Synthesis of sulfonic acid analogues of the non-reducing end trisaccharide of the antithrombin binding domain of heparin

Article abstract of DOI:10.1016/j.tetlet.2010.10.042

Three sulfonic acid trisaccharides related to the antithrombin-binding DEFGH domain of heparin were synthesised. Trisaccharides carrying the sulfonatomethyl moiety at position 2 or 6 were prepared in high yields by [DE+F] couplings using the same disaccha

Full text of DOI:10.1016/j.tetlet.2010.10.042

Tetrahedron Letters 51 (2010) 6711–6714
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of sulfonic acid analogues of the non-reducing end trisaccharide
of the antithrombin binding domain of heparin
László Lázár a, Mihály Herczeg a, Anikó Fekete a, Anikó Borbás a, , András Lipták a, Sándor Antus a,b
⇑
a Research Group for Carbohydrates of the Hungarian Academy of Sciences, H-4010 Debrecen, PO Box 94, Hungary
b Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 20, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Three sulfonic acid trisaccharides related to the antithrombin-binding DEFGH domain of heparin were
synthesised. Trisaccharides carrying the sulfonatomethyl moiety at position 2 or 6 were prepared in high
yields by [DE+F] couplings using the same disaccharide uronate donor and the appropriate sulfonic acid
acceptor, respectively. The trisaccharide with a 3-deoxy-3-sulfonatomethyl function could be obtained
with high efficacy by a [D+EF] coupling where the carboxylic function of the EF uronate acceptor was cre-
ated at a disaccharide level.
Received 10 August 2010
Revised 28 September 2010
Accepted 8 October 2010
Available online 21 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Heparin is a well-known member of the glycosaminoglycans
and plays a crucial role in maintaining the haemostatic state of
blood through interaction with antithrombin III (AT-III), a serine
protease inhibitor that blocks thrombin and factor Xa in the
coagulation cascade.1 Heparin has been used clinically as an anti-
coagulant for more than seven decades.2 Despite its usefulness,
heparin-based therapy also leads to adverse effects including
bleeding complications and heparin-induced thrombocytopenia
(HIT).3
The isolation and structural elucidation of the antithrombin-
binding pentasaccharide domain of heparin2,4 led to the develop-
ment of fondaparinux (1), the first synthetic antithrombotic drug,
marketed in 2001 in Europe and in the USA under the name
Arixtra.5 Fondaparinux selectively inhibits factor Xa, minimises
the risk factors in anticoagulant therapy and, compared to heparin
and low molecular-weight heparin, it has a longer duration of
action (Fig. 1).
and phosphonate analogues of mannose-6-phosphate proved to
be highly active towards mannose-6-phosphate receptors.7–9
Therefore, we decided to prepare sulfonatomethyl-containing
analogues of the heparin pentasaccharide by systematic replace-
ment of the sulfate esters with a sodium sulfonatomethyl moiety.
Idraparinux (2) was chosen as a reference compound, since it has
increased anticoagulant activity and, having a non-glycosamino-
glycan-type structure, it is much easier to synthesize compared
to fondaparinux.10,11 We have previously reported the synthesis
of sulfonatomethyl analogues of the EF and GH fragments of
compound 2.12
Here, we present the synthesis of the trisaccharide sulfonic acid
analogues of the DEF fragment of idraparinux (2).
By retrosynthetic analysis, application of the common DE
disaccharide as donor (6) and the three sulfonic acid containing
D
E
F
G
H
Structure–activity relationship studies on a series of synthetic
analogues of heparin pentasaccharide revealed that the type of
negatively charged groups is crucial, the carboxylate groups may
not be exchanged for sulfate esters, and an essential sulfate moiety
cannot be exchanged for a phosphate without affecting the activ-
ity.6 However, replacement of the sulfate group with an isosteric
sulfonatomethyl moiety has not been investigated until now. We
envisaged that isosteric sulfonate analogues of the AT-III binding
pentasaccharide of heparin might provide further information on
structure–activity relationships and might afford bioactive
derivatives. It is interesting to note that the isosteric sulfonate
-
OSO3
O
-
-
OSO3
OSO3
O
OH
O
O
-OOC
COO-
O
HO
-O3SHN
HO
O
OMe
O
HO
O
-O3SO
O
-O3SHN
HO
-O3SO
-O3SHN
HO
1
-
OSO3
O
-
-
OSO3
O
OSO3
O
O
OMe
O
-OOC
-O3SO-
COO-
MeO
O
OMe
O3SO
O
-O3SO
O
MeO
MeO
O
MeO
MeO
-O3SO
MeO
2
⇑
Corresponding author. Tel.: +36 52 512 900/22462; fax: +36 52 512 900/22342.
