Synthesis of annelated pyranosides: a rapid and efficient entry to highly functionalized optically pure branched-pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2007.09.048

Pyrazolo-pyranosides prepared from methyl-2,3:4,6-di-O-benzylidene-α-d-mannopyranoside were functionalized to design new scaffolds suitable for peptidomimetic construction. Under certain acidic conditions, they undergo only pyranose ring-opening generatin

Full text of DOI:10.1016/j.tetlet.2007.09.048

Tetrahedron Letters 48 (2007) 7978–7981
Synthesis of annelated pyranosides: a rapid and efficient entry
to highly functionalized optically pure branched-pyrazoles
Issa Samb, Nadia Pellegrini-Mo¨ıse* and Yves Chapleur*
Groupe S.U.C.R.E.S, UMR 7565 Nancy Universite´, CNRS, BP 239, F-54506 Nancy Vandoeuvre, France
Received 10 July 2007; revised 13 August 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—Pyrazolo-pyranosides prepared from methyl-2,3:4,6-di-O-benzylidene-a-D-mannopyranoside were functionalized to
design new scaffolds suitable for peptidomimetic construction. Under certain acidic conditions, they undergo only pyranose ring-
opening generating highly functionalized optically pure pyrazoles bearing an aldehyde function.
Ó 2007 Elsevier Ltd. All rights reserved.
The use of scaffolds for the construction of biologically
active compounds is now a well-accepted concept.1 Chi-
ral carbohydrate-based scaffolds are well suited for
introducing stereodiversity in the final compounds.2–4
Our preliminary results on the design of peptidomimet-
ics based on sugar scaffolds led us to the conclusion that
a challenge in this area is to construct platforms larger
than a single pyranose ring.5,6 In this regard pyranose-
fused ring systems deserve some attention.7,8 We have
successfully used keto-sugars for pyranosidic homologa-
tion using hetero Diels–Alder reactions.9–11 More
recently, we became interested in the construction of
nitrogen containing heterocycles fused to the pyranose
ring and pyrazole has been chosen as the first target.
made to develop efficient synthetic methods for
preparing functionalized pyrazole derivatives. In this
context, we report our preliminary results in the con-
struction of pyrazolo-pyranose which lead to new scaf-
folds and afford a direct route to acyclo-pyrazole
nucleosides.17
Starting from the known methyl 2,3:4,6-di-O-benzyl-
idene a-D-mannopyranoside 1, 2-deoxy-3-ulo derivative
2 was prepared by the action of BuLi on 1 as previously
described.9,10 The condensation of N,N-dimethylform-
amide dimethylacetal gave branched-chain ulose 3 in
good yield. Pyrazole-annelated pyranoside4 was pre-
pared in 80% yield by the treatment of 3 with hydrazine
hydrate (Scheme 1).18
Pyrazole derivatives are known to exhibit a wide range
of biological properties such as anti-hyperglycemic,
analgesic, anti-inflammatory, anti-pyretic and sedative-
hypnotic activities. Particularly, arylpyrazoles were re-
ported to have non-nucleoside HIV-1 reverse transcrip-
tase inhibitory activity.12,13 The most common method
to prepare pyrazole heterocycles involves the condensa-
tion of hydrazine derivatives with b-dicarbonyl
compounds or with a,b-unsaturated carbonyl com-
pounds.14–16 However, the generality of this method is
somewhat vitiated by the severe reaction conditions or
the multistep sequence usually required to access the
starting materials. Thus, continuing efforts have been
In order to construct scaffolds for peptidomimetic
design, the reactivity of compound 4 was explored
Ph
Ph
O
Ph
Ph
O
i
O
O
ii
O
O
O
70%
81%
O
1
O
2
OMe
OMe
6
O
Ph
O
N
O
O
5
2
O
4
O
iii
3
1
80 %
OMe
N
O
OMe
7
H
4
3
N
H 8
Keywords: Pyrazoles; Pyranosides; Ring pyran opening; Scaffold.
