Synthesis of L-iduronic acid derivatives via [3.2.1] and [2.2.2] L-iduronic lactones from bulk glucose-derived cyanohydrin hydrolysis: A reversible conformationally switched superdisarmed/rearmed lactone route to heparin disaccharides

Article abstract of DOI:10.1021/jo502776f

l-Idofuranoside cyanohydrin 1 is converted on large scale into a mixture of l-IdoA methyl pyranosides and furanosides, which is converged to provide short 2-step routes to bicyclic [3.2.1] or [2.2.2] l-iduronate lactones. The former is obtained via a 100

Full text of DOI:10.1021/jo502776f

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Article
Synthesis of L-iduronic acid derivatives via [3.2.1] and [2.2.2]
L-iduronic lactones from bulk glucose-derived cyanohydrin
hydrolysis: A reversible conformationally-switched super-
disarmed/re-armed lactone route to heparin disaccharides
Steen Uldall Hansen, Charlotte E Dalton, Marek Barath, Glenn Kwan, James
Raftery, Gordon Charles Jayson, Gavin John Miller, and John Michael Gardiner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502776f • Publication Date (Web): 03 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Synthesis of
L-iduronic acid derivatives via [3.2.1] and [2.2.2]
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L
-iduronic lactones from bulk glucose-derived cyanohydrin
hydrolysis: A reversible conformationally-switched super-
disarmed/re-armed lactone route to heparin disaccharides
Steen U. Hansen,a Charlotte E. Dalton,a Marek Baráth,¶a Glenn Kwan,a James Raftery,b Gordon C. Jayꢀ
son,c Gavin J. Millera and John M. Gardinera*
aManchester Institute of Biotechnology and the School of Chemistry, 131 Princess Street, The University of Manchester,
Manchester M1 7DN, UK
bThe School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
cInstitute of Cancer Sciences, Christie Hospital and University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
* Eꢀmail: gardiner@manchester.ac.uk
KEYWORDS Iduronic acid; Carbohydrates; Lactones; Heparin Disaccharides
ABSTRACT:
furanosides which is converged to provide short 2ꢀstep routes to bicyclic [3.2.1] or [2.2.2]
tained via a 100 gꢀscale synthesis of 3ꢀOBn ꢀIdoA. A twoꢀstep conversion of this mixture provides either pure anomer of the novel
[2.2.2] ꢀiduronate thioglycoside lactones. Both [3.2.1] and [2.2.2] lactones are converted into GlcNꢀIdoA heparin precursor disacꢀ
LꢀIdofuranoside cyanohydrin 1 is converted on large scale into a mixture of
LꢀIdoA methyl pyranosides and
Lꢀiduronate lactones. The former is obꢀ
L
L
charides. The [2.2.2] lactone enables a scalable 3ꢀstep route from 1 to a new type of highly disarmed Oꢀ4 iduronate thioglycoside
which is an effective acceptor with glucoazide thioglycoside donors. The resulting new iduronic [2.2.2]ꢀlactone disaccharides are
readily reꢀarmed by mild methanolysis to provide GlcNꢀIdoA thiophenyl disaccharide donors, intercepting their established utility
for the assembly of both heparinꢀ and heparan sulfateꢀlike oligosaccharides. The [2.2.2] lactonization acts as a conformational
switch to superꢀdisarm iduronate components, reversible by lactone ringꢀopening. In addition, the separated 2,4ꢀdiacetates also proꢀ
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vide short access to all four anomeric and ring size isomers of
Lꢀiduronic acid methyl glycosides, including the first syntheses of the
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parent idofuranosides. Xꢀray structures are reported for a [2.2.2] iduronate lactone and examples of both methyl Lꢀidopyranoside
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and novel methylꢀLꢀidofuranoside systems.
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ꢀ INTRODUCTION
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The heparin/heparan sulfate (H/HS) family of glycosaminoglycans (GAGs) are oligosaccharides with pervasive roles in regulating a
wide range of signalling processes.1 These poly/oligosaccharides are very heterogeneous, consisting of alternating
Dꢀglucosamine
and uronic acid monomers, with significant variability in the Nꢀ and Oꢀ6 functionality of the
DꢀGlcN unit, alongside incorporation
of variable levels of ꢀglucuronic or ꢀiduronic acid. The diverse roles of such heterogeneous H/HS structures in many key host
D
L
cell processes, as well as in many pathogen interactions, ensures that understanding their structureꢀspecific effects is a major chalꢀ
lenge in carbohydrate chemical biology.1e,2 This is underpinned by enabling synthetic access to different backbones, controlling
sequence, end groups and the diversity of funtionalization, and this has seen significant examples of strategies to deliver H/HS synꢀ
theses.3 Access to monoꢀ and disaccharide H/HS building blocks dominates the key upstream requirement for synthetic capacity to
such oligosaccharides. Within this, access to derivatives of the rare
Lꢀiduronic acid and exploitation of their reactivity has been an
area that has seen many elegant approaches,4 and remains central to delivering improved and scalable syntheses of synthetic H/HS
targets. Several H/HS syntheses have employed iditol, then including a late stage oxidation to the
Lꢀiduronic acid, postꢀ
glycosylation(s).5 This has recently been exploited in the work of the Hung lab for synthesis of a large disaccharide library, where
the late stage oxidation involves synthesis of an iduronic [2.2.2]ꢀlactone.6 To date, there has been no exploration of the synthesis and
capabilities of iduronate lactones for the assembly of heparinꢀrelated disaccharide building blocks. Herein we report a new apꢀ
proach to herapinꢀlike oligosaccharide synthesis which exploits reversible conformatinal control of arming/disarming iduronate
thoglycoside functionality, and provides a short new route to such key disaccharides.
We have previously shown cyanohydrin 1 (accessible on kg scale)7 to be a convenient starting material for access to various
Lꢀ
iduronic acid intermediates,7,8 including thioglycosides, underpinning the large scale assembly of heparinꢀrelated oligosaccharides
up to the 12ꢀmer, and the synthesis of a low molecular weight heparin (LMWH)ꢀlike perꢀ6ꢀOꢀsulfated dodecasaccharide,10 in which
all synthesis directs through early incorporation of the iduronic caboxylic group.9 We reported that cyanohydrin 1 was converted
into a mixture of Lꢀidopyranosides and L
ꢀidofuranosides, which were not separable (Scheme 1),10 but which were converted into
their diacetates to enable separation of the pyranosides, 2 from furanosides, 3, with the former then elaborated for oligosaccharide
synthesis.
However, there would be considerable value if the large scalability of the conversion of 1 into 2+3 were exploited to provide direct
throughput to high value Lꢀiduronic acid reagents, without the need for furanoside/pyranoside separation. This could provide short,
large scale processes towards high value iduronate targets from bulk scale precursors. Additionally, the facility to develop new reaꢀ
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gents allowing for disaccharide syntheses via exploiting a new, conformationallyꢀswitched, disarming/reꢀarming anomeric reactiviꢀ
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ty of new iduronic acid derivatives would also be a valuable advance.
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Scheme 1. Large scale conversion of L-ido cyanohydrin 1 into L
-iduronate methyl glycosides mixture 2 + 3a,10
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aReagents and conditions: (a) AcCl, MeOH, 77%.
Herein we report short, scalable routes from the bulk crude 2+3 mixture to H/HS precursor disaccharides, which demonstrate a new
disarmed (superꢀdisarmed) ꢀIdoA acceptor lactone, which provides both convenient complete control of the acceptor protection
L
(reversibly sequestering O2 through lactone formation) and access to thioglycoside H/HS disaccharides, using just one type of doꢀ
nor functionality and thus obviating the need for any anomeric interconversions. We also report separation of all four ring and anoꢀ
meric isomers of 2 and 3, demonstrating further synthetic utility for 1, as a cheap and scalable precursor to a diversity of
idopyranoses and ꢀidofuranoses.
Lꢀ
L
ꢀ RESULTS AND DISCUSSION
This work reports that the mixture of 2+3 can be employed to provide large scale access to new Lꢀiduronic acid derivatives, specifiꢀ
cally novel [3.2.1] and [2.2.2] lactones and the application of the latter in synthesis of heparinꢀrelated disaccharide reagents, continꢀ
gent on discovery of the highly disarmed capabilites of [2.2.2] iduronate thioglycosides providing reversible conformationallyꢀ
regulated reactivity.
These new strategies were based on two iduronic acid lactones, whose syntheses are mediated via the conformational promiscuity
of the iduronic acid ring system. Both 1ꢀOH and 2ꢀOH of the iduronic acid system could form bridged lactones. Thus, free sugar
1
derivatives of iduronic acid could lactonize either via the C4 conformer (Route A, Figure 1) or an alternative 2,6ꢀlactonization
would be possible, but via the boat B2,5 conformer (Route B, Figure 1) or closelyꢀrelated OS2 skewꢀboat. Strategically, route A would
directly protect O1 as a cyclic acyl whilst route B would instead selectively protect O2. It may be anticipated that the free sugar
1
would proceed via the C4 pathway (A), whilst replacing the anomeric hydroxyl (B) with a different group (e.g. SPh) would then
only leave the possible lactonization pathway via the skewꢀboat. Of particular interest was the control of glycosylation reactivity of
the thioglycoside [2.2.2] lactone.
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Figure 1. Conformationallyꢀdirected regioselective lactonization approaches to protected iduronate bicyclic lactones.
Thus, the mixture of 2+3 was saponified on large scale (>200 g), followed directly by acid hydrolysis of the methyl glycoside to
afford 3ꢀOꢀbenzyl ꢀiduronic acid 4 (Scheme 2). This provides a practicable large scale 2ꢀstep process to afford 100 g batch access
to ꢀiduronic acid derivative, 4, requiring no purification or separation at the intermediate step, with the material isolated by preꢀ
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cipitation and filtration. This offers a significant scale and process advantage over previous syntheses of parent
rivatives.
Lꢀiduronic acid deꢀ
Scheme 2. Large scale conversion of glycosides 2 and 3 into 3-OBn L
-iduronic acid and derived lactones.a
aReagents and conditions: (a) (i) KOH, THF/MeOH/H2O (ii) HCl, H2O; (b) TsCl, MeꢀImidazole, CH3CN (additional 12% of 6).
With a short and scalable access to 4 in hand, we then investigated methods to differentially protect groups within 4 through lacꢀ
tonization. This envisaged the temporary protection of the anomeric OH via a [3.2.1]ꢀlactone (1,6ꢀcyclization) or of the 2ꢀOH via a
[2.2.2]ꢀlactone (1,6ꢀcyclization; thereby de facto ensuring 4ꢀOH as the only acceptor OH site). We reasoned that either lactone
could be exploited for synthesis of new lactone O4 acceptors, but also then be elaborated to intercept (via ringꢀopening)
monoꢀ or disaccharide derivatives.
Lꢀiduronic
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Reaction of 4 with TsCl in the presence of Meꢀimidazole converted 4 into the novel crystalline
Lꢀiduronate [3.2.1] lactone 5, via
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cyclization of the 1ꢀOH onto the intermediate tosylated carboxylate. The direction of lactonization was largely to the [3.2.1] outꢀ
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come, with only small amounts of the alternative crystalline [2.2.2] lactone 6 isolated from the reaction mixture.
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We investigated the regioselective protection of diol 5, aiming to deliver a new O4 Lꢀiduronic acceptor. Whilst benzoylation of 5
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provided poor regioselectivity (7:5 of Oꢀ2 vs Oꢀ4), treatment of 5 with pivaloyl chloride afforded a better ratio (3:1) of the Oꢀ2/Oꢀ4
pivaloylated regioisomers, with the desired Oꢀ2 pivaloate 7 isolable by crystallisation on gram scale, making this a practicable proꢀ
cess. (Scheme 3).
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Scheme 3. Conversion of [3.2.1] iduronate lactone into disaccharide and L
-iduronate thiophenyl glycosidea
aReagents and conditions: (a) PivꢀCl, MeꢀImidazole, THF, ꢀ15 ºC. (b) NIS, AgOTf, DCM. (c) (i) TsCl, MeꢀImidazole, CH3CN. (ii) Ac2O, MeꢀImidazole,
MeCN. (d) MeOH, pyr. (e) (i) CCl3CN, DBU, DCM. (ii) PhSH, TMSOTf, toluene. (iii) NaOMe, MeOH.8
The utility of lactone 7 as a glycosyl acceptor was evaluated via glycosylation with glucosamineꢀderived donor 8.8 The disacchaꢀ
ride product 9 was obtained as a pure αꢀanomer, though isolated in modest yield (32%), along with recovery of almost all the unreꢀ
acted acceptor 7 and traces of a succinamide donor adduct. This indicated low acceptor capability for 7 with donor 8, and provided
an interesting addition to our prior reports using this donor, the trichloracetimidate and other modified
LꢀIdoA acceptors, which had
reported that ꢀiduronate ester and the 5ꢀCN analogue are good acceptors, whilst the ꢀiduronamide performs even more poorly
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than 7.7,8 This provides further data that the nature of the C5 functionality strongly influences the reactivity of
LꢀIdoA derivatives
for Oꢀ4 glycosylations.
