Synthesis of B2,5 type conformationally constrained glucopyranosides

Article abstract of DOI:10.1016/S0040-4039(03)01631-9

Isopropyl and p-nitrophenyl α- and β-D-glucopyranosides restrained in a conformation close to B_2,5 have been synthesized. They are all hydrolyzed at similar rates, close to those observed for the parent unlocked glucosides.

Full text of DOI:10.1016/S0040-4039(03)01631-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6687–6690
Synthesis of B2,5 type conformationally constrained
glucopyranosides
Yves Ble´riot,a Subramanian K. Vadivel,a Ian R. Greig,b Anthony J. Kirbyb,* and Pierre Sinay¨a,*
aEcole Normale Supe´rieure, De´partement de Chimie, UMR CNRS 8642, 24 rue Lhomond, 75231 Paris Cedex 05, France
bUniversity Chemical Laboratory, Cambridge CB2 1EW, UK
Received 25 June 2003; revised 30 June 2003; accepted 30 June 2003
Abstract—Isopropyl and p-nitrophenyl a- and b-D-glucopyranosides restrained in a conformation close to B2,5 have been
synthesized. They are all hydrolyzed at similar rates, close to those observed for the parent unlocked glucosides.
© 2003 Elsevier Ltd. All rights reserved.
The chemical and enzymatic hydrolyses of glycopyrano-
sides are important events in a wide range of chemical
and biological glycoprocesses. Glycoside hydrolysis is
indeed one of the most studied reactions in carbohy-
drate chemistry and a wealth of data has been
reported.1 Substantial carbenium ion character is
present at the anomeric center in the transition state,
which is best accommodated in a sugar conformation in
which C-5, O-5, C-1 and C-2 are held in a planar
array,2 ideally set up for the stabilization of the
alkoxycarbenium.3
coplanarity requirement is met. In nature, these boat
type conformations have recently been convincingly
observed, using kinetic isotope effects or crystal struc-
ture analysis of complexes between substrate, substrate
analogues and/or inhibitors of the studied enzyme, for
some glycosidases that perform substrate distortion
4
away from the ground state C1 conformation before
enzymatic hydrolysis.6
If the ground-state conformation prior to oxygen–car-
bon cleavage is indeed B2,5 (or 2,5B), this implies that
the Antiperiplanar Lone Pair effect7 is not operating in
the hydrolytic process. Such a cleavage would rather be
compatible with a synperiplanar assistance8 and be
simultaneously in agreement with the relevant least
nuclear motion effect.9
Looking at the complete map of pyranoid ring inter-
conversions, including the boat/skew-boat pseudorota-
tional itinerary of the pyranoid ring4 and as earlier
advocated,5 not only 4H3 and 3H4, but also B2,5 and 2,5
B
conformations (Fig. 1) are possible candidates for the
conformation of the glucopyranosyl cation, wherein the
In this context we thus considered as important to
evaluate the ease of acid hydrolysis of monosaccharides
conformationally constrained in such a boat conforma-
tion. Herein, we would like to report on the synthesis of
p-nitrophenyl and isopropyl a- and b-D-glucopyrano-
sides locked in a B2,5 conformation and disclose prelim-
inary results concerning their hydrolysis under acidic
conditions. The selected constrained targets are 1–4
(Fig. 2), with carbon atoms 2 and 5 connected through
an oxymethylene bridge.10 In acid-catalyzed hydrolysis,
particularly of conformationally restricted glycosides,
the possibility of endocyclic cleavage is always present.
The use of isopropyl and p-nitrophenyl glycosides will
enable us to tell if this mechanism is operative because
hydrolysis of nitrophenyl glycosides would be orders of
magnitude slower than isopropyl ones in an endocyclic
pathway.
Figure 1. The two conformers of the boat/twist-boat pseudo-
rotational itinerary of the pyranoid ring wherein a coplanarity
of C-5, O, C-1 and C-2 is met.
Keywords: carbohydrates; conformation; hydrolysis.
* Corresponding authors. Tel.: (+33) 1-44323390; fax: (+33) 1-
44323397 (P.S.); tel.: (+44) 1223 336370; fax: (+44) 1223 336913
(A.K.); e-mail: ajk1@cam.ac.uk; pierre.sinay@ens.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01631-9

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Y. Ble´riot et al. / Tetrahedron Letters 44 (2003) 6687–6690
Figure 2. Structure of the conformationally constrained a- and b-
D-glucopyranosides 1–4, showing the syn-periplanarity of one
pyranoside orbital of the intracyclic oxygen and of the glycosidic bond.