E-mail address: borbasa@puma.unideb.hu (A. Borbás).
Figure 1. Structures of the synthetic antithrombotic drug fondaparinux (1) and the
non-glycosaminoglycan anticoagulant idraparinux (2).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.042

6712
L. Lázár et al. / Tetrahedron Letters 51 (2010) 6711–6714
D
E
F
OBn
O
-
OSO3
MeO
MeO
O
R3
O
COOMe
O
i
ii, iii
COO-
MeO
MeO
MeO
6
10 + 11
MeO
O
O
O
O
MeO
R2
MeO
R1
OMe
AcO
MeO
OAc
16
3 R1= CH2SO3-,R2=R3=OSO3
-
4 R2= CH2SO3-, R1=R3=OSO3-
-
Scheme 2. Formation of the disaccharide uronate donor 6. Reagents and condi-
tions: (i) NIS, AgOTf, CH2Cl2, 4 Å MS, ꢀ45 °C, 1 h (72%, + 4% b-coupled disaccharide);
(ii) THF, BnNH2, rt, 5 h (92%); (iii) CH2Cl2, CCl3CN, DBU, 0 °C, 30 min (85%).
5 R3= CH2SO3-, R1=R2=OSO3
OBn
O
F
D
E
The synthesis of the methylsulfonatomethyl-containing accep-
tors 7–9 was described recently,12 the key step in their preparation
being the stereoselective addition of a hydrogensulfite radical an-
ion onto the exomethylene moiety of the appropriate glycoside
derivatives.14
MeO
MeO
R3
COOMe
O
HO
+
MeO
R2
O
O
O
MeO
CCl3
R1
OAc
OMe
NH
7 R1= CH2SO3Me
6
The non-reducing end building block 10 was prepared from
phenyl 1-thio-b-D-glucopyranoside (12) via a series of routine
R2=R3=OBn
8 R2= CH2SO3Me
R1=R3=OBn
transformations (Scheme 1). Tritylation and methylation followed
by detritylation of the starting compound resulted in 13,15 benzy-
lation of which gave the donor 10. Synthesis of the uronate
acceptor 11 started from the known 4,6-O-benzylidene-3-O-
9 R3= CH2SO3Me
R1=R2=OBn
OBn
COOMe
O
O
MeO
MeO
HO
methyl-D
-glucopyranose (14).16 Acetylation and subsequent deac-
SPh +
MeO
OMe
AcO
etalation of compound 14 afforded the 4,6-diol derivative 15. In or-
der to avoid protecting group manipulations to discriminate the
primary and secondary hydroxy groups of 15, TEMPO-based selec-
tive oxidation17 was applied using calcium hypochlorite as co-oxi-
dant.18 Oxidation afforded the intermediate glucuronate, which
after acidic work-up, was transformed into the methyl ester 11
by treatment with ethereal diazomethane. The product could be
OAc
11
10
Figure 2. Retrosynthetic analysis of compounds 3–5.
OH
O
OH
O
i - iii
iv
HO
HO
MeO
MeO
isolated in pure
a-anomeric form by chromatographic purification.
