Synthesis of new hexosaminyl D- and L-chiro-inositols related to putative insulin mediators

Article abstract of DOI:10.1002/ejoc.200300252

We have developed an efficient synthetic strategy to HexNH ₂-α(1→3)-L-chiro-inositol (XII-XIII) and HexNH ₂-α(1→2)-D-chiro-inositol (XIV-XV) based on the regio and stereoselective glycosylation of tetrabenzoyl-L-chiro-inositol 2 and

Full text of DOI:10.1002/ejoc.200300252

FULL PAPER
Synthesis of New Hexosaminyl
D
- and
L
-chiro-Inositols Related to Putative
Insulin Mediators
[b]
[a]
[a]
[a]
´
´
M. Belen Cid, Julia B. Bonilla, Francisco Alfonso, and Manuel Martın-Lomas*
Keywords: Carbohydrates / Cyclitols / Glycosylations / Oligosaccharides
We have developed an efficient synthetic strategy to
HexNH2-α(1Ǟ3)- -chiro-inositol (XII−XIII) and HexNH2-
α(1Ǟ2)- -chiro-inositol (XIV−XV) based on the regio and
stereoselective glycosylation of tetrabenzoyl- -chiro-inositol
2 and tetrabenzyl-
may constitute the central structural motifs of inositolphos-
phoglycans, which have been proposed as putative insulin reactivities. The results obtained provide a practical synthetic
ation of an
L-chiro inositol diequatorial diol system (2) and a
L
D-chiro inositol axial/equatorial diol system (14), respectively.
D
To establish the experimental conditions to achieve the best
L
reactivity−selectivity balance, the glycosylation reactions
D-chiro-inositol 14. Compounds XII−XV were studied using
D-gluco- and D-galacto-configured 2-az-
ido-2-deoxytrichloacetimidate glycosyl donors with different
mediators, and their syntheses have been designed on the
basis of biosynthetic considerations. The syntheses of
route and new reactivity−selectivity data.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
XII−XIII and XIV−XV involve the selective monoglycosyl- Germany, 2003)
Introduction
variety of compounds with the structural motifs
IVϪVIII[1c,1g,1h] because we found incidentally that some
We have reported the synthesis and three-dimensional of them behaved as P-type IPGs in inducing cellular differ-
structure in solution of a variety of substances containing entiation in cultures of chicken embryo,[4] but there is no
the structural motifs α--glucosaminyl-(1Ǟ6)-myo-inositol solid experimental evidence for the presence of these struc-
(IϪIII) and α- and β--gluco- and galactosaminyl-(1Ǟ1)- tural motifs in the family of naturally occurring P-type
-chiro-inositol (IVϪVIII) (Figure 1).[1] This earlier study IPGs. On the contrary, assuming that chiro-inositol-con-
was based on the finding that some unidentified inositol- taining GPIs are biosynthesized by the same pathway as
phosphoglycans (IPGs), which may contain these structural their myo-inositol counterparts, it has been reasoned that
motifs, are involved in insulin signalling.[2] These IPGs, their chiro-inositol moieties would have the 1- configura-
which are thought to be generated from glycosylphosphati- tion.[5] Furthermore, it has been shown experimentally that
dylinositols (GPIs) by receptor-activated phospholipases both 1-phosphatidyl--myo-inositol and 2-phosphatidyl--
(PLs), have been reported to be either inhibitors of c-AMP- chiro-inositol are substrates for phospholipase C (PI-PLC)
dependent protein kinase (PKA) (A-type IPGs, containing (Figure 2).[6]
myo-inositol) or activators of pyruvate dehydrogenase phos-
phatase (PDH) (P-type IPGs, containing chiro-inositol).[2]
Although the precise chemical structure of the biologically
active IPGs remains elusive, the existing structural data for
A-type IPGs reveal close structural similarities with the
GPI anchors (IX) (Figure 3).[3] This finding provided the
basis for the design and synthesis of compounds carrying
the structural motifs IϪIII.[1a,1b,1d,1e] There is no general
consensus, however, regarding the structure of P-type chiro-
inositol-containing IPGs.[4d] Previously, we synthesized a
[a]
Grupo de Carbohidratos, Instituto de Investigaciones
´
Quımicas, CSIC,
´
Americo Vespucio, Isla de La Cartuja, 41092 Seville, Spain
Fax: (internat.) ϩ34-95-4460565
E-mail: Manuel.Martin-Lomas@iiq.cartuja.csic.es
[b]
´
´
Instituto de Quımica Organica General (CSIC)
c/ Juan de la Cierva 3, 28006 Madrid, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Previously synthesized IPG-type structures
Eur. J. Org. Chem. 2003, 3505Ϫ3514
DOI: 10.1002/ejoc.200300252
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3505

´
M. B. Cid, J. B. Bonilla, F. Alfonso, M. Martın-Lomas
FULL PAPER
ing blocks for the construction of the structural motifs
sought (X and XI) through regio- and stereoselective mono-
glycosylation. The reactivityϪselectivity balance in glycos-
ylation reactions is a matter of current interest that has par-
ticular importance when unprotected polyhydroxylated gly-
cosyl acceptors are involved.[8] In addition to disclosing di-
rect synthetic routes to structures like X and XI, the results
reported herein provide further data to the wealth of exper-
imental information available on selective glycosylation of
diol systems.
Figure 2. Stereochemical relationship between phosphatidylinosi-
tols of the -myo and -chiro series
This finding may have important consequences, particu-
larly if the IPG mediators are generated following GPI-PLC
cleavage. In this case, the chiro-inositol-containing GPIs
would most likely contain an -chiro-inositol unit carrying a
phosphodiester linkage at position 2 and, seeking maximum
similarity with the GPI anchor structure IX (Figure 3), the
glycan chain would be attached at position 3 (X). On the
other hand, it has also been postulated that chiro-inositol-
containing GPIs could be generated from myo-inositol-con-
taining GPIs after isomerisation.[7] Should this be the case,
the chiro-inositol unit of natural P-type IPGs would rather
belong to the  series and would present the phosphodiester
linkage at position 1 and the glycan chain at position 2
(XI). Figure 3 summarises these two possible mechanisms
proposed for the generation of chiro-inositol-containing
IPGs and shows the stereochemical relationship between
the myo- and chiro- series.
Scheme 1. Reagents and conditions: ii) a) TIPDSCl2, DMAP,
DMF, imidazole, r.t, 16 h; b) BzCl, DMAP, Py, room temp., 16 h,
36% (two steps); iii) (HF)nPy, THF, Ϫ15 °C, 90%
Results and Discussion
Within our programme investigating the structure, syn-
The -chiro-inositol building block 2 was prepared in four
thesis and biological activity of IPG mediators,[1] it became steps from naturally occurring -quebrachitol as shown in
a key issue to have access to compounds bearing the struc- Scheme 1. The methyl ether group of -quebrachitol was
tural motifs X and XI to investigate their behaviour as sub- cleaved as previously reported[9] to give -chiro-inositol.
strates of GPI-PLC and as activators of PDH. In this paper Treatment of -chiro-inositol with the bifunctional protect-
we report synthetic routes for the preparation of these types ing
agent
1,3-dichoro-1,1,3,3-tetraisopropyldisiloxane
of molecules, the effectiveness of which is illustrated by the (TIPDSCl2) under carefully controlled experimental con-
synthesis of the basic pseudodisaccharide structures present ditions[1c] gave a mixture of silylated derivatives that was
in X and XI, namely XII, XIII, XIV, and XV. These synth- directly submitted to conventional benzoylation to give
eses involve the preparation of two conveniently func- compounds 1a (36%), 1b (22%), and 1c (15%). Removal of
tionalized diols derived from - (compound 2, Scheme 1) the silyl protecting group in 1a afforded diol 2 in 90% yield.
and - (compound 14, see Scheme 4) chiro-inositol as build- This diequatorial diol was a potentially useful candidate for
Figure 3. - and -chiro-inositol containing IPG-type structures which may be generated from GPI anchors
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3505Ϫ3514

Synthesis of New Hexosaminyl D- and L-chiro-Inositols
FULL PAPER
the construction of the structural motif X — if experimental
conditions could be established that allowed regioselective
glycosylation at position 3. Thus, we undertook an investi-
gation of the glycosylation of 2 with glycosyl donors con-
taining the needed 2-azido-2-deoxy function as a non-part-
icipating amine-precursor group. The reactivity of 2 as a
glycosyl acceptor was expected to be relatively low and the
use of activated glycosyl donors seemed, in principle, advis-
able to achieve a reasonable reactivityϪselectivity balance
to drive the reaction primarily to the desired α-monoglycos-
ylation stage. Our wide experience[1] also led us to use trich-
loroacetimidates[10a] as glycosyl donors and to carefully ad-
just the reaction conditions, particularly the temperature
and solvent.
Therefore, we first investigated the reaction of 2 with the
activated 2-azido-2-deoxy--glucopyranosyl trichloroaceti-
midate[11] 3a. Glycosylation of 2 with 1.2 equiv. of 3a at low
temperature (Ϫ40 Ǟ Ϫ5 °C) in diethyl ether gave a mixture
of the α(1Ǟ3)- (5) and α(1Ǟ2)- (6) pseudodisaccharides in
an 86:14 ratio and 67% combined yield (Scheme 2). The
unpredicted higher reactivity of the 3-OH group of 2 per-
Scheme 3. Reagents and conditions: a) i) TMSOTf (0.08 equiv.); 2
(1 equiv.), 4a (1.2 equiv.), diethyl ether, Ϫ40 °C for 1 h and then
Ϫ40 °C to 5 °C over 2 h, 48%, α(1Ϫ3)-8a (42%)/α(1Ϫ2)-9a (6%) ϭ
88:12. ii) MeONa/MeOH, r.t., overnight,100%. iii) H2/Pd/C, EtOH/
H2O (4:1), overnight, 80%. b) i) TMSOTf (0.15 equiv.); 2 (1 equiv.),
4b (1.2 equiv.), diethyl ether, Ϫ40 °C to Ϫ5 °C over 2 h and then
r.t., 1 h, 72% as a mixture of pseudodisaccharides α(1Ϫ3)-8b (48%)/
α(1Ϫ2)-9b (24%) ϭ 67:33. ii) MeONa/ MeOH, r.t., overnight, 88%.
iii) H2/Pd/C, EtOH/H2O (4:1), overnight, 98%
spectroscopy) pseudodisaccharides was formed (Scheme 3).
