New accesses to L-iduronyl synthons

Article abstract of DOI:10.1016/S0040-4039(99)02080-8

(PhS)₃CLi adds with a total L-ido selectivity onto 3-O-benzyl-1,2-O- isopropylidene-α-D-xylo-dialdose 2, opening the way to the most efficient preparation of 1,2,4-tri-O-acetyl-3-O-benzyl-L-iduronyl synthon 8. Alternatively, in view of combinat

Full text of DOI:10.1016/S0040-4039(99)02080-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 307–311
New accesses to L-iduronyl synthons
A. Lubineau, O. Gavard, J. Alais and D. Bonnaffé ∗
Laboratoire de Chimie Organique Multifonctionnelle, associé au CNRS, Institut de Chimie Moléculaire d’Orsay,
Université Paris Sud, 91405 Orsay, France
Received 4 October 1999; accepted 29 October 1999
Abstract
(PhS)3CLi adds with a total L-ido selectivity onto 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-dialdose 2, open-
ing the way to the most efficient preparation of 1,2,4-tri-O-acetyl-3-O-benzyl-L-iduronyl synthon 8. Alternatively,
in view of combinatorial syntheses, aldehyde 2 allows a good access to vinylic L-ido and D-gluco synthons which
may be converted into uronic acid by a sequence involving a new aldehyde oxidation by m-CPBA in aqueous
solution. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: L-idose; L-iduronic acid; glycosaminoglycans; heparin; organometallic; oxidation.
Glycosaminoglycans (GAGs) are linear sulfated polymers of 2-amino sugars and hexuronic acids.
They are essential components of connective tissues and are also present at the cell surface, where they
bind and regulate the activity of various proteins.1 The well known heparin, but also heparan sulfate
and dermatan sulfate, are GAGs in which the hexuronic moiety is mainly L-iduronic acid. Synthetic
oligosaccharide fragments are precious tools to study GAG/protein interactions,1a–c but L-idose or L-
iduronic are not readily accessible from natural sources. The preparation of L-ido synthons is thus a key
point in GAG oligosaccharide synthesis and there is a constant need for their efficient preparation.2 The
dialdose 2 has never been considered as a precursor to L-ido compounds, since the addition of Grignard
reagents onto dialdose derivatives like 2 was reported to exhibit low diastereofacial selectivity.3,4 We
however, undertook a study of the addition of masked carboxylate nucleophiles on 2, feeling confident
that reagents or reaction conditions favouring an L-ido selectivity might be found (Scheme 1).
We began our investigations with vinylic organometallic reagents, since an alkenic moiety may be a
good precursor to a carboxylic function. As reported, the addition of vinylmagnesium bromide on 2 in
Et2O gave an L-ido 3a to D-gluco 4a ratio of around 60/40,4 and variations in the reaction temperature
or solvent did not result in significant changes in the diastereoselectivity (Table 1). We then turned to
other vinylic organometallic reagents but, neither divinylzinc5 nor vinyllithium6 led to an increase of
the proportions of the D-gluco stereomer,7 while the vinyl cerium reagent8 led only to degradation
of the starting material. Due to the furanose ring conformational flexibility and various chelation
∗
Corresponding author. Fax: 33 (0) 1 69 15 47 15; e-mail: david.bonnaffe@icmo.u-psud.fr (D. Bonnaffé)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02080-8
tetl 16008

