L-chiro-inositol derivatives from myo-inositol. Building blocks for inositolphosphoglycans

Article abstract of DOI:10.1055/s-2003-40339

A straightforward synthesis of L-chiro-inositol, deoxy L-chiro-inositol derivatives and L-chiro-inositol building blocks for the preparation of inositolphosphoglycans, is reported from myoinositol. Glycosylation with 2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-g

Full text of DOI:10.1055/s-2003-40339

1370
LETTER
L-chiro-Inositol Derivatives from myo-Inositol. Building Blocks for Inositol-
phosphoglycans
L-
chiro
-
Inositol
D
eriva
.
tives Belén Cid,b Francisco Alfonso,a Manuel Martín-Lomas*a
a
Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Américo Vespucio, Isla de La Cartuja, 41092 Seville, Spain
b
Instituto de Química Orgánica General (CSIC), c/ Juan de la Cierva 3 28006 Madrid, Spain
Fax +34(95)4460565; E-mail: Manuel.Martin-Lomas@iiq.cartuja.csic.es
Received 28 March 2003
Dedicated to the late Professor R. U. Lemieux.
R2
OH
OH
OH
O
Abstract: A straightforward synthesis of L-chiro-inositol, deoxy L-
chiro-inositol derivatives and L-chiro-inositol building blocks for
the preparation of inositolphosphoglycans, is reported from myo-
inositol. Glycosylation with 2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-
glucopyranosyl trichloroacetimidate gave the corresponding
pseudodisaccharide derivatives.
O
HO
HO
O
R1
HO
HO
HO
O
NH2HO
HO
HO
NH2
R3O
NH2
OH
HO
O
O
HO
OH
HO
OH
OH
HO
HO
HO
OR4
I
IIa
IIb
Key words: carbocycles, isomerization, natural products, glyco-
R1=H, R2=OH or R1=OH, R2=H;
R3=H or Me R4=H
R1=OH, R2=H; R3=H R4=PO3H-
sylation, oligosaccharides
Figure 1
With the exception of myo-inositol, D- and L-chiro-inosi-
tols are the most abundant naturally occurring inositols.
As myo-inositol itself, D- and L-chiro-inositols and their
derivatives play important roles in biological functions.
1D-chiro-inositol has ovulatory and metabolic effects in
polycystic ovary syndrome1 and appears to be related to
insulin resistence.2 1L-chiro-inositol 2,3,5-triphosphate
has been proposed as an inhibitor of the enzymes involved
in the metabolism of 1D-myo-Inositol 1,4,5-triphosphate3
and as a partial agonist at the platelet myo-inositol 1,4,5-
triphosphate receptor.4 chiro-Inositol has also been pro-
posed as constituent of inositolphosphoglycans involved
in the insulin signalling process.5,6
ro-inositol derivatives which involves desymmetrization
of myo-inositol, triflation and inversion at position 1 of the
obtained L-myo-inositol derivative. These L-chiro-inositol
derivatives have been used as building blocks for the syn-
thesis of conveniently protected 2-amino-2-deoxy-D-glu-
cosaminyl a(1→1) L-chiro-inositols and of 2-amino-2-
deoxy-D-glucosaminyl a (1→1) L-chiro-inositol.
Protected L-chiro-inositol derivatives with free hydroxyl
groups at positions 1 and 2 have been previously prepared
by intramolecular pinacol cyclization from sorbitol14a or
from D-xylose14b and from conduritol intermediates enzy-
matically resolved and previously prepared from myo-
inositol.14c A synthesis of L-chiro-inositol based on a pe-
ripheral oxygenation of a diene-diol prepared by oxida-
tion of bromobenzene has been reported15 and several L-
chiro-inositol phosphates have been synthesized from
methyl a-D-mannopyranoside.16 All diastereomers of
inositol have been prepared through Pd(II)-mediated Fer-
rier-II rearrangement of 6-O-acetyl-5-enopyranosides and
reduction of the b-hydroxyketones obtained.17
In the frame of an ongoing program on the synthesis of
glycosyl inositols related to inositolphosphoglycans,7–9
we have previously synthesized several 2-amino-2-
deoxy-D-gluco and galactosaminyl-(a 1→1) D-chiro-
inositols (I).10–12 These structures have been evaluated as
inhibitors or as activators of key enzymes involved in the
insulin signaling process.13 In the course of these studies
the corresponding glycosyl (1→1) L-chiro-inositols (II)
were needed (Figure 1).
