reported separately.
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