Conversion of 5 into known Lꢀidopyranosides with donor funtionality requires opening of the lactone. The 1,6ꢀlactone is attractive
as a new construct as this offers a temporary protection of the anomeric hydroxyl, the utlility of such protection demonstrated by
conversion of 4 into iduronates 11 and thence 12 (Scheme 3). Thus, 4 provided 80% yield of a 2,4ꢀOꢀdiacetylated derivative 10 in a
single potꢀprocess and on 40 g scale (along with formation of about 10% of diacylated 2,6ꢀlactone 6), with subsequent methꢀ
anoloysis of the lactone affording
Lꢀiduronate derivative 11 (Scheme 3). Iduronate 11 was separable from the residual material and
unreacted diacylated derivative of 2,6ꢀlactone 6. Iduronate 11 could be converted into
LꢀIdoA thiolglycoside donor 12, a previously
described8 key precursor for the
Lꢀiduronate unit employed in our syntheses of a diversity of longer heparanoids.
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Whilst [3.2.1] lactone 5 was thus shown to be converted into the key thioglycoside iduronate 12 in only 4 steps from the feedstock
mixture of glycosides 2 and 3 (22% overall yield), we also established that this iduronate methyl glycoside mixture 2+3 could be
directly converged into 12 in just one step (Scheme 4). Under typical thioglycosylation conditions, 2+3 was converted directly into
12, and though only isolated in modest yield (37%, α/β 1:3), this achieves the same conversion in one step and competitive overall
yields.
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No evidence of thiophenyl furanosides, nor any methyl furanoside starting material was observed. Our previously reported iodineꢀ
based workꢀup (oxidizing residual thiophenol) was also successful here, in facilitating a simple extraction suitable on scale.
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Although evaluation of a range of changes to reaction conditions and reagents did not lead to further yield optimization, this syntheꢀ
sis now provides by far the shortest route described to such key Lꢀiduronate thioglycosides, replacing multiple step routes by a one–
pot conversion of 2+3 into 12.
Scheme 4. Convergent conversion of iduronic pyranoside/furanoside mixture into anomerically pure [2.2.2]
tones and their opening to anomerically-pure iduronic thioglycosidesa
L-iduronic lac-
aReagents and conditions: (a) (i) PhSH, BF3.OEt2, DCM. (ii) I2, NaHCO3. (b) (Bu3Sn)2O, toluene. (c) KOH, THF/MeOH/H2O. (d) TsCl, Meꢀimidazole,
CH3CN. (e) Et3N, MeOH, 1.5 h. (f) BzCl, pyridine, DCM.
The use of tin reagents to deliver regioselective protections is a common strategy in carbohydrate synthesis.11 The dibutyl tinꢀoxideꢀ
mediated Oꢀ2 benzoylation of 12 is the approach we and others have previously employed.8 We report here that a second type of
Lꢀ
iduronate lactone can be efficiently prepared from thioglycoside 12, thereby differentiating Oꢀ2 vs Oꢀ4 functionalization by tempoꢀ
rary protection of Oꢀ2 through lactonization. Thus, we found that 12 can be converted into the [2.2.2] lactone system 13 via cycloꢀ
transesterification in two ways. Firstly, by directly heating 12 with bis(tributyltin) oxide (stannyl oxideꢀmediated cyclization of an
OTDS glycoside analogue of 12 was reported previously).3d However, we also found that conversion to the 2,4ꢀdiacetate α/β–14
and then complete ester hydrolysis, followed by tosylationꢀmediated lactonization of the resulting diol acid α/β–15 provided a seꢀ
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cond route to thioglycoside lactones of type α/β–13. The use of iduronate lactones as synthetic building blocks has been very limꢀ
ited. The use of a 1ꢀOTDS glycoside iduronate [2.2.2] lactone as an acceptor employed for synthesis of a heparinꢀrelated disacchaꢀ
ride was reported by MartinꢀLomas et al,3d providing valuable precedent for the use here of the thioglycosidic [2.2.2] system as an
acceptor. However, this prior report required subsequent conversion of the glycosidic ether into a donor functionality and is thus not
related to modifying reactivity characteristics with a single anomeric group. Whereas inclusion of the thioglycosidic lactone reportꢀ
ed here could, we reasoned, if the lactone were suitably disarmed with respect to glucoꢀthioglycosides, directly provide donorꢀready
heparin disaccharides without changing the anomeric group.
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At this stage, the anomers of Lꢀiduronate lactone 13 could be separated to provide multiꢀgram quantities of the pure thioglycoside
anomers α–13 and β–13 (~1:3). The anomers of these novel lactones offer separability advantages on larger scale compared to
monocyclic thioglycosides such as 12 and 14.The βꢀanomer was 4ꢀOꢀbenzoylated providing crystalline material β–16, for which an
Xꢀray structure determination was obtained (Figure 2. Unit Cell see Supplementary Data).12
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Figure 2. XꢀRay Structure of [2.2.2] lactone βꢀ16 and H solution state 3J NMR coupling constants (400 MHz). [H5 not shown: J4,5=4.4Hz]. The 1H specꢀ
trum also shows 4J couplings for H2ꢀH5 of 0.4ꢀ0.9 Hz.
We next evaluated the methanoloysis of α–13 and β–13 to regenerate a free 2ꢀOH and concurrently install the iduronate methyl
ester, thereby providing anomerically pure quantities of 2,4ꢀdiol 12. This proceeded in essentially quantitative yields for both
anomers within 1.5 h at room temperature (Scheme 4). This thereby provides an alternative and scalable route to these anomerially
pure methyl iduronate thioglycosides, α– and β–12, offering valuable process advantages. The differential protection of Oꢀ2 in
these systems has been exploited previously for the synthesis of iduronate acceptors for heparin fragment syntheses by us and othꢀ
ers (vide supra) and this de facto provides routes to both anomeric series of these.
Formation of a [2.2.2] lactone provides concurrent protection of Oꢀ2 and the carboxylate, leaving Oꢀ4 uniquely free which could
provide two further possible advantages for the synthesis of heparinꢀrelated building blocks. Firstly, the selective protection of Oꢀ2
via lactone formation could enable specific protection of Oꢀ4, where reꢀopening the lactone would then provide differential funcꢀ
tionalization of Oꢀ2 and Oꢀ4 (i.e. for donor iduronate thioglycosides). Secondly, the potential use of the [2.2.2] system as a glycosyl
acceptor in coupling with Dꢀglucosamine donors, with subsequent lactone opening after formation of disaccharide systems, would
provide a useful addition to the use of lactone systems. Most significantly, were the thioglycoside relative reactivity suitably differꢀ
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entiated from monocyclic thioglycoside glucosyl donors, then such lactones could be employed as a conformationallyꢀcontrolled
disarming/reꢀarming switch.
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To evaluate the first of these approaches, for monosaccharide iduronate manipulations, the free 4ꢀOH of α– and β–13 was protected
as its TBDMS ether, affording α– or β–17, respectively. The same methanolysis conditions effective in the esterolytic opening of
13 were evaluated. We observed that the methanolysis which had been equivalently facile on either anomer of 13, showed notable
kinetic differences between the two anomers of 17, with a 4ꢀOTBDMS installed. Thus, whilst methanolysis opening of α–17 to α–
18 was complete in 18 h at room temperature, the same conditions led to little conversion for β–17 to β–18, for which a prolonged
reaction time (~72 h) was required to effect the same ring opening (Scheme 5).
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Scheme 5. Protection and ring opening of anomers of [2.2.2] iduronic lactonesa
aReagents and conditions: (a) TBDMSCl, ImH, DCM. (b) MeOH, Et3N, 72 h, r.t. (c) MeOH, Et3N, 16 h, r.t. (d) DMAP, Ac2O. pyr., DCM
.
This large difference in rate of esterolysis of α– and β–17, and the dramatic difference to the behavior of the 4ꢀOH analogues, we
rationalize is at least in part due to the steric effects of two large substituents (SPh and OTBDMS) which hinder attack from either
face of the ester carbonyl (Figure 3). The ring opened β–18 was also a notably poor substrate for Oꢀ2 benzoylation (also supportive
of a steric crowding at O2), but was efficiently acylated to 19. These ringꢀopened iduronates 18 are only five steps from our largeꢀ
scale feedstock cyanohydrin 1 and thus offer considerable scope for further diversification to various anomericallyꢀpure, fullyꢀ
differentiated new and known iduronic acid derivatives.
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Figure 3. Esterolysis of β–17 is considerably slower than α–17, rationalized on the basis of steric hindrance of both carbonyl faces in βꢀ17.
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The second utlilization of [2.2.2] lactone 13 demonstrates its capability as an effective acceptor for reaction with glucoazide donors
to afford disaccharides suitable for oligosaccharide synthesis.. Thus, β–13 was reacted with 2ꢀazido gluco trichloroacetimidate 208
to provide novel lactoneꢀdisaccharide 21 in good yield and with high anomeric selectivity (Scheme 6). Whilst this parallels the
precedent for the 1ꢀOTDS analogue of 13,3d significantly, we found that the lactone thioglycoside is sufficiently disarmed that it can
also be converted to disaccharide 21 using the 2ꢀazido thioglycoside donor 8 in excellent yield (6:1 α:β). This yield was notably
higher using toluene (90%) rather than DCM (60%).
This reactivity control provides a critical addition to the utility of such a lactone acceptor, exploiting the disarmed nature of the
lactone thioglycoside to provide access directly to thioglycoside donor disaccharides via such lactoneꢀOFF to openedꢀON glycosylꢀ
ation donor capability. Methanolysis of the lactone of disaccharide 21 provided novel disaccharide 22 (under slightly stronger basic
conditions for this β–lactone opening, cf. Scheme 5) which was then Oꢀ2 benzoylated to provide GlcNꢀIdoA thioglycoside disacꢀ
charide 23, previously prepared by nonꢀlactone intermediates13 and suitable for direct use in established oligosaccharide homologaꢀ
tions.9
In addition, lactone 13 was also a viable acceptor reacting with 4,6ꢀbenzylidineꢀprotected 2ꢀazido thioglycoside donor 24 to give
lactone disaccharide 25. This lactone also underwent similar methanolysis and benzoylation to afford a second example disacchaꢀ
ride thioglycoside 26, similarly intercepting our recently reported nonꢀlactone route.13
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Scheme 6. [2.2.2] Iduronic lactone as disarmed thioglycoside acceptor for HS disaccharide synthesis via post-glycosylation
lactone esterolysisa
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aReagents and conditions: (a) TMSOTf, DCM. (b) NIS, AgOTf, toluene. (c) NaOMe, MeOH, (d) BzCl, MeꢀImidazole, DCM.
Bicyclization has been previously employed in LꢀIdoA units to influence the stereocontrol of the glycosidation using these as an
acceptor.3d,7 However, here, as we have already established previously that the analogous monocyclic iduronates act as effective
donors for highly stereoselective glycosylations, the current work provides a new conformationallyꢀcontrolled on/off regulation of
iduronate thioglycoside donor capability.
This is strategically significant as it now enables synthetic approaches to diverse longer H/HS targets with all glycosylations being
effected using shelfꢀstable thiophenyl glycosides of both the DꢀGlcN and LꢀIdoA components. Since we report here multigram
scale 2ꢀstep access to pure 13 from the crude glycoside mixture 2+3, overall this provides a useful route to key heparin disaccharide
donors in only 5 steps from 2+3, and 6 steps from bulk cyanohydrin 1.
Disaccharide 23 contains a 6ꢀOBn protecting group, which, in our prior syntheses enabled the introduction of a 6ꢀOH into the final
oligosaccharide target.9 Disaccharide 26 was also converted into the analogous 4ꢀOTCA/6ꢀOꢀBn disaccharide 27 (Scheme 7) and
also its 6ꢀOBz analogue 29, via diol 28. We also included 6ꢀOBz in previous deacasaccride synthesis to programme perꢀ6ꢀOꢀ
sulfation.10 Thus, benzylidineꢀprotected 26 provides a divergent route to disaccharides whose Oꢀ6 protection programmes towards
either 6ꢀOH or 6ꢀOSO3Na oligosaccharides, and thus either of the O6 modifications seen in heparinꢀ or heparan sulfate structures.
Scheme 7. Synthesis of β–thioglycoside GlcN-IdoA heparin-related disaccharidesa
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aReagents and conditions: (a) (i) Et3SiH, BF3.OEt2, DCM. (ii) pyridine, CCl3COCl. DCM (b) EtSH, pꢀToluenesulfonic acid (cat.), DCM. (c) BzCl,
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pyridine, DCM then CCl3COCl.8
In summary, this work provides a number of significant process advantages in demonstrating that a bulk mixture of Lꢀiduronate
glycosides 2+3 can be converged to important monosaccharide iduronates, but also provides a new approach to fully differentiate
Oꢀ2 and Oꢀ4, concurrent with a new conformationalꢀregulator which deꢀactivates the thioglycosides as a donor. The impact of this
on synthetic design for oligosaccharide synthesis is significant, enabling introduction of all glycosidic bonds by thioglycoside couꢀ
plings, with no need to interconvert any anomeric groups. The interception of previouslyꢀexploited disaccharides providing thereby
a formal total synthetic approach to heparinꢀlike and heparinꢀsulfate like oligosaccharides, based on use of thiophenyl glycoside
couplings alone.
Having previously only separated the pyranoside/furanoside mixture 2+3 as anomeric mixtures of their diacetates,10 we also wished
to illustrate that this mixture could also provide a practicable route to all four ring size/anomeric parent iduronic acid glycosides.