A thorough rationalization of the above results requires
further investigation. The outcome of the reaction with the
activated donors, however, was good enough for practical
purposes, particularly regarding the simplicity of the overall
process, and no additional experiments were carried out at
this stage to improve the construction of the structural mo-
tif X. Furthermore, the isolation of the 2-O-glycosyl deriva-
tives 6, 9a, and 9b as by-products, confers additional value
to this synthetic route providing an entry into the glycosam-
inyl-α(1Ǟ2)--chiro-inositol structural motif. Additionally,
the protecting group pattern in compounds 5, 8a, and 8b
allows further installation of the phosphodiester linkage at
position 2 after conventional manipulation. Deacylation of
5 gave 7, which was submitted to hydrogenation to be trans-
formed into XII in 55% yield from diol acceptor 2
(Scheme 2). Similarly, deacylation of 8aϪb gave 10aϪb,
Scheme 2. Reagents and conditions: i) TMSOTf (0.08 equiv.); 2 (1
equiv.), 3a (1.2 equiv.), diethyl ether, Ϫ40 °C to Ϫ5 °C over 3 h and
then r.t., 1 h, 67% (5/6 ϭ 86:14). ii) MeONa/ MeOH, r.t, overnight,
quantitative. iii) H2/Pd/C, EtOH/H2O (4:1), overnight, 95%
mitted the desired compound 5 to be isolated in 58% yield. respectively, which afforded compound XIII after hydrogen-
This enhanced reactivity of the 3-OH group was similarly ation (Scheme 3).
observed when the glycosylation reaction was carried out
Building block 14 was chosen as a conveniently funtion-
under the same experimental conditions with the activated alised -chiro-inositol unit for the synthesis of the -chiro-
donor[11] 4a having the -galacto configuration (Scheme 3). inositol-containing structural motif XI. Compound 14 was
In this case, an 88:12 mixture of the α(1Ǟ3)- (8a) and prepared from -chiro-inositol as shown in Scheme 4. Treat-
α(1Ǟ2)- (9a) pseudodisaccharides was formed, although in ment of -chiro-inositol with 1 equiv. of 2,2-dimethoxypro-
lower yield (48% combined). Compound 8a was isolated pane caused a rapid transformation into mono- (11,
from this reaction mixture in 42% yield. The balance was 30%)[13] and di- (12, 22%)[14] isopropylidene derivatives.
not so favorable when using the deactivated 2-azido-2-de- Conventional benzylation of 11 gave the tetra-O-benzyl de-
oxy--galactopyranosyl trichloroacetimidate 4b.[12] Under rivative 13, which was converted into diol 14.[15] As dis-
these conditions, a 67:33 mixture of the α(1Ǟ3)- (8b, 48% cussed above for compound 2, diol 14 was considered as a
by NMR spectroscopy) and α(1Ǟ2)- (9b, 24% by NMR useful candidate for obtaining the basic pseudodisaccharide
Eur. J. Org. Chem. 2003, 3505Ϫ3514
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´
M. B. Cid, J. B. Bonilla, F. Alfonso, M. Martın-Lomas
FULL PAPER
structural motif XI. In this case, the different orientation of formed in 52% yield. The α(1Ǟ2) pseudodisaccharide (18)
the free hydroxyl functions of 2 predicted a far more favor- was isolated in 33% yield from this mixture. Glycosylation
able regioselective outcome of the glycosylation reaction to of 14 with donor 3c, which may permit elongation of the
give the 2-O-glycosyl structure.
glycan chain of the basic structural motifs after manipu-
lation of the 4,6-O-benzylidene group of the resulting
pseudodisaccharides, gave an 8:1:1 mixture of the α(1Ǟ2)-
(21), β(1Ǟ2)- (22), and α(1Ǟ1)- (23) compounds in 66%
overall yield. Pseudodisaccharide 21 was isolated in 52%
yield from this mixture.
Scheme 4. Reagents and conditions: i) 2,2-Dimethoxypropane (1
equiv.), pTsOH, DMSO, 100 °C, 30 min, 52% (11, 30%; 12, 22%).
ii) BnBr (6 equiv.), NaH (6 equiv.), DMF, 12 h, room temp., 90%.
iii) AcOH/THF (5:1), 80 °C, 8 h, 100%
The regioselective monoglycosylation of 14 was first at-
tempted with a deactivated donor with -galacto configura-
tion. Reaction of 4b (1.2 equiv.) and 14 at Ϫ40 °C took
place in diethyl ether with complete regioselectivity to af-
ford a 94:6 mixture of the α(1Ǟ2)- (15b) and β(1Ǟ2)- (16b)
pseudodisaccharides in 70% overall yield (Scheme 5). The
regioselectivity was not affected when the reaction was car-
ried out with the more-reactive glycosyl donor 4a, although
the stereoselectivity and yield decreased considerably to af-
ford a 70:30 mixture of the α(1Ǟ2)- (15a) and β(1Ǟ2)-
Scheme 6. Reagents and conditions. R1/R2 ϭ Bn, 3a: i) TMSOTf
(0.04 equiv.), diethyl ether, Ϫ40 °C to room temp., 6 h (18, 33%;
mixture of 3 pseudodisaccharides, 19%). iii) 18, H2/Pd/C, MeOH/
H2O, overnight, 100%. R1/R2 ϭ Ac, 3b: i) TMSOTf (0.14 equiv.),
diethyl ether, Ϫ40 °C, 4 h; 3 h at room temp. (19/20 ϭ 93:7, 63%);
ii) Mix. of 19 and 20, MeONa/MeOH, 30 min, 98%; iii) 24, H2/
Pd/C, MeOH/H2O, overnight, 93%. R1 ϭ PhCH, R2 ϭ Bn, 3c:
i) TMSOTf (0.12 equiv.), diethyl ether, Ϫ40 °C, 4 h (21, 52%, 22,
7%, 23, 7%)
The free α(1Ǟ2)-linked pseudodisaccharide XV was ob-
tained in 58% overall yield from 4b and 14 after conven-
tional deacetylation of 15b to give 17 and then subsequent
hydrogenolysis (Scheme 5). Similarly, the free α(1Ǟ2)-
linked disaccharide XIV was formed in quantitative yield
by hydrogenolysis of 18 or from the mixture of 19 and 20
after deacetylation and hydrogenolysis of pure 24
(Scheme 6). The phosphorylated pseudodisaccharide XVI
has been reported previously starting from (Ϫ)-quinic
acid,[16] and compound XVII has been isolated previously
from jojoba beans and also synthesized using a -chiro-in-
ositol unit prepared in twelve steps from -xylose.[16b]
Scheme 5. Reagents and conditions. 4a (R ϭ Bn): i) TMSOTf (0.06
equiv.), diethyl ether, Ϫ40 °C, 4 h, 58% (15a, 40%, 16a, 18%). 4b
(R ϭ Ac): i) TMSOTf (0.12 equiv.), diethyl ether, Ϫ40 °C, 4 h, 70%
(15b, 66%, 16b, 4%). ii) MeONa/MeOH, 30 min, 100%. iii) H2/Pd/
C, MeOH/H2O, overnight, 100%
(16a) pseudodisaccharides in 58% overall yield (Scheme 5).
The results obtained in the -gluco series are summarized
in Scheme 6. Under the above experimental conditions, the
glycosylation of 14 with 3b gave a 97:3 mixture of the
α(1Ǟ2)- (19) and α(1Ǟ1)- (20) regioisomers in 63% yield
that only could be partially separated after deacetylation, Conclusion
affording pure 24 (Scheme 6). When the reaction was con-
ducted using the more-reactive glycosyl donor 3a, a glycos-
This paper describes a practical approach to the synthesis
ylation mixture containing all the possible isomers was of -glycosaminyl-(1Ǟ3)--chiro-inositols and -glycosami-
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Eur. J. Org. Chem. 2003, 3505Ϫ3514

Synthesis of New Hexosaminyl D- and L-chiro-Inositols
FULL PAPER
15:1) to give 1a (212 mg, 0.25 mmol, 36%), 1b (102 mg, 0.12 mmol,
22%) and 1c (47 mg, 0.06 mmol, 15%). Rf (Hex/EtOAc, 10:1): 0.41.
nyl-(1Ǟ2)--chiro-inositols. On the basis of biosynthetic
considerations, these pseudodisaccharide structures could
be parts of inositolphosphoglycans that have been postu-
lated to be involved in insulin signalling. The access to these
inositolphosphoglycan substructures may permit the prep-
aration of a diverse range of substances bearing these struc-
tural motifs for biological investigation. We conclude, there-
fore, that in providing new substances, the relatively simple
and straightforward procedures here reported herein rep-
1
[α]2D0 ϭ Ϫ40 (c ϭ 1.2, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ
8.10 (d, J ϭ 8.0 Hz, 2 H, Hortho), 8.06 (d, J ϭ 8.0 Hz, 2 H, Hortho),
7.98 (d, J ϭ 8.0 Hz, 2 H, Hortho), 7.77 (d, J ϭ 8.0 Hz, 2 H, Hortho),
7.65Ϫ7.21 (m, 12 H, Bz), 6.00 (m, 1 H, H4), 5.92 (br. t, J ϭ 3.5 Hz,
1 H, H6), 5.84Ϫ5.75 (m, 2 H, H5, H1), 4.44 (m, 2 H, H2, H3),
1.09Ϫ0.79 (m, 28 H, 4 CH and 8 CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 165.8 (2 CO), 165.0, 164.9 (2 CO), 133.9, 133.6, 133.4,
133.2 (4 CHpara, Bz), 130.0Ϫ128.4 (16 CH, 4 C, Bz), 75.1, 73.7 (C2,
resents an important step in our ongoing studies on the C3), 72.2 (C4), 70.9 (C1), 70.3 (C5), 69.0 (C6), 17.6Ϫ17.0 (4 CH),
13.0 (4 CH3), 12.5, 12.0 (4 CH3) ppm. C46H54O11Si2 (839.102):
calcd. C 65.84, H 6.49; found C 65.82, H 6.14. HR-FABMS: calcd.
for C46H54O11Si2ϩNaϩ, 861.3102; found, 861.3070.
role of receptor-activated phospholipases in the signalling
process. Importantly, the construction of the pseudodisac-
charide structures has been carried out by studying the re-
gio- and stereoselectivity of the glycosylation reaction of a
diequatorial and an axialϪequatorial diol system using 2-
azido-2-deoxy--glycopyranosyl trichloroacetimidates as
glycosylating agents. The influence of the glycosyl acceptor
in the outcome of glycosylation reactions is not completely
1,4,5,6-Tetra-O-benzoyl-L-chiro-inositol (2): A solution of 1a
(228 mg, 0.27 mmol, 1 equiv.) in THF (10 mL) was treated with
(HF)nPy (0.73 mL) at Ϫ15 °C. The reaction mixture was stirred for
3 h at room temperature, whereupon it was diluted with EtOAc and
quenched with a saturated solution of NaHCO3 until pH ϭ 7. The
understood. The selectivity of these reactions when the gly- layers were separated and the aqueous phase was extracted exten-
sively with EtOAc. The combined extracts were dried (MgSO4) and
concentrated under vacuum to provide a residue that was purified
by flash chromatography (Hex/ EtOAc, 2:1) to give 2 (146 mg,
0.24 mmol, 90%) as a white solid. M.p: 148Ϫ150 °C; Rf (Hex/
EtOAc, 1:2): 0.45. [α]2D0 ϭ Ϫ37 (c ϭ 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ ϭ 8.13 (d, J ϭ 8.0 Hz, 2 H, Hortho), 8.05 (d,
J ϭ 8.0 Hz, 2 H, Hortho), 8.00 (d, J ϭ 8.0 Hz, 2 H, Hortho), 7.78 (d,
J ϭ 8.0 Hz, 2 H, Hortho), 7.65Ϫ7.22 (m, 12 H, Bz), 5.93 (br. t, J ϭ
4.5 Hz, 1 H, H6), 5.91Ϫ5.88 (m, 2 H, H5, H4), 5.80 (t, J ϭ 4.5 Hz,
1 H, H1), 4.37 (dt, JH2ϪH3 ϭ 8.5, JH2ϪH1 ϭ JH2-OH ϭ 4.5 Hz, 1 H,
H2), 4.28 (td, JH3ϪH2 ϭ JH3ϪH4 ϭ 8.5, JH3-OH ϭ 4.5 Hz, 1 H, H3),
2.91 (d, J ϭ 4.5 Hz, 1 H, C3OH), 2.76 (d, J ϭ 4.5 Hz, 1 H, C2OH)
ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 166.9, 165.8, 165.7, 164.9
(4 CO), 134.0 (2 CHpara), 134.6, 133.5 (2 CHpara), 130.3Ϫ128.5 (4
C, Ph), 130.3, 130.2, 130.1, 130.0, 128.9, 128.8, 128.6, 128.5 (16
CH, Bz), 72.9 (C5), 72.7 (C3), 71.4 (C2), 70.5 (C1), 70.1 (C4), 69.1
(C6) ppm. C34H28O10 (596.591): calcd. C 68.45, H 4.73; found C
68.14, H 5.01; HR-CIMS: calcd. for [C34H28O10]ϩ, 597.1761;
found, 597.1759.
cosyl donor contains a 2-azido-2-deoxy functionality as a
non-participating amino-masking group is still far from
predictable. While a thorough rationalisation of the results
in this paper requires further experimentation and extensive
elaboration, the data reported herein constitute a solid con-
tribution to the understanding of the different factors gov-
erning the selectivity of these processes.