*
Scheme 1. Reagents and conditions: (i) 1/BuLi/THF/ꢀ30 °C; 2/
Corresponding author. Tel.: +33 383 68 47 76; fax: +33 383 68 47
80; e-mail: nadia.pellegrini@sucres.uhp-nancy.fr
NH4Cl; (ii) HCNMe2(OMe)2/CH2Cl2; (iii) NH2NH2/MeOH.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.048

I. Samb et al. / Tetrahedron Letters 48 (2007) 7978–7981
7979
6
Ph
Ph
O
O
Ph
or
O
HO
Ph
O
N
O
O
O
OH
O
4
4
HO
O
i
3
2
N
2
OMe
5a-d
N
N
CHO
N1
R
OMe
OMe
Ph
O
N
1
O
N
R
N
R
N
O
i
R
+
9a-d
7a-d
OMe
5a-d
N
H
4
O
O
O
6
4
Ph
2
HO
HO
O
Ph
O
O
OH
CHO
O
O
N
4
OMe
6a-d
i
or
O
3
R
1N
2
R
N
N
N
OMe
OMe
R
1
R
N
N
N
a : R = CH3, b : R = CH2-CH=CH2
c: R = CH2Ph, d : R= CH2COOMe
6a-d
8 a-d
10 a-d
a : R = CH3, b : R = CH2-CH=CH2
c : R = CH2Ph, d : R = CH2COOMe
Scheme 2. Reagents and conditions: (i) method A: RX, NaH, THF;
method B: RX, K2CO3, DMF; method C: RX, C6H6, NaOH,
Bu4NOH.
Scheme 3. Reagents and conditions: (i) for 7 and 8 formation: method
A: PTSA (20%)/MeOH; for 9 and 10 formation: method B: PTSA
(20%)/THF.
(Scheme 2). N-Alkylation of the pyrazole moiety with
alkyl halides was investigated using three different meth-
ods A, B and C. In method A, NaH was used as the base
and dry THF as the solvent. In method B, K2CO3 was
used as the base and dry DMF as the solvent. Phase
Transfer Catalysis (PCT) was used in method C, alkyl-
ation reactions being performed by stirring equimolar
amounts of pyrazole and the appropriate alkyl halide
in the presence of 40% aqueous sodium hydroxide and
40% aqueous tetrabutylammonium hydroxide in
benzene. Different alkyl halides (MeI, BnBr, BrCH2-
COOMe and allylbromide) were selected as mimics of
amino-acid side chains: methyl group for alanine, benzyl
group for phenylalanine and methyl acetate for aspartic
acid side chain. The chemical manipulation of the allyl
group could serve for further functionalization.
method A, provided only regioisomer 5c (entry 7). The
ratio of compound 6c increased with both methods B
and C (entries 8 and 9). Modest yields observed with
methods A and B can be explained by the opening of
the sugar ring forming aldehyde 9c (Scheme 3). The
introduction of ester functionality was achieved in good
yield by alkylation with methyl bromoacetate. A mix-
ture of regioisomers 5d and 6d in equal amounts was ob-
tained with both methods A and B (entries 10 and 11).
The structures of regioisomers 5 and 6 have been estab-
lished by 1D and 2D NMR (1H, 13C, COSY, HMBC,
HMQC). Heteronuclear correlations (HMBC) between
C7/H8 and C3/H8 strongly support the structure of
substituted pyrazoles 5d and 6d, respectively (Fig. 1).
Moreover, the chemical shift of H7 is upfield in regio-
isomer 6d (7.46 ppm) as compared to regioisomer 5d
(7.75 ppm), whereas the chemical shift of C7 is down-
field in regioisomer 6d (136.8 ppm) versus regioisomer
5d (131.5 ppm). These variations on chemical shifts were
observed for all regioisomers and strongly support the
structure of the substituted pyrazolo-pyranosides.
Because of the two equivalent resonance forms of pyr-
azole 4 anion, a regioisomeric mixture of 5 and 6 is ex-
pected from N-alkylation, as described in the literature
for unsymmetrical substituted pyrazoles.19 Depending
on the reaction conditions used, the three methods fur-
nished two separable regioisomers 5 (N1-alkylated)
and 6 (N2-alkylated) in different ratio (Table 1) except
for allylbromide (entries 4–6) for which only regioisomer
5b was obtained in good yield. Using method A, alkyl-
ation with methyl iodide gave mainly regioisomer 5a
(entry 1). This ratio is reversed using method B and C
(entries 2 and 3). Alkylation with benzyl bromide using
In order to develop the functionalization of the bicyclic
scaffolds 5 and 6, the cleavage of the benzylidene acetal
of both compounds was considered.
