Intramolecular C-glycosylation of 2-O-benzylated pentenyl mannopyranosides: Remarkable 1,2-trans stereoselectivity

Article abstract of DOI:10.1016/j.tetlet.2003.10.006

The IDCP-promoted intramolecular C-glycosylation of pentenyl α-mannopyranosides carrying, at O-2, an activated benzyl group gave, unexpectedly, the 1,2-trans-fused bicyclic product which corresponds to an α-C-aryl mannopyranose derivative. This remarkable, strained C-glycosyl compound was rapidly epimerized to the more stable 1,2-cis product on treatment with BF₃·Et₂O. The IDCP-reaction product could be elaborated into a 2-(α-C-mannopyranosyl)-3,4,5-trimethoxybenzyl alcohol derivative.

Full text of DOI:10.1016/j.tetlet.2003.10.006

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8971–8974
Intramolecular C-glycosylation of 2-O-benzylated pentenyl
mannopyranosides: remarkable 1,2-trans stereoselectivity
Nicolas Girard, Cyril Rousseau and Olivier R. Martin*
Institut de Chimie Organique et Analytique (ICOA), Faculte´ des Sciences and CNRS, BP 6759, 45067 Orle´ans cedex 2, France
Received 27 August 2003; revised 22 September 2003; accepted 1 October 2003
Abstract—The IDCP-promoted intramolecular C-glycosylation of pentenyl a-mannopyranosides carrying, at O-2, an activated
benzyl group gave, unexpectedly, the 1,2-trans-fused bicyclic product which corresponds to an a-C-aryl mannopyranose
derivative. This remarkable, strained C-glycosyl compound was rapidly epimerized to the more stable 1,2-cis product on treatment
with BF3·Et2O. The IDCP-reaction product could be elaborated into a 2-(a-C-mannopyranosyl)-3,4,5-trimethoxybenzyl alcohol
derivative.
© 2003 Elsevier Ltd. All rights reserved.
We have recently shown1 that 4-pentenyl glucosides
constituted useful substrates for the intramolecular C-
arylation reactions of 2-O-benzylated glycosides,2 par-
ticularly with Lewis-acid sensitive benzyl groups. Using
this methodology, we were able to achieve the first
synthesis of bergenin-related natural products by way
of an intramolecular C-glycosylation process.1 The
chemoselective activation of pentenyl glycosides3 com-
bined with a sufficiently reactive benzyl group provide
conditions for the intramolecular reaction that are
much milder than the previously used hard Lewis acids
such as SnCl4, BF3·Et2O, etc.4 In order to investigate
further the reactivity of benzylated pentenyl glycosides
and generalize their use in such processes, we have
carry the anomeric configuration most commonly
found in natural C-aryl glycosides. However, this
expectation was not born out by experiment. We wish
to report in this communication these unexpected
results.
The required precursor, partially protected 4-pentenyl
a-
D
-mannopyranoside 4, was prepared from tetra-O-
-mannopyranosyl bromide 1 (Scheme 1). The
acetyl-a-
D
reaction of 1 with 4-pentenyl alcohol in the presence of
tetrabutylammonium bromide in collidine5 gave a good
yield of the corresponding orthoester 2 (69%, 33
g-scale). Curiously, the formation of this compound
under similar conditions had been reported to be unsuc-
cessful;6 the reactions of pentenyl orthoesters in the
manno series have been performed so far most fre-
quently from the phenyl-substituted orthoesters.7 The
acetyl groups of 2 were replaced by benzyl groups, and
examined the behavior of 4-pentenyl
D-mannopyrano-
sides carrying various benzyl groups at O-2. In this
context, the interest in the manno series is the possibility
of creating b-linked C-aryl glycosidic structures, which
Scheme 1. Reagents and conditions: (a) 4-penten-1-ol (3 equiv.), nBu4NBr (0.3 equiv.), collidine, 69–71%; (b) KOH, BnBr, THF,
D, 92%; (c) i. TMSOTf (cat.), CH2Cl2, 0°C, 2 h, ii. MeONa, MeOH, 75%; (d) ArCH2Cl, NaH, DMF, 70%.
Keywords: C-aryl glycosides; C-glycosylation.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.006