Experimental Section
General Remarks: Diethyl ether was distilled from sodium benzo-
phenone. Dichloromethane was distilled from calcium hydride. Mo-
˚
lecular sieves (4 A, powdered) were pre-dried in an oven and acti-
vated for 5 min under vacuum at 300 °C. All reactions were run
under an atmosphere of dry argon using oven-dried glassware and
freshly distilled and dried solvents, unless otherwise stated. TLC
was performed on Silica gel GF254. Silica gel (230Ϫ400 mesh) was
used for flash chromatography and eluents are given as volume-to-
volume ratios (v/v). All aqueous solutions were saturated unless
otherwise stated. Chemical shifts are given in ppm and coupling
constants are reported in Hz. Resonances were assigned by means
of 2D spectra (COSY, HMQC).
2-Azido-2-deoxy-3,4,6-tri-O-benzyl-
1,4,5,6-tetra-O-benzoyl- -chiro-inositol (5) and 2-Azido-2-deoxy-
3,4,6-tri-O-benzyl- -glucopyranosyl-α-(1Ǟ2)-1,4,5,6-tetra-O-
benzoyl- -chiro-inositol (6): Toluene was evaporated three times
from a mixture of 3a (197 mg, 0.32 mmol, 1.2 equiv.) and 2
D-glucopyranosyl-α-(1Ǟ3)-
L
D
L
1,4,5,6-Tetra-O-benzoyl-2,3-O-(tetraisopropyldisiloxane-1Ј,3Ј-diyl)- (158 mg, 0.26 mmol, 1 equiv.) and then the residue was dried under
˚
L
-chiro-inositol (1a): TIPDSCl2 (432 µL, 1.33 mmol, 1.2 equiv.) was vacuum overnight. Freshly activated 4 A molecular sieves and di-
added dropwise to
a
solution of -chiro-inositol (200 mg,
ethyl ether (10 mL) were added under argon and the mixture was
stirred for 1 h at room temperature. A solution of TMSOTf in di-
ethyl ether (0.1 , 225 µL, 0.08 equiv.) was added at Ϫ40 °C and
the reaction mixture was stirred for 3 h between Ϫ40 °C and Ϫ5
1.11 mmol, 1 equiv.), imidazole (189 mg, 2.78 mmol, 2.5 equiv.),
and dimethylaminopyridine (54 mg, 0.44 mmol, 0.4 equiv.) in DMF
(15 mL). The reaction mixture was stirred overnight at room tem-
perature, diluted with EtOAc, washed twice with a saturated solu- °C and then additionally for 1 h at room temperature. The suspen-
tion of ammonium chloride and then with water and brine, dried
with magnesium sulfate, and then the solvent was evaporated under
vacuum. The residue was immediately dissolved in pyridine
(20 mL) and then benzoyl chloride (1.4 mL, 8.90 mmol, 8.0 equiv.)
sion was filtered through a short pad of celite and the solvent was
evaporated under vacuum to provide a residue that was purified by
flash chromatography (toluene/acetone, 35:1) to obtained
5
(158 mg, 0.15 mmol, 58%) and 6 (24 mg, 0.02 mmol, 9%) as white
and dimethylaminopyridine (8 mg, 0.06 mmol, 0.05 equiv.) were solids. Data for 5: M.p. 125Ϫ128 °C; Rf (toluene/acetone, 3:1): 0.67.
1
added and the mixture was stirred overnight. The pyridine was eva-
porated and the residue was diluted with CH2Cl2, quenched with
ammonium hydroxide (0.2 mL), washed with a saturated solution
of ammonium chloride and then with brine, dried with magnesium
sulfate, and then the solvent was evaporated under vacuum. The
crude product was purified by flash chromatography (Hex/EtOAc,
[α]2D0 ϭ Ϫ14 (c ϭ 0.6, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ
8.16 (d, J ϭ 10.0 Hz, 2 H, Hortho), 8.08 (d, J ϭ 10.0 Hz, 2 H, Hortho),
8.00 (d, J ϭ 10.0 Hz, 2 H, Hortho), 7.76 (d, J ϭ 10.0 Hz, 2 H, Hortho),
7.64 (t, J ϭ 10.0 Hz, 2 H, Hpara), 7.61Ϫ7.04 (m, 25 H, Bz, Ph),
6.02 (t, J ϭ 10.0 Hz, 1 H, H4e), 5.92 (br. s, 1 H, H6), 5.89 (br. s, 1
H, H1), 5.82 (dd, JH5ϪH4 ϭ 10.0, JH5ϪH6 ϭ 2.0 Hz, 1 H, H5), 5.19
Eur. J. Org. Chem. 2003, 3505Ϫ3514
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3509

´
M. B. Cid, J. B. Bonilla, F. Alfonso, M. Martın-Lomas
FULL PAPER
(d, J ϭ 3.5 Hz, 1 H, H1Ј), 4.90 (AB, J ϭ 11.0 Hz, 1 H, CH-Ph), washed with water and finally lyophilized to give the fully depro-
4.83 (AB, J ϭ 1.0 Hz, 1 H, CH-Ph), 4.68 (AB, J ϭ 11.0 Hz, 1 H, tected pseudodissacharide XII (6.1 mg, 0.02 mmol, 95%). Rf
CH-Ph), 4.49 (m, 2 H, H2, C2OH), 4.48 (m, 1 H, H2), 4.39 (AB,
(EtOAc/MeOH/H2O/AcOH, 2:2:1:1): 0.34. [α]2D0 ϭ ϩ38 (c ϭ 0.2,
1
J ϭ 11.0 Hz, 1 H, CH-Ph), 4.25Ϫ4.20 (m, 2 H, H3, CH-Ph), 3.99 H2O). H NMR (500 MHz, D2O): δ ϭ 5.36 (d, J ϭ 3.8 Hz, 1 H,
(t, J ϭ 10.0 Hz, 1 H, H3Ј), 3.88 (AB, J ϭ 11.0 Hz, 1 H, CH-Ph),
3.73Ϫ3.66 (m, 2 H, H4Ј, H5Ј), 3.60 (dd, JH2Ј-H3Ј ϭ 10.0, JH2Ј-H1Ј
H1Ј), 4.04 (dt, JH5Ј-H4Ј ϭ 10.0, JH5Ј-H6aЈ ϭ JH5-H6bЈ ϭ 3.0 Hz, 1 H,
H5Ј), 3.99 (t, J ϭ 3.5 Hz, 1 H, H6), 3.96 (t, J ϭ 3.5 Hz, 1 H, H1),
ϭ
3.5 Hz, 1 H, H2Ј), 3.22 (br. d, J ϭ 11.2 Hz, 1 H, H6aЈ), 2.69 (br. d, 3.92 (dd, JH2ϪH3 ϭ 9.5, JH2ϪH1 ϭ 3.5 Hz, 1 H, H2), 3.82 (t, J ϭ
J ϭ 11.2 Hz, 1 H, H6bЈ) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ
10.0 Hz, 1 H, 1 H, H3Ј), 3.80 (m, 2 H, H6aЈ, H6bЈ), 3.74 (dd,
165.8, 165.5, 165.1, 164.7 (4 CO), 138.0 (C, Ph), 137.6 (2 C, Ph), JH5ϪH4 ϭ 9.5, JH5ϪH6 ϭ 3.5 Hz, 1 H, H5), 3.66 (t, J ϭ 9.5 Hz, 1
133.8Ϫ133.2 (4 CHpara, Bz), 130.1Ϫ127.9 (35 C, Bz, Ph), 100.4
H, H3), 3.62 (t, J ϭ 9.5 Hz, 1 H, H4), 3.50 (t, J ϭ 10.0 Hz, 1 H,
(C1Ј), 83.2 (C3), 80.9 (C3Ј), 77.7 (C4Ј), 75.7, 74.7, 73.4 (3 CH2Ph), H4Ј), 3.16 (dd, JH2Ј-H3Ј ϭ 10.5, JH2Ј-H1Ј ϭ 3.8 Hz, 1 H, H2Ј) ppm.
72.0 (C5Ј), 70.9 (C2), 70.7 (C5), 70.6 (C4), 69.7 (C1), 68.6 (C6), 67.0 13C NMR (D2O, 125 MHz): δ ϭ 97.1 (C1Ј), 80.2 (C3), 71.7 (C5Ј),
(C6Ј), 64.6 (C2Ј) ppm. C61H55N3O14 (1054.121): calcd. C 69.50, H 71.4 (C1), 70.9 (C6), 70.7 (C4), 70.6 (C3Ј), 70.5 (C5), 70.1 (C2), 68.9
5.26, N 3.99 found C 69.55, H 5.25, N 3.99. HR-FABMS: calcd.
(C4Ј), 59.6 (C6Ј), 54.2 (C2Ј) ppm. HR-FABMS: calcd. for
for [C61H55N3O14 ϩ Na]ϩ, 1076.3582; found, 1076.3616; Data for [C12H23NO10 ϩ Na]ϩ, 364.1220; found, 364.1225.