308
Scheme 1.
possibilities, the stereochemical outcome of organometallic reagent additions on dialdose derivatives
like 2 are very difficult to predict, and sterical factors have been shown to be of major importance in the
catalyzed addition of allylsilanes.4 We thus decided to examine the addition of the bulkier carboxylic acid
equivalents 2-furyllithium9 and tris-(phenylthio)methyllithium.10 We found that the L-ido diastereomer
proportion increased with the steric bulk of the nucleophile (Table 1, entry 7, 9 and 10), and were pleased
to find that the reaction was totally stereoselective with (PhS)3CLi,11 giving compound 3c as the sole
product in 92% yield.12
Table 1
The totally stereoselective addition of (PhS)3CLi is a key step in the short preparation of synthon 8
(Scheme 2). Orthothioesters were previously converted to the corresponding methyl esters using mercuric
salts as catalysts14 but we found that the much less toxic copper salts mixture CuCl2/CuO15 allows
the same transformation in even better yields. Methyl ester 5 was thus prepared in 94% from 3c,16
instead of 85% with mercuric salts. The furano derivative 5 was then converted into its acetylated pyrano
counterpart 8, a useful synthon in which position 3 is already differentiated.1a,2a The overall yield of this
new preparation is 65% from commercial diacetone glucose 1, whereas previously reported yields are
in the range of 25 to 30%,1a,2a,f making our strategy the most attractive access to the useful L-iduronyl
synthon 8.
We have recently prepared a combinatorial library of GAGs sulfo-forms in which the hexuronic acid
was restricted to D-glucuronic acid.17 In order to obtain libraries encompassing the whole of GAGs
molecular diversity we also needed to introduce L-iduronic acid in the oligosaccharidic framework. We
thus decided to take advantage of the possibility to prepare 3a and 4a in an equimolar ratio (Table 1, entry
4) to synthesize L-ido and D-gluco synthons having the same protecting group pattern and thus suitable
for GAGs combinatorial syntheses. Compounds 3a and 4a were easily separated by flash chromatography
and further converted to their acetylated pyrano counterparts 9 and 10 (Scheme 3).

309
Scheme 2.
Scheme 3.
Compounds 9 and 10 are new L-iduronyl and D-glucuronyl synthons, in which a double bond is used
as a carboxylic acid precursor, and preliminary works have shown that they may be transformed into
efficient glycosyl donors. Their alkenic moiety may be easily converted into a carboxymethyl function
using a three-step protocol involving a new aldehyde oxidation by m-CPBA in aqueous solution18
(Scheme 4). Aldehyde 11, generated by ozonolysis of 9 followed by reductive workup, was thus oxidized
into a free carboxylic acid which was further esterified into compound 8 in 77% overall yield. This
‘double bond’ approach is thus an attractive alternative, in GAGs syntheses, to the use of uronic acids
which are always prone to β-elimination or epimerisation in basic conditions.
Scheme 4.
The 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-dialdose 2 is thus a versatile precursor of useful L-ido
and D-gluco synthons for GAGs fragments synthesis. Our new stereoselective access to the L-iduronyl
synthon 8 is a keystone in the synthesis of heparin type C2-symmetric neoconjugates,19 while the alkenic
uronyl synthons 9 and 10 are currently used for the preparation of combinatorial libraries of L-iduronyl
and D-glucuronyl containing GAGs.

