Synthesis of bergenin-related natural products by way of an intramolecular C-glycosylation reaction

Article abstract of DOI:10.1016/S0957-4166(99)00484-X

The peracetate of tri-O-methylnorbergenin 16 as well as the cis-fused epimer of 16, which constitutes the core C-aryl glycosidic fragment of castacrenin B, were prepared by way of the IDCP-mediated intramolecular C-arylation of a pentenyl β-D-glucopyranos

Full text of DOI:10.1016/S0957-4166(99)00484-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 409–412
Synthesis of bergenin-related natural products by way of an
intramolecular C-glycosylation reaction
Cyril Rousseau and Olivier R. Martin ∗
Institut de Chimie Organique et Analytique ( I.C.O.A.), Faculté des Sciences, BP 6759, 45067 Orléans cedex 2, France
Received 21 October 1999; accepted 2 November 1999
Abstract
The peracetate of tri-O-methylnorbergenin 16 as well as the cis-fused epimer of 16, which constitutes the core C-
aryl glycosidic fragment of castacrenin B, were prepared by way of the IDCP-mediated intramolecular C-arylation
of a pentenyl β-D-glucopyranoside carrying, at O-2, a 3,4,5-trimethoxybenzyl substituent. © 2000 Elsevier Science
Ltd. All rights reserved.
Bergenin 11 and its derivatives norbergenin 22 and tri-O-methylnorbergenin 33 are gallotannin-related
natural products having the unusual structure of internal C-aryl glycosides (Fig. 1).4 Bergenin and its
congeners occur widely in a number of plants and have been found as ingredients in plant extracts used in
Indian folk medicine to treat veneral diseases.3 Recently, the cis-fused epimer of norbergenin was found
to occur as a fragment of an ellagitannin metabolite, namely castacrenin B, isolated from the Japanese
chestnut tree.5 The structures of bergenin and of castacrenin B are inviting targets for a synthesis by
way of an intramolecular C-glycosylation procedure. However, attempts to prepare bergenin by such a
strategy have failed so far.6
Fig. 1.
∗
Corresponding author. E-mail: olivier.martin@univ-orleans.fr
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00484-X
tetasy 3120

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C. Rousseau, O. R. Martin / Tetrahedron: Asymmetry 11 (2000) 409–412
Bergenin itself has been obtained in very low yield by the reaction of acetobromoglucose with methyl
4-O-methyl gallate,1 and its dimethyl ether 3 by a multistep synthesis by way of a C-glucopyranosyl
benzene derivative.7 In preliminary studies,8 we have established that the internal C-glycosylation of
gluco- and mannopyranose derivatives carrying, at O-2, a 3,4,5-trimethoxybenzoyl substituent could not
be achieved, in spite of promising results in the furanose series.9 As a consequence, we examined a
synthetic approach to these natural products by way of a two-step strategy, namely internal C-arylation of
2-O-benzylated pyranosides, followed by oxidation of the benzylic position to form the lactone function.
While the intramolecular alkylation of the benzyl group took place readily in sugars carrying, at O-
2, a 3-methoxybenzyl or a 3,5-dimethoxybenzyl substituent,8,9 the conditions of the reaction (SnCl4,
BF3·Et2O, etc.) were not compatible with a 3,4,5-trimethoxybenzyl group as they promoted rapid de-O-
benzylation of the substrate. A solution was found to this problem by using, as the anomeric activator, a
pentenyl glycoside,10 a function that can be activated selectively using a soft Lewis acid. We report herein
the first synthesis of tri-O-methylnorbergenin and of the core C-glycosidic structure of castacrenin B by
way of an internal C-glycosylation reaction.
The required precursor, partially protected pentenyl β-D-glucopyranoside 8, was prepared in 59% over-
all yield from tetra-O-acetyl-α-D-glucopyranosyl bromide 5 by the orthoester procedure11,12 (Scheme 1):
O-pentenyl orthoester 6 was obtained from 5 under Lemieux–Morgan conditions,11 the acetyl groups of
6 were replaced by benzyl groups, and the orthoester 7 was rearranged into the corresponding pentenyl β-
glycoside 8 by treatment with trimethylsilyl triflate13 followed by de-O-acetylation at O-2. Benzylation of
8 with highly reactive 3,4,5-trimethoxybenzyl chloride (from 3,4,5-trimethoxybenzyl alcohol and SOCl2)
provided substrate 9 (80%).
Scheme 1. Reagents and conditions. (a) 4-Penten-1-ol (3 equiv.), nBu4NBr, collidine; 83%. (b) KOH, BnBr, THF, ∆; 84%. (c)
(i) TMSOTf (cat.), CH2Cl2, 0°C, 2 h; (ii) MeONa, MeOH; 84%. (d) ArCH2Cl, NaH, DMF; 80%
The treatment of 9 with iodonium dicollidine perchlorate (IDCP)14 promoted the desired internal C-
arylation reaction in excellent yield and without premature cleavage of the benzyl group at O-2 (Scheme
2). The resulting product was exclusively the kinetically favored,15 cis-fused tricyclic system 10 (‘α-
linked’). It is also noteworthy that iodination of the activated aromatic ring did not compete with
the internal alkylation.16 Selective removal of the benzyl groups of 10 was realized by brief catalytic
hydrogenation and the resulting product was acetylated to afford 11. The benzylic position of 11 could
then be oxidized using catalytic ruthenium tetroxide17 to give compound 12 (39% yield), a protected
form of the core C-aryl glycoside of castacrenin B.
The NMR data of 1218 were found to be in excellent agreement with those reported for the correspond-
ing derivative of castacrenin B.5 Deacetylation of 12 gave the tri-O-methyl analog, compound 13.19
3
It is of interest to note that the JH,H coupling constants in the pyranose ring of both 11 and 12 are
3
all small (J1,2=3Hz, other JH,H=3.8–5 Hz) which indicate that the conformation with an inverted chair
(1C4-type, see I in Fig. 2) is much more favorable for these compounds than the alternate 4C1 chair form
in which the C-aryl substituent would be axial.
The synthesis of bergenin and congeners required an epimerization at the newly created benzylic
position (C-1). This inversion of configuration was deemed possible on the basis of the expected greater