6: M.p. 122Ϫ126 °C; Rf (toluene/acetone, 3:1): 0.51. [α]2D0 ϭ Ϫ39
1
2-Azido-2-deoxy-3,4,6-tri-O-benzyl-
1,4,5,6-tetra-O-benzoyl- -chiro-inositol (8a) and 2-Azido-2-deoxy-
3,4,6-tri-O-benzyl- -galactopyranosyl-α-(1Ǟ2)-1,4,5,6-tetra-O-
benzoyl- -chiro-inositol (9a). These pseudodisaccharides were pre-
D-galactopyranosyl-α-(1Ǟ3)-
(c ϭ 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ 8.13 (d, J ϭ
8.0 Hz, 2 H, Hortho), 8.02 (m, 4 H, Hortho), 7.76 (d, J ϭ 8.0 Hz, 2
H, Hortho), 7.64 (t, J ϭ 8.0 Hz, 2 H, Hpara), 7.55Ϫ7.00 (m, 25 H,
Bz, Ph), 6.01 (t, J ϭ 9.8 Hz, 1 H, H4), 5.93 (t, J ϭ 4.0 Hz, 1 H,
H6), 5.82 (m, 2 H, H1, H5), 5.24 (d, J ϭ 3.5 Hz, 1 H, H1Ј), 4.68
(AB, J ϭ 10.5 Hz, 1 H, CH-Ph), 4.65 (AB, J ϭ 11.5 Hz, 1 H, CH-
Ph), 4.61 (AB, J ϭ 10.5 Hz, 1 H, CH-Ph), 4.57 (AB, J ϭ 12.0 Hz,
1 H, CH-Ph), 4.49 (td, JH3ϪH2 ϭ JH3-H4 ϭ 9.8, JH3-OH ϭ 2.0 Hz,
1 H, H3), 4.42 (AB, J ϭ 11.2 Hz, 1 H, CH-Ph), 4.35 (AB, J ϭ
12.0 Hz, 1 H, CH-Ph), 4.22 (dd, JH2ϪH3 ϭ 9.8, JH2ϪH1 ϭ 3.5 Hz,
1 H, H2), 3.88 (d, J ϭ 2.0 Hz, 1 H, C3OH), 3.80 (br. d, 1 H, J ϭ
9.5 Hz, H6aЈ), 3.73Ϫ3.61 (m, 4 H, H3Ј, H4Ј, H5Ј,H6aЈ), 3.54 (dd, JH2Ј-
L
D
L
pared from 4a (62 mg, 0.10 mmol, 1.2 equiv.) and 2 (50 mg,
0.08 mmol, 1 equiv.) as described for the preparation of 5, stirring
the reaction mixture for 1 h at Ϫ40 °C, 2 h between Ϫ40 °C and
Ϫ30 °C and then overnight at room temperature, yielding 8a
(37 mg, 0.04 mmol, 42%) and 9a (5 mg, 0.005 mmol, 6%) after flash
chromatography (toluene/acetone, 40:1). Data for 8a: Rf (toluene/
acetone, 15:1): 0.48. [α]2D0 ϭ Ϫ5 (c ϭ 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ ϭ 8.14 (d, J ϭ 8.0 Hz, 2 H, Hortho), 8.06 (d,
J ϭ 7.5 Hz, 2 H, Hortho), 7.99 (d, J ϭ 7.2 Hz, 2 H, Hortho), 7.72 (d,
J ϭ 8.0 Hz, 2 H, Hortho), 7.63 (m, 2 H, Hpara), 7.52 (m, 4 H, Hmeta),
7.46 (t, J ϭ 7.2 Hz, 1 H, Hpara), 7.41Ϫ6.98 (m, 20 H, Bz, Ph), 6.02
(t, J ϭ 10.0 Hz, 1 H, H4), 5.88 (br. t, J ϭ 3.5 Hz, 1 H, H6), 5.83
ϭ 9.5, JH2Ј-H1Ј ϭ 3.5 Hz, 1 H, H2Ј) ppm. 13C NMR (125 MHz,
H3Ј
CDCl3): δ ϭ 166.1, 165.6, 165.0, 164.7 (4 CO), 138.0, 137.7, 137.5
(3 C, Ph), 138.1, 137.7, 137.6, 137.5 (4 CHpara, Bz) 130.1Ϫ127.3
(35 C, Bz, Ph), 100.9 (C1Ј), 80.7 (C2, C3Ј), 77.8 (C4Ј), 75.5, 74.4,
73.5 (3 CH2Ph), 71.9 (C3), 71.8 (C5Ј), 71.5 (C4), 70.0, 69.8 (C1, C5),
68.7 (C6), 67.6 (C6Ј), 64.3 (C2Ј) ppm. C61H55N3O14 (1054.121):
calcd. C 69.50, H 5.26, N 3.99 found C 69.35, H 5.39, N 4.08. HR-
FABMS: calcd. for [C61H55N3O14 ϩ Na]ϩ, 1076.3582; found,
1076.3602.
(br. t, J ϭ 3.5 Hz, 1 H, H1), 5.79 (dd, JH5ϪH4 ϭ 10.5, JH5ϪH6
ϭ
3.5 Hz, 1 H, H5), 5.16 (d, J ϭ 3.5 Hz, 1 H, H1Ј), 4.72Ϫ4.64 (m, 3
H, CH-Ph, CH2-Ph), 4.45 (m, 1 H, H2), 4.36 (AB, J ϭ 11.5 Hz, 1
H, CH-Ph), 4.21 (t, J ϭ 9.5 Hz, 1 H, H3), 4.08 (dd, JH2Ј-H3Ј ϭ 10.0,
JH2Ј-H1Ј ϭ 3.0 Hz, 1 H, H2Ј), 4.02Ϫ3.89 (m, 3 H, H3Ј, H4Ј, H5Ј) 3.28
(t, J ϭ 8.5 Hz, 1 H, H6aЈ), 2.72 (dd, JH6bЈ-H6aЈ ϭ 8.5 Hz, JH6bЈ-
2-Azido-2-deoxy-3,4,6-tri-O-benzyl-
D
-glucopyranosyl-α(1Ǟ3)-
L
-
ϭ 8.0 Hz, 1 H, H6bЈ) ppm. 13C NMR (CDCl3, 125 MHz): δ ϭ
H6aЈ
chiro-inositol (7): MeONa in MeOH (2 , 7 mL) was added at room
166.0, 165.6, 165.2, 164.9 (4 CO), 138.4, 137.8, 137.6 (3 C, Ph),
temperature to a solution of 5 (101 mg, 0.10 mmol, 1.0 equiv.) in 133.9Ϫ133.4 (4 CHpara, Bz), 130.2Ϫ127.8 (31 CH, Bz, Ph), 100.2
MeOH (10 mL). The solution was stirred overnight and then it was
quenched with Amberlite IRA-120 resin. The solvent and BzOMe
were evaporated by heating at 50 °C under vacuum to provide the
solid 7 (61 mg, 0.1 mmol, quantitative). M.p. 148Ϫ152 °C; Rf (ace-
(C1Ј), 82.7 (C3), 78.4 (C3Ј), 70.0 (CH2Ph), 73.2 (C4Ј), 72.8, 72.1 (2
CH2Ph), 70.9 (C2), 70.5 (C5), 70.1, 70.0 (C1, C5Ј), 68.7 (C6), 67.5
(C6Ј), 61.2 (C2Ј) ppm. C61H55N3O14 (1054.121): calcd. C 69.50, H
5.26, N 3.99 found C 69.51, H 5.12, N 4.13. HR-FABMS: calcd.
tone): 0.61. [α]2D0 ϭ ϩ67 (c ϭ 0.6, MeOH). 1H NMR (400 MHz, for [C61H53N3O14 ϩ Na]ϩ, 1076.3592; found, 1076.3585. Some of
[D6]acetone): δ ϭ 7.37Ϫ7.24 (m, 15 H, Ph), 5.44 (d, J ϭ 3.6 Hz, 1 the most significant data for 9a: 1H NMR (500 MHz, CDCl3): δ ϭ
H, H1Ј), 4.88 (AB, 2 H, 2 CH-Ph), 4.80 (AB, J ϭ 10.8 Hz, 1 H,
CH-Ph), 4.64 (AB, J ϭ 10.8 Hz, 1 H, CH-Ph), 4.56 (AB, 2 H, 2
CH-Ph), 4.38 (m, 1 H, H5Ј), 4.02Ϫ3.92 (m, 5 H, H1, H6, H4, H5,
H3Ј), 3.80Ϫ3.63 (m, 5 H, H2, H3, H4Ј, H6aЈ, H6bЈ), 3.42 (dd, 1 H,
5.26 (d, J ϭ 5.3 Hz, 1 H, H1Ј), 3.91 (br. s, 1 H, H4Ј), 3.75 (dd, JH3Ј-
ϭ 9.5, JH3Ј-H4Ј ϭ 2.5 Hz, 1 H, H3Ј) ppm.
H2Ј
2-Azido-3,4,6-tri-O-benzyl-D-galactopyranosyl-α(1Ǟ3)-L-chiro-
JH2ЈH3Ј ϭ 10.0, JH2Ј-H1Ј ϭ 3.6 Hz, H2Ј), 2.82 (s, 5 H, OH) ppm. 13
C
inositol (10a): This compound was prepared from the fully pro-
tected pseudodisaccharide 8a (29 mg, 0.03 mmol, 1.0 equiv.), using
the procedure described for the preparation of 7, to yield 10a
(18 mg, 0.03 mmol, quantitative). Rf (acetone): 0.33. [α]2D0 ϭ ϩ9
NMR (100 MHz, [D6]acetone): δ ϭ 139.4 (3 C, Ph), 130.5Ϫ129.6
(15 CH, Ph), 98.0 (C1Ј), 81.0, 79.5 (C3, C2), 75.4, 75.3, 73.7 (3
CH2Ph), 73.1, 72.7, 72.6, 72.4, 72.3, 72.2 (C1, C4, C5, C6, C3Ј, C4Ј),
71.3, (C5Ј), 69.6 (C6Ј), 64.7 (C2Ј) ppm. C33H39N3O10 (637.688):
calcd. C 62.16, H 6.165, N, 6.589; found C 61.68, H 6.043, N 6.236.
HR-FABMS: calcd. for [C33H39N3O10 ϩ Na]ϩ, 660.2533; found,
660.2543.