Thus, the previously separated diacetates of the pyranosides and furanosides were elaborated as shown in Scheme 8A. The pyraꢀ
noside anomers were separated (as we previously described10) as their 2ꢀOꢀbenzoates 32 and 33, with subsequent hydrolysis and
hydrogenolysis then affording the pure known α– and β–idopyranosides 36 and 37, respectively. In the case of the furanosides,
diols 38 and 39 proved separable directly, and were then also similarly elaborated to their novel parent idofuranoside glycosides 42
and 43. This thus employs the 2+3 mixture for a convenient divergence/separation approach to afford all four ring and anomeric
isomers of Lꢀiduronic acid methyl glycosides. This is particularly notable in providing the first syntheses of the previously unknown
furanosides of this important hexoside.
Additionally, we obtained Xꢀray structures for examples of each ring size, as shown in Scheme 8b. The pyranoside 34 adopts a 1C4
chair in the crystal (Scheme 8B), consistent with evidence from NMR data for previous derivatives,8 whilst the previously unknown
furanoside 39 adopts a 2T3 conformation (Scheme 8C).
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Scheme 8. Synthesis of all four iduronic methyl pyranosides and furanosides and X-ray structures of example idofuranoside
and idopyranosidea
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(A) aReagents and conditions: (a) NaOMe, MeOH. (b) aq. KOH (1 equiv. 0.4 or 0.6 M), THF/MeOH (2:1). (c) H2, Pd(OH)2/C.
(B) ORTEP of idopryanoside 3412; (C) ORTEP of idofuranoside 39.12
ꢀ CONCLUSIONS
This work reports that the crude hydrolysis products from
conveniently reꢀconverged to elaborated ꢀidopyranosides. This is a valuable process advantage providing short routes for large
batch scale synthesis from inexpensive feedstocks. Particularly, this mixture is converted via an idopyranoside thioglycoside into a
new [2.2.2] thioglycoside ꢀido lactone. This concurrently protects the carboxylate and Oꢀ2, leaving the key Oꢀ4 glycosylation site
Lꢀidocyanohydrin 1 – available on multiꢀhundred gram scales ꢀ can be
L
L
free. This lactone can be prepared on multiꢀgram scales, and we show that it can act directly as an effective acceptor for the syntheꢀ
sis of GlcNꢀIdoA disaccharides. This lactone is substantively disarmed relative to other thioglycosides and varied glucoazide thioꢀ
glycosides can be employed as donors, with subsequent nearꢀquantitative opening of the lactone in the derived disaccharide, reꢀ
arming the ido thioglycoside via ringꢀopening, thereby providing short access to several heparinꢀrelated disaccharide thioglycoside
donors. These disaccharides have already been shown to be key units for assembling long synthetic heparinꢀrelated oligosacchaꢀ
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rides and are now available in 4 or 6 steps directly from the crude glycoside mixture 2+3, which is preparable on 200 g batch scales.
This route from a bulk glycoside mixture (2+3) via a novel lactone advances the practicability of total synthesis of a range of highly
important H/HS oligosaccharides by significantly reducing the number of steps for, and with enhanced scalability of, the synthesis
of such important units, underpinned by our introduction of a new type of conformational control of anomeric reactivity in such
building blocks. Additionally, the 2+3 mixture is shown to be a precursor to provide short access (4 or 5 steps) to all the possible
iduronic acid methyl glycosides in both pyranoside and furanoside forms, affording the first synthesis of parent idofuranosides.
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ꢀ EXPERIMENTAL SECTION
3-O-Benzyl-β-L-idopyranuronic acid 4
Crude 2/3 (210 g, 0.673 mol) was dissolved in a mixture of THF/MeOH (800 mL 3:1 v:v) and KOH (37.8 g, 0.674 mol) dissolved in H2O
(300 mL) added over 30 min (exothermic reaction). The reaction mixture was stirred for another 90 min. and then evaporated. To the crude
carboxylate product was added H2O (860 mL) and conc. HCl (140 mL) with stirring and then heated to 100 °C for 1 h. The acidic solution
was treated with solid NaHCO3 (88.3 g) until pH ~ 3, water was evaporated, the product redissolved in THF (1 L) using sonication, salts
filtered off and washed with THF (5x300 mL). The organic fractions were combined and solvent removed in vacuo to give crude 4 (154 g).
Purification was achieved by resuspending the crude in a CHCl3/MeOH (600 mL/30 mL) mixture followed by sonication and filtration of
the fine precipitate. This yielded 4 (97.1 g, 51%) as a white powder. Rf 0.03 (EtOAc + 1% HCOOH); 1H NMR (400 MHz; CD3SOCD3) δ
12.73ꢀ12.53 (broad s, 1H, COOH), 7.39ꢀ7.26 (m, 5H, Ph), 6.79ꢀ6.68 (broad s, 1H, OH), 5.17ꢀ5.10 (broad s, 1H, OH), 4.82ꢀ4.80 (m, 1H, Hꢀ
1), 4.64ꢀ4.62 (m, 2H, CH2Ph), 4.30 (d, J = 1.6 Hz, 1H, Hꢀ5), 3.88ꢀ3.85 (m, 1H, Hꢀ4), 3.71 (t, J = 3.2 Hz, 1H, Hꢀ3), 3.60ꢀ3.58 (m, 1H, Hꢀ2);
13C NMR (101 MHz; CD3SOCD3) δ 170.5, 138.2, 128.4, 127.7, 127.6, 92.9, 76.7, 73.8, 71.1, 67.9, 67.3; HRMS (TOF ES–) calcd for
C13H15O7 [MꢀH]ꢀ: 283.0823, found: 283.0816; Elemental analysis calcd (%) for C13H16O7: C 54.93, H 5.67; found C 54.81, H 5.71.
3-O-Benzyl-β-L-idopyranurono-1,6-lactone 5+6
Iduronic acid 4 (27.9 g, 0.098 mol) was dissolved in dry CH3CN (300 mL) and cooled to 0 °C in an ice bath. 1ꢀMethylimidazole (7.8 mL,
0.098 mol) was then added and after 15 min tosyl chloride (16.9 g, 0.088 mol) added in portions over 30 min. The reaction mixture was
stirred for another 1 h and another portion of 1ꢀmethylimidazole (7.8 mL, 0.098 mol) added over 10 min. The mixture was stirred another 1
h and the solvent evaporated. The crude was purified by silica gel flash column chromatography (dry loaded, EtOAc/hexane 1:1 to 1:0 v:v)
to give a mixture of 1,6ꢀ and 2,6ꢀlactone products (9:1, estimated from 1H NMR). Further purification of the 1,6ꢀlactone was achieved by
crystallization (dissolved in EtOAc and two times volume hexane then added) yielding 5 (16.8 g, 69%) as white needles. Rf 0.31
1
(EtOAc/hexane 1:1 v:v); mp 159ꢀ161 °C; [α]D20 = +99.3 (c = 0.35, acetone); H NMR (400 MHz; CD3COCD3) δ 7.41ꢀ7.23 (m, 5H, Ph),
5.77 (d, J = 2.1 Hz, 1H, Hꢀ1), 5.09 (d, J = 4.9 Hz, 1H, OHꢀ4), 4.99 (d, J = 6.5 Hz, 1H, OHꢀ2), 4.91 (d, J = 11.6 Hz, 1H), 4.87 (d, J = 11.6
Hz, 1H), 4.39 (d, J = 4.6 Hz, 1H, Hꢀ5), 3.98 (dt, J = 8.4, 4.7 Hz, 1H, Hꢀ4), 3.85 (ddd, J = 7.9, 6.4, 2.1 Hz, 1H, Hꢀ2), 3.57 (t, J = 8.4 Hz,
1H, Hꢀ3); 13C NMR (101 MHz; CD3COCD3) δ 170.7, 140.1, 128.9, 128.4, 128.1, 104.7, 84.7, 75.4, 73.7, 73.4, 70.7; HRMS (TOF ES+)
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calcd for C13H14NaO6 [M+Na]+: 289.0683, found: 289.0680. The ido 2,6ꢀlactone 6 was isolated from the above mixture of lactones by
careful column chromatography (EtOAc/hexane 1:2 v:v) followed by crystallization (dissolved in EtOAc and enough hexane added until
the solution begins to appear cloudy) yielding 6 (1.5 g, 5.6 mmol, 12%) as long needles. mp 154ꢀ156 °C; [α]D20 = +79.7 (c = 0.68, aceꢀ
tone); 1H NMR (400 MHz; CD3COCD3) δ 7.42ꢀ7.31 (m, 5H, Ph), 6.12 (broad s, 1H, OH), 5.49 (s, 1H, Hꢀ1), 5.10 (broad s, 1H, OH), 4.80ꢀ
4.70 (m, 2H, CH2Ph), 4.78 (dt, J = 4.4, 0.8 Hz, 1H, Hꢀ2), 4.18 (dd, J = 4.1, 0.5 Hz, 1H, Hꢀ5), 4.16 (dd, J = 4.0, 2.2 Hz, 1H, Hꢀ4), 3.87 (dd,
J = 4.2, 2.1 Hz, 1H, Hꢀ3); 13C NMR (101 MHz; CD3COCD3) δ 169.1, 138.6, 129.2, 128.6, 88.7, 80.0, 76.6, 73.4, 72.5, 72.1; HRMS (TOF
ES+) calcd for C13H15O6 [M+H]+: 267.0864, found: 267.0860.
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2-O-Pivaloyl-3-O-benzyl-β-L-idopyranurono-1,6-lactone 7
Lactone 5 (16.8 g, 0.063 mol) was dissolved in dry THF (200 mL) and cooled to ꢀ15 °C. 1ꢀMethylimidazole (5.0 mL, 0.063 mol) was then
added followed by pivaloyl chloride (7.77 mL, 0.063 mol). The mixture was stirred 1 h and the solvent removed in vacuo. The crude prodꢀ
uct was purified by silica gel flash column chromatography (dry loaded, EtOAc/hexane 1:2 to 1:1 v:v). From NMR it was determined to be
a mixture of O2ꢀ/O4ꢀpivaloate products (3:1). Pure O2ꢀpivaloate regioisomer was isolated by crystallization (dissolved in EtOAc and three
20
times volume of hexane added) yielding 7 (8.0 g, 36%) as a white powder. Rf 0.22 (EtOAc/hexane 1:3 v:v); mp 201ꢀ203 °C; [α]D
=
+130.2 (c = 0.27, acetone); 1H NMR (400 MHz; CD3COCD3) δ 7.35ꢀ7.26 (m, 5H, Ph), 5.92 (d, J = 2.0 Hz, 1H, Hꢀ1), 5.36 (d, J = 4.9 Hz,
1H, OH), 4.94 (dd, J = 8.8, 2 Hz, 1H, Hꢀ2), 4.91 (d, J = 11.2 Hz, 1H, CH2Ph), 4.71 (d, J = 11.2 Hz, 1H, CH2Ph) 4.51 (d, J = 4.7 Hz, 1H, Hꢀ
5), 4.13 (dt, J = 8.4, 4.7 Hz, 1H, Hꢀ4), 3.78 (t, J = 8.4 Hz, 1H, Hꢀ3), 1.21 (s, 9H); 13C NMR (101 MHz; CD3COCD3) δ 177.8, 170.0, 139.3,
128.9, 128.3, 128.3, 101.1, 81.4, 75.5, 73.5, 73.3, 70.8, 39.3, 27.2; HRMS (TOF ES+) calcd for C18H22NaO7 [M+Na]+: 373.1258, found:
373.1269.
2-Azido-3,6-di-O-benzyl-2-deoxy-4-O-p-methoxybenzyl-α-D-glucopyranosyl-(1⟶4)-2-O-pivaloyl-3-O-benzyl-β-L-idopyranurono-
1,6-lactone 9
Acceptor lactone 7 (350 mg, 1.0 mmol) and thioglycoside donor 8 (656 mg, 1.1 mmol) were dissolved in dry DCM (10 mL) under N2.
Freshly activated 4Å powdered molecular sieves (300 mg) were added and the solution kept at RT. After 10 min NIS (742 mg, 3.0 mmol)
was added, and after another 10 min AgOTf (12 mg, 0.05 mmol) was added. The suspension changed colour from pale yellow to deep
purple, was stirred for 15 min and then quenched into a separating funnel containing a mixture of DCM (30 mL), saturated aqueous Naꢀ
HCO3 (20 mL) and Na2S2O3 (10 mL, 10% aqueous). After shaking until the iodine colour was removed, the suspension was filtered
through a short pad of Celite® washing with water and DCM. The layers were separated and the aqueous extracted with DCM (30 mL).