The L-chiro-inositol building blocks required for the syn-
thesis of II could be obtained from L-quebrachitol using
similar strategies as those previously established from D-
chiro-inositol for the preparation of their D-chiro-inositol
counterparts.11,12a However, L-quebrachitol is a relatively
expensive starting material and we decided to develop a
practical synthetic route to the protected L-chiro-inositol
glycosyl acceptors from myo-inositol. Here we report a
straightforward synthesis of conveniently protected L-chi-
We started from myo-inositol which was desymmetrized
as the 1,2-D-camphor ketal to obtain the enantiomerically
pure L-myo-inositol 2 that was transformed into the tetra-
benzylated derivative 3.18 (Scheme 1). Compound 2 has
been recently used for the synthesis of D-chiro-inositol.19
Regioselective triflation of 3 took place with quantitative
yield to afford 4. A similar regioselective tosylation of ra-
cemic 3 using stannylidene acetal mediated regioselective
activation has been reported.20a
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1370,1372,ftx,en;S03803ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
L-chiro-Inositol Derivatives
1371
For the desired inversion at C1 to proceed avoiding the
formation of 5 the axially oriented 2-OH group in 4 had to
be protected. Conventional acetylation of 4 gave acetate 8
which upon heating in DMF–H2O afforded the L-chiro-
inositol derivative 9 (Scheme 3). The configuration of 9
was confirmed by sequential deacetylation and debenzy-
lation to give L-chiro-inositol, [a]D –58.2° (c, 1.3, H2O).
Values reported for L-chiro-inositol in the literature are
–56.3° (c, 0.2, H2O)17 and –61.6° (c, 0.37, H2O).25
D-Camphor
ii,iii
O
BnO
BnO
BnO
HO
OH
i
myo-inositol
OH
OBn
OH
HO
HO
O
2
Ref 18
3
OH
BnO
OBn
OTf
iv
BnO
BnO
4
Scheme 1 Reagent and conditions: i) D-Camphor, DMSO, H2SO4,
55 ºC, 56%; ii) BnBr, NaH, DMF, –20 ºC,100%; iii) CH3COOH 80%,
100 ºC, 85%; iv) Tf2O, Py/CH2Cl2, –78 ºC,100%.
OAc
OAc
BnO
BnO
BnO
BnO
BnO
OBn
i
ii
OBn
OTf
BnO
4
OH
8
9
All attempts to invert the configuration at C1 in 4 using
different nucleophiles resulted in the formation of (–)-2-
v, vi
iii, iv
OH
deoxy-scyllo-inosose
5
and aromatic compounds
(Scheme 2). This ketone 5,21 which could be obtained in
quantitative yield when 4 was treated for 48 hours at room
temperature with cesium trifluoroacetate in the presence
of DMAP,22 has been previously prepared as a racemate20a
and used as starting material for the synthesis of 2-deoxy-
scillo-inosamine.20b The formation of 5 from 4 can be ac-
counted for by a E2 type elimination process through a
boat like conformation (A) to give an enol intermediate
(Scheme 2). The stereochemistry of 5 was determined af-
ter NaBH4 reduction to give a mixture of known alcohols
6 and 7. (Scheme 2). Thus, treatment of 5 with NaBH4 in
methanol gave a 71:29 mixture of L-1-deoxy-3,4,5,6-tet-
ra-O-benzyl-myo-inositol (6) and D-2-deoxy-3,4,5,6-tet-
ra-O-benzyl-myo-inositol (7). Alcohol 6, a derivative of
L-1-deoxy-chiro-inositol (vibo-quercitol or viburnitol),
showed [a]D –6° (c, 0.95, CHCl3) which is of the same or-
der of magnitude than that reported in the literature ([a]D
–3°).23 On the other hand, the [a]D value for 7 was +19º (c,
0.90, CHCl3) also in agreement with those previously de-
scribed of its enantiomer ([a]D –20.1° and –24°).24,18
OH
HO
BnO
BnO
OBn
OAll
HO
HO
OH
BnO
OH
10
[α]D –58.2 (c=1.3, H2O)
[α]D –56.3 (c=0.2, H2O)
Scheme 3 Reagent and conditions: i) Ac2O, DMAP, Pyr, r.t.,
100%; ii) H2O, DMF, 90 ºC, 68%; iii) MeONa/MeOH 1 M, MeOH/
THF, 100%; iv) H2, Pd/C, EtOH/MeOH/H2O, 100%; v) Pd2(dba)3,
dppb, Allylmethylcarbonate, THF, 70 ºC, 71%; vi) MeONa/MeOH
(1 M) MeOH/THF.