1
(c ϭ 0.9, CHCl3). H NMR (500 MHz, CDCl3): 7.40Ϫ7.17 (m, 15
H, 3Ph), 4.99 (d, J ϭ 4.0 Hz, 1 H, H1Ј), 4.83 (AB, J ϭ 11.5 Hz, 1
H, CH-Ph), 4.71 (s, 2 H, CH2Ph), 4.49 (AB, J ϭ 11.5 Hz, 1 H, CH-
Ph), 4.46 (AB, J ϭ 11.5 Hz, 1 H, CH-Ph), 4.39 (AB, J ϭ 11.5 Hz, 1
H, CH-Ph), 4.15Ϫ4.10 (m, 3 H, H1, H2Ј, H6), 4.07 (dd, JH5Ј-H6aЈ
ϭ
2-Amino-2-deoxy-
Compound 7 (12 mg, 0.02 mmol, 1.0 equiv.) and 10% Pd/C (5 mg, H4Ј ϭ 2.5 Hz, 1 H, H3Ј), 3.87 (dd, JH2ϪH3 ϭ 10.0, JH2ϪH1 ϭ 3.0 Hz,
0.04 mmol) were stirred overnight in ethanol/water (4:1) under a
1 H, H2), 3.82 (d, JH4Ј-H3Ј ϭ 2.5 Hz, 1 H, H4Ј), 3.78 (dd, JH5ϪH4 ϭ
hydrogen atmosphere. The slurry was filtered through celite and 9.2, JH5ϪH6 ϭ 2.5 Hz, 1 H, H5), 3.59 (m, 2 H, H4, H6aЈ), 3.51 (t, J ϭ
D-glucopyranosyl-α(1Ǟ3)-L
-chiro-inositol (XII): 9.2, JH5Ј-H6bЈ ϭ 3.0 Hz, 1 H, H5Ј), 3.90 (dd, JH3Ј-H2Ј ϭ 9.5, JH3Ј-
3510
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3505Ϫ3514

Synthesis of New Hexosaminyl D- and L-chiro-Inositols
FULL PAPER
10.0 Hz, 1 H, H3), 3.24 (dd, JH6bЈ-H6bЈ ϭ 9.2, JH6bЈ-H5Ј ϭ 3.0 Hz, 1 fully deprotected α(1Ϫ2)-pseudodisaccharide 9b. Rf (EtOAc/
1
H, H6bЈ) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 137.9, 137.7, MeOH/H2O/AcOH, 2:2:1:1): 0.39. [α]2D0 ϭ ϩ29 (c ϭ 0.1, H2O). H
137.3 (3 C, Ph), 128.8Ϫ128.0 (15 CH, Ph), 99.2 (C1Ј), 86.9 (C3),
NMR (500 MHz, D2O): δ ϭ 5.44 (d, J ϭ 3.8 Hz, 1 H, H1Ј), 4.29
79.0 (C2), 74.6, 73.9 (CH2Ph), 73.1 (C4Ј), 72.6 (CH2Ph), 71.8 (C5), (m, 1 H, H5Ј), 4.07 (dd, JH3Ј-H2Ј ϭ 10.5, JH3Ј-H4Ј ϭ 3.0 Hz, 1 H,
71.4 (C5Ј), 71.2 (C3Ј), 70.7, 70.63, 70.59 (C1, C4, C6), 70.0 (C6Ј), H3Ј), 4.02 (d, J ϭ 3.0 Hz, 1 H, H4Ј), 3.99 (br. t, J ϭ 3.5 Hz, 1 H,
61.5 (C2Ј) ppm. HR-FABMS: calcd. for [C33H39N3O10 ϩ Na]ϩ, H6), 3.96 (br. t, J ϭ 3.5 Hz, 1 H, H1), 3.91 (dd, JH2ϪH3 ϭ 9.5,
660.2533; found, 660.2589.
JH2ϪH1 ϭ 3.5 Hz, 1 H, H2), 3.76 (dd, JH5ϪH4 ϭ 9.5, JH5ϪH6
ϭ
3.5 Hz, 1 H, H5), 3.71 (m, 2 H, H6aЈ, H6bЈ), 3.69 (t, J ϭ 9.5 Hz, 1
H, H3), 3.63 (t, J ϭ 9.5 Hz, 1 H, H4), 3.47 (dd, JH2Ј-H3Ј ϭ 10.5,
JH2Ј-H1Ј ϭ 3.8 Hz, 1 H, H2Ј) ppm. 13C NMR (125 MHz, D2O): δ ϭ
95.8 (C1Ј), 79.9 (C3), 71.4 (C1), 70.9 (C6), 70.7 (C5Ј), 79.59, 70.57
(C2, C4), 70.0 (C5), 67.6 (C4Ј), 66.0 (C3Ј), 60.2 (C6Ј), 50.9 (C2Ј) ppm.
HR-FABMS: calcd. for [C12H23NO10 ϩ Na]ϩ, 364.1220; found,
364.1226.
2-Azido-2-deoxy-3,4,6-tri-O-acetyl-D-galactopyranosyl-α-(1Ǟ3)-
1,4,5,6-tetra-O-benzoyl-L-chiro-inositol (8b): These pseudodisac-
charides were prepared from 4b (70 mg, 0.15 mmol, 1.2 equiv.) and
2 (72 mg, 0.12 mmol, 1 equiv.) using the procedure described for
the preparation of 5, adding of a solution of TMSOTf (0.1 , 0.15
equiv.) and stirring the reaction mixture for 2 h between Ϫ40 °C
and Ϫ5 °C, to yield, after flash chromatography (toluene/acetone,
30:1), a 2:1 mixture of 8b and 9b (81 mg, 72%). Data for 8b: Rf
(toluene/acetone, 4:1): 0.40. [α]2D0 ϭ ϩ18 (c ϭ 0.9, CHCl3, enriched
mixture of pseudodisaccharides, α(1Ϫ3) 8b /α(1Ϫ2) 9b ϭ 1:0.1). 1H
NMR (500 MHz, CDCl3): δ ϭ 8.16 (d, J ϭ 7.5 Hz, 2 H, Hortho),
8.08 (d, J ϭ 7.5 Hz, 2 H, Hortho), 7.98 (d, J ϭ 7.5 Hz, 2 H, Hortho),
7.72 (d, J ϭ 7.5 Hz, 2 H, Hortho), 7.67Ϫ7.17 (m, 27 H, Bz, Ph), 6.01
(t, J ϭ 10.5 Hz, 1 H, H4), 5.91 (m, 1 H, H6), 5.87 (m, 1 H, H1),
5.82 (dd, JH5ϪH4 ϭ 10.5, JH5ϪH6 ϭ 3.0 Hz, 1 H, H5), 5.38 (dd,
JH3Ј-H2Ј ϭ 11.0, JH3Ј-H4Ј ϭ 3.0 Hz, 1 H, H3Ј), 5.29 (br. s, 1 H, H4Ј),
5.26 (d, J ϭ 3.5 Hz, 1 H, H1Ј), 4.50 (br. d, JH2ϪH3 ϭ 9.5 Hz, 1 H,
H2), 4.26 (s, 1 H, C2OH), 4.22 (t, J ϭ 10.5 Hz, 1 H, H3), 4.08 (m,
1 H, H5Ј), 3.94 (dd, JH2Ј-H3Ј ϭ 11.0, JH2Ј-H1Ј ϭ 3.5 Hz, 1 H, H2Ј),
3.74 (t, J ϭ 10.2 Hz, 1 H, H6aЈ), 3.06 (dd, JH6bЈ-H6aЈ ϭ 10.2, JH6bЈ-
1,2-O-Isopropylidene-D-chiro-inositol (11): A mixture of -chiro-in-
ositol (1 g, 5.55 mmol), 2,2-dimethoxypropane (0.68 mL,
5.55 mmol) and p-toluenesulfonic acid monohydrate (10 mg,
0.05 mmol) in dry DMSO (3 mL) was stirred at 100 °C for 30 min,
at which time a clear solution was obtained. The reaction mixture
was then cooled and triethylamine (0.1 mL) was added. The solu-
tion was concentrated and purified by flash chromatography
(CH2Cl2/MeOH, 20:1 to 1:1) to give a mixture of bisacetal 12
(0.32 g, 22%) and monoacetal 11 (0.37 g, 30%). Data for 11: M.p.
150Ϫ155 °C. [α]2D0 ϭ ϩ82 (c ϭ 0.28, MeOH). 1H NMR (500 MHz,
DMSO): δ ϭ 4.95 (d, J ϭ 4.6 Hz, 1 H, OH), 4.83 (d, J ϭ 5.1 Hz,
1 H, OH), 4.67 (d, J ϭ 4.6 Hz, 1 H, OH), 4.64 (d, J ϭ 4.6 Hz, 1
H, OH), 4.03 (dd, J ϭ 6.1, 1.6 Hz, 1 H, H1), 3.85 (dd, J ϭ 7.9,
1.6 Hz, H2), 3.78 (m, 1 H, H6), 3.37 (m, 1 H, H5), 3.28 (m, 1 H,
H4), 3.19 (m, 1 H, H3), 1.33 (s, 3 H, CH3), 1.20 (s, 3 H, CH3)
ppm.13C NMR (125 MHz, DMSO): δ ϭ 108.9 (C), 79.8 (CH), 78.6
(CH), 76.8 (CH), 74.1 (CH), 73.9 (CH), 70.2 (CH), 29.0 (CH3),
28.7 (CH3) ppm. C9H16O6 (220.219): calcd. C 49.0, H 7.32; found
C 49.12, H 7.30. MALDI-TOF-MS: calcd. for [C9H16O6 ϩ Na]ϩ,
243.2, found, 244.3.
ϭ 4.5 Hz, 1 H, H6bЈ), 2.09, 1.96, 1.91 (3s, 9 H, CH3CO) ppm.
H5Ј
13C NMR (125 MHz, CDCl3):
δ ϭ 134.0Ϫ133.2 (4 CO),
130.1Ϫ128.3 (42 C, Bz, Ph), 100.0 (C1Ј), 83.2 (C3), 71.0 (C2), 70.6,
70.5 (C4, C5), 69.8, 69.7 (C1, C3Ј), 68.4 (C6), 67.1 (C5Ј), 66.6 (C4Ј),
59.8 (C6Ј), 59.0 (C2Ј), 20.7, 20.6, 20.5 (3 CH3CO) ppm. HR-
FABMS: calcd. for [C46H43N3O17 ϩ Na]ϩ, 932.2490; found,
932.2523. Some of the most significant data for 9b: 1H NMR
(500 MHz, CDCl3): δ ϭ 6.15 (t, J ϭ 10.2 Hz, 1 H, H4), 5.19 (d,
JH4Ј-H5Ј ϭ 2.1 Hz, 1 H, H4Ј), 5.17 (br. s, 1 H, H1Ј) ppm.
1,2-O-Isopropylidene-3,4,5,6-tetra-O-benzyl-D-chiro-inositol (13):
1,2-O-Isopropylidene--chiro-inositol (11; 1 g, 4.54 mmol) in DMF
(30 mL) at Ϫ20 °C was added to a suspension of sodium hydride
(60% in mineral oil; 1.09 g, 27.24 mmol). The resulting mixture was
stirred at 0 °C for 30 min and then benzyl bromide (3.24 mL,
27.27 mmol) was added dropwise. After 12 h at room temperature
the reaction was complete and the mixture was treated with MeOH.
The solvent was evaporated and the residue diluted with CH2Cl2
and washed with a saturated solution of ammonium chloride and
brine. The organic layer was dried with sodium sulfate, filtered, and
concentrated. The residue was purified by column chromatography
(Hex/EtOAc, 8:1) to give 13 as a white solid (2.35 g, 90%). M.p.