Compounds 1–4 are confined for stringent geometri-
12 with sodium bromate and sodium dithionite in ethyl
acetate/water12 simultaneously performed the opening
of the benzylidene acetal and the cleavage of the benzyl
ether to afford a mixture of 4-O-benzoate derivative 14
and 6-O-benzoate derivative 15 in 74%. Treatment of
14 and 15 with sodium methoxide in methanol afforded
the b-p-nitrophenyl glucoside 1† in 73% yield. The same
sequence was uneventfully applied to compound 13 to
afford the a-p-nitrophenyl glucoside 2‡ in 84% yield
over two steps from 13. Treatment of 10 with dry
isopropanol in the presence of NCS gave the a-glu-
coside 11 along with traces of the corresponding b-glu-
coside. Hydrogenolysis of 11 under various conditions
led only to decomposition products. Reduction with
Na-liq. NH3 afforded the pure a-glucoside 4§ after
cal reasons to the following conformational domain
of the boat/skew-boat itinerary close to B2,5
:
(1S5 X B2,5 X 0S2).
The strategy used to synthesize compounds 1–4 starts
from the known vinyl derivative 5.11 It was first con-
verted into the protected restrained glycosyl donor 10
as explained in Scheme 1. Compound 10 is an interest-
ing conformationally locked glycosyl donor which can
give access to the conformationally locked glycosides 1,
2 and 4. When compound 10 was treated with parani-
trophenol in the presence of NIS and triflic acid in
dichloromethane, the paranitrophenyl b-glycopyrano-
side 12 and the a-glycopyranoside 13 were obtained in
high yield and in a 4/1 ratio (Scheme 2). Treatment of
Scheme 1. Synthesis of the glycosyl donor 10. Reagents and conditions: (a) IR-120 H+ resin, dioxan, H2O, 90°C, 18 h; (b) Ac2O,
DMAP, pyridine, rt; (c) PhSH, BF3·OEt2, anhydrous CH2Cl2, rt; (d) CH3ONa, CH3OH, rt, 16 h; (e) PhCH(OMe)2, CSA, DMF,
rt, 14 h; (f) O3, CH2Cl2, −78°C, 30 min; (g) NaBH4, EtOH, rt, 18 h; (h) TsCl, DMAP, pyridine, rt, 15 h; (i) NaH, DMF, rt, 18
h.
† Selected data for compound 1: [h]D22=−128 (c 0.55 in CH3OH); 1H NMR (400 MHz, D2O): l=8.21 (d, 2H, J=9.0 Hz, (PhNO2), 7.21 (d, 2H,
J=9.0 Hz, PhNO2), 6.01 (dd, J=1.0 Hz, 2.6 Hz, 1H, H-1), 4.12 (app. t, J=2.7 Hz, 1H, H-2), 4.06 (m, 1H, H-3), 4.02 (dd, J=1.6 Hz, 5.1 Hz,
1H, H-4), 3.91 (d, J=9.8 Hz, 1H, H-7), 3.76 (dd, J=1.6 Hz, 9.8 Hz, 1H, H-7%), 3.68 (d, J=12.8 Hz, 1H, H-6), 3.64 (d, J=12.8 Hz, 1H, H-6%);
13C NMR (100 MHz, D2O): l=[161.51, 142.67, (2×Cipso)], 126.37 (Ph), 116.97 (Ph), 97.09 (CH-1), 76.76 (CH-1), 76.76 (C-5), 74.62, 73.59,
67.99 (CH-2, CH-3, CH-4), 62.46, 60.48 (CH2-6, CH2-7); MS (CI, NH3): m/z (%): 331 (100) [M+NH4+]; HRMS (positive-ion CI, NH3): calcd
for C13H19O8N2 (M+NH4+) 331.1141, found 331.1140.