The organic layers were combined, dried (MgSO4) and solvent removed in vacuo. The crude product was purified by silica gel flash colꢀ
umn chromatography (EtOAc/hexane 1:2) to give 9 (274 mg, 32%) as a white foam. 7 (249 mg, 71%) was also recovered. Rf 0.35
(EtOAc/hexane 1:3); [α]D20 = +48.8 (c = 1.15, CH2Cl2); 7.42ꢀ7.28 (18 H, m, Ph), 7.15 (2 H, d, J = 8.7 Hz, PMB), 6.87 (2 H, d, J = 8.7 Hz,
PMB), 5.87 (1 H, d, J = 2.1 Hz, Hꢀ1), 5.18 (1 H, d, J 3.9, H’ꢀ1), 5.07 (1 H, d, J = 10.6 Hz, CH2Ph), 4.97 (2 H, m, CH2Ph, Hꢀ2), 4.91 (1 H,
d, 10.4 Hz, CH2Ph), 4.85 (1 H, d, J = 3.9 Hz, Hꢀ5), 4.79 (1 H, d, J = 10.7 Hz, CH2Ph), 4.71 (1 H, d, J = 10.6 Hz, CH2Ph), 4.63 (1 H, d, J =
12.1, CH2Ph), 4.53 (2 H, dd, J =11.4, 3.5, CH2Ph), 4.33 (1 H, dt, J = 10.1, 3.2, H’ꢀ5’), 4.00ꢀ3.95 (3 H, m, Hꢀ3, H’ꢀ3, Hꢀ4), 3.85ꢀ3.82 (3 H,
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s, PMB OCH3), 3.74 (2 H, d, J = 3.4 Hz, H’ꢀ6a/b), 3.68 (1 H, dd, J = 9.9, 9.1 Hz, H’ꢀ4), 3.59 (1 H, dd, J = 10.3, 3.8 Hz, Hꢀ2’), 1.28 (10 H,
s, C(CH3)3). 13C NMR (100 MHz; CDCl3) δ 177.8, 169.3, 159.4, 137.8, 137.72, 129.6, 128.5, 128.2, 128.0, 127.9, 127.8, 127.7, 113.9,
100.7, 100.1, 80.3, 79.0, 78.6, 78.0, 77.5, 77.2, 76.9, 75.8, 75.6, 74.6, 73.5, 73.5, 71.5, 70.9, 68.6, 63.9, 55.3, 38.9, 27.1; HRMS (TOF ES+)
calcd for C46H51N3NaO12 [M+Na]+: 860.3365, found: 860.3361.
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Methyl 2,4-di-O-acetyl-3-O-benzyl-α/β-L-idopyranuronate 10
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Iduronic acid 4 (40.9 g, 0.144 mol) was dissolved in dry CH3CN (500 mL) and cooled to 0 °C in an ice bath. 1ꢀMethylimidazole (11.5 mL,
0.144 mol) was then added and after 5 min tosyl chloride (24.9 g, 0.130 mol) added in one portion. The reaction mixture was stirred for 90
min and another portion of 1ꢀmethylimidazole (11.5 mL, 0.144 mol) added over 10 min. The mixture was stirred another 1 h, acetic anhyꢀ
dride (30 mL, 0.317 mol) added, left over night and the solvent evaporated. The crude was extracted with DCM (600 mL)/ H2O (2 x 500
mL) and NaHCO3 (sat.) /brine (1:1, 500 mL). The organic phase was dried (MgSO4), filtered and evaporated. The crude mixture was puriꢀ
fied by silica gel flash column chromatography (toluene/acetone 20:1 to 10:1 v:v). Further purification could be achieved by crystallization
(dissolved in EtOAc and three times volume hexane added) yielding 10 (40.4 g, 80%) as white plates. Analytical data matched those preꢀ
viously reported.8
Methyl 2,4-di-O-acetyl-3-O-benzyl-α/β-L-idopyranuronate 11
The lactone mixture 10 (40.4 g, 0.115 mol, 9:1) was dissolved in MeOH (500 mL), pyridine (5 mL) added and heated to 50 °C for 12 h.
After evaporation of solvents the crude was purified using silica flash column chromatography (EtOAc/hexane, 1:1 v:v). This yielded 11
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(39.4 g, 89%, α/β 2:1) as an oil. Also unreacted diacylated 2,6ꢀlactone (4.07 g, 10%) was isolated. Rf 0.10 (EtOAc/hexane 1:1 v:v); H
NMR (400 MHz; CDCl3) δ 7.35ꢀ7.26 (m, 5H, Ph), 5.32ꢀ5.31 (m, 0.6H, Hꢀ1α), 5.19 (t, J = 2.6 Hz, 0.6H, Hꢀ4α), 5.16 (d, J = 1.7 Hz, 0.3H,
Hꢀ1β), 5.12ꢀ5.10 (m, 0.3H, Hꢀ4β), 5.02 (d, J = 2.3 Hz, 0.6H, Hꢀ5α), 4.90ꢀ4.88 (m, 0.3H, Hꢀ2β), 4.82ꢀ4.81 (m, 0.6H, Hꢀ2α), 4.78ꢀ4.70 (m,
2H, CH2Ph), 4.66 (d, J = 2.0 Hz, 0.3H, Hꢀ5β), 3.95 (t, J = 2.9 Hz, 0.3H, Hꢀ3β), 3.88 (dt, J = 3.0, 1.3 Hz, 0.6H, Hꢀ3α), 3.75 (s, 2H,
COOCH3), 3.73 (s, 1H, COOCH3), 2.08 (s, 1H, CH3CO), 2.02 (s, 2H, CH3CO), 2.01 (s, 2H, CH3CO), 1.99 (s, 1H, CH3CO); 13C NMR (101
MHz; CDCl3) δ 170.3, 169.9, 169.7, 169.7, 169.0, 168.2, 149.3, 136.8, 136.5, 128.6, 128.6, 128.5, 128.4, 128.2, 128.0, 127.8, 123.9, 92.9,
92.0, 73.1, 73.0, 72.8, 72.5, 71.8, 68.0, 67.2, 67.1, 67.0, 65.7, 52.6, 20.9, 20.8, 20.7, 20.6; HRMS (TOF ES+) calcd for C18H22NaO9
[M+Na]+: 405.1156, found: 405.1152.
Diacylated 6: Rf 0.23 (EtOAc/hexane 1:3). [α]D20 = +51.4 (c = 0.55, CH2Cl2). 1H NMR (400 MHz; CDCl3) δ 7.36ꢀ7.28 (m, 5H, Ph), 6.40
(d, J = 1.2 Hz, 1H, Hꢀ1), 5.13 (ddd, J = 4.4, 1.7, 0.6 Hz, 1H, Hꢀ4), 4.77ꢀ4.58 (m, 3H, Hꢀ2, CH2Ph), 4.47 (d, J = 4.1 Hz, 1H, Hꢀ5), 3.92 (dd,
J = 4.4, 1.8 Hz, 1H, Hꢀ3), 2.10 (s, 3H, COCH3), 2.04 (s, 3H, COCH3). 13C NMR (101 MHz; CDCl3) δ 169.5, 169.1, 166.1, 136.2, 128.8,
128.6, 128.2, 87.8, 75.4, 74.1, 72.7, 71.0, 69.4, 21.0, 20.6. HRMS (TOF ES+) calcd for C17H18O8Na [M+Na]+: 373.0894, found: 373.0888.
Methyl (3-O-benzyl-1-thiophenyl-α,β-L-idopyranoside) uronate 12
The methyl furanoside/pyranoside mixture 2+3 (89.0 g, 0.285 mol) was dissolved in DCM (1.8 L), powdered molecular sieves 4Å (93 g)
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and thiophenol (34 mL, 0.33 mol) added. To the vigorously stirred mixture was added BF3 OEt2 (105 mL, 0.86 mol) and left for 45 min.
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The reaction mixture was slowly poured into a 5 L beaker with saturated aqueous NaHCO3 (300 g in 1.8 L H2O) with stirring (NOTE:
Heavy foaming observed). To the stirred mixture was added iodine until the dark red colour persisted (NOTE: this converts thiophenol
into diphenyl disulfide thus removing the excess of the odorous toxic reagent). To remove the excess iodine a small amount of Na2S2O3
(10% aqueous) was added. The organic layer was separated, dried (MgSO4) and solvent removed in vacuo. The crude was purified by siliꢀ
ca gel flash column chromatography (EtOAc/hexane gradient 1:2 to 1:1 v:v) to give 12 (41.5 g, 37%, α/β 1:3) as a viscous oil. Also startꢀ
ing material pyranoside (8.2 g, 9 %) could be recovered. Analytical data matched those previously reported.3d
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Lactone α,β-13 was also converted into α,β-12 by methanolysis on 1g scale (MeOH (20 mL), Et3N (0.05 mL) for 2 h, removal of solvents
and crystallization from EtOAc:hexane (30 mL, 1:2, v:v)).
Methyl (3-O-benzyl-1-thiophenyl-β-L-idopyranoside) uronate β−12
From β−18: TBDMS protected iduronate β−18 (114 mg, 0.23 mmol) was dissolved in dry THF (2 mL) and the solution cooled to 0 °C.
Tetrabutylammonium fluoride solution (250 ꢁL, 1 M in THF) was added dropwise and the reaction stirred at 0 °C for 30 min. The solvents
were removed and the crude product purified by silica gel flash column chromatography (hexane/ethyl acetate 1:1 v:v) to afford β−12 as a
yellow oil (61 mg, 0.16 mmol, 70%).
From β−13: Lactone β−13 (104 mg) was stirred in MeOH (2 mL), Et3N (0.04 mL, 1 eq.) for 1.5 h, removal of solvents and chromatogꢀ
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raphy isolating β−12. Rf 0.38 (1:1 EtOAc/hexane); [α]D = +37.9 (c = 0.10, CH2Cl2); H NMR (400 MHz, CDCl3): 7.56–7.54 (2 H, m,
ArH), 7.34–7.26 (8 H, m, ArH), 5.20 (1 H, d, J = 1.1 Hz, Hꢀ1), 4.63 (1 H, d, J = 11.2 Hz, CH2Ph), 4.59 (1 H, d, J = 12.1 Hz, CH2Ph), 4.53
(1 H, d, J = 1.3 Hz, Hꢀ5), 4.15 (1 H, dt, J = 3.0, 1.4 Hz, Hꢀ4), 4.01–4.00 (1 H, m, Hꢀ2), 3.95 (1 H, t, J = 3.2 Hz, Hꢀ3), 3.82 (3 H, s,
CO2CH3); δc (100 MHz, CDCl3): δ 169.8 (C=O), 137.4 (Ar C), 134.3 (Ar C), 131.6 (Ar CH), 129.2 (Ar CH), 128.8 (Ar CH), 128.3 (Ar
CH), 127.9 (Ar CH), 127.7 (Ar CH), 87.2 (Cꢀ1), 76.2 (Cꢀ5), 75.5 (Cꢀ3), 72.7 (CH2Ph), 69.7 (Cꢀ2), 67.6 (Cꢀ4), 52.8 (CH3); HRMS calcd for
C20H26O6SN [M+NH4]+: 408.1475, found 408.1472.
Methyl (phenyl 3-O-benzyl-1-thiophenyl-α-L-idopyranoside) uronate α−12
From α−18: Prepared as β–12, Rf 0.44 (EtOAc/hexane 1:1); [α]D20 = –226.8 (c = 0.55, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.54ꢀ7.52
(m, 2 H, Ph), 7.45ꢀ7.25 (m, 8 H, Ph), 5.59 (s, 1H, Hꢀ1), 5.25 (d, J = 1.5 Hz, 1 H, Hꢀ5), 4.79 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.64 (d, J = 11.9
Hz, 1 H, CH2Ph), 4.20ꢀ4.17 (m, 2 H, Hꢀ2, Hꢀ4), 3.84 (td, J = 3.3, 0.9 Hz, 1 H, Hꢀ3), 3.82 (s, 3 H, COOCH3); 13C NMR (101 MHz; CDCl3)
δ 170.7, 137.4, 136.3, 130.9, 129.0, 128.6, 128.0, 127.7, 127.3, 89.4, 74.4, 72.4, 68.9, 68.8, 68.5, 52.6; HRMS (TOF ES+) calcd for
C20H26O6SN [M+NH4]+: 408.1475, found: 408.1472. Data collected matched those previously reported (ref 3d titles as β).3d
From α−13: Lactone α−13 (76 mg) was stirred in MeOH (2 mL), Et3N (0.04 mL, 1 eq.) for 1.5 h, removal of solvents and crystallization
from EtOAc:hexane (1:3) providing α−12.
3-O-Benzyl-1-thiophenyl-α/β-L-idopyranoside urono-2,6-lactone 13
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Method A – 2 steps) Step 1: The thioglycoside diacetate 14 (12.0 g, 25.3 mmol) was dissolved in THF / MeOH (130 mL 10:3 v:v), cooled
to 0 °C and KOH (4.33 g, 77.1 mmol) dissolved in H2O (80 mL) added. After stirring for 2 h, the reaction was extracted with EtOAc (300
mL)/ HCl 0.3 M (300 mL) and the organic phase dried (MgSO4), filtered and evaporated. The crude was purified using silica gel flash
column chromatography (EtOAc/hexane, 1:1 v:v + 1% HCOOH). This yielded intermediate iduronic acid thioglycoside 15 (9.1 g, 95%,
α/β 1:3) as a foam. HRMS (ES+) calcd for C19H20NaSO6 [M+Na]+: 399.0873, found: 399.0875. The α/βꢀanomers could not be separated
and were used as such for the next step.
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Step 2: The iduronic acid thioglycoside mixture 15 (9.5 g, 25.3 mmol) was dissolved in dry DCM (200 mL), cooled to 0 °C, 1ꢀ
methylimidazole (2.11 mL, 26.6 mmol) and after 5 min., tosyl chloride (5.05 g, 26.5 mmol) added in one portion. The reaction mixture
was stirred for 1 h and another portion of 1ꢀmethylimidazole (2.12 mL, 26.7 mmol) added over 10 min. After stirring for 3 h, the reaction
was extracted with DCM (300 mL)/ H2O (2 x 200 mL) and the organic phase dried (MgSO4), filtered and evaporated. The crude was puriꢀ
fied using silica gel flash column chromatography (toluene/acetone 30:1 to 20:1) separating the α/βꢀanomers. This yielded α–13 (2.2 g,
22%) and β–13 (6.1 g, 68%) as white solids after crystallization (dissolved in EtOAc and 4 times volume of hexane).