2-Azido-D-galactopyranosyl-α(1Ǟ3)-L-chiro-inositol (10b): Com-
pound 10b was obtained from a 1:0.2 mixture of 8b and 9b (40 mg,
0.04 mmol, 1.0 equiv.) following the same experimental procedure
as described for the preparation of 7 to yield a mixture of pseudodi-
saccharide α(1Ϫ3) (10b) and the partially deprotected α(1Ϫ2)-
pseudodisaccharide of 9b (1:0.2, 14 mg, 0.04 mmol, 88%) after pre-
cipitating with diethyl ether. [α]2D0 ϭ ϩ78 [c ϭ 0.6, MeOH mixture
of pseudodisaccharides α(1Ϫ3)/α(1Ϫ2)
ϭ
1:0.2]. 1H NMR
(500 MHz, [D4]MeOH): 5.35 (d, J ϭ 4.0 Hz, 1 H, H1Ј), 4.26 (br. t,
J ϭ 5.5 Hz, 1 H, H5Ј), 4.01 (dd, JH3Ј-H2Ј ϭ 10.5, JH3Ј-H4Ј ϭ 3.0 Hz,
1 H, H3Ј), 3.94Ϫ3.85 (m, 4 H, H4Ј, H1, H5, H6), 3.77Ϫ3.55 (m, 5
109Ϫ114 °C. [α]2D0 ϭ ϩ33 (c ϭ 1.4, CHCl3). H NMR (300 MHz,
1
H, H2, H3, H4, H6aЈ, H6bЈ), 3.51 (dd, JH2Ј-H3Ј ϭ 10.8, JH2Ј-H1Ј
ϭ
CDCl3): δ ϭ 7.4Ϫ7.2 (m, 20 H, 4Ph), 4.9 (d, 1 H, AB), 4.78Ϫ4.53
(m, 7 H, AB), 4.46 (dd, J ϭ 6.7, 5.6 Hz, 1 H), 4.40 (dd, J ϭ 8.5,
6.7 Hz, 1 H), 3.92 (dd, J ϭ 5.6, 1.7 Hz, 1 H), 3.81Ϫ3.74 (m, 2 H),
3.58 (dd, J ϭ 8.5, 6.9 Hz, 1 H), 1.5 (s, 3 H, CH3), 1.38 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 138.7 (C), 138.5 (C),
138.3 (C), 138.2 (C), 128.4 (2 CH), 128.35 (2 CH), 128.3 (2 CH),
128.2 (2 CH), 128.0 (2 CH), 127.9 (2 CH), 127.7 (CH), 127.6 (CH),
127.6 (2 CH), 127.55 (2 CH), 127.5(CH), 127.4 (CH), 109.5 (C),
83.2 (CH), 81.3 (CH), 78.4 (CH), 78.2 (CH), 77.5 (CH), 74.0 (CH),
27.6 (CH3) 27.3 (CH3) ppm. C37H40O6 (580.717): calcd. C 76.52,
H 6.94; found C 76.62, H 7.02. MALDI-TOF-MS: calcd. for
[C37H40O6 ϩ Na]ϩ, 603.7, found, 603.9.
4.0 Hz, 1 H, H2Ј) ppm. 13C NMR (125 MHz, [D4]MeOH): δ ϭ
100.2 (C1Ј), 81.3 (C3), 72.3, 71.92, 71.88, 71.5 (C1, C4, C5, C6), 71.2
(C2), 70.9 (C5Ј), 69.6 (C4Ј), 68.3 (C3Ј), 61.4 (C6Ј), 60.9 (C2Ј) ppm.
HR-FABMS: calcd. for [C12H21N3O10 ϩ Na]ϩ, 390.1125; found,
390.1125.
2-Amino-2-deoxy--galactopyranosyl-α(1Ǟ3)-L-chiro-inositol (XIII):
The fully deprotected pseudodisaccharide XIII was obtained fol-
lowing the same experimental procedure as described for XII start-
ing from 10a (14 mg, 0.022 mmol, 1.0 equiv.) and after purification
by reverse-phase flash chromatography (H2O/MeOH, 95:5; yield ϭ
6 mg, 80%) or by starting from a 1:0.2 mixture of α(1Ϫ3)-pseudodi-
saccharide 10b and the partially deprotected α(1Ϫ2)-disaccharide
of 9b (6.0 mg, 0.016 mmol, 1.0 equiv.) to give a 1:0.2 mixture
(5.1 mg, 0.015 mmol, 94%) of α(1Ϫ3)-pseudodisaccharide XIII and
3,4,5,6-Tetra-O-benzyl-
D-chiro-inositol (14): Acetic acid (80%,
50 mL) was added to a solution of 13 (2.35 g, 4.05 mmol) in THF
Eur. J. Org. Chem. 2003, 3505Ϫ3514
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3511

´
M. B. Cid, J. B. Bonilla, F. Alfonso, M. Martın-Lomas
FULL PAPER
(10 mL). The reaction mixture was stirred under reflux at 80 °C for
8 h. The solvent was evaporated and the residue co-evaporated four
times with toluene to dryness. The residue was purified by flash
chromatography (Hex/EtOAc, 3:1) to yield 14 as a white solid
(2.18 g, quantitative). M.p. 69Ϫ73 °C. [α]2D0 ϭ ϩ36 (c ϭ 0.4,
H4Ј, and H2Ј), 3.57 (br. s, 1 H, H5Ј), 3.48 (dd, J ϭ 12 and 4 Hz, 1 H,
H6aЈ), 3.25 (br. d, 1 H, J ϭ 12 Hz, H6bЈ) ppm. 13C NMR (125 MHz,
CDCl3):
δ ϭ 138.9 (C), 138.6 (C), 138.5 (C), 138.4 (C),
128.5Ϫ127.4 (12 CH), 94.6 (CH), 81.6 (CH), 80.5 (CH), 80.1 (CH),
76.8 (CH), 75.7 (CH), 75.7 (CH2),73.9 (CH2), 73.3 (CH2), 70.8
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 7.4Ϫ7.2 (m, 20 H, 4Ph), (CH), 69.9 (CH), 68.7 (CH), 66.5 (CH),63.4 (CH2) 63.3 (CH2), 61.4
5.05 and 4.60 (m, 8 H, AB), 4.07 (t, J ϭ 3.3 Hz, 1 H, H1), 3.98 (t,
(CH) ppm. C40H45O10N3 (727.806): calcd. C 66.01, H 6.23, N 5.77;
J ϭ 9.0 Hz, 1 H, H4), 3.92Ϫ3.86 (m, 3 H, H6, H5, and H2), 3.65 found C 65.95, H 6.13, N 5.73. MALDI-TOF-MS: calcd. for
(t, J ϭ 9.1 Hz, 1 H, H3), 2.33 (s, 1 H, OH), 2.29 (s, 1 H, OH) ppm. [C40H45O10N3 ϩ Na]ϩ, 750.5, found, 750.7.
13C NMR (75 MHz, CDCl3): δ ϭ 138.7 (C), 138.6 (C), 138.5 (C),
2-Amino-2-deoxy-D-galactopyranosyl-α(1Ǟ2)-D-chiro-inositol (XV):
138.3 (C), 128.6, 128.3, 128.25, 128.0 127.85, 127.6, 127.55, 127.45
(8 CH, 4 CH), 81.6 (CH), 81.5 (CH), 80.4 (CH), 75.7 (CH), 75.5
(CH2), 75.3 (CH2), 73.5 (CH2), 73.1 (CH2), 71.2 (CH), 69.4 (CH)
ppm. C34H36O6 (540.652).: calcd. C 75.52, H 6.71; found C 75.47,
H 6.67. MALDI-TOF-MS: calcd. for [C34H36O6 ϩ Na]ϩ, 563.6,
found, 564.1 Da.
Compound 17 (13 mg, 0.018 mmol) and 10% Pd/C in a mixture of
MeOH, EtOH, and H2O (10:3:1, 3 mL) was saturated with a
stream of H2 for 30 min and then stirred under H2 overnight. The
slurry was filtered through celite and the solvent was evaporated to
give XV (6 mg, quantitative). [α]2D0 ϭ ϩ95 (c ϭ 0.2, MeOH). 1H
NMR (500 MHz, D2O): δ ϭ 5.15 (d, J ϭ 3.6 Hz, 1 H, H1Ј), 4.21
(t, J ϭ 3.0 Hz, 1 H, H1), 4.17 (t, J ϭ 6.2 Hz, 1 H, H5Ј), 4.03 (t,
J ϭ 3.4 Hz, 1 H, H6), 3.96 (d, J ϭ 2.6 Hz, 1 H, H4Ј), 3.92 (dd, J ϭ
10.7, 2.6 Hz, 1 H, H3Ј), 3.82 (dd, J ϭ 9.6, 3.0 Hz, 1 H, H2), 3.76
(dd, J ϭ 9.6, 3.4 Hz, 1 H, H5), 3.72 (m, 2 H, H6aЈ and H6bЈ), 3.67
(t, J ϭ 9.6 Hz, 1 H, H3), 3.61 (t, J ϭ 9.6 Hz, 1 H, H4), 3.21 (dd,
J ϭ 10.7, 3.6 Hz, 1 H, H2Ј) ppm. 13C NMR (125 MHz, D2O): δ ϭ
94.2, 74.7, 72.2, 70.9, 70.8, 70.7, 69.9, 68.5, 67.9, 67.0, 60.5, and
50.2 ppm. C12H23O10N (341.310): calcd. C 42.22, H 6.79, N 4.10;
found C 42.35, H 6.73, N 4.15. MALDI-TOF-MS: calcd. for
3,4,6-Tri-O-acetyl-2-azido-2-deoxy-
3,4,5,6-tetra-O-benzyl- -chiro-inositol (15b) and 3,4,6-Tri-O-acetyl-
2-azido-2-deoxy- -galactopyranosyl-β(1Ǟ2)-3,4,5,6-tetra-O-benzyl-
-chiro-inositol (16b): These pseudodisaccharides were prepared
D-galactopyranosyl-α(1Ǟ2)-
D
D
D
from 4b (50 mg, 0.105 mmol) and 14 (56 mg, 0.105 mmol) using
the procedure described for the preparation of 5, by adding a solu-
tion (108 µL, 0.12 equiv.) of TMSOTf (100 µL in 5 mL of ether)
in four portions (one per hour) at Ϫ40 °C. After 4 h the reaction
mixture was quenched with Et3N, concentrated and purified by
flash chromatography (toluene/acetone, 30:1) to yield of 15b [C12H23O10N ϩ Na]ϩ, 364.0; found, 365.0.
(59 mg, 66%) and of 16b (3 mg, 4%). Data for 15b: [α]2D0 ϭ ϩ71
1
2-Azido-3,4,6-tri-O-benzyl-2-deoxy-
3,4,5,6-tetra-O-benzyl- -chiro-inositol (15a) and 2-Azido-3,4,6-tri-O-
benzyl-2-deoxy- -galactopyranosyl-β(1Ǟ2)-3,4,5,6-tetra-O-benzyl-D-
D-galactopyranosyl-α(1Ǟ2)-
(c ϭ 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ 7.4Ϫ7.2 (m,
20 H, 4 Ph), 5.27 (dd, J ϭ 10.8, 3.25 Hz, 1 H, H3Ј), 5.11 (br. d,
J ϭ 2.25 Hz, 1 H, H4Ј), 5.05Ϫ4.57 (m, 8 H, AB), 4.9 (d, J ϭ 3.6 Hz,
1 H, H1Ј), 4.15 (t, J ϭ 6.5 Hz, 1 H, H5Ј), 4.1Ϫ3.9 (m, 5 H), 3.85
(dd, J ϭ 10.8, 7.2 Hz, 1 H, H2Ј), 3.77 (dd, J ϭ 11, 6.5 Hz, 1 H,
H6aЈ), 3.76 (m, 1 H), 3.68 (dd, J ϭ 11, 6.5 Hz, 1 H, H6bЈ), 2.15 (s,
3 H, CH3), 2.1 (s, 3 H, CH3), 1.85 (s, 3 H, CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 170.2 (CO), 169.9 (CO), 169.7 (CO), 138.7
(C), 138.65 (C), 138.6 (C), 138.4 (C), 128Ϫ127.6 (12 CH), 94.2
(CH), 81.7, 80.2, 80.1, 76.0, 75.7, 75.6, 73.9, 73.4, 69.6, 67.4, 66.7,
66.5, 66.4, 61.1, 58.4, 20.8 (CH3), 20.65 (CH3), 20.6 (CH3) ppm.