‡
Selected data for compound 2: [h]2D2=+106 (c 0.94 in CH3OH); 1H NMR (400 MHz, CD3OD): l=8.38 (d, 2H, J=9.2 Hz, PhNO2), 7.44 (d,
2H, J=9.2 Hz, PhNO2), 6.07 (d, J=1.4 Hz, 1H, H-1), 4.18 (dd, J=1.6 Hz, 4.5 Hz, 1H, H-3), 4.16 (dd, J=1.4 Hz, 4.5 Hz, 1H, H-2), 4.16 (d,
J=9.4 Hz, 1H, H-7), 4.12 (dd, J=1.0 Hz, 9.4 Hz, 1H, H-7%), 3.97 (m, 1H, H-4), 3.79 (d, J=12.3 Hz, 1H, H-6), 3.75 (d, J=12.3 Hz, 1H, H-6%);
13C NMR (100 MHz, CD3OD): l=[164.01, 143.91, (2×Cipso)], 126.97 (Ph), 118.02 (Ph), 97.16 (CH-1), 79.34 (C-5), 75.36, 74.38, 71.92 (CH-2,
CH-3, CH-4), 65.07, 63.18 (CH2-6, CH2-7); MS (CI, NH3): m/z (%): 331 (52) [M+NH4+]; elemental analysis: calcd (%) for C13H15O8N (313.26):
C, 49.84; H, 4.83; N, 4.47; found: C, 49.87; H, 4.87; N, 4.30.
§ Selected data for compound 4: [h]D22=+20 (c 0.44 in CH3OH); 1H NMR (400 MHz, CD3OD): l=5.36 (d, J=1.6 Hz, 1H, H-1), 4.27 (m, J=6.2
Hz, 1H, H-8), 4.13 (dd, J=1.3 Hz, 9.0 Hz, 1H, H-7), 4.07 (dd, J=1.6 Hz, 4.5 Hz, 1H, H-3), 4.03 (dd, J=0.9 Hz, 9.0 Hz, 1H, H-7%), 3.85 (dd,
J=1.6 Hz, 4.5 Hz, 1H, H-2), 3.83 (m, 1H, H-4), 3.73 (s, 2H, H-6, H-6%), 1.47 (d, J=6.2 Hz, 3H, CH3-9), 1.35 (d, J=6.2 Hz, 3H, CH3-9%); 13C
NMR (100 MHz, CD3OD): l=95.86 (CH-1), 77.83 (C-5), 75.72 (CH-3), 74.88 (CH-4), 72.69 (CH-2), 71.12 (CH-8), 65.00 (CH2-7), 63.77
(CH2-6), 24.56 (CH3-9), 22.41 (CH3-9%); MS (CI, NH3): m/z (%): 252 (100) [M+NH4+]; HRMS (positive-ion CI, NH3): calcd for C10H22O6N
(M+NH4+) 252.1447, found 252.1448.

Y. Ble´riot et al. / Tetrahedron Letters 44 (2003) 6687–6690
6689
Scheme 2. Synthesis of compounds 1, 2 and 4. Reagents and conditions: (a) NCS, dry isopropanol, rt; (b) Na, liq. NH3; (c)
paranitrophenol, NIS, TfOH, CH2Cl2, −30°C, 30 min; (d) NaBrO3, Na2S2O4, EtOAc, H2O, rt; (e) CH3ONa, CH3OH, rt.
Scheme 3. Synthesis of compound 3. Reagents and conditions: (a) TMSOTf, dry isopropanol, rt; (b) CH3ONa, CH3OH, rt; (c)
PhCH(OMe)2, CSA, DMF, rt, 14 h; (d) O3, CH2Cl2, −78°C, 30 min; (e) NaBH4, EtOH, rt, 18 h; (f) TsCl, DMAP, pyridine, rt,
15 h; (g) NaH, DMF, rt, 18 h; (h) H2, Pd/C, CH3OH, rt.
careful column chromatography. The last member 3¶ of
the required set was prepared as shown in Scheme 3.
1H NMR data for compounds 1–4 are in agreement
13
with a conformation close to B2,5
.
Furthermore, such
a conformation was confirmed by the crystal structure14
in the case of the a-anomer 2 (Fig. 3).