C. Rousseau, O. R. Martin / Tetrahedron: Asymmetry 11 (2000) 409–412
411
Scheme 2. Reagents and conditions. (a) IDCP (2 equiv.), CH2Cl2, 3 h, rt; 83%. (b) (i) H2, Pd/C, MeOH; (ii) Ac2O, pyridine;
98%. (c) RuCl3 (cat.), NaIO4, CCl4/MeCN/H2O, 18 h; 39%. (d) MeONa, MeOH; quant.
stability of the trans-fused (β-linked) bicyclic system (II) with respect to the cis-fused (α-linked)
structure (I, Fig. 2) and of the likely sensitivity of the endocyclic benzylic C1–O5 bond to Lewis acids.
Fig. 2.
The treatment of 10 with an oxophilic Lewis acid promoted indeed the desired epimerization, albeit
in a yield not exceeding 50%. The best results were obtained using BF3·Et2O. The resulting product, 14
(Scheme 3), was deprotected by hydrogenolysis and reacetylated to give 15, and the remaining primary
1
benzylic position oxidized under the same conditions as 11 to give lactone 16 (68%). The H and 13C
NMR data of this product 1620 were found to match those reported for the triacetate of tri-O-methyl-
norbergenine.3,7
Scheme 3. Reagents and conditions. (a) BF3·Et2O (cat.), CH2Cl2, 2 h, 0°C to rt; 48%. (b) (i) H2, Pd/C, MeOH; (ii) Ac2O,
pyridine; 95%. (c) RuCl3 (cat.), NaIO4, CCl4/MeCN/H2O, 18 h; 68%
In conclusion, we have achieved the first synthesis of tri-O-methylnorbergenin triacetate, as well
as of the core C-aryl glycoside of castacrenin B by way of an intramolecular C-glycosylation. This
work demonstrates that pentenyl glycosides constitute very convenient substrates for the internal alkyl-
ation/glycosylation of highly Lewis-acid sensitive benzyl groups.
References
1. Hay, J. E.; Haynes, L. J. J. Chem. Soc. 1958, 2231.
2. Taneyama, M.; Yoshida, S.; Kobayashi, M.; Hasegawa, M. Phytochemistry 1983, 1053.
3. Ramaiah, P. A.; Row, L. R.; Reddy, D. S.; Anjaneyulu, A. S. R.; Ward, R. S.; Pelter, A. J. Chem. Soc., Perkin Trans. 1 1979,
2313.