Unexpectedly, acid hydrolysis using a catalytic amount
of PTSA in methanol at room temperature for one hour
gave a mixture of 4,6-diols 7 or 8 and pyrazoles 9 or 10,
respectively (Scheme 3). Prolonged stirring (12 h at
Table 1. Alkylations of pyrazolo-pyranoside 4
Entry
Alkyl halide
Method
Yielda (%)
5/6 ratio
1
2
3
4
5
6
7
8
9
CH3I
CH3I
CH3I
AllylBr
AllylBr
AllylBr
BnBr
BnBr
BnBr
A
B
C
A
B
C
A
B
C
A
B
87
88
90
80
75
80
56
40
79
70
71
71:29
26:74
32:68
100:0
100:0
100:0
100:0
39:61
56:44
43:57
59:41
6
6
O
O
N
Ph
O
5
2
Ph
O
5
2
4
4
O
O
3
1
3
1
C(ppm) = 138.2
δ
N
8
8
7
OMe
MeOOC
OMe
H
N
N
7 H
δC(ppm) = 131.5
δ
H (ppm) = 5.05
δH(ppm) = 5.08
COOMe
5d
6d
10
11
BrCH2COOMe
BrCH2COOMe
Figure 1. Heteronuclear correlations (HMBC) of substituted pyrazoles
5d and 6d, respectively.
a Yields refer to pure products after chromatography.

7980
I. Samb et al. / Tetrahedron Letters 48 (2007) 7978–7981
Table 2. Hydrolysis of compounds 5 and 6
2. Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30,
Entry
R
4,6-Diola (%)
Aldehydeb (%)
1278–1301.
3. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino,
J.; Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A.
B., III; Strader, C. D.; Cascieri, M. A.; Candelore, M. R.;
Donaldson, C.; Vale, W.; Maechler, L. J. Am. Chem. Soc.
1992, 114, 9217–9218.
4. Cipolla, L.; Peri, F.; Ferla, B. L.; Redaelli, C.; Nicotra, F.
Curr. Org. Synth. 2005, 2, 153–173, and references cited
therein.
1
2
3
4
5
6
7
Me
Allyl
Bn
CH2COOMe
Me
Bn
7a (76)
7b (75)
7c (72)
7d (70)
8a (78)
8c (73)
8d (79)
9a (78)
9b (66)
9c (68)
9d (70)
10a (63)
10c (63)
10d (71)
CH2COOMe
a Yields refer to pure isolated compounds after chromatography
´
5. Moitessier, N.; Minoux, H.; Maigret, B.; Chretien, F.;
Chapleur, Y. Lett. Pept. Sci. 1998, 5, 75–78.
(method A).
b Yields refer to pure isolated compounds after chromatography
(method B).
´
6. Moitessier, N.; Dufour, S.; Chretien, F.; Thiery, J. P.;
Maigret, B.; Chapleur, Y. Bioorg. Med. Chem. 2001, 9,
511–523.
7. La Ferla, B.; Cardona, F.; Perdiga, I.; Nicotra, F. Synlett
2005, 2641–2642.
8. Cervi, G.; Peri, F.; Battistini, C.; Gennari, C.; Nicotra, F.
Bioorg. Med. Chem. 2006, 14, 3349–3367.
room temperature) gave only diols 7 and 8 in good yield
(Table 2).20
Polyhydroxylated pyrazoles are often considered as
nucleoside acyclic analogues of biological interest.17
Thus, we have developed optimized conditions for the
formation of 9 and 10 in good yield. The replacement
of methanol by THF in acidic hydrolysis allows the for-
mation of only aldehydes 9 and 10 giving an efficient ac-
cess to yet unknown optically active polyhydroxylated
pyrazoles (Table 2) bearing an aldehyde function at
the 4-position of the pyrazole ring.21
9. Chapleur, Y. Chem. Commun. 1983, 3, 141–142.
10. Chapleur, Y.; Euvrard, M. N. Chem. Commun. 1987, 12,
884–885.
11. Mayon, P.; Euvrard, M. N.; Moufid, N.; Chapleur, Y.
Chem. Commun. 1994, 4, 399–401.
12. Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.;
Swaney, S. M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L.
J. Med. Chem. 2000, 43, 1034–1040.
13. Price, M. L.; Jorgensen, W. L. J. Am. Chem. Soc. 2000,
122, 9455–9466.
14. Elguero, J.. In Comprehensive Heterocyclic Chemistry;
Katritsky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 3, pp 1–75.
15. Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem.
1966, 6, 347–429.
16. (a) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M.
V.; Steel, P. J. J. Org. Chem. 2001, 66, 6787–6791; (b)
Rosati, O.; Curini, M.; Marcotullio, M. C.; Macchiarulo,
A.; Perfumi, M.; Mattioli, L.; Rismondo, F.; Cravotto, G.
Bioorg. Med. Chem. 2007, 15, 3463–3473; (c) Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2005, 46,
5387; (d) Wang, Z.; Qin, H. Green Chem. 2004, 6, 90–
92.
All these data suggest that acetal hydrolysis takes place
first at the anomeric centre then at the benzylic centre.
As soon as the six-membered benzylidene acetal is
cleaved, glycosylation of the free sugar then occurs in
methanol to provide compounds 7 or 8. This unusual
glycoside sensitivity towards acid hydrolysis could be ex-
plained by the strain induced by the tricyclic system and
by the 2-deoxy nature of compounds 5 and 6. In tetrahy-
drofuran, only the most sensitive glycosidic bond is
cleaved giving aldehyde 9 or 10.
In conclusion, we have described a rapid and efficient
synthesis of enantiomerically pure highly functionalized
pyrano-pyrazoles. From the two acetals present on these
scaffolds, both can be selectively cleaved depending on
the acidic hydrolysis conditions. Anomeric acetal hydro-
lysis is obtained in THF and gives access to new chiral
pyrazoles functionalized at position 3 and 4 in good
yields. Benzylidene acetal acidic hydrolysis of these pyr-
azolo-pyranosides occurs only in methanol yielding
bicyclic scaffolds bearing hydroxyl functions at C4-
and C6-position of the sugar ring. Further functionali-
zation of these templates for the design peptidomimetics
is under investigation.
17. (a) Peseke, K.; Feist, H.; Cuny, E. Carbohydr. Res. 1992,
230, 319–325; (b) Kuhla, B.; Peseke, K.; Thiele, G.;
Michalik, M. J. Prakt. Chem. 2000, 342, 240–244; (c)
Methling, K.; Kopf, J.; Michalik, Ma.; Reinke, H.;
Buerger, C.; Oberender, H.; Peseke, K. J. Carbohydr.
Chem. 2003, 22, 537–548; (d) Ruiz, R. M.; Martinez, I. O.;
Michalik, M.; Reinke, H.; Suarez, J. Q.; Peseke, K. J.
Carbohydr. Chem. 2004, 23, 337–351; (e) Otero, I.;
Methling, K.; Feist, H.; Michalik, M.; Quincoces, J.;
Reinke, H.; Peseke, K. J. Carbohydr. Chem. 2005, 24, 809–
829.
18. To a stirred methanolic solution of 3 (0.5 g, 1.56 mmol),
hydrazine hydrate (0.2 mL, 6.24 mmol) was added. The
reaction was monitored by TLC. After reaction comple-
tion, the solvent was evaporated and the solid was
recrystallized from ethanol. Compound 4: White powder,
mp 221 °C, Rf (SiO2, CH2Cl2/MeOH, 95:5) 0.5, [a]D +88.3
Acknowledgements
(c 1.0, CHCl3), IR m 3271 cmꢀ1 1H NMR (250 MHz,
,
CDCl3): dH (ppm) 3.45 (s, 3H, OMe), 3.97 (td, 1H, H5, J5–
We wish to thank B. Fernette and S. Adach for technical
assistance.
0
6 = 9.9 Hz, J4–5 = 8.8 Hz, J5–6 ¼ 4:4 Hz), 4.01 (t, 1H, H6,
0
0
0
J5–6 ¼ J6–6 ¼ 9:9 Hz), 4.41 (dd, 1H, H6 , J5–6 ¼ 4:4 Hz,
0
J6–6 ¼ 9:9 Hz), 4.76 (d, 1H, H4, J4–5 = 8.8 Hz), 5,64 (s,
1H, H1), 5.89 (s, 1H, H benzylidene), 7.4–7.6 (m, 5H,
aromatic), 7.75 (s, 1H, H7), 12.95 (s, 1H, H8); 13C NMR
(DMSO, 63 MHz): d (ppm) 55.7 (OMe), 65.3 (C5), 69.2
(C6), 74.8 (C4), 96.5 (C1), 101.9 (C benzylidene), 115.7
(C2), 127.3, 129.02 (C aromatic), 129.9 (C7), 138.6 (C
References and notes
1. Belanger, P. C.; Dufresne, C. Can. J. Chem. 1986, 64,
1514–1520.