Compound 9 was transformed into building block 10 by
Pd mediated allylation followed by deacetylation. Both 9
and 10 contain the required substitution pattern for the
construction of structures such as II. We previously
prepared structures of type I by glycosylation of the enan-
tiomer of 10, obtained from either methyl a-D-
glucopyranoside10 or D-chiro-inositol,12a with 2-azido-2-
deoxy-D-glucopyranosyl trichloroacetimidates. We ex-
pect that a comparative study of the glycosylation of both
enantiomers may provide interesting new data to be ana-
lyzed in the frame of the double stereodifferentiation
concept26 in the carbohydrate field.27
OTf
BnO
BnO
BnO
BnO
BnO
OBn
i
BnO
4
OH
BnO
OH
H
Glycosylation of 9 with trichloroacetimidate 1128 in
dichloromethane at –25 ºC using TMSOTf as a promoter
gave a 1:1 mixture of the a (12) and b (13) in 84% yield.
(Scheme 4). The corresponding fully deprotected a and b
(1→1) pseudodisaccharides IIa and IIb were obtained by
deallylation and subsequent debenzylation.29
Base
A
OH
BnO
OBn
BnO
BnO
6
[α]D –3 (c=0.95, CHCl3) (Ref 23)
[α]D –5.8 (c=0.90, CHCl3)
BnO
ii
OBn
BnO
BnO
In conclusion, a simple and practical access to L-chiro-
inositol, deoxy L-chiro-inositol derivatives and L-chiro-
inositol building blocks is described starting from readily
available and inexpensive myo-inositol. The L-chiro-inos-
itol building blocks have been used to prepare convenient-
ly protected pseudodisaccharide building blocks for the
synthesis of inositolphosphoglycans. From pseudodisac-
charides 12 and 13, 2-amino-2-deoxy-D-glucopyranosyl a
and b (1→1) L-chiro-inositol (IIa and IIb), required for
comparison purposes, have been synthesized.
+
O
BnO
OBn
OH
5
BnO
BnO
7
[α]D –20.1 (c=0.95, CHCl3) ( –7, Ref 24)
[α]D 19 (c=0.90, CHCl3)
Scheme 2 Reagent and conditions i) CF3CO2Cs, Toluene, DMAP,
r.t., 48 h, 100%; ii) NaBH4 (2 equiv) MeOH, 100%.
Synlett 2003, No. 9, 1370–1372 ISSN 1234-567-89 © Thieme Stuttgart · New York

1372
M. B. Cid et al.
LETTER
(12) (a) Cid, M. B.; Bonilla, J. B.; Dumarcay, S.; Alfonso, F.;
BnO
BnO
BnO
BnO
10 (1.6 equiv)
O
Martín-Lomas, M. Eur. J. Org. Chem. 2002, 881.
(b) Bonilla, J.; Bmuñoz-Ponce, J. L.; Nieto, P. M.; Cid, M.
B.; Khiar, N.; Martín-Lomas, M. Eur. J. Org. Chem. 2002,
889.
BnO
BnO
O
O
+
BnO
i
N3
+
N3
BnO
O
BnO
BnO
O
BnO
OBn
AllO
BnO
OBn
BnO
BnO
N3
(13) Review:Jones, D. P.; Varela-Nieto, I. Mol. Med. 1999, 5,
505.
BnO
TCA
11 (1 equiv)
OAll
(14) (a) Chiara, J. L.; Valle, N. Tetrahedron: Asymmetry 1995, 6,
1895. (b) Kornienko, A.; d’Alarcao, M. Tetrahedron Lett.
1997, 53, 6497. (c) Kwon, Y.-U.; Lee, C.; Chung, S.-K. J.
Org. Chem. 2002, 67, 3327.
(15) Brammer, L. E. Jr.; Hudliky, T. Tetrahedron: Asymmetry
1998, 9, 2011.
(16) Sung-Kee Chung, S.-K.; Yu, S. H. Biorg. Biomed. Chem.