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N. Girard et al. / Tetrahedron Letters 44 (2003) 8971–8974
of BF3·Et2O; this promoted the essentially instanta-
neous epimerization at C-1 and the 1,2-cis-epimer 8
could be isolated in 81% yield.11 This result established
that compound 6 is the kinetic product and that it is, as
expected, markedly less stable than the cis structure.
the resulting orthoester 3 was rearranged into the corre-
sponding pentenyl a-mannoside 4 by treatment with
trimethylsilyl triflate8 followed by de-O-acetylation at
O-2. Benzylation of 4 with 3,4,5-trimethoxybenzyl chlo-
ride (from 3,4,5-trimethoxybenzyl alcohol and SOCl2)
provided substrate 5 (58%).
In order to be able to investigate the internal reaction
of a 4-pentenyl glycoside under both soft and hard
Lewis acidic conditions,12 we prepared the 2-O-(3,5-
dimethoxybenzyl) analog of 5, compound 10, by benzyl-
ation of 4 with 3,5-dimethoxybenzyl chloride (86%).
Compound 10 was then reacted with IDCP (Scheme 3).
Although the yield of the transformation was low
because of extensive iodination of the starting mate-
rial,13 the reaction gave, again, a mixture of two prod-
ucts (11 and 12) in which the trans isomer (11) was
predominant (ratio ꢀ4/1). Both products also con-
tained an iodine atom,12 and were deiodinated in high
yield with Zn in AcOH, to give 13 and 14, respectively.
Upon treatment with IDCP (iodonium dicollidine per-
chlorate),9 compound 5 underwent rapid ring closure
by an internal Friedel–Crafts type process; the clean
reaction led however, to two products (6 and 8) in a
ꢀ5:1 ratio (Scheme 2). The two products could be
readily separated by chromatography and isolated in 70
and 16% yields, respectively. The NMR analysis of the
major product revealed that it had the unexpected
1,2-trans configuration (a-C-mannosyl arene), and
1
existed in an inverted C4-type conformation, and the
minor product was the cis-fused structure 8 (b-C-man-
nosyl arene). Diagnostic NMR data10 for the corre-
sponding triacetates 7 and 9 are provided in Figure 1;
in particular, the very large, J1,2-coupling constant in 7
is characteristic of a nearly diaxial relationship between
these two protons. This result is extremely surprising
since it appeared that, for both steric and stereoelec-
tronic reasons, the 1,2-cis product should have been
favored in this intramolecular reaction. In order to
evaluate the relative stability of the two products, the
trans epimer 6 was treated with an equimolar amount
With BF3·Et2O as the promoter, the glycoside 10
underwent a great deal of degradation, but the cis-
fused structure 14 could be isolated in 17% yield as the
only cyclization product. A better yield of the same
product (43%) was obtained by treating 10 with sulfuric
acid in AcOH.2
The surprising stereoselectivity of the internal C-glyco-
sylation of 5 promoted by IDCP, which occurs with
Scheme 2. Reagents and conditions: (a) IDCP (2 equiv.), CH2Cl2, 3 h, rt, 86%; (b) i. H2, Pd/C, AcOEt, ii. Ac2O, pyr; (c) BF3·Et2O,
CH2Cl2.
Figure 1. J-values (Hz).