SPh
SPh
10
11
Glycosylation of uronate acceptor 11 with phenylthioglucoside
OH
12
OMe
13
10 in the presence of NIS and AgOTf at ꢀ45 °C gave the desired
a-
coupled disaccharide 16 in 72% yield, and the stereoisomeric disac-
charide with a b-interglycosidic linkage was formed in a yield of
only 4%. Selective deacetylation of the anomeric position with ben-
zylamine and preparation of the corresponding imidate with tri-
chloroacetonitrile and DBU afforded disaccharide donor 6 in 85%
yield (Scheme 2).19
OH
O
O
Ph
vii-viii
O
v-vi
O
HO
MeO
MeO
OAc
OH
OH
OAc
15 (α : β=16:1)
14
Glycosylation of the 2-deoxy-2-methylsulfonatomethyl accep-
tor 7 with disaccharide imidate 6 upon trimethylsilyl triflate acti-
vation afforded trisaccharide 17, isolated exclusively in the b-
coupled form due to the presence of the 2-O-acetyl participating
group of the donor. The fully protected trisaccharide was deacety-
lated under Zemplén conditions to liberate the 20-OH group. Treat-
ment of the 20-hydroxy derivative with methyl iodide and sodium
hydride afforded the 20-O-methyl ether in high yield. In addition,
transformation of the sulfonic acid methyl ester into a sodium sul-
fonate moiety also occurred as a result of nucleophilic attack of the
in situ formed sodium iodide. Next, the uronic ester was hydroly-
sed with sodium hydroxide to give the sodium uronate. Subse-
quent catalytic hydrogenation followed by O-sulfation afforded
trisaccharide 3, as the first isosteric sulfonatomethyl analogue of
Scheme 1. Synthesis of the monosaccharide building blocks. Reagents and condi-
tions: (i) TrCl, pyridine; (ii) MeI, NaH, DMF; (iii) 80% AcOH, 70 °C (80% over three
steps); (iv) BnBr, NaH in DMF (96%); (v) Ac2O, pyridine (93%); (vi) AcOH 80%, 70 °C
(88%); (vii) TEMPO, Ca(ClO)2, CH2Cl2, NaHCO3, KBr, Bu4NBr; (viii) CH2N2 (Et2O), THF
(59%).
monosaccharides as the acceptors 7–9 seemed to be the most
efficient procedure for the preparation of the planned trisaccha-
rides 3–5 (Fig. 2). The carboxylic acid function of unit E could be
elaborated either at the disaccharide or the monosaccharide
level.13 The latter route was chosen since we assumed that the rel-
atively inactive uronate acceptor 11 may increase the
during formation of the interglycosidic bond of 6.
a-selectivity
-
OBn
O
OSO3
O
MeO
MeO
MeO
MeO
R2
O
COO-
COOMe
O
R2
O
R2
O
i
ii - vi
HO
MeO
MeO
O
6
+
O
O
BnO
O
O
MeO
MeO
R1
BnO
-O3SO
MeO
OMe
OAc
R1
OMe
R1
OMe
17 R1= CH2SO3Me, R2=OBn
18 R2= CH2SO3Me, R1=OBn
7 R1= CH2SO3Me, R2=OBn
9 R2= CH2SO3Me, R1=OBn
3 R1= CH2SO3-,R2=OSO3
-
5 R2= CH2SO3-, R1=OSO3
-
Scheme 3. Construction of trisaccharide sulfonic acids 3 and 5. Reagents and conditions: (i) TMSOTf, CH2Cl2, 4 Å MS, ꢀ30 °C to rt, 12 h (67% for 17, 54% for 18); (ii) MeOH,
MeONa (80% from 17, 88% from 18); (iii) NaH, MeI, DMF (90% for 17, 89% for 18); (iv) 0.1 M NaOH, MeOH (92% for 17, 92% for 18); (v) H2, Pd/C (10%); (vi) SO3ꢁpy, DMF (71% for
3 over two steps, 75% for 5 over two steps).

L. Lázár et al. / Tetrahedron Letters 51 (2010) 6711–6714
6713
OBn
O
24. Methylation of the two liberated hydroxy groups and conver-
sion of the uronic ester into sodium uronate followed by catalytic
hydrogenolysis and subsequent O-sulfation afforded the target tri-
saccharide 4 possessing the sulfonatomethyl moiety at position 3.
Methylation of diol 24 proved to be the crucial step of this reaction
path since b-elimination at the uronic acid residue also occurred. It
is interesting to note, that the former reaction path required the
introduction of only one methyl ether and did not give rise to
elimination. Nevertheless, despite the moderate yield of the meth-
ylation step, this reaction route resulted in a significant improve-
ment in the yield of compound 4, due to the high yielding
glycosylations as well as the avoidance of the laborious synthesis
of the glucuronic acceptor 11. The overall yield of 4 via this route
from 10 and 22 was 29% (Scheme 6).