Method B) The thioglycoside diol mixture 12 (1.20 g, 3.08 mmol) was dissolved in toluene (50 mL) and (Bu3Sn)2O (0.80 mL, 1.54 mmol)
added. The reaction mixture was heated to reflux for 3 h, solvent evaporated and the crude was purified using silica flash column chromaꢀ
tography (EtOAc/hexane 1:3). This yielded 13 (0.86 g, 78%, α/β 1:3). α–13: Rf 0.25 (EtOAc/hexane 1:3); mp 112ꢀ113 °C; [α]D20 = ꢀ236.7
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(c = 0.55, CH2Cl2); H NMR (400 MHz; CDCl3) δ 7.54ꢀ7.28 (m, 10H, Ph), 5.50 (dd, J = 2.0, 1.6 Hz, 1H, Hꢀ3), 4.98ꢀ4.96 (m, 1H, Hꢀ2),
4.81 (d, J = 11.6 Hz, CH2Ph), 4.72 (d, J = 11.6 Hz, CH2Ph), 4.43 (t, J = 3.6 Hz, 1H, Hꢀ4), 4.31 (d, J = 3.7 Hz, 1H, Hꢀ5), 3.90 (dt, J = 3.5,
1.4 Hz, 1H, Hꢀ3), 3.18ꢀ3.14 (broad s, 1H, OH); 13C NMR (101 MHz; CDCl3) δ 168.4, 136.8, 135.6, 131.2, 129.4, 128.7, 128.4, 128.1,
127.9, 83.1, 80.5, 74.7, 72.5, 71.9, 71.2; MS (TOF ES+) calcd for C19H18NaO5S [M+Na]+: 381.0768, found: 381.0769; β–13: Rf 0.19
(EtOAc/hexane 1:3); mp 77ꢀ78°C; [α]D20 = +149.8 (c = 0.56, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.52ꢀ7.30 (m, 10H, Ph), 5.70 (d, J =
0.8 Hz, 1H, Hꢀ1), 4.88 (d, J = 4.2 Hz, 1H, Hꢀ2), 4.73ꢀ4.58 (m, 2H, CH2Ph), 4.35 (d, J = 4.2 Hz, 1H, Hꢀ5), 4.22ꢀ4.20 (m, 1H, Hꢀ4), 3.87
(dd, J = 4.2, 1.8 Hz, 1H, Hꢀ3), 3.19ꢀ3.15 (broad s, 1H, OH); 13C NMR (101 MHz; CDCl3) δ 168.7, 136.7, 132.7, 132.5, 129.3, 128.8,
128.5, 128.2, 128.1, 80.9, 79.1, 77.0, 72.5, 71.8, 71.5; HRMS (TOF ES+) calcd for C19H18NaO5S [M+Na]+: 381.0768, found: 381.0769.
4-O-Benzoyl-3-O-benzyl-1-thiophenyl-β-L-idopyranoside urono-2,6-lactone 16
The thiolactone 13 (1.03 g, 2.88 mmol) was dissolved in dry DCM (10 mL), pyridine (0.30 mL, 3.74 mmol) and benzoyl chloride (0.40
mL, 3.46 mmol) added. After stirring 4 h the reaction was extracted with DCM (100 mL)/H2O (100 mL) and NaHCO3 sat. (50 mL). The
organic phase was dried (MgSO4), filtered and evaporated. The crude was purified using silica flash column chromatography
(EtOAc/hexane 1:3 v:v). This yielded 16 (1.15 g, 87%) as cubic crystals after crystallization (dissolved in EtOAc and 4 times volume of
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hexane). Rf 0.32 (EtOAc/hexane 1:4 v:v); mp 122ꢀ123 °C; [α]D20 = +166.2 (c = 0.66, CH2Cl2); H NMR (400 MHz; CDCl3) δ 7.94ꢀ7.91
(m, 2H, Bz), 7.58ꢀ7.24 (m, 13H, Ph), 5.80 (d, J = 1.0 Hz, 1H, Hꢀ1), 5.39 (ddd, J = 4.4, 1.8, 0.8 Hz, 1H, Hꢀ4), 4.89 (dt, J = 4.4, 0.9 Hz, 1H,
Hꢀ2), 4.79 (d, J = 11.8 Hz, 1H), 4.59 (d, J = 11.8 Hz, 1H), 4.52 (dd, J = 4.4, 0.4 Hz, 1H, Hꢀ5), 4.00 (ddd, J = 4.4, 1.8, 0.6 Hz, 1H, Hꢀ3);
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13C NMR (101 MHz; CDCl3) δ 166.5, 164.7, 136.3, 134.1, 132.6, 132.5, 130.0, 129.3, 128.8, 128.7, 128.59, 128.4, 128.3, 128.2, 81.5,
76.8, 76.5, 72.7, 71.9, 69.2; HRMS (TOF ES+) calcd for C26H22NaO6S [M+Na]+: 485.1029, found: 485.1030.
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3-O-Benzyl-4-O-t-butyldimethylsilyl-1-thiophenyl-β-L-idopyranoside urono-2,6-lactone β–17. Lactone β–13 (3.01 g, 8.41 mmol), was
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dissolved in dry DCM (50 mL), imidazole (858 mg, 1.5 eq., 12.60 mmol) and TBDSMCl (1.65 g, 1.3 eq., 10.9 mmol) were added and the
reaction mixture was stirred overnight. Imidazole (170 mg, 0.3 eq., 2.50 mmol) and TBDSMCl (250 mg, 0.2 eq., 1.65 mmol) were added
and the reaction mixture was stirred overnight. The crude product was extracted with DCM (300 mL)/ H2O (2 x 150 mL), the organic
phase was dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (5:1 hexane/EtOAc) yielded β–17 as a
yellow oil (2.70 g, 5.72 mmol, 68%). Rf 0.47 (EtOAc/hexane 1:7); [α]D20 = +92.5 (c = 0.40, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.51ꢀ
7.49 (2 H, m, Bz), 7.38ꢀ7.26 (8 H, m, Ph), 5.66 (1 H, d, J = 0.8 Hz, Hꢀ1), 4.84 (1 H, d, J = 4.2 Hz, Hꢀ2), 4.65 (1 H, d, J = 11.7, CH2Ph),
4.56 (1 H, d, J = 11.7, CH2Ph), 4.19 (1 H, d, J = 4.4 Hz, Hꢀ5), 4.14 (1 H, ddd, J = 4.0, 1.2, 0.7 Hz, Hꢀ4), 3.84 (1 H, ddd, J = 4.2, 1.8, 0.4
Hz, Hꢀ3), 0.87 (9 H, s, OSiC(CH3)3), 0.10 (6 H, s, OSi(CH3)2); 13C NMR (101 MHz; CDCl3) δ 167.0, 136.7, 132.6, 129.3, 128.9, 128.6,
128.1, 128.0, 81.0, 80.7, 76.3, 72.8, 72.7, 72.2, 25.6, 17.9, ꢀ4.5, ꢀ4.8; HRMS (TOF ES+) calcd for C25H36O5SSiN [M+NH4]+: 490.2078,
found: 490.2067.
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3-O-Benzyl-4-O-t-butyldimethylsilyl-1-thiophenyl-α-L-idopyranoside urono-2,6-lactone α–17. Prepared as β–17 (6.8g scale). Rf 0.43
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(EtOAc/hexane 1:7 v:v); [α]D20 = –153.4 (c = 0.90, CH2Cl2); H NMR (400 MHz; CDCl3) δ 7.51ꢀ7.48 (2 H, m, Bz), 7.43ꢀ7.30 (8 H, m,
Ph), 5.48 (1 H, t, J = 1.6 Hz, Hꢀ1), 4.97 (1 H, ddd, J 3.5, 2.1, 0.6 Hz, Hꢀ2), 4.82 (1 H, d, J = 11.6 Hz, CH2Ph), 4.64 (1 H, d, J = 11.6 Hz,
CH2Ph), 4.37 (1 H, ddd, J = 3.9, 3.1, 0.6 Hz, Hꢀ4), 4.19 (1 H, d, J = 3.9 Hz, Hꢀ5), 3.86 (1 H, td, J = 3.3, 1.4 Hz, Hꢀ3), 0.86 (9 H, s,
OSiC(CH3)3), 0.11 (6 H, d, J = 6.3 Hz, OSi(CH3)2); 13C NMR (101 MHz; CDCl3) δ 167.2, 136.5, 135.7, 131.0, 129.3, 128.6, 128.3, 128.2,
127.8, 83.3, 81.5, 74.0, 72.5, 72.4, 72.3, 25.5, 17.8, ꢀ4.73, ꢀ4.88; HRMS (TOF ES+) calcd for C25H36O5SSiN [M+NH4]+: 490.2078, found:
490.2064.
Methyl (3-O-benzyl-4-O-t-butyldimethylsilyl-1-thiophenyl-β-L-idopyranoside) uronate β–18. Lactone β–17 (2.70 g, 5.70 mmol) was
dissolved in MeOH (30 mL), Et3N (790 ꢁL, 1 eq., 5.70 mmol) added and the reaction mixture stirred at RT for 72 h. Et3N (790 ꢁL, 1 eq.,
5.70 mmol) was added and the reaction stirred for another 3 h. The solvent was removed and the crude product purified by column
chromatography (hexane/ethyl acetate 7:1 v:v) to afford β–18 as a clear solid (1.73 g, 3.41 mmol, 60%) along with recovered starting
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material (500 mg, 1.06 mmol, 19%). Rf 0.30 (EtOAc/hexane 1:7 v:v); [α]D20 = +52.9 (c = 0.90, CH2Cl2); H NMR (400 MHz; CDCl3) δ
7.57ꢀ7.55 (2 H, m, Bz), 7.37ꢀ7.29 (8 H, m, Ph), 5.19 (1 H, d, J = 1.1 Hz, Hꢀ1), 4.68 (1 H, d, J = 12.0 Hz, CH2Ph), 4.58ꢀ4.55 (2 H, m,
CH2Ph, Hꢀ5), 4.12 (1 H, t, J = 1.6 Hz, Hꢀ4), 3.94ꢀ3.93 (1 H, m, Hꢀ2), 3.81 (3 H, s, COOCH3), 3.75 (1 H, t, 3.2 Hz, Hꢀ3), 0.86 (9 H, s,
OSiC(CH3)3), ꢀ0.01 (6 H, d, J = 3.1 Hz, OSi(CH3)2); 13C NMR (101 MHz; CDCl3) δ 169.2, 137.1, 135.7, 130.7, 128.9, 128.7, 128.4, 128.0,
127.0, 87.5, 77.4, 77.1, 76.8, 76.5, 75.4, 72.4, 69.8, 69.0, 52.3, 25.6, 17.9, ꢀ4.9, ꢀ5.4; HRMS (TOF ES+) calcd for C26H40O6SSiN
[M+NH4]+: 522.2340, found: 522.2328.
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Methyl (3-O-benzyl-4-O-t-butyldimethylsilyl-1-thiophenyl-α-
L
-idopyranoside) uronate α–18. Lactone α–17 (15 mg, 40 ꢁmol) was
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crude product purified by column chromatography (7:1 hexane/ethyl acetate) to afford α–18 as a clear solid (17 mg, 36 ꢁmol, 90%).Rf 0.38
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(EtOAc/hexane 1:7); [α]D20 = –131.9 (c = 0.85, CH2Cl2); H NMR (400 MHz; CDCl3) δ 7.53ꢀ7.50 (2 H, m, Bz), 7.42ꢀ7.30 (7 H, m, Ph),
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4.18ꢀ4.17 (1 H, m, Hꢀ4), 4.06ꢀ4.05 (1 H, m, Hꢀ2), 3.79 (3 H, s, COOCH3), 3.66 (1 H, t, J = 2.8 Hz, Hꢀ3), 0.83 (9 H, s, OSiC(CH3)3), ꢀ0.02
(6 H, d, J = 7.4 Hz, OSi(CH3)2); 13C NMR (101 MHz; CDCl3) δ 169.8, 137.3, 136.6, 130.7, 129.0, 128.6, 128.2, 127.9, 127.1, 89.7, 74.0,
72.2, 69.9, 69.1, 68.9, 52.3, 25.5, 17.8, ꢀ4.8, ꢀ5.6; HRMS (TOF ES+) C26H40O6SSiN [M+NH4]+: 522.2340, found: 522.2329.
