Synthesis of a C-glycosylpyranonaphthoquinone related to medermycin

Article abstract of DOI:10.1016/S0040-4039(00)00289-6

The synthesis of a 2-deoxyglucosyl analogue 2 of the pyranonaphthoquinone antibiotic medermycin 1 is reported. The critical β C- glycoside linkage was introduced at an early stage in the synthesis by direct C-glycosylation of naphthol 7 with benzyl protected glycosyl donor 4. Conversion of C-glycoside 8 to 2-acetyl-1,4-naphthoquinone 3 then allowed assembly of the pyranonaphthoquinone skeleton via a furofuran annulation - oxidative rearrangement strategy. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00289-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2991–2994
Synthesis of a C-glycosylpyranonaphthoquinone related to
medermycin
Margaret A. Brimble ∗ and Timothy J. Brenstrum
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
Received 14 January 2000; accepted 14 February 2000
Abstract
The synthesis of a 2-deoxyglucosyl analogue 2 of the pyranonaphthoquinone antibiotic medermycin 1 is repor-
ted. The critical β C-glycoside linkage was introduced at an early stage in the synthesis by direct C-glycosylation of
naphthol 7 with benzyl protected glycosyl donor 4. Conversion of C-glycoside 8 to 2-acetyl-1,4-naphthoquinone 3
then allowed assembly of the pyranonaphthoquinone skeleton via a furofuran annulation–oxidative rearrangement
strategy. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: C-glycosides; naphthols; 2-trimethylsilyloxyfuran; pyranonaphthoquinones.
The pyranonaphthoquinone antibiotic medermycin 1 was isolated1 from Streptomyces tanashiensis
and was shown to contain a C-glycoside linkage to the aminosugar, D-angolosamine. Medermycin 1
exhibits significant activity against Gram-positive bacteria,2 including staphylococci which are resistant
to several antibiotics. It showed cytotoxity for cell lines of K-562 human myeloid leukemia, P-388 murine
leukemia and antibiotic-resistant cell lines of L5178Y lymphoblastoma in culture.3 Platelet aggregation4
and biomolecule synthesis are also inhibited by medermycin 1.5
The only synthesis of medermycin 1 to date has been reported by Tatsuka et al.6 and requires over 30
steps with the key step involving assembly of a pyranonaphthalene via addition of a sulfonyl-phthalide
to an enone. The key sulfonyl-phthalide itself required 17 steps for its preparation. Our approach to
the synthesis of analogues of medermycin 1 has focused on construction of the C-glycoside linkage
in a flexible manner such that various C-glycosides can be attached to the pyranonaphthoquinone
skeleton. We herein report an efficient synthesis of the 2-deoxyglucosyl analogue of medermycin
∗
Corresponding author. Department of Chemistry, 23 Symonds St., Auckland, New Zealand. Tel: +64 9 3737599, ext. 8259;
fax: +64 9 3737422; e-mail: m.brimble@auckland.ac.nz (M. A. Brimble)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00289-6
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2, from 2-deoxyglucosylnaphthoquinone 3, making use of our furonaphthofuran annulation–oxidative
rearrangement strategy, as previously applied to the synthesis of the aglycone, kalafungin.7
C-Glycosylnaphthoquinone 3, which contains an acetyl group at C-3 (required in order to control the
regiochemistry of the ensuing furofuran annulation), was the focus of our initial attention (Scheme 1).
Whilst direct C-glycosylation8 of 3-acetylnaphthol 5 or 3-bromonaphthol 6 with 2-deoxyglucosyl donor
4 appeared an obvious route to the required C-glycosylnaphthoquinone 3, this approach was hampered
by the formation of rearranged bicyclic acetals in which the glycosyl donor 4 had undergone an unusual
1,6-hydride shift.9 Our successful synthesis of C-glycosylnaphthoquinone 3, therefore, focused on the
C-glycosylation of naphthol 7 followed by regioselective introduction of the required 3-acetyl group.
Scheme 1.
Addition of boron trifluoride diethyletherate to naphthol 710 and glycosyl acetate 411 in dry acetonitrile
at 0°C afforded the desired β C-glycoside 812,13 in 73% yield after flash chromatography (Scheme 2).
After protection of naphthol 8 as a methyl ether 9,14 conversion to naphthoquinone 10, followed by
reductive monomethylation, afforded naphthol 11 which allows regioselective introduction of an acetyl
substituent at C-3.
Scheme 2. Reagents and conditions: (i) BF3·Et2O, CH3CN, 0°C, 20 min, 73%; (ii) MeI, NaH, DMF, 0°C, 12 h, 85%; (iii) CAN,
CH3CN, 0.5 h, 93%; (iv) Na2S2O4 then Me2SO4, K2CO3, acetone, reflux, 2–4 h, 82%; (v) Br2, CCl4, 0°C, 2 min, 77%; (vi)
NaOH, Me2SO4, DMF/H2O, 15 min, 0°C, 84%; (vii) Pd(PPh3)2Cl2, Bu3SnC(OEt)_CH2, toluene, 100°C, N2, 16 h then H3O+,
97%; (viii) AgO, HNO3, dioxane, 20 min, 93%
Attempted Fries’ rearrangement of acetate 12 derived from naphthol 11 was ineffective and, therefore,
the acetyl group was introduced indirectly from bromide 13. After conversion of bromonaphthol 13