310
References
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Tetrahedron Lett. 1999, 40, 1511–1504, and references cited therein. (g) Adinolfi, M.; Barone, G.; De Lorenzo, F.; Iadonisi,
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6. Seyferth, D.; Weiner, M. A. J. Am. Chem. Soc. 1961, 83, 3583–3585.
7. The D-gluco isomer 4a corresponds to the non-chelated Felkin–Ahn product (Table 1 entry 8 and Ref. 4) but, in the absence
of chelating agent, the change in stereoselectivity observed with divinylzinc or vinyllithium may be explained by a preferred
chelation of zinc or lithium with the aldehyde carbonyl and the C3 oxygen instead of the endocyclic oxygen.
8. Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49,
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10. Seebach, D. Angew. Chem., Int. Ed. Engl. 1967, 6, 442–443.
11. In addition to steric effects, the exceptional diastereoselectivity observed in the addition of (PhS)3CLi may also take its
source in the presence of the sulfur atoms which may promote the formation of a complex between the two reactants.
12. A solution of tris-(phenylthio)methane (2.635 g, 7.74 mmol, 1.2 equiv.) in 10 mL dry THF was cooled to −78°C and n-
butyllithium (5 mL of 1.4 M solution in hexane, 7.09 mmol, 1.1 equiv.) was added. The mixture was kept under stirring at
−78°C for 1 h 30 min and then a solution of 1.8 g aldehyde 2 (6.45 mmol) in 10 mL dry THF was added dropwise. After 1 h
at −78°C and warming to room temperature, the reaction was quenched with 50 mL aqueous saturated NH4Cl solution. The
aqueous phase was extracted with Et2O (3×50 mL), the combined organic phases were washed with brine (50 mL), dried
over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting first the excess
tris-(phenylthio)methane with AcOEt/petroleum ether 10/90 and then 3c with AcOEt/ CH2Cl2 20/80, giving 3.7 g (5.93
mmol, 92%) which may be recrystallized from AcOEt/ petroleum ether 20/80 : mp 110°C. 1H NMR (250 MHz, CDCl3, ref.
TMS) δ 7.730–7.650 (m, 6H, Ph), 7.380–7.190 (m, 12H, Ph), 7.110–7.030 (m, 2H, Ph), 6.004 (d, 1H, J=3.5 Hz, H1), 4.805
(dd, 1H, J=3.5, 2.5 Hz, H4), 4.525 (d, 1H, J=3.5, H2), 4.492 (d, 1H, J=12.0 Hz, CH2Ph), 4.220 (dd, 1H, J=7.0, 2.5 Hz, H5),
4.215 (d, 1H, J=12.0 Hz, CH2Ph), 3.604 (d, 1H, J=3.5 Hz, H3), 3.280 (d, 1H, J=6.5 Hz, OH), 1.496 and 1.323 (2s, 6H,
CMe2). 13C NMR (62.9 MHz) δ: 136.9–136.5, 131.3, 129.1–127.6 (arom.), 112.1 (CMe2), 104.1 (C1), 83.0/81.8 (C4/C5),
79.9 (C(SPh)3), 77.7 (C2), 72.8 (C3), 27.1/26.5 (CMe2). Anal. calcd for C34H34O5S3: C, 65.99; H, 5.54; O, 12.93; S, 15.54.
Found: C, 65.71; H, 5.56; O, 13.23; S, 15.32. [α]3D2=13 (CHCl3, 1.1). IR (KBr) : 3525 cm−1 (νOH); 3047 cm−1 (νCH arom).
13. For the vinyl derivatives 3a and 4a the diastereomeric ratio was determined using peaks at δ 116.86/115.75 (_CH2; L-
ido/D-gluco); 111.69/111.48 (CMe2 L-ido/D-gluco); 104.93/104.80 (C1; D-gluco/L-ido). For the 2-furyl derivatives 3b and
4b, signals at δ 107.49/107.31 and 66.07/65.64 were used, the stereochemistry of the major product being ascertained after
ozonolysis (Schmidt, G.; Fukuyama, T.; Akaska, K.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259–261) and methylation with
diazomethane which gave compound 5. For the tris-phenylthio product 4c, only one stereomer was detected by 1H and 13
C
NMR.

311
14. Woessner, W. D. Chem. Lett. 1976, 43–46.
15. This combination has been used to reveal aldehyde from thioacetals (Mukayama, T.; Narasaka, K.; Furusato, M. J. Am.
Chem. Soc. 1972, 94, 8641–8642) and thiazole (Dondoni, A.; Marra, A.; Perrone, D. J. Org. Chem. 1993, 58, 275–277).
16. We used 4 equiv. of CuCl2 and 1.7 equiv. of CuO in a 12/1 MeOH/H2O mixture, adding the minimum amount of CH2Cl2
needed to dissolve the starting material.
17. Lubineau, A.; Bonnaffé, D. Eur. J. Org. Chem. 1999, 2, 2523–2532.
18. This aldehyde oxidation with m-CPBA is rather general and other examples including oxidation of acid-labile compounds
in buffered conditions will be published in due course.
19. Lubineau, A.; Escher, S.; Alais, J.; Bonnaffé, D. Tetrahedron Lett. 1997, 38, 4087–4090.