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Methyl (2-O-acetyl-3-O-benzyl-4-O-t-butyldimethylsilyl-1-thiophenyl-β-L-idopyranoside) uronate β–19: Iduronate β–18 (104 mg,
0.21 mmol) was dissolved in dry CH2Cl2 (5 mL), pyridine (25 ꢁL, 0.31 mmol) and DMAP (10 mg, 0.10 mmol) were added, Ac2O (60 ꢁL,
0.63 mmol) was added dropwise and the reaction mixture stirred ar RT for 72 h. EtOH (2 mL) was added, the solvents were removed and
the resulting oil purified by column chromatography (6:1 hexane/EtOAc) to afford 19 as a clear oil (91 mg, 0.17 mmol, 79%). Rf = 0.28
(EtOAc/hexane 1:7); [α]D20 = +22.8 (c = 0.55, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.46 (2 H, dt, J = 6.4, 1.7 Hz, Bz), 7.27ꢀ7.15 (10 H,
m, Ph), 5.05 (1 H, d, J = 1.8, Hꢀ1), 4.98 (1 H, dt, J = 3.0, 1.3 Hz, Hꢀ5), 4.66 (1 H, d, J = 12.1 Hz, CH2Ph), 4.51 (1 H, d, J = 12.1 Hz,
CH2Ph), 4.37 (1 H, d, J = 1.8 Hz, Hꢀ2), 3.87 (1 H, dt, J = 3.0, 1.3 Hz, Hꢀ3), 3.70 (3 H, s, COOCH3), 3.59 (1 H, t, J = 2.6 Hz, Hꢀ4), 2.02 (3
H, s, COCH3), 0.70 (9 H, s, OSiC(CH3)3), ꢀ0.21 (3 H, s, OSi(CH3)2), ꢀ0.32 (3 H, s, OSi(CH3)2); 13C NMR (101 MHz; CDCl3) δ 171.2,
169.5, 137.4, 135.4, 131.6, 131.1, 129.3, 129.0, 128.8, 128.7, 128.3, 127.8, 85.2, 74.6, 72.7, 69.8, 68.3, 52.6, 26.0, 21.4, 18.3, ꢀ4.3, ꢀ5.3;
HRMS (TOF ES+) C28H42O7SSiN [M+NH4]+: 564.2446, found: 564.2440.
2-Azido-3,6-di-O-benzyl-2-deoxy-4-O-p-methoxybenzyl-α-D-glucopyranosyl-(1⟶4)-(phenyl 3-O-benzyl-1-thio-β-L-idopyranoside)
urono-2,6-lactone 21
Acceptor thioglycoside βꢀ13 (2.72 g, 7.59 mmol) and thioglycoside donor 20 (5.62 g, 9.41 mmol) were dissolved in dry toluene (50 mL)
under N2. Freshly activated 4Å powdered molecular sieves (2.7 g) were added and the solution cooled to 0 °C in an ice bath. After 10 min
NIS (4.21 g, 18.7 mmol) was added, and after another 10 min AgOTf (38 mg, 0.15 mmol) was added. The suspension changed colour from
pale yellow to deep red, was stirred for 30 min and more AgOTf (13 mg, 0.05 mmol) added. After another 30 min the reaction was
quenched into a separating funnel containing a mixture of CH2Cl2 (300 mL), saturated aqueous NaHCO3 (200 mL) and Na2S2O3 (40 mL,
10% aqueous). After shaking until the iodine colour was removed the suspension was filtered through a short pad of Celite washing with
water and CH2Cl2. The layers were separated and the aqueous extracted with DCM (30 mL). The organic layers were combined, dried
(MgSO4) and solvent removed in vacuo. The crude was purified by silica gel flash column chromatography (EtOAc/hexane 1:5 to 1:4 v:v)
20
to give 21 (5.20 g, 81%) as a white foam. The βꢀanomer product (0.90 g, 14 %) was also isolated. Rf 0.15 (EtOAc/hexane 1:4 v:v); [α]D
=
+132.5 (c = 0.28, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.57ꢀ7.32 (m, 20H, Ph), 7.11 (d, J = 8.8 Hz, 2H, PMB), 6.86 (d, J = 8.8 Hz, 2H,
PMB), 5.75 (d, J = 0.8 Hz, 1H, HAꢀ1), 5.04 (d, J = 3.8 Hz, 1H, HBꢀ1), 4.96 (d, J = 10.7 Hz, 1H, CH2Ph), 4.91ꢀ4.87 (m, 2H, HAꢀ5, CH2Ph),
4.77 (d, J = 12.0 Hz, 1H, CH2Ph), 4.74 (d, J = 2.4 Hz, 1H, HAꢀ2), 4.71ꢀ4.66 (m, 3H, CH2Ph), 4.54ꢀ4.49 (m, 2H, CH2Ph), 4.11 (dd, J = 3.9,
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2.4 Hz, 1H, HAꢀ4), 4.03 (dd, J = 4.0, 2.4 Hz, 1H, HAꢀ3), 3.93ꢀ3.76 (m, 5H, HBꢀ3, HBꢀ4, HBꢀ5, HBꢀ6ab), 3.82 (s, 3H, PhOCH3), 3.45 (dd, J =
10.2, 3.7 Hz, 1H, HBꢀ2); 13C NMR (101 MHz; CDCl3) δ 167.0, 159.3, 137.9, 137.8, 136.5, 132.7, 132.5, 130.0, 129.5, 129.3, 128.8, 128.6,
128.5, 128.2, 128.1, 128.0, 128.0, 127.8, 113.8, 100.4, 81.1, 81.0, 79.7, 77.8, 77.6, 76.5, 75.5, 74.6, 73.6, 72.4, 71.9, 70.4, 68.0, 63.2, 55.3;
HRMS (TOF ES+) calcd for C47H47N3NaO10S [M+Na]+: 868.2875, found: 868.2836.
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Methyl 2-azido-3,6-di-O-benzyl-2-deoxy-4-O-p-methoxybenzyl-α-
β- -idopyranoside) uronate 23
D-glucopyranosyl-(1⟶4)-(phenyl 3-O-benzyl-2-O-benzoyl-1-thio-
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To 21 (4.40 g, 5.21 mmol) was added dry MeOH/DCM (60 mL 1:1 v:v) and a catalytic amount of NaOMe (25% in MeOH, 0.1 mL) while
kept under N2. The mixture was stirred for 6 h, quenched by addition of AcOH (0.1 mL) and solvent evaporated. The crude was extracted
with DCM (200 mL)/H2O (200 mL) and NaHCO3 sat. (200 mL). The organic phase was dried (MgSO4), filtered and evaporated. The crude
was purified by silica gel flash column chromatography (EtOAc/hexane 1:4 to 1:3 v:v) to yield disaccharide 22 (4.05 g, 89%) as a white
foam. Rf 0.22 (EtOAc/hexane 1:3 v:v); [α]D20 = +98.6 (c = 1.4, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.62ꢀ7.28 (m, 20H, Ph), 7.09 (d, J
= 8.8 Hz, 2H, PMB), 6.85 (d, J = 8.8 Hz, 2H, PMB), 5.22 (d, J = 1.1 Hz, 1H, HAꢀ1), 5.10 (d, J = 3.8 Hz, 1H, HBꢀ1), 4.89ꢀ4.47 (m, 9H, HAꢀ
5, 4xCH2Ph), 4.28ꢀ4.27 (m, 1H, HAꢀ4), 4.05ꢀ4.02 (m, 2H, HAꢀ2, HAꢀ3), 4.02ꢀ3.59 (m, 6H, HBꢀ2, HBꢀ3, HBꢀ4, HBꢀ5, HBꢀ6ab), 3.82 (s, 3H,
PhOCH3), 3.81 (s, 3H, COOCH3); 13C NMR (101 MHz; CDCl3) δ 169.2, 159.2, 137.75, 137.7, 136.8, 135.4, 132.2, 130.9, 130.3, 129.2,
129.0, 129.0, 129.0, 128.7, 128.6, 128.6, 128.5, 128.5, 128.4, 128.2, 128.1, 128.0, 128.0, 127.9, 127.8, 127.2, 113.7, 94.7, 87.8, 81.2, 77.2,
75.9, 75.4, 74.4, 73.6, 72.7, 71.9, 71.6, 70.4, 69.3, 67.7, 63.6, 55.3, 52.7; HRMS (TOF ES+) calcd for C48H51N3NaO11S [M+Na]+:
900.3137, found: 900.3144. The 2ꢀOH disaccharide intermediate 22 (7.92 g, 9.03 mmol) was dissolved in dry CH2Cl2 (100 mL), 1ꢀ
methylimidazole (1.07 mL, 13.5 mmol) and benzoyl chloride (1.36 mL, 11.7 mmol) were added. After stirring 8 h the reaction was exꢀ
tracted with DCM (300 mL)/H2O (300 mL) and washed with brine (100 mL). The organic phase was dried (MgSO4), filtered and evapoꢀ
rated. The crude was purified using silica flash column chromatography (EtOAc/hexane 1:4 v:v). This yielded 23 (6.43 g, 73%) as a white
foam. Analytical data matched those previously reported.8
2-Azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-D-glucopyranosyl-(1⟶4)-( phenyl 3-O-benzyl-1-thio-β-L-idopyranoside) urono-
2,6-lactone 25
Acceptor thioglycoside 13 (3.68 g, 10.3 mmol) and thioglycoside donor 24 (6.66 g, 14.0 mmol) was dissolved in dry DCM (50 mL) under
N2. Freshly activated 4Å powdered molecular sieves (2.7 g) were added and the solution cooled to 0 °C in an icebath. After 10 min. NIS
(4.53 g, 20.1 mmol) was added, and after another 10 min. AgOTf (65 mg, 0.26 mmol) was added. The suspension changed colour from
pale yellow to deep red, was stirred for 1 h, more AgOTf (62 mg, 0.25 mmol) added. After another 1 h the reaction was quenched into a
separating funnel containing a mixture of CH2Cl2 (300 mL), saturated aqueous NaHCO3 (250 mL) and Na2S2O3 (50 mL, 10% aqueous).
After shaking until the iodine colour was removed, the suspension was filtered through a short pad of Celite®, washing with water and
CH2Cl2. The layers were separated and the aqueous extracted with CH2Cl2 (50 mL). The organic layers were combined, dried (MgSO4) and
solvent removed in vacuo. The crude was purified by silica gel flash column chromatography (EtOAc/hexane 1:5 to 1:4 to 1:3 v:v) to give
25 (4.20 g, 57%) as white needles after crystallization (dissolved in EtOAc and 3 times the volume of hexane added). Rf 0.14
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(EtOAc/hexane 1:4 v:v); mp 143ꢀ144 °C; [α]D20 = +109.2 (c = 0.45, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.53ꢀ7.32 (m, 20H, Ph), 5.71
(d, J = 0.8 Hz, 1H, HAꢀ1), 5.56 (s, 1H, O2CH), 4.98 (d, J = 11.0 Hz, 1H, CH2Ph), 4.91 (d, J = 3.9 Hz, 1H, HBꢀ1), 4.87 (d, J = 4.2 Hz, 1H,
HAꢀ2), 4.79 (d, J = 11.0 Hz, 1H, CH2Ph), 4.75 (d, J = 11.8 Hz, 1H, CH2Ph), 4.66 (d, J = 11.8 Hz, 1H, CH2Ph), 4.53 (d, J = 4.0 Hz, 1H, HAꢀ
5), 4.43 (dd, J = 10.1, 4.9 Hz, 1H, HBꢀ6a), 4.08 (dd, J = 4.0, 2.3 Hz, 1H, HAꢀ4), 4.02ꢀ3.96 (m, 2H, HBꢀ3, HAꢀ4), 3.87 (dt, J = 9.9, 4.9 Hz,
1H, HBꢀ5), 3.73ꢀ3.67 (m, 2H, HBꢀ4, HBꢀ6b), 3.41 (dd, J = 10.0, 3.9 Hz, 1H, HBꢀ2); 13C NMR (101 MHz; CDCl3) δ 166.7, 137.8, 137.2,
136.5, 132.6, 132.6, 129.3, 129.1, 128.8, 128.6, 128.5, 128.3, 128.3, 128.2, 128.0, 126.2, 101.5, 100.3, 82.3, 81.1, 81.0, 77.7, 76.5, 76.0,
75.2, 72.5, 70.5, 68.5, 63.8, 62.8; HRMS (TOF ES+) calcd for C39H37N3NaO9S [M+Na]+: 746.2143, found: 746.2124.
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Methyl
2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-D-glucopyranosyl-(1⟶4)-(phenyl-2-O-benzoyl-3-O-benzyl-1-thio-β-L-
idopyranoside) uronate 26
To 25 (3.49 g, 4.83 mmol) was added dry MeOH/ CH2Cl2 (90 mL, 8:1 v:v) and a catalytic amount NaOMe (25% in MeOH, 0.3 mL) while
kept under N2. The mixture was stirred 2 h, quenched by addition of AcOH (0.1 mL) and solvent evaporated. The crude was extracted with
CH2Cl2 (300 mL)/H2O (200 mL) and NaHCO3 sat. (200 mL). The organic phase was dried (MgSO4), filtered and evaporated. The crude
was purified by silica gel flash column chromatography (EtOAc/hexane 1:4 to 1:3 v:v) to yield intermediate 2ꢀOH disaccharide (2.92 g,
80%) as white needles after crystallization (dissolved in EtOAc and hexane 4 times the volume added). Rf 0.26 (EtOAc/hexane 1:3 v:v);
mp 197ꢀ198 °C; [α]D20 = +78.3 (c = 0.26, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.61ꢀ7.24 (m, 20H, Ph), 5.54 (s, 1H, PhCHO2), 5.19 (d,
J = 1.4 Hz, 1H, HAꢀ1), 4.94ꢀ4.90 (m, 2H, CH2Ph, HBꢀ1), 4.78 (d, J = 10.6 Hz, 1H, CH2Ph), 4.69ꢀ4.61 (m, 3H, HAꢀ5, 2xCH2Ph), 4.29 (dd, J
= 10.1, 4.7 Hz, 1H, HBꢀ6a), 4.21ꢀ4.20 (m, 1H, HAꢀ4), 4.08ꢀ4.01 (m, 2H, HAꢀ2, HBꢀ4), 3.95 (t, J = 2.8 Hz, 1H, HAꢀ3), 3.89 (s, 3H,
COOCH3), 3.74ꢀ3.56 (m, 4H, HBꢀ2, HBꢀ3, HBꢀ5, HBꢀ6b); 13C NMR (101 MHz; CDCl3) δ 169.1, 137.7, 137.2, 136.8, 135.4, 131.1, 129.2,
129.0, 128.8, 128.5, 128.4, 128.3, 128.0, 127.8, 127.3, 126.1, 101.6, 95.3, 88.1, 81.9, 78.0, 75.5, 75.2, 72.6, 72.2, 71.1, 69.2, 68.3, 63.4,
63.0, 53.0; HRMS (TOF ES+) calcd for C40H42N3O10S [M+H]+: 756.2586, found: 756.2587.