N. Girard et al. / Tetrahedron Letters 44 (2003) 8971–8974
8973
Scheme 3. Reagents and conditions: (a) IDCP (2 equiv.), CH2Cl2, 3 h, rt; (b) Zn, AcOH; (c) H2SO4/AcOH, 43%.
Scheme 4. Reagents and conditions: (a) RuCl3, NaIO4/CCl4–CH3CN–H2O, 41%; (b) LiAlH4, THF, then Ac2O, py, 40%.
retention of configuration, is probably best explained
by a double displacement mechanism. Possible nucle-
ophiles to promote the first substitution include col-
lidine and the perchlorate anion which are liberated
upon I+ consumption; however, an intermediate b-N-
glycosylated collidinium ion would have a very strong
propensity to exist in an equatorial disposition (for-
merly known as reverse anomeric effect)14 thus making
as mannosides give access stereoselectively to a-C-aryl
glycosides whereas equivalent intermolecular processes
generally lead to the thermodynamically more favor-
able b-epimers.20,21
In conclusion, 4-pentenyl mannopyranosides carrying
an activated benzyl group at O-2 revealed unusual
behavior in the intramolecular C-arylations promoted
by IDCP, by giving the kinetically favored trans-fused
product. Further work is in progress to determine the
origin of this unexpected stereoselectivity.
the 1,2-trans attack difficult. Alternatively,
a b-
perchlorate15 might force the mannopyranose ring to
1
adopt the inverted C4 chair conformation present in
the final product and thus occupy the axial position
favored by its strong anomeric effect; this would
provide the highly reactive 1,2-cis intermediate neces-
sary for the alkylation of the electron-rich 2-O-aryl-
methyl group by a 1,2-trans trajectory. Clearly, the
reaction does not occur by way of a ‘free’ oxocarbe-
nium ion since a 1,2-cis attack on such a species would
be much more favorable than the 1,2-trans process.
These observations may have important repercussions
on the interpretation of the mechanism of other reac-
tions of 4-pentenyl glycosides.
References
1. Rousseau, C.; Martin, O. R. Tetrahedron: Asymmetry
2000, 11, 409–412.
2. Martin, O. R.; Hendricks, C. A. V.; Deshpande, P. P.;
Cutler, A. B.; Kane, S. A.; Rao, S. P. Carbohydr. Res.
1990, 196, 41–58 and references cited therein.
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4. See for example: (a) Martin, O. R.; Rao, S. P.; Hen-
dricks, C. A. V.; Mahnken, R. E. Carbohydr. Res. 1990,
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Fiecchi, A.; Scala, A. Carbohydr. Res. 1990, 208, 264–
266. For the reaction of a benzylated glycosyl chloride
promoted by AgBF4, see: (c) Verlhac, P.; Leteux, C.;
Toupet, L.; Veyrie`res, A. Carbohydr. Res. 1996, 291,
11–20.
The synthetic usefulness of the intramolecular C-aryla-
tion process described above was demonstrated by the
elaboration of 7 into an a-C-mannosylated benzene
derivative (Scheme 4): oxidation of the primary benz-
ylic position in 7 using catalytic ruthenium tetroxide16
afforded the bergenin-related lactone 15.17 The lactone
was then cleaved reductively with LiAlH4 to provide,
after reacetylation, the a-C-mannosyl trimethoxybenzyl
acetate 16, a compound whose structure is related to
that of the chaetiacandins.18 The sugar substituent of
the C-aryl glycoside 16 remains for steric reasons in the
1C4 conformation.19 It is important to note that the
internal C-arylation of 4-pentenyl glucosides1,4c as well
5. Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43,
2199–2204.
6. Merritt, J. R.; Naisang, E.; Fraser-Reid, B. J. Org. Chem.
1994, 59, 4443–4449.