Lett. 1996, 6, 1461.
(17) Takahashi, H.; Kittaka, H.; Ikegani, S. J. Org. Chem. 2001,
66, 2705.
α (1–1) 12 42%
β (1–1) 13 42%
ii (62 %)
iii (100%)
ii ( 62%)
iii (100 %)
HO
HO
HO
HO
HO
HO
O
O
O
NH2
H2N
HO
O
HO
OH
HO
HO
HO
OH
HO
HO
HO
(18) Pietrusiewicz, K. M.; Salamonczyk, G. M.; Bruzik, K. S.
Tetrahedron 1992, 48, 5523.
IIa
IIb
(19) Takahashi, Y.; Nakayama, H.; Katagiri, K.; Ichikawa, K.;
Ito, N.; Takita, T.; Takeuchi, T.; Miyatake, T. Tetrahedron
Lett. 2001, 42, 1053.
Scheme 4 Reagent and conditions i) TMSOTf 0.06 equiv M.S. 4 Å
CH2Cl2, –25 ºC (30 min) to r.t. (10 min); ii) PdCl2 (3 equiv),
CH3COONa (8 equiv), CH3COOH–H2O (20:1), r.t., 6 h; iii) H2, Pd/C,
EtOH/MeOH/H2O, r.t. 12 h.
(20) (a) Yu, J.; Spencer, J. B. J. Org. Chem. 1996, 61, 3234.
(b) Yu, J.; Spencer, J. B. Tetrahedron Lett. 2001, 42, 1053.
(21) (–)2-Deoxy-scyllo-inosose (5). To a solution of 3,4,5,6-
tetra-O-benzyl-1-O-trifluoromethanesulfonyl-L-myo-
inositol (4, 105 mg, 0.156 mmol), in a mixture of dry toluene
and DMF (1/1, 5 mL), cesium trifluoracetate (192 mg, 0.781
mmol) and a catalytic amount of DMAP, were added. After
48 h at room temperature, the resulting slurry was diluted
with EtOAc, washed with water, brine, dried over Na2SO4
and concentrated. The solvent was evaporated and the
residue purified by flash chromatography (hexane/EtOAc,
4:1), to give 81 mg (0.155 mmol, 100%). [a]D –22.0° (c= 0.5,
CHCl3). Anal. Calcd. for C34H34O5: C, 78.13%; H, 6.55%;
found : C, 77.70%; H, 6.66%.
Acknowledgment
We thank the DGES (grant PB96-0820) and Rodaris Pharmaceuti-
cals for financial support.
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inositol (IIa): 1H NMR (500 MHz, D2O): d = 5.08 (d, 1 H,
J = 3.65 Hz, H1¢); 4.13 (t, 1 H, J = 3.81 Hz, H1); 4.0 (t, 1 H,
J = 3.51 Hz, H6); 3.88–3.85 (m, 2 H, H6¢a and H5); 3.79–3.71
(m, 3 H, H6¢b, H4 and H2); 3.65 (m, 1 H, H5¢); 3.58 (t, 1 H,
J = 9.61 Hz, H3); 3.53 (t, 1 H, J = 9.61 Hz, H3¢); 3.38 (t, 1 H,
J = 9.31 Hz, H4¢) and 2.73 (dd, 1 H, J = 10.4 Hz, 3.51 Hz,
H2¢). FAB HRMS calcd for C12H23NO10 + Na+: 364.1219,
found 364.1209. 2-Amino-2-deoxy-D-glucopyranosyl-
b(1→1)-l-chiro-inositol (IIb): 1H NMR (500 MHz, D2O):
d = 4.43 (d, 1 H, J = 8.24 Hz, H1¢); 4.17 (t, 1 H, J = 3.66 Hz,
H1); 4.14 (t, 1 H, J = 3.60 Hz, H6); 3.88–3.68 (m, 6 H, 2H6¢,
H2, H5, H3 and H4); 3.46 (m, 1 H, H5¢); 3.40 (t, 1 H, J = 8.85
Hz, H4¢); 3.36 (t, 1 H, J = 9.31 Hz, H3¢) and 2.69 (dd, 1 H,
J = 9.30 Hz, 8.24 Hz, H2¢). FAB HRMS calcd for
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Synlett 2003, No. 9, 1370–1372 ISSN 1234-567-89 © Thieme Stuttgart · New York