¶ Selected data for compound 3: [h]D22=−58 (c 1.65 in CH3OH); 1H
NMR (400 MHz, CD3OD): l=5.47 (dd, J=1.5 Hz, 2.7 Hz, 1H,
H-1), 4.24 (m, J=6.2 Hz, 1H, H-8), 4.05 (dd, J=1.8 Hz, 4.3 Hz,
1H, H-4), 3.99 (d, J=9.2 Hz, 1H, H-7), 3.92 (m, 1H, H-3), 3.87
(app. t, J=2.7 Hz, 1H, H-2), 3.78 (s, 2H, H-6, H-6%), 3.77 (dd,
J=1.8 Hz, 9.2 Hz, 1H, H-7%), 1.43 (d, J=6.2 Hz, 3H, CH3-9), 1.34
(d, J=6.2 Hz, 3H, CH3-9%); 13C NMR (100 MHz, D2O): l=99.20
(CH-1), 77.71 (CH-3), 76.79 (C-5), 76.77 (CH-4), 72.15 (CH-8),
69.64 (CH-2), 63.62 (CH2-7), 62.96 (CH2-6), 24.33 (CH3-9), 22.24
(CH3-9%); MS (CI, NH3): m/z (%): 252 (100) [M+NH4+]; HRMS
(positive-ion CI, NH3): calcd for C10H22O6N (M+NH4+) 252.1447,
found 252.1450.
Figure 3. Crystallographic structure of the constrained para-
nitrophenyl a- -glucopyranoside 2
D

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Y. Ble´riot et al. / Tetrahedron Letters 44 (2003) 6687–6690
These compounds were then submitted to acidic condi-
tions (1 M aq. HCl) at three temperatures in the ranges
60–70°C and the rate of hydrolysis for each compound
was determined.15 Preliminary results16 show that the
four compounds 1–4 are hydrolyzed at a similar rate,
the rates observed being close to those reported for the
parent unlocked glucosides.17 This confirms that B2,5
transient conformations of glycosides can indeed be
acceptable candidates for direct acid hydrolysis. The
ongoing piece of work by Davies and Withers6 indeed
nicely brings into light the frequent occurrence of such
boat conformations in the context of the enzymatic
hydrolysis of glycosides.
G. N.; Gilbert, H. J.; Szabo, L.; Stoll, D.; Withers, S. G.;
Davies, G. J. Angew. Chem. 2002, 114, 2948–2951;
Angew. Chem., Int. Ed. 2002, 41, 2824–2827; (d) Vasella,
A.; Davies, G. J.; Bo¨hm, M. Curr. Opin. Chem. Biol.
2002, 6, 619–629; (e) Varrot, A.; MacDonald, J.; Stick, R.
V.; Pell, G.; Gilbert, H. J.; Davies, G. J. Chem. Commun.
2003, 946–947.
7. Deslongchamps, P. In Anomeric Effect and Associated
Stereoelectronic Effects; Thatcher, G. R. J., Ed.; ACS
Symposium Series 539, 1993; pp. 27–54.
8. (a) Deslongchamps, P.; Jones, P. G.; Li, S.; Kirby, A. J.;
Kuusela, S.; Ma, Y. J. Chem. Soc., Perkin Trans. 2 1997,
2621–2626; (b) Li, S.; Kirby, A. J.; Deslongchamps, P.
Tetrahedron Lett. 1993, 34, 7757–7758; (c) Li, S.;
Deslongchamps, P. Tetrahedron Lett. 1993, 34, 7759–
7762.
Acknowledgements
9. Sinnott, M. L. Adv. Phys. Org. Chem. 1988, 24, 113–204.
10. We have previously developed such an oxymethylene
bridge to lock flexible
L-iduronic acid derivatives: (a)
The authors would like to thank Dr. C. Guyard-
Duhayon from the Centre des Re´solutions de Struc-
tures at Universite´ Pierre & Marie Curie for solving the
crystal structure.
Das, S. K.; Mallet, J.-M.; Esnault, J.; Driguez, P.-A.;
Duchaussoy, P.; Sizun, P.; Herbert, J.-M.; Petitou, M.;
Sinay¨, P. Angew. Chem. 2001, 113, 1723–1726; Angew.
Chem., Int. Ed. Engl. 2001, 40, 1670–1673; (b) Das, S. K.;
Mallet, J.-M.; Esnault, J.; Driguez, P.-A.; Duchaussoy,
P.; Sizun, P.; Herault, J.-P.; Herbert, J.-M.; Petitou, M.;
Sinay¨, P. Chem. Eur. J. 2001, 7, 4821–4834.
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