MeO
MeO
COOMe
O
MeO
ii - vi
O
i
OBn
O
from 19β
6 + 8
MeO
4
O
AcO
MeO3S
BnO
OMe
19α,β
Scheme 4. Construction of trisaccharide 4 using uronate donor 6. Reagents and
conditions: (i) CH2Cl2, 4 Å MS, TMSOTf, ꢀ30 °C to rt, 12 h (80% for the 1:1 mixture of
the a- and the b-coupled product, 30% for 19b); from 19b: (ii) MeOH, MeONa (71%);
(iii) NaH, MeI, DMF (82%); (iv) 0.1 M NaOH, MeOH (97%); (v) H2, Pd/C (10%); (vi)
SO3ꢁpy, DMF (81% over two steps).
In summary, three methanesulfonic acid trisaccharides as bio-
isosteric analogues of the DEF trisaccharide fragment of the fully
O-sulfated, O-methylated non-glycosaminoglycan anticoagulant,
idraparinux were synthesised.21 A synthetic strategy based upon
a [DE+F] coupling utilising a common disaccharide uronate donor
proved to be very efficient to obtain the 2-sulfonatomethyl and
6-sulfonatomethyl derivatives. However, this method proved inef-
ficient in the case of the 3-sulfonatomethyl-containing analogue 4
due to steric hindrance between the carboxylate group of the do-
nor and the sulfonate moiety of the acceptor next to the glycosyl-
ation position. An improved synthesis of this trisaccharide was
carried out by construction of an EF disaccharide applying a glu-
cose donor and post-glycosidation oxidation. Biological investiga-
tion of the trisaccharides obtained as well as exploitation of the
results for the synthesis of pentasaccharide sulfonic acid analogues
are in progress.
the DEF fragment of idraparinux. Synthesis of trisaccharide 5 was
accomplished analogously, starting from acceptor 9 and donor 6
(Scheme 3).
Preparation of the third trisaccharide 4 was attempted in an
analogous fashion. However, glycosylation of acceptor 8 possessing
the sulfonatomethyl moiety at position 3 afforded the correspond-
ing trisaccharide as a 1:1 mixture of the
ucts; the targeted b-coupled trisaccharide could only be isolated
in a yield of 30%. The unexpected formation of the -linkage can
a- and b-coupled prod-
a
occur as a result of steric hindrance between the carboxylic moiety
of the donor and the sulfonate group of the acceptor, both situated
on the b-side. Although the subsequent transformations leading to
trisaccharide 4 took place smoothly and with high yields, the over-
all yield of the synthesis outlined in Scheme 4 was only 14%.
In order to improve the yield of the desired trisaccharide 4 an-
other synthetic route involving a reverse sequence of glycosyla-
tions and oxidation to a carboxylate at a disaccharide level was
elaborated. Compound 20, prepared from 12 in two steps, was used
as a donor to glycosylate acceptor 8 in the presence of the NIS-
AgOTf promoter system, with the b-coupled disaccharide 21 being
isolated exclusively. This reaction demonstrated that it was not the
3-sulfonatomethyl moiety per se, but the interaction between the
carboxylate and sulfonate moieties which influenced unfavourably
the glycosylation of 6 and 8. Deacetalation of the fully protected 21
followed by TEMPO-catalysed selective oxidation using [bis(acet-
oxy)iodo]benzene (BAIB) as co-oxidant20 and subsequent methyl
esterification afforded uronate acceptor 22 (Scheme 5).
Acknowledgement
This work was supported by the Hungarian Research Fund (K
62802 to A.B.).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.042.