C46H51O13N3 (853.917): calcd. C 64.70, H 6.02, N 4.92; found C
64.73, H 6.07, N 5.05. MALDI-TOF-MS: calcd. for [C46H51O13N3
ϩ Na]ϩ, 876.8; found, 875.9. Data for 16b: 1H NMR (500 MHz,
C6D6): 7.70Ϫ7.01 (m, 20 H, 4 Ph), 5.39 (br. d, J ϭ 3.3 Hz, 1 H,
H4Ј), 5.20 and 5.09 (m, 2 H, AB), 5.15 and 5.0 (m, 2 H, AB), 4.90
and 4.60 (m, 2 H, AB), 4.9 (dd, J ϭ 10.7, 3.3 Hz, 1 H, H3Ј), 4.67
and 4.54 (m, 2 H, AB), 4.56 (d, J ϭ 8.1 Hz, 1 H, H1Ј), 4.39Ϫ4.33
(m, 2 H, H4 and H2), 4.25 (m, 1 H, H1), 4.21Ϫ4.16 (m, 2 H, H3
and H5), 4.11Ϫ4.01 (m, 3 H, H6aЈ, H6bЈ and H6), 3.98 (dd, J ϭ
10.7, 8.1 Hz, 1 H, H2Ј), 3.00 (br. t, J ϭ 5.7 Hz, 1 H, H5Ј), 2.03 (br.
s, 1 H, C1-OH), 1.77 (s, 3 H, CH3), 1.72 (s, 3 H, CH3), 1.78 (s, 3
H, CH3) ppm. C46H51O13N3 (853.917): calcd. C 64.70, H 6.02, N
4.92; found C 64.58, H 5.93, N 4.82.
D
D
chiro-inositol (16a): These pseudodisaccharides were prepared from
4a (57 mg, 0.09 mmol) and 14 (50 mg, 0.09 mmol) using the pro-
cedure described for the preparation of 5, adding TMSOTf [0.06
equiv.; 48 µL of a solution of TMSOTf (100 µL) in ether (100 mL)]
in three portions (one per half hour) at Ϫ40 °C. The reaction was
quenched with Et3N after 2 h from the initial addition to yield 15a
(36 mg, 40%) and 16a (16 mg, 18%) after flash chromatography
(toluene/acetone, 30:1). Data for 15a: [α]2D0 ϭ ϩ57 (cϭ 0.7,
CHCl3).1H NMR (500 MHz, CDCl3): δ ϭ 7.40Ϫ7.20 (m, 35 H, 7
Ph), 4.93Ϫ4.20 (m, 14 H, AB), 4.86 (d, J ϭ 3.8 Hz, 1 H, H1Ј), 4.11
(m, 1 H, H5Ј), 4.03 (dd, J ϭ 10.1, 3.8 Hz, 1 H, H2Ј), 4.02 (br. s, 1
H, H1), 4.0Ϫ3.96 (m, 3 H, H3, H5, H6), 3.91 (dd, J ϭ 9.7, 2.7 Hz,
1 H, H2), 3.88 (br. d, 1 H, J ϭ 2.6 Hz, H4Ј), 3.81 (dd, J ϭ 10.2,
2.6 Hz, 1 H, H3Ј), 3.75 (t, J ϭ 9.0 Hz, 1 H, H4), 3.50 (t, J ϭ 8.8 Hz,
1 H, H6aЈ), 3.42 (dd,1 H, J ϭ 8.8, 5.7 Hz, H6bЈ), 3.07 (s, 1 H, C1-
OH) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 139.2 (C), 138.9 (C),
138.7 (C), 138.7 (C), 138.3 (C), 137.7 (2 C), 128.8Ϫ127.6 (21 CH),
94.9 (CH), 81.8 (CH), 80.6 (CH), 80.3 (CH), 78.3 (CH), 77.5 (CH),
76.1 (CH), 76.0 (CH2), 75.8 (CH2), 75.1 (CH2), 74.1 (CH2), 73.6
(CH2), 73.5 (CH2), 73.3 (CH), 72.2 (CH2), 69.9 (CH), 68.3 (CH2),
66.6 (CH), 61.0 (CH) ppm. HR-FABMS: calcd. for [C61H63O10N3
ϩ Na]ϩ, 1020.4411; found, 1020.4426. Data for 16a: [α]2D0 ϭ ϩ0.8
(CHCl3, cϭ 0.6). 1H NMR (500 MHz, CDCl3): δ ϭ 7.4Ϫ7.2 (m,
35 H, 7 Ph), 4.93Ϫ4.38 (m, 14 H, AB), 4.35 (d, J ϭ 8.0 Hz, 1 H,
H1Ј), 4.08 (br. t, J ϭ 3.3 Hz, 1 H, H1), 4.01 (dd, J ϭ 9.2, 3.3 Hz, 1
H, H2), 3.94 (t, J ϭ 9.2 Hz, 1 H, H4), 3.89Ϫ3.87 (m, 2 H, H5 and
H6), 3.86 (br. s, 1 H, H4Ј), 3.84 (t, J ϭ 9.2 Hz, 1 H, H3), 3.81 (dd,
J ϭ 10.4, 8.0 Hz, 1 H, H2Ј), 3.52 (dd, J ϭ 9.0, 7.3 Hz, 1 H, H6aЈ),
3.46 (dd, J ϭ 9.0, 5.7 Hz, 1 H, H6bЈ), 3.42 (m, 1 H, H5Ј), 3.29 (dd,
J ϭ 10.4, 2.7 Hz, 1 H, H3Ј), 2.55 (s, 1 H, C1-OH) ppm. 13C NMR
2-Amino-2-deoxy-
D-galactopyranosyl-α(1Ǟ2)-3,4,5,6-tetra-O-
benzyl- -chiro-inositol (17): A solution of 15b (27 mg, 0.031 mmol)
D
in MeOH/THF (10:1, 2.2 mL) was treated under argon with solu-
tion of MeONa in MeOH (1 , 0.4 mL). After 15 min at room
temperature, the reaction was neutralized with acidic IR-120 resin
to pH ϭ 7, filtered, concentrated, and purified by flash chromatog-
raphy (Hex/EtOAc, 1:2) to yield 17 (20 mg, 88%). [α]2D0 ϭ ϩ53 (c ϭ
1
0.9, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ 7.40Ϫ7.20 (m, 20
H, 4 Ph), 5.03Ϫ4.45 (m, 8 H, AB), 4.80 (d, J ϭ 2.3 Hz, 1 H, H1Ј), (125 MHz, CDCl3): δ ϭ 139.3 (C), 139.2 (C), 139.1 (C), 138.9 (C),
3.97 (m, 3 H, H1, H6 and H3 or H4), 3.86 (m, 2 H, H2 and H5),
3.79 (dd, J ϭ 9.7, 2.1 Hz, 1 H, H3Ј), 3.75Ϫ3.65 (m, 3 H, H4 or H3, 82.0 (CH), 81.7 (CH), 81.3 (CH), 81.0 (CH), 80.2 (CH), 76.5 (CH),
138.4 (C), 138.0 (C), 137.7 (C), 128.9Ϫ127.7 (21 CH), 102.6 (C),
3512
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3505Ϫ3514

Synthesis of New Hexosaminyl D- and L-chiro-Inositols
FULL PAPER
76.1 (CH2), 75.1 (CH2), 73.8 (2 CH2), 73.7 (CH), 73.7 (CH2), 73.5 0.120 mmol) using the procedure described for the preparation of
(CH2), 72.8 (CH2), 72.2 (CH), 69.8 (CH), 68.6 (CH2), 63.7 (CH) 5, adding TMSOTf [0.04 equiv.; 42 µL of a solution of TMSOTf
ppm. HR-FABMS: calcd. for [C61H63O10N3 ϩ Na]ϩ, 1020.4411;
found, 1020.4421.
(100 µL) in ether (5 mL)] at Ϫ40 °C in two portions (one per hour).
The reaction mixture was warmed to room temperature and then
stirred for 4 h to yield of 18 (40 mg, 33%) and a mixture of three
pseudodisaccharides (18 mg, 19%) after flash chromatography
2-Azido-3,4,6-tri-O-acetyl-2-deoxy-
3,4,5,6-tetra-O-benzyl- -chiro-inositol (19) and 2-Azido-3,4,6-tri-O-
acetyl-2-deoxy- -glucopyranosyl-α(1Ǟ1)-3,4,5,6-tetra-O-benzyl-
D-glucopyranosyl-α(1Ǟ2)-
D
(toluene/acetone, 30:1). Data for pseudodisaccharide 18: [α]2D0
ϭ
D
D-
ϩ43.0 (c ϭ 0.7, CHCl3). 1H NMR (500 MHz, CDCl3): δ ϭ
7.40Ϫ7.10 (m, 35 H, 7 Ph), 4.97Ϫ4.8 (m, 7 H, AB and H1Ј),
4.75Ϫ4.56 (m, 5 H, AB), 4.51 (d, J ϭ 13 Hz, 1 H, AB), 4.48 (d,
J ϭ 13 Hz, 1 H, AB), 4.43 (d, J ϭ 11 Hz, 1 H, AB), 4.02Ϫ3.87 (m,
7 H, H5Ј, H3Ј, H1, H2, H3 or H4, H5, H6), 3.76Ϫ3.69 (m, 2 H, H4
or H3 and H4Ј), 3.57Ϫ3.52 (dd, J ϭ 10, 3.2 Hz, 1 H, H2Ј), 3.30 (d,
chiro-inositol (20): These pseudodisaccharides were prepared from
3b (40 mg, 0.84 mmol) and 14 (45 mg, 0.84 mmol) using the pro-
cedure described for the preparation of 5, adding TMSOTf [0.14
equiv.; 108 µL of a solution of TMSOTf (100 µL) in ether (5 mL)]
at Ϫ40 °C in four portions (one per hour). After an additional 3 h
at room temperature, the reaction was quenched by adding Et3N
to yield, after flash chromatography (toluene/acetone, 30:1), mix-
ture of pseudodisaccharides α-(1Ǟ2) 19 and α-(1Ǟ1) 20 that could
not be separated (45 mg, 63%; 93:7). Data for 19: 1H NMR
(500 MHz, CDCl3): δ ϭ 7.40Ϫ7.20 (m, 20 H, 4 Ph), 5.40 (t, J ϭ
9.8 Hz, 1 H, H3Ј), 5.05Ϫ4.57 (m, 8 H, AB), 4.93 (t, J ϭ 9.8 Hz, 1
H, H4Ј), 4.86 (d, J ϭ 3.7 Hz, 1 H, H1Ј), 4.08 (m, 1 H, H5Ј),
4.02Ϫ3.89 (m, 5 H, H1, H2, H5, H6, and H3 or H4), 3.76 (t, J ϭ
9.4 Hz, 1 H, H3 or H4), 3.72 (dd, J ϭ 12.8, 2.9 Hz, 1 H, H6aЈ), 3.65
(dd, J ϭ 12.8, 1.6 Hz, 1 H, H6bЈ), 3.62 (dd, J ϭ 10, 3.7 Hz, 1 H,
J ϭ 11.0 Hz, 1 H, H6aЈ), 3.22 (d, J ϭ 11.0 Hz, 1 H, H6bЈ) ppm. 13
C
NMR (125 MHz, CDCl3): δ ϭ 138.85 (C), 138.65 (C), 138.45 (C),
138.4 (C), 138.25 (C), 137.8 (C), 137.7 (C), 128.5Ϫ127.4 (14 CH2,
7 CH), 94.2 (C1Ј), 81.6 (CH), 81.2 (CH), 80.15 (2 CH), 78.1 (CH),
77.9 (CH), 75.9 (CH2), 75.8 (CH2), 75.7 (CH), 75.6 (CH2), 74.7
(CH2), 73.8 (CH2), 73.4 (CH2), 73.3 (CH2), 70.9 (CH), 67.5(CH2),
66.45 (CH), 64.0 (CH) ppm. C61H63O10N3 (998.179): calcd. C
73.40, H 6.36, N 4.20; found C 73.33, H 6.26, N 4.33.