The intermediate 2ꢀOH disaccharide (2.83 g, 3.74 mmol) was dissolved in dry DCM (50 mL), 1ꢀmethylimidazole (0.44 mL, 5.61 mmol)
and benzoyl chloride (0.57 mL, 4.86 mmol) added. After stirring 12 h the reaction was extracted with DCM (200 mL)/H2O (200 mL) and
brine (100 mL). The organic phase was dried (MgSO4), filtered and evaporated. The crude was purified using silica flash column chromaꢀ
tography (EtOAc/hexane 1:4 v:v). This yielded 26 (2.48 g, 77%) as white needles after crystallization (dissolved in EtOAc and hexane 4
times the volume added). Rf 0.11 (EtOAc/hexane 1:4 v:v). mp 172ꢀ173 °C; [α]D20 = +4.2 (c = 0.35, CH2Cl2); 1H NMR (400 MHz; CDCl3)
δ 8.28ꢀ8.26 (m, 2H, Bz), 7.63ꢀ7.09 (m, 23H, Ph), 5.51 (s, 1H, PhCHO2), 5.34 (d, J = 1.8 Hz, 1H, HAꢀ1), 5.31ꢀ5.29 (m, 1H, HAꢀ2), 4.90 (d, J
= 11.6 Hz, 1H, CH2Ph), 4.80 (d, J = 11.6 Hz, 1H, CH2Ph ), 4.63 (d, J = 3.7 Hz, 1H, HBꢀ1), 4.60 (d, J = 1.5 Hz, 1H, HAꢀ5), 4.39 (dd, J =
10.1, 4.9 Hz, 1H, HBꢀ6a), 4.35 (t, J = 2.5 Hz, 1H, HAꢀ3), 4.29 (d, J = 10.6 Hz, 1H, CH2Ph), 4.08ꢀ4.02 (m, 2H, HAꢀ4, HBꢀ5), 3.84 (s, 3H,
COOCH3), 3.76ꢀ3.73 (m, 1H, CH2Ph), 3.64 (t, J = 10.2 Hz, 1H, HBꢀ6b), 3.57ꢀ3.49 (m, 2H, HBꢀ3, HBꢀ4), 3.23 (dd, J = 9.5, 3.6 Hz, 1H, HBꢀ
2); 13C NMR (101 MHz; CDCl3) δ 168.7, 166.2, 137.9, 137.6, 137.0, 134.7, 133.3, 131.4, 130.2, 129.7, 129.1, 129.1, 128.9, 128.6, 128.4,
128.3, 128.0, 127.8, 127.7, 126.2, 101.4, 99.9, 85.9, 82.3, 77.0, 75.7, 75.5, 74.8, 73.0, 70.1, 68.5, 63.5, 63.2, 52.5; HRMS (TOF ES+) calcd
for C47H45N3NaO11S [M+Na]+: 882.2668, found: 882.2631.
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1
Methyl 2-azido-3,6-di-O-benzyl-2-deoxy-4-O-trichloroacetyl-α-
-idopyranoside) uronate 27
D-glucopyranosyl-(1⟶4)-(phenyl-2-O-benzoyl-3-O-benzyl-1-thio-β-
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The disaccharide 26 (777 mg, 0.902 mmol) was dissolved in dry CH2Cl2 (8 mL), cooled to 0 °C, triethylsilane (0.29 mL, 1.80 mmol) and
borontrifluoride etherate (0.22 mL, 1.80 mmol) added. After stirring 2 h more reagents, triethylsilane (0.29 mL, 1.80 mmol) and borontriꢀ
fluoride etherate (0.22 mL, 1.80 mmol) added and stirred another 2 h. The reaction was extracted with CH2Cl2 (50 mL)/ NaHCO3 sat. (50
mL). The organic phase was dried (MgSO4), filtered and evaporated. The crude was purified using silica flash column chromatography
(EtOAc/hexane 1:3 v:v). This yielded 27 (583 mg, 75%) as a foam. Also starting material 26 (80 mg, 10%) and the 4,6ꢀdiꢀOH product (99
mg, 14%) were isolated from the column. Analytical data for this compound and the subsequent 4ꢀOH acylation step (with trichloroacetyl
chloride) are as reported previously.8
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Methyl
2-azido-3-O-benzyl-2-deoxy-α-D-glucopyranosyl-(1⟶4)-(phenyl-2-O-benzoyl-3-O-benzyl-1-thio-β-L-idopyranoside)
uronate 28
The disaccharide 26 (740 mg, 0.859 mmol) was dissolved in dry CH2Cl2 (10 mL), EtSH (0.6 mL, 8.6 mmol) and pꢀtoluenesulfonic acid (20
mg, 0.086 mmol) added. After stirring 90 min. the reaction was quenched with NEt3 (5 drops) and solvents removed. The reaction was
extracted with CH2Cl2 (50 mL)/NaHCO3 sat. (50 mL). The organic phase was dried (MgSO4), filtered and evaporated. The crude was puriꢀ
fied using silica flash column chromatography (EtOAc/hexane 1:1 v:v). This yielded 28 (662 mg, 99%) as a foam. Rf 0.15 (EtOAc/hexane
1:1); [α]D20 = +67.0 (c = 0.40, CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 8.29ꢀ8.27 (m, 2H, Bz), 7.60ꢀ7.09 (m, 18H, Ph), 5.31 (d, J = 1.9 Hz,
1H, HAꢀ1), 5.26ꢀ5.25 (m, 1H, HAꢀ2), 4.91ꢀ4.77 (m, 2H, CH2Ph), 4.57 (d, J = 3.6 Hz, 1H, HBꢀ1), 4.56 (d, J = 1.5 Hz, 1H, HAꢀ5), 4.33 (t, J =
2.5 Hz, 1H, HAꢀ3), 4.01ꢀ4.00 (m, 1H, HAꢀ4), 3.96 (d, J = 10.9 Hz, 1H, CH2Ph), 3.86 (d, J = 10.8 Hz, CH2Ph), , 3.83ꢀ3.75 (m, 3H, HBꢀ5,
HBꢀ6ab), 3.81 (s, 3H, COOCH3), 3.43 (dt, J = 9.3, 4.2 Hz, 1H, HBꢀ4), 3.43 (dd, J = 10.0, 8.8 Hz, 1H, HBꢀ3), 3.09 (dd, J = 10.1, 3.6 Hz, 1H,
HBꢀ2), 2.65 (d, J = 4.3 Hz, 1H, 4ꢀOH), 2.49 (t, J = 5.7 Hz, 1H, 6ꢀOH); 13C NMR (101 MHz; CDCl3) δ 169.0, 166.3, 137.9, 137.0, 134.6,
133.5, 131.5, 130.3, 129.8, 129.2, 128.9, 128.7, 128.5, 128.5, 128.4, 127.9, 127.8, 99.5, 86.2, 80.3, 75.7, 75.4, 74.8, 73.0, 72.8, 72.7, 71.3,
70.2, 63.4, 62.3, 52.7; HRMS (TOF ES+) calcd for C40H42N3O11S [M+H]+: 772.2535, found: 772.2532.
Methyl 2-azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-trichloroacetyl-α-
1-thio-β- -idopyranoside) uronate 29
D-glucopyranosyl-(1⟶4)-(phenyl 3-O-benzyl-2-O-benzoyl-
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The disaccharide 28 (600 mg, 0.776 mmol) was dissolved in dry DCM (10 mL), pyridine (0.16 mL, 1.94 mmol) and benzoyl chloride (99
ꢀL, 0.854 mmol) added. After stirring 3 h trichloroacetyl chloride (104 ꢀL, 0.931 mmol) was added and left overnight. The reaction was
extracted with DCM (50 mL)/ H2O (50 mL) and NaHCO3 sat. (20 mL). The organic phase was dried (MgSO4), filtered and evaporated.
The crude was purified using silica flash column chromatography (EtOAc/hexane 1:4). This yielded 29 (606 mg, 77%) as a foam. Also the
diꢀ4,6ꢀOꢀtrichloroacetyl product 113 mg (14%) and the 6ꢀOꢀbenzoylꢀ4ꢀOH product 55 mg (8%) were isolated from the column. Rf 0.13
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(EtOAc/hexane 1:4); [α]D20 = +108.6 (c = 0.21, CH2Cl2); H NMR (400 MHz; CDCl3) δ 8.27ꢀ8.25 (m, 2H, Bz), 7.98ꢀ7.96 (m, 2H, Bz),
7.53ꢀ6.94 (m, 21H, Ph), 5.27 (d, J = 1.9 Hz, 1H, HAꢀ1), 5.21ꢀ5.16 (m, 2H, HAꢀ2, HBꢀ4), 4.84 (d, J = 11.7 Hz, 1H, CH2Ph), 4.76ꢀ4.71 (m,
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2H, HBꢀ6a, CH2Ph), 4.56 (d, J = 1.6 Hz, 1H, HAꢀ5), 4.54 (d, J = 3.7 Hz, 1H, HBꢀ1), 4.31 (t, J = 2.5 Hz, 1H, HAꢀ3), 4.20ꢀ4.15 (m, 2H, HBꢀ5,
HBꢀ6b), 3.89ꢀ3.86 (m, 2H, HBꢀ4, CH2Ph), 3.81 (s, 3H, COOCH3), 3.57 (d, J = 10.1 Hz, 1H, CH2Ph), 3.52 (t, J = 9.6 Hz, 1H, HBꢀ3), 3.30
(dd, J = 10.0, 3.6 Hz, 1H, HBꢀ2); 13C NMR (101 MHz; CDCl3) δ 168.6, 166.2, 166.1, 160.6, 136.9, 136.7, 134.7, 133.6, 133.3, 131.2,
130.2, 130.0, 129.9, 129.6, 129.2, 129.0, 128.7, 128.6, 128.5, 128.1, 128.0, 127.8, 99.9, 89.6, 86.1, 77.9, 77.4, 76.8, 75.8, 75.0, 74.5, 73.1,
72.4, 70.4, 68.5, 63.8, 61.4, 52.7; HRMS (FT MS) calcd for C49H48Cl3N4O13S [M+NH4]+: 1037.1999, found: 1037.1999.
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Methyl (methyl 3-O-benzyl-α,β-L-idofuranoside) uronate 38 and 39
The diacetylated α,βꢀfuranoside mixture 3110 (5.37 g, 13.6 mmol) was dissolved in dry MeOH (50 mL) and a catalytic amount of sodium
added. After 90 min the solution was quenched by addition of Amberlite® IR 120 H+ resin (0.5 g) and stirred for 15 min. The resin was
filtered off and solvent removed in vacuo to give the crude material as a clear oil. This was purified by silica gel flash chromatography
(EtOAc/Hexane 2:3) to give 39 (1.13 g, 3.94 mmol, 26%) and 38
, 9.3 mmol, 70%) as oils. Further purification of 38 was
achieved by crystallization (dissolved in EtOAc and added 4 times volume hexane) to yield transparent needles. 39: Rf = 0.36
(EtOAc/hexane 3:2); [α]D20 = +2.00 (c = 0.55 CH2Cl2); 1H NMR (400 MHz; CDCl3) δ 7.29ꢀ7.21 (m, 5H, Ph), 4.69 (d, J = 2.8 Hz, 1H, Hꢀ
1), 4.66 (d, J = 12.1 Hz, 1H, CH2Ph), 4.56 (d, J = 12.1 Hz, 1H, CH2Ph), 4.53 (dd, J = 7.6, 2.0 Hz, 1H, Hꢀ4), 4.38 (dt, J = 5.2, 2.8 Hz, 1H,
Hꢀ2), 4.27 (dd, J = 10.0, 2.0 Hz, 1H, Hꢀ5), 4.10 (dd, J = 7.6, 6.0 Hz, 1H, Hꢀ3), 3.84 (d, J = 10.0 Hz, 1H, OH), 3.68 (s, 3H, COOCH3), 3.33
(s, 3H, OCH3), 3.13 (d, J = 5.2 Hz, 1H, OH); 13C NMR (100 MHz; CDCl3) δ 172.9, 137.6, 128.6, 128.0, 127.8, 109.7, 83.9, 81.4, 80.1,
73.0, 70.2, 56.2, 52.4; MS (ESI+) m/z calcd for C15H21O7 [M+H]+ 313.1282, found 313.1279. 38: Rf = 0.24 (EtOAc/hexane 3:2 v:v); Mp
85ꢀ86 °C; [α]D20 = +125.6 (c = 0.29, CH2Cl2). 1H NMR (400 MHz; CDCl3) δ 7.28ꢀ7.21 (m, 5H, Ph), 4.84 (d, J = 4.8 Hz, 1H, Hꢀ1), 4.81 (d,
J = 12.0 Hz, 1H, CH2Ph), 4.59 (d, J = 12.0 Hz, 1H, CH2Ph), 4.43 (dd, J = 7.6, 1.6 Hz, 1H, Hꢀ4), 4.38ꢀ4.33 (m, 2H, Hꢀ2, Hꢀ5), 4.12 (t, J =
7.2 Hz, 1H, Hꢀ3), 3.71 (s, 3H, COOCH3), 3.35 (s, 3H, OCH3), 3.18 (d, J = 5.6 Hz, 1H, OH), 2.65 (d, J = 9.2 Hz, 1H, OH); 13C NMR (100
MHz; CDCl3) δ 172.8, 137.6, 128.5, 127.9, 127.7, 101.5, 82.8, 77.9, 76.6, 72.5, 69.9, 55.8, 52.7; HRMS (ESI+) m/z calcd for C15H20NaO7
[M+Na]+ 335.1101, found 335.1100; Elemental analysis calcd (%) for C15H20O7: C 57.69, H 6.45; found C 57.52, H 6.32.