412
C. Rousseau, O. R. Martin / Tetrahedron: Asymmetry 11 (2000) 409–412
4. Frick, W.; Hofmann, J.; Fischer, H.; Schmidt, R. R. Carbohydr. Res. 1991, 210, 71.
5. Tanaka, T.; Ueda, N.; Shinohara, H.; Nonaka, G.-I.; Fujioka, T.; Mihashi, K.; Kouno, I. Chem. Pharm. Bull. 1996, 44, 2236.
6. Schmidt, R. R.; Effenberger, G. Carbohydr. Res. 1987, 171, 59. However, the structure of compounds 23 and 24 in that
reference were later shown to be in error: see Ref. 4.
7. Frick, W.; Schmidt, R. R. Carbohydr. Res. 1991, 209, 101.
8. Martin, O. R.; Deshpande, P. P., unpublished results.
9. Martin, O. R.; Hendricks, C. A. V.; Deshpande, P. P.; Cutler, A. B.; Kane, S. A.; Rao, S. P. Carbohydr. Res. 1990, 196, 41.
10. Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottoson, H.; Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927.
11. Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2199.
12. For other examples of O-pentenyl orthoesters, see: (a) Roberts, C.; Madsen, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1995,
117, 1546. (b) Allen, J. G.; Fraser-Reid, B. J. Am. Chem. Soc. 1999, 121, 468.
13. (a) Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res. 1981, 93, C6. (b) Gass, J.; Strobl, M.; Loibner, A.; Kosma, P.;
Zaehringer, U. Carbohydr. Res. 1993, 244, 69.
14. Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64, 2780. For its use in O-glycosylation reactions, see Ref. 10.
15. The internal C-arylation of a 2-O-benzyl glucopyranosyl chloride gave exclusively the α-linked (cis-fused) product:
Verlhac, P.; Leteux, C.; Toupet, L.; Veyrières, A. Carbohydr. Res. 1996, 291, 11.
16. Partial iodination of the ring occurred in the course of the internal C-arylation of the 2-O-(3,5-dimethoxybenzyl) derivative
of 8 using IDCP.
17. Carlsen, P. J. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.
1
18. M.p.: 141–142°C; [α]D +20.8 (c=1.5, CHCl3); H NMR (250 MHz, CDCl3): δ 2.08 (s, 6H), 2.12 (s, 3H) (3OAc), 3.89,
3.91, 3.93 (3s, 9H, 3OMe), 4.12 (m, 1H, J4,5=3.8 Hz, H-5), 4.32 (dd, 1H, J5,6a=4.7, J6a,6b=12.0 Hz, H-6a), 4.45 (br t, 1H,
J=3.3 Hz, H-2), 4.53 (dd, 1H, J5,6b=7.2Hz, H-6b), 4.94 (t, 1H, J=4.1 Hz, H-4 or 3), 5.19 (d, 1H, J1,2=3.0 Hz, H-1), 5.31 (t,
1H, J=4 Hz, H-3 or 4), 7.45 (s, 1H, HAr); 13C NMR (62.9 MHz): δ 20.75 (3C), 56.28, 60.84 (C-6), 61.02, 61.91, 65.85,
68.09, 73.11, 73.54, 108.81 (ArCH), 119.97, 122.89, 147.46, 150.76, 154.8, 162.5, 168.75, 169.9, 170.53.
19. 13C NMR (62.9 MHz, CD3OD): δ 57.2, 61.43, 61.98, 62.54, 63.12, 69.58, 73.51, 80.87, 81.62, 109.94, 121.82, 126.07,
149.41, 152.93, 156.49, 166.01.
20. [α]D –8.7±0.8 (c=1.3, CHCl3) {lit.7 [α]D –8 (c=1, CHCl3)}; 1H NMR (250 MHz, CDCl3): δ 2.05, 2.08, 2.09 (3s, 3×3H,
3OAc), 3.84, 3.89, 3.93 (3s, 3×3H, 3OMe), ∼3.85 (occluded m, 1H, H-5), 4.24–4.35 (m, 2H, H-6a,6b), 4.28 (t, 1H, J=10
Hz, H-2), 4.81 (d, 1H, J1,2=10.3 Hz, H-1), 5.10 (t, 1H, J=9.6 Hz, H-4 or 3), 5.50 (t, 1H, J=9.4 Hz, H-3 or 4), 7.43 (s, 1H,
Har); 13C NMR (62.9 MHz): δ 20.63, 20.74, 20.82, 56.28, 61.08, 61.71, 62.46, 68.87, 72.31, 72.50, 77.20, 109.92, 118.8,
124.95, 148.92, 151.3, 154.05, 163.0, 169.75, 170.16, 170.59; one carbon hidden by the 13CDCl3 signal.