Glycosylation of acceptor 22 with thioglycoside donor 10 gave
rise to the exclusive formation of the desired trisaccharide 23 in
high yield. Removal of the O-acetyl groups of 23 resulted in the diol
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OBn
O
OBn
O
+ 8
iii
PMB
PMB
O
O
O
HO
O
O
O
O
O
O
i-ii
iv-vi
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AcO
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21
22
Scheme 5. Formation of the uronate donor 22 by post-glycosidation oxidation. Reagents and conditions: (i) 4-methoxybenzaldehyde dimethyl acetal, p-toluenesulfonic acid,
CH3CN, reflux (82%); (ii) Ac2O, pyridine (94%); (iii) NIS, AgOTf, CH2Cl2, 4 Å MS, ꢀ20 °C to rt, 1 h (68%); (iv) 80% AcOH, rt, 1 h (81%); (v) BAIB, TEMPO, CH2Cl2, H2O, 1 h; (vi)
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OSO3
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-
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O
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i
iii-vi
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-O3SO
BnO
-O3S
OR
23 R = Ac
24 R = H
MeO
OMe
OMe
SO3Me
ii
4
Scheme 6. Improved synthesis of trisaccharide sulfonic acid 4. Reagents and conditions: (i) NIS, AgOTf, CH2Cl2, 4 Å MS, ꢀ45 °C to ꢀ35 °C, 1 h (84%); (ii) MeOH, MeONa (87%);
(iii) NaH, MeI, DMF (49%); (iv) 0.1 M NaOH, MeOH (97%); (v) H2, Pd/C (10%); (vi) SO3ꢁpy, DMF (81% over two steps).

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(d, 1H, J6a
= 10.8 Hz, H-600a), 4.13 (d, 1H, H-600b), 4.05 (m, 1H, H-5), 3.93 (t,
0 0,6b0 0
1H, J = 9.3 Hz, H-4), 3.90 (t, 1H, J = 9.6 Hz, H-40), 3.87 (t, 1H, J = 9.3 Hz, H-500),
3.72 (d, 1H, J4 ,5 = 9.8 Hz, H-50), 3.63, 3.62, 3.60, 3.58, 3.56 (5 ꢂ s, 15H,
5 ꢂ OCH3), 3.53 (m, 2H, H-300, H-30), 3.43 (m, 1H, CH2aSO3ꢀ), 3.41 (s, 3H, OCH3),
3.32 (m, 2H, H-400, H-200), 3.26 (t, 1H, J = 9.6 Hz, H-20), 3.07, (dd, 1H,
Jgem = 12.8 Hz, JCH2b,2 = 3.2 Hz, CH2bSO3ꢀ), 2.42 (m, 1H, H-2); 13C NMR (D2O,
125 MHz): d 175.9 (CO), 102.1 (C-10), 99.4 (C-1), 96.9 (C-100), 86.6 (C-300), 83.9
(C-20), 82.8 (C-30), 81.4 (C-200), 79.0 (C-3), 78.0 (C-400), 77.8 (C-5), 75.3 (C-40),
74.8 (C-4), 70.5 (C-50), 69.6 (C-500), 67.2 (C-6), 66.9 (C-600), 61.2, 60.8, 60.3, 59.9,
56.2, (6 ꢂ OCH3), 48.8 (CH2SO3ꢀ), 43.6 (C-2); Anal. Calcd for C25H39Na5O28S4
(1030.77): C, 29.13; H, 3.81; S, 12.44. Found: C, 29.12; H, 3.82; S, 12.46.
0
0
Compound 4: [
670 cmꢀ1 1H NMR (D2O, 360 MHz): d 5.47 (d, 1H, J1
1H, J1,2 = 3.3 Hz, H-1), 4.59 (d, 1H, J1 ,2 = 7.8 Hz H-10), 4.41–4.26 (m, 4H, H-2, H-
6a,b, H-600a), 4.14 (d, 1H, J5 = 10.1 Hz, H-600b), 4.05 (m, 1H, H-5), 3.91 (t, 1H,
a
]D: +69.7 (c 0.07, H2O); IR mmax (KBr): 3448, 1632, 1219, 772,
= 3.6 Hz, H-100), 5.08 (d,
0 0 ,20 0
;
0
0
00 ,60 0
J = 9.3 Hz, H-40), 3.85 (d, 1H, J5
= 9.9 Hz, H-500), 3.82 (t, 1H, J = 9.5 Hz,
00 ,60 0
J = 10.3 Hz, H-4), 3.72 (d, 1H, J = 9.7 Hz, H-50), 3.63–3.45 (m, 21H, CH2aSO3ꢀ, H-
30, H-300, 6 ꢂ OCH3), 3.38–3.26 (m, 3H, H-20, H-200, H-400), 3.19 (dd, 1H,
JCH2b,3 = 3.9 Hz, Jgem = 14.7 Hz, CH2bSO3ꢀ), 2.52 (m, 1H, H-3); 13C NMR (D2O,
90 MHz): d 175.2 (CO), 101.7 (C-10), 96.6 (C-1), 96.2 (C-100), 85.7 (C-30), 83.0 (C-
20), 82.0 (C-300), 80.5 (C-200), 78.1 (C-400), 76.9 (C-50), 75.9 (C-2), 74.6 (C-4), 74.4
(C-4), 70.2 (C-5), 68.9 (C-500), 66.4 (C-6), 66.2 (C-600), 60.6, 60.4, 60.1, 59.5, 59.1,
55.3 (6 ꢂ OCH3), 49.1 (CH2SO3ꢀ), 37.4 (C-3); Anal. Calcd for C25H39Na5O28S4,
(1030.77): C, 29.13; H, 3.81; S, 12.44. Found: C, 29.11; H, 3.80; S, 12.43.