Methyl 3-O-benzyl-α-L-idopyranoside uronic acid 34
Monosaccharide 32 (283 mg, 0.70 mmol) was dissolved in THF / MeOH (4 mL, 3:1 v:v). The solution was cooled to 0 °C and KOH (107
mg, 2.09 mmol) in H2O (1 mL) was added dropwise. The solution was stirred for 2 h at this temperature. The reaction was extracted with
EtOAc (2 x 15 mL) and HCl (0.1 M, 15 mL) and then dried (Na2SO4), filtered and solvent removed in vacuo to give the crude material.
This was purified by crystallization from EtOAc/hexane (dissolved in 15 mL EtOAc and hexane 15 mL added) to give 34 (130 mg, 0.44
mmol, 63%) as transparent needles. [α]D20 = ꢀ71.7 (c = 0.32, acetone); 1H NMR (400 MHz; MeOD) δ 7.41ꢀ7.30 (m, 5H, Ph), 4.97 (brs, 2H,
OH), 4.80ꢀ4.79 (m, 1H, Hꢀ1), 4.72 (d, J = 11.8 Hz, 1H, CH2Ph), 4.66ꢀ4.64 (m, 2H, CH2Ph, Hꢀ5), 4.06 (dddd, J = 3.6, 1.3, 1.1, 0.9 Hz, 1H,
Hꢀ4), 3.73 (ddd, J = 3.9, 2.4, 1.3 Hz, 1H, Hꢀ2), 3.69 (td, J = 3.9, 0.9 Hz, 1H, Hꢀ3), 3.44 (s, 3H, OCH3). Other analytical data matched those
previously reported by the group.14
Methyl 3-O-benzyl-β-L-idopyranoside uronic acid 35
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Monosaccharide 33 (333 mg, 0.82 mmol) was dissolved in THF / MeOH (3 mL, 2:1 v:v). The solution was cooled to 0 °C and KOH (96
mg, 1.72 mmol) in H2O (1 mL) was added dropwise. The solution was stirred for 4 h at this temperature. The reaction was extracted with
EtOAc (2 x 20 mL) and HCl (0.1 M, 15 mL) and then dried (Na2SO4), filtered and solvent removed in vacuo to give the crude material.
This was purified by silica gel flash chromatography (EtOAc/Hexane 1:1 + 1% HCOOH) to yield 35 (200 mg, 0.67 mmol, 82%) as an oil.
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Rf = 0.11 (EtOAc/hexane 1:1 + 1% HCOOH); [α]D20 = +78.6 (c = 0.29, CH2Cl2); H NMR (400 MHz; CDCl3) δ 7.41ꢀ7.25 (m, 5H, Ph),
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4.76 (d, J = 0.8 Hz, 1H, Hꢀ1), 4.70 (d, J = 11.7 Hz, 1H, CH2Ph), 4.63 (d, J = 11.7 Hz, 1H, CH2Ph), 4.57 (d, J = 1.6 Hz, 1H, Hꢀ5), 4.14ꢀ4.12
(m, 1H, Hꢀ4), 3.98 (t, J = 3.4 Hz, 1H, Hꢀ3), 3.89ꢀ3.87 (m, 1H, Hꢀ2), 3.63 (s, 3H, OCH3); 13C NMR (100 MHz; CDCl3) δ 172.1, 137.4,
128.6, 128.1, 127.8, 99.8, 75.8, 74.4, 72.5, 68.0, 67.5, 57.2; HRMS (ESI+) m/z calcd for C14H22O7N1 [M+NH4]+ 316.1391, found 316.1388;
IR νmax 3422, 2901, 1733, 1454, 1215, 1043 cmꢀ1.
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Methyl α-
L-idopyranoside uronate sodium salt 36
Compound 36 was prepared analogously to compound 37 and analyzed as reported previously.15
Methyl β-L-idopyranoside uronate sodium salt 37
Monosaccharide 35 (113 mg, 0.38 mmol) was ion exchanged with Amberlite® IRC 86 Na+ to give the sodium salt and then dissolved in
MeOH/H2O (0.5 mL/4 mL). To the flask was attached a 3ꢀway tap and purged with N2, 10ꢀ20% Pd(OH)2/C (64 mg) was added and the
system purged with H2. Vigorous stirring having a balloon with H2 attached (1 atm.) was continued for 8 h. The suspension was then filꢀ
tered through Celite® and solvents removed in vacuo to afford 37 (83 mg, 0.36 mmol, 95%) as a clear glass. Analytical data matched those
previously reported.15
Methyl 3-O-benzyl-α-L-idofuranoside uronate sodium salt 40
Monosaccharide 37 (98 mg, 0.31 mmol) was dissolved in THF (1 mL) and MeOH (0.5 mL). The solution was cooled to 0 °C and KOH (18
mg, 0.31 mmol) in H2O (0.5 mL) was added dropwise. The solution was stirred for 2 h at this temperature. The reaction was extracted with
EtOAc (2 x 15 mL) and HCl (0.1 M) (15 mL) and then dried (Na2SO4), filtered and solvent removed in vacuo to give the crude material.
This was purified by silica gel flash chromatography (EtOAc/Hexane 1:1 + 1% HCOOH) followed by ion exchange with Amberlite® IRC
86 Na+ to give the sodium salt 40 (97 mg, 0.33 mmol, 98%) as an oil. Rf = 0.11 (EtOAc/hexane 2:1 + 1% HCOOH); [α]D20 = +133.0 (c =
0.20, MeOH); 1H NMR (400 MHz; CD3OD) δ 7.41ꢀ7.25 (m, 5H, Ph), 4.83ꢀ4.67 (m, 3H, Hꢀ1, CH2Ph), 4.55 (dd, J = 7.6, 1.6 Hz, 1H, Hꢀ4),
4.41 (dd, J = 7.6, 4.8 Hz, 1H, Hꢀ2), 4.28ꢀ4.24 (m, 2H, Hꢀ3, Hꢀ5), 3.38 (s, 3H, OCH3); 13C NMR (100 MHz; CD3OD): δ 177.3, 139.5,
129.4, 128.8, 128.7, 102.9, 83.5, 79.3, 77.2, 73.9, 71.2, 55.6; MS (ESI+) m/z calcd for C14H22O7N1 [M+NH4]+ 316.1391, found 316.1389.
Methyl 3-O-benzyl-β-L-idofuranoside uronate sodium salt 41
Monosaccharide 39 (125 mg, 0.40 mmol) was dissolved in THF (1 mL) and MeOH (0.5 mL). The solution was cooled to 0 °C and KOH
(22 mg, 0.40 mmol) in H2O (1 mL) was added dropwise. The solution was stirred for 2 h at this temperature. The reaction was extracted
with EtOAc (2 x 15 mL) and HCl (0.1 M) (15 mL) and then dried (MgSO4), filtered and solvent removed in vacuo to give the crude mateꢀ
rial. This was purified by silica gel flash chromatography (EtOAc/Hexane 1:1 + 1% HCOOH) followed by ion exchange with Amberlite®
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IRC 86 Na+ to give the sodium salt 41 (96 mg, 0.32 mmol, 75%) as an oil. Rf = 0.28 (EtOAc + 1% HCOOH); [α]D20 = ꢀ34.7 (c = 0.43,
MeOH); 1H NMR (400 MHz; CD3OD) δ 7.39ꢀ7.25 (m, 5H, Ph), 4.76 (d, J = 2.0 Hz, 1H, Hꢀ1), 4.72 (d, J = 11.7 Hz, 1H, CH2Ph), 4.65 (dd,
J = 6.8, 3.6 Hz, 1H, Hꢀ4), 4.60 (d, J = 11.7 Hz, 1H, CH2Ph), 4.30 (dd, J = 4.2, 2.0 Hz, 1H, Hꢀ2), 4.24 (d, J = 3.6 Hz, 1H, Hꢀ5), 4.12 (dd, J
= 6.8, 4.4 Hz, 1H, Hꢀ3), 3.40 (s, 3H, OCH3); 13C NMR (100 MHz; CD3OD) δ 176.2, 139.2, 129.3, 129.0, 128.8, 111.1, 85.4, 82.9, 80.0,
73.7, 71.7, 56.3; HRMS (ESIꢀ) m/z calcd for C14H18O7Na [M+Na]+ 321.0945, found 321.0941.
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Methyl α-L-idofuranoside uronate sodium salt 42
Monosaccharide 40 (25 mg, 91 ꢁmol) was dissolved in H2O (3 mL). To the flask was attached a 3ꢀway tap and purged with N2, 10ꢀ20%
Pd(OH)2/C (70 mg) was added and the system purged with H2. Vigorous stirring having a balloon with H2 attached (1 atm) was continued
for 12 h. The suspension was then filtered through Celite® and solvents removed in vacuo to provide 42 (12 mg, 52 ꢁmol, 57%) as a clear
glass. Rf = 0.09 (EtOAc); [α]D20 = +1.65 (c = 0.75, H2O); 1H NMR (400 MHz; D2O) δ 4.84 (d, J = 4.7 Hz, 1H, Hꢀ1), 4.42 (dd, J = 7.5, 2.4
Hz, 1H, Hꢀ4), 4.29 (t, J = 7.5 Hz, 1H, Hꢀ3), 4.19 (d, J = 2.4 Hz, 1H, Hꢀ5), 4.15 (dd, J = 7.5, 4.7 Hz, 1H, Hꢀ2), 3.33 (s, 3H, OCH3); 13C
C7H11O7 [MꢀNa]ꢀ 207.0510, found 207.0508.
ꢀ
NMR (100 MHz; D2O) δ 101.6, 78.8, 75.7, 74.3, 70.0, 55.5; HRMS (ESI ) m/z calcd for
Methyl β-L-idofuranoside uronate sodium salt 43
Monosaccharide 41 (23 mg, 63 ꢁmol) was dissolved in H2O (3 mL). To the flask was attached a 3ꢀway tap and purged with N2, 10ꢀ20%
Pd(OH)2/C (20 mg) and NaHCO3 (25 mg, 0.30 mmol) was added and the system purged with H2. Vigorous stirring having a balloon with
H2 attached (1 atm) was continued for 8 h. The suspension was then filtered through Celite® and solvents removed in vacuo to reveal 43
(15 mg, 65 ꢁmol, quant.) as a clear glass. Rf = 0.06 (EtOAc); [α]D20 = ꢀ3.30 (c = 1.0, H2O); 1H NMR (400 MHz; D2O) δ 4.84 (d, J = 1.5 Hz,
1H, Hꢀ1), 4.37 (t, J = 5.6 Hz, 1H, Hꢀ3), 4.21 (dd, J = 5.6, 3.0 Hz, 1H, Hꢀ4), 4.18ꢀ4.15 (m, 2H, Hꢀ5, Hꢀ2), 3.38 (s, 3H, OCH3); 13C NMR
(100 MHz; D2O) δ 171.1, 108.5, 83.7, 79.4, 75.6, 71.7, 55.5; HRMS (ESI–) m/z calcd for C7H11O7 [MꢀNa]– 207.0510, found 207.0513.
ꢀ AUTHOR INFORMATION
Corresponding Author
* Tel: (+44) 161 306 4530. Eꢀmail: gardiner@manchester.ac.uk
Present Addresses
†¶ Present address: Institute of Chemistry, Centre of Glycomics, Dubravska Cesta 9, 845 38 Bratislava, Slovakia.
ꢀ ACKNOWLEDGEMENTS
The CRUK [C2075/A9106] and MRC [G0601746 and G902173] are thanked for project grant funding. EPSRC for NMR instrumentation
(GR/L52246) and the EPSRC National Mass Spectrometry Service, Swansea are also thanked for mass spectroscopic analyses.
ꢀ SUPPORTING INFORMATION
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Copies of 1H and 13C NMR, COSY and HMQC spectra for new compounds, and mass spectra. This material is available free of charge via
the Internet at http://pubs.acs.org. CIF files for Xꢀray structures are available free from the CCDC.12
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1223 336033.
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