2993
to bromomethoxynaphthalene 14, introduction of the acetyl group via lithiation of the bromide was
unsuccessful due to the highly basic nature of the naphthyl anion. An alternative approach employing
α-ethoxyvinyltributyl tin as a masked acetylating agent afforded 3-acetylnaphthalene 15 which was
smoothly oxidised to naphthoquinone 3.
With the key C-glycosylnaphthoquinone 3 in hand, attention then focused on conversion to C-
glycosylpyranonaphthoquinone 2 (Scheme 3). Addition of 2-trimethylsilyloxyfuran 16 to naphthoqui-
none 3 afforded a 1:1 mixture of the furonaphthofuran adducts 17 and 18 in moderate yield. Treatment
of furo[3,2-b]naphthofurans 17 and 18 with aqueous ceric ammonium nitrate (CAN) effected smooth
conversion to furonaphthopyrans 19 and 20 which were separable upon purification by low temperature
(−20°C)15 flash chromatography. Subsequent reduction of the lactols 19 and 20, using triethylsilane
and trifluoroacetic acid, afforded cyclic ethers 21 and 22 which were also separable by low temperature
flash chromatography.15 Finally, use of boron tribromide to effect deprotection of the benzyl ethers on
pyranonaphthoquinones 21 and 22, in which the bridgehead proton at C3a is cis to the methine proton
at C5, afforded the more stable epimeric pyranonaphthoquinones 2 and 24, in which these two protons
were trans to each other.16 This epimerisation has been reported on simpler pyranonaphthoquinones.17
Scheme 3. Reagents and conditions: (i) CH3CN, 0°C, 1 h, then MeOH, silica gel, 18 h, 60%; (ii) CAN, CH3CN, 20 min, 85%;
(iii) CF3CO2H, Et3SiH, −10°C, 72 h, 86%; (iv) BBr3, CH2Cl2, −48°C to room temperature, 30 min, 67%
In summary, the successful synthesis of the 2-deoxyglucosyl analogue 2 of the pyranonaphthoquinone
antibiotic medermycin 1 has been achieved. Moreover, the synthesis can be easily modified for the

2994
preparation of medermycin 1 itself, and other analogues, by simply varying the nature of the glycosyl
donor used in the initial C-glycosylation step.
Acknowledgements
The authors thank the Australian Research Council and the University of Sydney for financial support
and Dr. David Larsen (University of Otago) for helpful advice.
References
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0
0
0 0
13. The β stereochemistry was confirmed by vicinal coupling constants for the anomeric proton, J1 ,2 ax=11.0 and J1 ,2 eq=1.8
Hz.
14. All new compounds gave satisfactory elemental and spectroscopic analysis.
15. Performing flash chromatography at room temperature resulted in substantial decomposition of the product.
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temperature flash chromatography; however, assignment of exact stereochemistry to an individual compound in a given
pair was not possible using NMR spectroscopy.
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