I. Samb et al. / Tetrahedron Letters 48 (2007) 7978–7981
7981
aromatic), 146.0 (C3). MS (ESI) m/z 312 [M+H+Na]+,
311 [M+Na]+.
(C2), 127.4 (C7), 149.7 (C3). MS (ESI) m/z 238
[M+H+Na]+, 237 [M+Na]+.
19. (a) Tarrago, G.; Ramdani, A.; Elguero, J.; Espada, M. J.
Heterocycl. Chem. 1980, 17, 137–142; (b) Malhotra, N.;
Falt-Hansen, B.; Becher, J. J. Heterocycl. Chem. 1991, 28,
1837–1839; (c) Montoya, V.; Pons, J.; Branchadell, V.;
Ros, J. Tetrahedron 2005, 61, 12377–12385.
21. Representative procedure: Compound 5 or 6 (0.5 mmol)
was treated with PTSA (20 mol %) in THF (15 mL) at
room temperature. The progress of the reaction was
monitored by TLC and after completion, the reaction
mixture was diluted with NaHCO3 saturated aqueous
solution and extracted with dichloromethane. The com-
bined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo and purified by column chroma-
tography on silica gel. Compound 9c: Rf (SiO2, hexane/
EtOAc, 1:1) 0.25, [a]D ꢀ29.3 (c 1.0, CHCl3); IR m 2845,
20. Representative procedure for diol formation: Compound
5 or 6 (0.5 mmol) was treated with PTSA (20 mol %) in
MeOH (15 mL) at room temperature. The progress of the
reaction was monitored by TLC and after completion, the
reaction mixture was diluted with NaHCO3 saturated
aqueous solution and extracted with dichloromethane.
The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo and purified by column
chromatography on silica gel. Compound 7a: Rf (SiO2,
CH2Cl2/MeOH, 9:1) 0.45, [a]D +0.8 (c 1.02, CHCl3); IR m
1
1672 cmꢀ1; H NMR (DMSO, 250 MHz): dH (ppm) 3.68
0
(t, 1H, H6, J6–6 ¼ J6–5 ¼ 10:3 Hz), 4.06 (td, 1H, H5,
0
J5–6 ¼ 4:9 Hz, J5–6 = 10.3 Hz, J5–4 = 9.5 Hz, J5-OH
=
¼
0
0
0
6.2 Hz), 4.25 (dd, 1H, H6 , J6–6 ¼ 10:3 Hz, J5–6
4:9 Hz), 4.99 (d, 1H, H4, J4–5 = 9.5 Hz), 5.29 (d, 1H,
OH, JOH-5 = 6.2 Hz), 5.72 (s, 1H, H benzylidene), 7.37–
7.40 (m, 10H aromatic), 8.57 (s, 1H, H7), 10.02 (s, 1H, H1);
13C NMR (DMSO, 63 MHz): d (ppm) 55.1 (C8), 64.0 (C5),
71.3 (C6), 77.5 (C4), 100.6 (C benzylidene), 121.6 (C2),
126.2, 127.9, 128.0, 128.2, 128.6, 128.7 (C aromatic), 135.4,
136.2 (C aromatic), 137.8 (C7), 150.8 (C3), 184.8 (C1). MS
(ESI) m/z 388 [M+H+Na]+, 387 [M+Na]+.
1
3378.15, 2924.36 cmꢀ1; H NMR (DMSO, 250 MHz): dH
0
(ppm) 3.39 (s, 3H, Me), 3.57–3.77 ðm; 3H; H6; H6 ; H5Þ,
3.82 (s, 3H, OMe), 4.37 (t, 1H, H4, J4–OH4 = 7.4 Hz, J4–
5 = 9.1 Hz), 4.77 (t, 1H, OH6, J5–OH6 = 5.8 Hz), 5.41 (d,
1H, OH4, JOH4–5 = 7.4 Hz), 5.49 (s, 1H, H1), 7.61 (s, 1H,
H7); 13C NMR (DMSO, 63 MHz): d (ppm) 38.5 (Me), 54.3
(OMe), 60.7 (C5), 62.2 (C6), 73.9 (C4), 94.1 (C1), 115.5