Synthesis of naphthyl C-glycosides of rearranged tri-O-benzyl-2-deoxy-D- glucose

Article abstract of DOI:10.1016/S0040-4039(99)02241-8

C-Glycosylation of 3-bromonaphthol 4 with benzyl-protected glycosyl donor 19 afforded rearranged bicyclic acetal 24 in which the glycosyl donor had undergone an unusual 1,6-hydride shift. Use of the regioisomeric 2- bromonaphthol 6 with the same glycosyl donor 19 afforded the expected β-C- glycoside 22. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02241-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1107–1110
Synthesis of naphthyl C-glycosides of rearranged
tri-O-benzyl-2-deoxy-D-glucose
Margaret A. Brimble ∗ and Timothy J. Brenstrum
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
Received 18 October 1999; accepted 29 November 1999
Abstract
C-Glycosylation of 3-bromonaphthol 4 with benzyl-protected glycosyl donor 19 afforded rearranged bicyclic
acetal 24 in which the glycosyl donor had undergone an unusual 1,6-hydride shift. Use of the regioisomeric
2-bromonaphthol 6 with the same glycosyl donor 19 afforded the expected β-C-glycoside 22. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: C-glycosides; 1,6-hydride shift; naphthols; 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
was found to be effective against gram positive organisms,2 antibiotic resistant cell lines of L5178Y
lymphoblastoma and Ehrlich carcinoma in mice and human leukemia K562 cells.3 Platelet aggregation4
and biomolecule synthesis are also inhibited by medermycin 1.5
Despite this important biological activity only one synthesis of medermycin 1 has been reported to
date.6 We have focused on development of an efficient synthesis of medermycin 1 that is flexible at
the point of introduction of the C-glycoside linkage such that a range of compounds with different
C-glycosides attached to the pyranonaphthoquinone skeleton can be prepared for biological evalua-
tion. Towards this end, we have concentrated on the synthesis of the 2-deoxyglycosyl analogue of
medermycin 2, starting from 2-deoxyglycosylnaphthoquinone 3, making use of our furonaphthofuran
annulation–oxidative rearrangement strategy, as previously applied to the synthesis of the aglycone,
kalafungin.7
∗
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(99)02241-8
tetl 16169

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Our immediate objective was to synthesize a C-glycosylnaphthalene which would serve as a suitable
precursor to C-glycosylnaphthoquinone 3, hence our attention focused on the direct C-glycosylation8
of 3-bromonaphthol 4 or 3-acetylnaphthol 5 with a 2-deoxyglucosyl donor. The reactivity of these
3-functionalized naphthols was also probed by comparison with the regiosomeric 2-functionalized
naphthols. The syntheses of naphthols 4 and 5, together with their respective regioisomers 6 and 7, from
juglone, are outlined (Schemes 1 and 2).
Scheme 1. Reagents and conditions: (i) Br2, AcOH, CHCl3, 70 min, 8 (76%), 9 (21%); (ii) BnBr, Ag2O, CHCl3, 2 h, 10 (89%),
11 (84%); (iii) aq. Na2S2O4, CH2Cl2/Et2O then Me2SO4, K2CO3, acetone, heat, 48 h, 12 (76%), 13 (79%); (iv) H2, Pd/C,
EtOAc, 8 h, 4 (98%), 6 (94%)
Scheme 2. Reagents and conditions: (i) nBuLi, −78°C, THF, 0.5 min, CH3CHO, 14 (98%), 16 (97%); (ii) TPAP, NMO, CH2Cl2,
3 h, 4 Å mol. sieves, 15 (80%), 17 (78%); (iii) H2, Pd/C, EtOAc, 8 h, 5 (53%), 7 (58%)
Bromination of juglone afforded a 3.6:1 mixture of 8 and 9 (97% yield).9 The bromides 8 and 9 were
separated, the hydroxy group at C-5 protected as benzyl ethers 10 and 1110 before reductive methylation
to the dimethyl ethers 12 and 13. Finally, removal of the benzyl group afforded the desired naphthols 4
and 6.
Acetylnaphthols 5 and 7 were prepared from the respective bromides 12 and 13 via halogen metal
exchange with nbutyllithium followed by immediate quenching with acetaldehyde to afford the benzylic
alcohols 14 and 16. Oxidation to the ketones 15 and 17 and hydrogenolysis of the benzyl group then
afforded acetylnaphthols 5 and 7.
Attempted C-glycosylation of acetylnaphthols 5 and 7 with glycosyl acetate 18 using either BF3·Et2O
(1.5–2.0 equiv.) or TMSOTf (1.5 equiv.) and AgClO4 (5 mol%) in acetonitrile afforded none of
the desired C-glycoside 21 and 23 (Table 1). 2-Bromonaphthol 6 proved more reactive than the 3-
bromonaphthol 4 affording the C-glycoside 22 in 48–57% yield using the same Lewis acids. The

1109
corresponding C-glycoside 20 derived from 3-bromonaphthol 4 was only obtained in 5% yield using
TMSOTf and AgClO4.
Table 1
Disappointed with the low yields obtained using glycosyl donor 18, we next turned to the use of
the more reactive glycosyl donor 19. Treatment of 3-bromonaphthol 4 with glycosyl donor 19 using
TMSOTf and AgClO4 or BF3·Et2O in acetonitrile predominantly afforded the rearranged C-glycoside
24 with the expected C-glycoside 20 as the minor component of the product mixture. By way of contrast,
use of 2-bromonaphthol 6 under the same reaction conditions afforded the usual β-C-glycoside product
22 (53%) with none of the rearranged C-glycoside 26 being formed. Acetylnaphthols 5 and 7 were less
reactive than the corresponding bromonaphthols 4 and 6 undergoing C-glycosylation in low yield using
BF3·Et2O as the Lewis acid, forming the rearranged C-glycosides 25 and 27, in preference to the normal
β-C-glycosides 21 and 23.
The rearranged C-glycosides 24, 25 and 27 observed in the present work can be rationalized (Scheme
3) by initial generation of an oxacarbenium ion followed by a 1,6-hydride shift to regenerate a glycal
producing a benzylic oxacarbenium ion. Attack of the glycal on this latter ion followed by trapping with
the appropriate substituted naphthol affords the unusual C-glycosides. An analogous rearrangement has
been observed by Steel et al.11 during investigations of the dimerization of tri-O-benzyl-D-glucal using
acetyl perchlorate. These authors also carried out deuterium labelling studies which provided evidence
for the critical 1,6-hydride shift. In our case the lack of vicinal coupling between H-1 and H-7 established

1110
that the naphthalene ring was endo to the bicyclic structure in products 24–27 whereas in the case of Steel
et al.11 a coupling constant of 4.4 Hz established that the substituent at this position was in fact exo to the
bicyclic system.
Scheme 3.
The work reported herein provides the first example of the C-glycosylation of this unusual rearranged
glycal skeleton. The fact that different C-glycosides are obtained depending upon whether the substituent
in the right hand ring of the naphthalene is at C-2 or C-3, illustrates the subtle nature of these C-
glycosylations. For our purposes the results described herein indicate that in order to synthesize the 3-
acetyl-C-glycosylnaphthoquinone 3 required for synthesis of the analogue of medermycin 2, a naphthol
which is unsubstituted at C-3 must be used in the C-glycosylation step. The required acetyl group at C-3
must then be introduced regioselectively after effecting the critical C-glycosylation step.
Acknowledgements
The authors thank the Australian Research Council and the University of Sydney for financial support
and Dr. Patrick Steel (University of Durham, UK) for supplying NMR spectra for compounds related to
the rearranged C-glycosides reported herein.
References
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