2-Amino-2-deoxy-D-glucopyranosyl-α(1Ǟ2)-D-chiro-inositol (XIV):
H2Ј), 2.10 (s, 3 H, CH3), 2.00 (s, 3 H, CH3), 1.90 (s, 3 H, CH3) The fully deprotected pseudodisaccharide XIV was obtained fol-
ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 170.4 (CO), 169.9 (CO), lowing the same experimental procedure as that describe for ob-
169.6 (CO), 138.7 (C), 138.6 (C), 138.5 (C), 138.4 (C), 128.4Ϫ127.3 taining XV starting from 19 (14 mg, 0.019 mmol) to yield XIV
(12 CH), 93.9 (CH), 81.6 (CH), 80.1 (CH), 79.8 (CH), 77.5 (CH), (6.5 mg, quantitative) or starting from 18 (23 mg, 0.023 mmol) to
1
75.7 (CH2), 75.6 (CH2), 75.5 (CH), 73.9 (CH2), 73.4 (CH2), 71.9 give XIV (7.3 mg, 93%). [α]2D0 ϭ ϩ80 (c ϭ 0.2, MeOH). H NMR
(CH), 67.7 (CH), 67.6 (CH), 66.5 (CH), 61.7 (CH), 60.9 (CH2), (500 MHz, D2O): δ ϭ 5.05 (d, J ϭ 3.5 Hz, 1 H, H1Ј), 4.19 (t, J ϭ
20.7 (CH3), 20.6 (CH3), 20.5 (CH3) ppm. C46H51O13N3 (853.917): 3.5 Hz, 1 H, H1), 4.02 (t, J ϭ 3.5 Hz, 1 H, H6), 3.98Ϫ3.93 (m, 1
calcd. C 64.70, H 6.02, N 4.92; found C 64.85, H 6.12, N 4.81.
H, H5Ј), 3.80 (m, 1 H, H2), 3.77 (m, 2 H, H6aЈ and H6bЈ), 3.75 (m,
Some of the most representative signals of the α(1Ǟ1)-pseudodi- 1 H, H5), 3.67 (t, J ϭ 9.6 Hz, 1 H, H3Ј), 3.66 (t, J ϭ 9.4 Hz, 1 H,
saccharide 20: 1H NMR (500 MHz, CDCl3): δ ϭ 5.29 (t, J ϭ H3), 3.59 (t, J ϭ 9.4 Hz, 1 H, H4), 3.43 (t, J ϭ 9.6 Hz, 1 H, H4Ј),
9.8 Hz, 1 H, H3Ј), 4.27 (m, 1 H, H5Ј), 3.46 (dd, J ϭ 10.0, 3.5 Hz, 1 2.84 (dd, J ϭ 10.2, 3.5 Hz, 1 H, H2Ј) ppm. 13C NMR (125 MHz,
H, H2Ј) ppm. Data for the 93:7 mixture of pseudodisaccharides α-
D2O): δ ϭ 95.3, 75.0, 72.8, 72.3, 71.7, 70.9, 70.8, 69.9, 69.2, 67.3,
(1Ǟ2) 19 and α-(1Ǟ1) 20: [α]2D0 ϭ ϩ81 (c ϭ 0.6, CHCl3). MALDI- 59.9, 54.3 ppm. C12H23O10N (341.310): calcd. C 42.22, H 6.79, N
TOF-MS: calcd. for [C46H51O13N3 ϩ Na]ϩ, 876.5; found, 877.8.
2-Azido-2-deoxy- -glucopyranosyl-α(1Ǟ2)-3,4,5,6-tetra-O-benzyl-D-
4.10; found C 42.09, H 6.65, N 4.18. MALDI-TOF-MS: calcd. for
[C12H23O10N ϩ Na]ϩ, 364.0; found, 364.9.
D
chiro-inositol (24): Compound 24 was obtained from a 93:7 mixture
of 19 and 20 (34 mg, 0.039 mmol) following the same experimental α(1Ǟ2)-3,4,5,6-tetra-O-benzyl-
procedure as that described for the preparation of 17 to yield, after
flash chromatography (Hex/EtOAc, 1:2), pure 24 (18 mg, 63%) and
2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-
-chiro-inositol (21), 2-Azido-3-O-
benzyl-4,6-O-benzylidene-2-deoxy- -glucopyranosyl-β(1Ǟ2)-3,4,5,6-
tetra-O-benzyl- -chiro-inositol (22), and 2-Azido-3-O-benzyl-4,6-O-
-glucopyranosyl-α(1Ǟ1)-3,4,5,6-tetra-O-
-chiro-inositol (23): These pseudodisaccharides were pre-
NMR (500 MHz, CDCl3): δ ϭ 7.40Ϫ7.20 (m, 20 H, 4 Ph), pared from 3c (31 mg, 0.06 mmol) and 14 (32 mg, 0.06 mmol) using
5.0Ϫ4.56 (m, 8 H, AB), 4.75 (d, J ϭ 3.7 Hz, 1 H, H1Ј), 4.02Ϫ3.95
the procedure described for the preparation of 15b, adding
D-glucopyranosyl-
D
D
D
a mixture of 15 and the deprotected α(1Ǟ1)-disaccharide of 20 benzylidene-2-deoxy-
D
(75:25; 7 mg, 25%). Data for 24: [α]2D0 ϭ ϩ42 (c ϭ 0.9, CHCl3). 1H
benzyl-
D
(m, 3 H, H1, H6, H3 or H4), 3.94Ϫ3.87 (m, 2 H, H2, H5), 3.84 (t, TMSOTf (0.12 equiv.) in five portions (one per half hour) at Ϫ40
J ϭ 9.4 Hz, 1 H, H3Ј), 3.72 (t, J ϭ 9.3 Hz, 1 H, H3 or H4), 3.62 °C. After 3 h from the initial addition, the reaction was quenched
(dt, J ϭ 9.7, 3.1 Hz, 1 H, H5Ј), 3.45 (t, J ϭ 9.4 Hz, 1 H, H4Ј), 3.37 with Et3N to yield, after flash chromatography (toluene/acetone,
(m, 3 H, H2Ј, H6aЈ, H6bЈ) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 30:1), 21 (28 mg, 52%), of 22 (4 mg, 7%) and of 23 (4 mg, 7%).
138.8 (C), 138.6 (C), 138.5 (C), 138.4 (C), 128.5Ϫ127.5 (12 CH),
Data for 21: [α]2D0 ϭ ϩ11.0 (c ϭ 0.5, CHCl3). 1H NMR (500 MHz,
94.7 (CH), 81.6 (CH), 80.2 (CH), 80.1 (CH), 77.9 (CH), 75.9 (CH2),
75.8 (CH), 75.5 (CH2), 73.9 (CH2), 73.3 (CH2), 73.2 (CH), 71.0
(CH), 70.9 (CH), 66.7 (CH), 63.7 (CH), 61.6 (CH2) ppm.
C40H45O10N3 (727.806): calcd. C 66.01, H 6.23, N 5.77; found C
C6D6): δ ϭ 7.60Ϫ7.10 (m, 30 H, 6Ph), 5.31 (s, 1 H, CHPh),
5.13Ϫ4.57 (m, 10 H, AB), 4.6 (d, J ϭ 3.3 Hz, 1 H, H1Ј), 4.34 (m,
2 H, H5Ј, H3 or H4), 4.25 (m, 2 H, H2 and H5), 4.19 (br. t, J ϭ 6.5,
3.5 Hz, 1 H, H6), 4.16 (br. t, J ϭ 6.7, 3.5 Hz, 1 H, H1), 4.14 (t, J ϭ
66.11, H 6.35, N 5.67. MALDI-TOF-MS: calcd. for [C40H45O10N3
9.5 Hz, 1 H, H3Ј), 4.08 (t, J ϭ 9.4 Hz, 1 H, H3 or H4), 4.0 (dd, J ϭ
ϩ Na]ϩ, 750.5; found, 750.3. Some of the most representative sig-
10.3, 5.0 Hz, 1 H, H6aЈ), 3.46 (t, J ϭ 9.5 Hz, 1 H, H4Ј), 3.37 (t, J ϭ
nals of the deprotected α(1Ǟ1)-pseudodisaccharide of 20: 4.62, (d,
10.3 Hz, 1 H, H6bЈ), 3.22 (dd, J ϭ 9.5, 3.3 Hz, 1 H, H2Ј) ppm. 13C
J ϭ 3.6 Hz, 1 H, H1Ј), 3.71 (dd, J ϭ 10.2, 9.3 Hz, 1 H, H3Ј), 3.23
NMR (125 MHz, CDCl3): δ ϭ 139.2 (C), 138.9 (C), 138.8 (C),
(dd, J ϭ 10.2, 3.6 Hz, 1 H, H2Ј) ppm.
138.4 (C), 137.9 (C), 137.7 (C), 129.3Ϫ126.4 (18 CH), 101.7 (CH),
2-Azido-3,4,6-tri-O-benzyl-2-deoxy-
3,4,5,6-tetra-O-benzyl- -chiro-inositol (18): This pseudodisacchar-
ide was prepared from 3a (74 mg, 0.120 mmol) and 14 (65 mg, (CH2), 73.6 (CH), 68.9 (CH2), 66.8 (CH), 64.0 (CH), 63.5 (CH)
D
-glucopyranosyl-α(1Ǟ2)- 95.2 (CH), 83.0 (CH), 81.9 (CH), 80.4 (CH), 80.1 (CH), 78.5 (CH),
D
76.3 (CH2), 76.2 (CH), 76.0 (CH2), 75.4 (CH2), 74.2 (CH2), 73.6
Eur. J. Org. Chem. 2003, 3505Ϫ3514
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3513

´
M. B. Cid, J. B. Bonilla, F. Alfonso, M. Martın-Lomas
FULL PAPER
ppm. C54H55O10N3 (906.039): calcd. C 71.58, H 6.11, N 4.63; found
C 71.69, H 6.11, N 4.58. HR-FAB MS: calcd. for [C54H55O10N3 ϩ
Na]ϩ, 928.3785; found, 928.3830.
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Received April 24, 2003
3514
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www.eurjoc.org
Eur. J. Org. Chem. 2003, 3505Ϫ3514