8974
N. Girard et al. / Tetrahedron Letters 44 (2003) 8971–8974
3,5-dimethoxybenzyl group. Isolated yields: iodinated
7. (a) Anilkumar, G.; Nair, L. G.; Fraser-Reid, B. Org.
starting material: 37%, 11: 18%, 12: 5%.
14. Tvarosˇka, I.; Bleha, T. Adv. Carbohydr. Chem. Biochem.
Lett. 2000, 2, 2587–2589; (b) Udodong, U. E.; Madsen,
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Fraser-Reid, B. J. Am. Chem. Soc. 1989, 111, 8540–8542.
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1989, 47, 45–123.
15. Glycosyl perchlorates have been reported. See: (a)
Zhdanov, Y. A.; Korol’chenko, G. A.; Dorofeenko, G.
N.; Zhungietu, G. I. Dokl. Akad. Nauk SSSR 1964, 154,
861–863; (b) Igarashi, K.; Honma, T.; Irisawa, J. Carbo-
hydr. Res. 1970, 15, 329–337. We thank a referee for
suggesting the possible involvement of
perchlorate.
16. Carlsen, P. J. H.; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936–3938.
a glycosyl
9. Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43,
2190–2198. For its use in O-glycosylation reactions, see
Ref. 3.
1
10. NMR data for 7: H NMR (250 MHz, CDCl3, attribu-
17. NMR data for 15: 1H NMR (250 MHz, C6D6, attribu-
tions verified by H,H-COSY): l 1.56, 1.71, 1.82 (3s,
3×3H, 3 COCH3), 3.26, 3.69, 3.75 (3s, 3×3H, 3 OMe),
4.09 (dd, 1H, J5,6a=5.7, J6a,6b=11.9 Hz, H-6a), 4.34 (dd,
1H, J=5.7, 9 Hz, H-5), 4.58 (dd, 1H, J1,2=10.7, J2,3=2.8
Hz, H-2), 4.93 (dd, 1H, J5,6b=9.1 Hz, H-6b), 5.08 (d, 1H,
tions verified by H,H-COSY): l 2.06, 2.11, 2.12 (3s,
3×3H, 3 COCH3), 3.78, 3.80, 3.88 (3s, 3×3H, 3 OMe),
3.81 (m, 1H, H-2), 4.24 (t, 1H, J=7.2, H-5), 4.53 (dd,
1H, J5,6a=6.7, J6a,6b=11.6 Hz, H-6a), 4.71 (dd, 1H,
J5,6b=7.8 Hz, H-6b), 4.71 (d, 1H, J7a,7b=14.8 Hz, H-7a),
4.92 (d, 1H, H-7b), 5.00 (d, 1H, J3,4=2.9 Hz, H-4), 5.11
(d, 1H, J1,2=9.8 Hz, H-1), 5.42 (t, 1H, J=2.3 Hz, H-3),
6.33 (s, 1H, HAr); 13C NMR (62.9 MHz, CDCl3, attribu-
tions verified by H,C-correlation): l 21.2, 21.3 (Ac), 56.5
(OMe), 61.0 (C-6), 61.1 (OMe), 61.6 (OMe), 62.6 (C-1),
69.0 (C-3), 69.7 (2C, C-4, C-7), 73.6 (C-2), 75.1 (C-5),
103.1 (C-6%), 119.7 (C-2%), 131,7 (C-1%), 142.2, 153.8, 154.1
(C-3%,4%,5%), 169.7, 169.8, 171.0 (MeCOO). For 9: 1H
NMR (250 MHz, CDCl3, attributions verified by H,H-
COSY): l 2.02, 2.06, 2.14 (3s, 3×3H, 3 COCH3), 3.83,
3.86, 3.96 (3s, 3×3H, 3 OMe), 3.78–3.99 (m, 2H, H-2,
H-5), 4.15 (dd, 1H, J5,6a=2.5, J6a,6b=12.2 Hz, H-6a),
4.23 (dd, 1H, J5,6b=5.9 Hz, H-6b), 4.62 (s, 1H, H-1), 4.66
(d, 1H, J7a,7b=15.5 Hz, H-7a), 4.96 (d, 1H, H-7b), 5.18
(dd, 1H, J2,3=3.7, J3,4=10.2 Hz, H-3), 5.39 (t, 1H,
J=9.8 Hz, H-4), 6.34 (s, 1H, H-6%).
J
3,4=3.1 Hz, H-4), 5.30 (d, 1H, J1,2=10.7 Hz, H-1), 5.61
(t, 1H, J=2.7 Hz, H-3), 7.52 (s, 1H, H-6%); 13C NMR
(62.9 MHz, C6D6, attributions verified by H,C-correla-
tion): l 20.8. 21.0 (Ac), 56.1, 61.2, 62.2 (3 OMe), 60.2
(C-6), 63.8 (C-1), 67.8 (C-3), 69.3 (C-4), 74.9 (C-2), 75.6
(C-5), 110.7 (C-6%), 120.5 (C-2%), 127.4 (C-1%), 149.9, 152.8,
154.8 (C-3%,4%,5%), 163.9 (C-7), 169.4, 169.6 (MeCOO).
18. Komori, T.; Itoh, Y. J. Antibiot. 1985, 38, 544–546.
19. The NMR spectrum of 16 was not complicated by slow
rotation about the C1–CAr linkage, and could be recorded
at room temperature, as observed by Kumazawa et al. for
a similar C-aryl a-mannoside.11 The product was con-
taminated by an unseparable by-product; identifiable
NMR signals appear to indicate that this product could
be a small amount of the cis-epimer of 16.
20. (a) Suzuki, K.; Matsumoto, T. In Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial
Products; Lukacs, G., Ed.; Springer Verlag: Berlin, 1993;
Vol. 2, pp. 352–403; (b) Jaramillo, C.; Knapp, S. Synthe-
sis 1993, 1–20.
11. For the related epimerization of an a-C-mannosylated
phloroacetophenone derivative, see: Kumazawa, T.; Sato,
S.; Matsuba, S.; Onodera, J.-I. Carbohydr. Res. 2001,
332, 103–108.
12. Compound 5 undergoes rapid 2-O-debenzylation in the
presence of hard, oxophilic Lewis acids.
13. The reaction gave iodinated starting material as the
major product, an indication that the reaction of the
aromatic residue with IDCP is faster than that of the
pentenyl group. Iodination took place at C-2 of the
21. a-C-Aryl glycosides have been obtained under certain
conditions. See for example Ref. 11 and (a) Stewart, A.
O.; Williams, R. M. J. Am. Chem. Soc. 1985, 107, 4289–
4296; (b) Cai, M.-S.; Qiu, D.-X. Carbohydr. Res. 1989,
191, 125–129; (c) Schmidt, R. R.; Effenberger, G. Liebigs
Ann. Chem. 1987, 825–831.