Compound 5: [
673 cmꢀ1 1H NMR (D2O, 500 MHz): d 5.46 (d, 1H, J1
1H, J1,2 = 3.5 Hz, H-1), 4.68 (d, 1H, J1 ,2 = 7.7 Hz, H-10), 4.59, (t, 1H, J = 9.1 Hz, H-
3), 4.38 (dd, 1H, J1,2 = 3.5 Hz, J2,3 = 9.6 Hz, H-2), 4.27 (d, 1H, J5 = 10.3 Hz, H-
a
]D: +40.2 (c 0.08, H2O); IR mmax (KBr): 3450, 1634, 1219, 772,
= 3.4 Hz, H-100), 5.11 (d,
0 0 ,20 0
;
0
0
0 0 ,600
600a), 4.12 (d, 1H, J5
= 10.1 Hz, H-600b), 3.96 (t, 1H, J = 7.9 Hz, H-5), 3.92 (m,
0 0,60 0
1H, H-40), 3.87 (m, 1H, H-500), 3.80 (t, 1H, J = 9.3 Hz, H-4), 3.74 (d, 1H, J = 9.7 Hz,
H-50), 3.63 (s, 9H, 3 ꢂ OCH3), 3.58 (s, 3H, OCH3), 3.56 (s, 3H, OCH3), 3.62–3.50
(m, 2H, H-30, H-300), 3.45 (s, 3H, OCH3), 3.38–3.27 (m, 3H, H-400, H-200, H-20),
3.15 (m, 1H, H-7a), 3.03 (m, 1H, H-7b), 2.44 (m, 1H, H-6a), 1.99 (m, 1H, H-6b);
13C NMR (D2O, 125 MHz): d 175.9 (CO), 102.5 (C-10), 97.8 (C-1), 96.9 (C-100),
86.5 (C-30), 83.9 (C-20), 82.8 (C-300), 81.3 (C-200), 78.9 (C-400), 78.0 (C-4), 77.6 (C-
50), 77.1 (C-3), 76.2 (C-2), 75.1 (C-40), 70.4 (C-5), 69.6 (C-500), 66.9 (C-600), 61.2,
60.8, 60.3, 59.9, 56.2, (6 ꢂ OCH3), 48.1 (C-7), 27.1 (C-6); Anal. Calcd for
C25H39Na5O28S4 (1030.77): C, 29.13; H, 3.81; S, 12.44. Found: C, 29.16; H, 3.83;
S, 12.42.
20. van den Bos, L. J.; Codée, J. D. C.; van der Toorn, J. C.; Boltje, T. J.; van Boom, J. H.
J.; Overkleeft, H. S.; van der Marel, G. A. Org. Lett. 2004, 6, 2165–2168.
21. Selected analytical data of key compounds: Compound 3: [
IR mmax (KBr): 3455, 1635, 1219, 772, 673 cmꢀ1 1H NMR (D2O, 500 MHz): d
5.45 (d, 1H, J1
= 3.6 Hz, H-100), 5.17 (d, 1H, J1,2 = 3.1 Hz, H-1), 4.65 (d, 1H,
a]D: +5.2 (c 0.17, H2O);
;
0 0,20 0
J1 ,2 = 7.7 Hz, H-10), 4.41 (t, 1H, J2,3 = 9.0 Hz, 1H, H-3), 4.38 (m, 2H, H-6a,b), 4.28
0
0