Total syntheses of palmarumycins CP1 and CP2 and CJ-12,371: Novel spiro-ketal fungal metabolites

Article abstract of DOI:10.1039/a800237a

Total syntheses of palmarumycins CP₁ 1 and CP₂ 9 and the structurally related CJ-12,371 11 are reported, thereby establishing a strategy for the synthesis of further natural products in the palmarumycins, diepoxines and preussomerines family.

Full text of DOI:10.1039/a800237a

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Total syntheses of palmarumycins CP1 and CP2 and CJ-12,371: novel
spiro-ketal fungal metabolites
Anthony G. M. Barrett,*† Dieter Hamprecht and Thorsten Meyer
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
OMe
Total syntheses of palmarumycins CP1 1 and CP2 9 and the
structurally related CJ-12,371 11 are reported, thereby
OMe
HO
OH
establishing a strategy for the synthesis of further natural
products in the palmarumycins, diepoxines and preussomer-
ines family.
i
+
O
O
The palmarumycins,1 diepoxines2 and preussomerines3 are a
structurally remarkable class of natural products isolated from
various fungi cultures. They all are graced with a spiro-ketal
entity formally derived from naphthalene-1,8-diol 6 and
1,4-naphthoquinone, yet at rich and varied oxidation levels. All
three classes of fungal metabolites are undoubtedly closely
interrelated biosynthetically and may well be derived from a
naphthalene-1,8-diol spiro-ketal with late introduction of the
unusual oxygenation patterns. These secondary metabolites are
O
6
5
ii
7
O
OR
O
OR
iv
O
O
O
O
O
O
O
OH
10 R = Me
1 R = H
8 R = Me
9 R = H
v
iii
O
Scheme 1 Reagents and conditions: i, TsOH (cat), PhH, Dean–Stark, 48 h,
reflux, 86%; ii, CrO3·HCl·bipy, ButOOH, Celite, PhH, 10 h, room temp.,
61%; iii, MgI2, PhH, 1.5 h, reflux, 84%; iv, DDQ, PhH, 10 h, reflux, 65%;
v, B-bromocatecholborane, DBU, CH2Cl2, 10 min, 5 °C, 50%
O
O
O
O
the methyl ether 8 with a freshly prepared solution of
magnesium iodide9 in benzene gave palmarumycin CP2
9
1
2
(84%). Deprotection using magnesium iodide was found to be
far superior to trimethylsilyl iodide (32%) or sodium ethane-
thiolate (63%).10 Oxidation of ketone 8 with DDQ11 followed
by deprotection of the methyl ether with B-bromocatechol-
borane12 gave palmarumycin CP1 1, the dehydro analogue of 9,
in 33% yield over two steps.
Finally, palmarumycin CP2 9 was converted into its corre-
sponding dihydro derivative 11 (60% yield, 93% ee)§ by
asymmetric reduction using (+)-B-chlorodiisopinocampheyl-
borane 1213 (Scheme 2). It is germane to mention that reduction
presumably takes place via intramolecular hydride delivery
thereby reversing the absolute stereochemistry of reaction seen
O
OH
O
O
OH
O
O
O
O
O
O
O
O
OH
3
4
O
OH
OH
OH
exemplified by palmarumycin CP1 1, palmarumycin CP3 2,
diepoxine s 3 and preussomerine E 4, which show diverse
biological effects including selective antifungal and antibac-
terial activities.4 Although Wipf and Jung have reported studies
towards the synthesis of diepoxine s 35 and Krohn et al. have
reported an elegant biomimetic cyclisation approach to a model
spiro-ketal array,6 there have been no reports on the total
synthesis of any natural product in this intriguing series. Herein
we now report the total syntheses of three natural products
palmarumycins CP1 1 and CP2 9 and CJ-12,371 11.
i
O
O
O
O
11 (60%, 93% ee)
9
Condensation of 5-methoxytetralone 5 and diol 67 under acid
catalysis gave spiro-ketal 7‡ in an 86% yield (Scheme 1).
Subsequent benzylic oxidation using bipyridinium chlorochro-
mate8 and a 30-fold excess of tert-butyl hydroperoxide gave the
corresponding ketone 8 in 61% yield. Alternative oxidants
including Jones’ Reagent or potassium permanganate were
much less efficient for the preparation of ketone 8. Reaction of
BCl
2
12
Scheme 2 Reagents and conditions: i, (+)-12, THF, room temp., 18 h, then
H2O2, KOH
Chem. Commun., 1998
809

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with simple alkyl aryl ketones.13 The product of reduction,
alcohol 11, is a natural product in its own right named CJ-
12,371 11,14 a DNA-gyrase inhibitor isolated from an uni-
dentified fungus (N983-46). The authenticity of both palmar-
umycins CP1 1 and CP2 9 were established by comparison of the
synthetic compounds with authentic samples (1H and 13C NMR
spectroscopy). Unfortunately, we have been unable to obtain an
authentic sample of CJ-12,371 11 and the characterisation of
our synthetic material rests on comparison of our data with
those published for the natural product.14
It is clear that the spiro-ketal 7 is a useful intermediate for
further redox manipulations and the synthesis of simple
palmarumycins. Further studies towards the total synthesis of
the more challenging and higher oxidation level diepoxines and
preussomerines are currently under investigation and will be
reported in due course.
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We thank SmithKline Beecham for support of our
research, Glaxo Wellcome Research Ltd. for an endowment (to
A. G. M. B.), the Wolfson Foundation for establishing the
Wolfson Centre for Organic Chemistry in Medical Science at
Imperial College and Professor Karsten Krohn for authentic
samples of palmarumycins CP1 1 and CP2 9.
Notes and References
† E-mail: m.stow@ic.ac.uk
‡ All new compounds were fully characterised by spectroscopic data,
microanalysis and HRMS
§ The enantiomeric excess was determined by chiral HPLC while the
absolute stereochemistry was determined by comparison of the optical
rotation [a]2D4 242.2, (c 0.45 in MeOH)] with the isolated natural product
[a]2D4 246.8 (c 0.23, MeOH)].
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Received in Liverpool, UK, 8th January 1998; 8/00237A
810
Chem. Commun., 1998