Carbasugar analogues of galactofuranosides: α-O-linked derivatives

Article abstract of DOI:10.3762/bjoc.6.129

Using an indirect method, we have synthesised α-linked carbasugar analogues of galactofuranosides for the first time. Ring opening of a ss-talo configured carbasugar 1,2-epoxide by alcohol nucleophiles under Lewis acidic conditions proceeded with very goo

Full text of DOI:10.3762/bjoc.6.129

Carbasugar analogues of galactofuranosides:
α-O-linked derivatives
Jens Frigell1 and Ian Cumpstey*1,2,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 1127–1131.
1Department of Organic Chemistry, The Arrhenius Laboratory,
Stockholm University, Stockholm 106 91, Sweden and 2Institut de
Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette,
France, Tel.: +33 (0)1 69 82 30 78; fax: +33 (0)1 69 07 72 47
doi:10.3762/bjoc.6.129
Received: 31 August 2010
Accepted: 05 November 2010
Published: 29 November 2010
Email:
Ian Cumpstey* - ian.cumpstey@icsn.cnrs-gif.fr
Associate Editor: D. Y. Gin
* Corresponding author
© 2010 Frigell and Cumpstey; licensee Beilstein-Institut.
License and terms: see end of document.
§ Alternative Email: ian.cumpstey@sjc.oxon.org
Keywords:
carbasugars; etherification; galactofuranose; glycomimetics;
pseudodisaccharides; regioselective
Abstract
Using an indirect method, we have synthesised α-linked carbasugar analogues of galactofuranosides for the first time. Ring opening
of a β-talo configured carbasugar 1,2-epoxide by alcohol nucleophiles under Lewis acidic conditions proceeded with very good
regioselectivity to give α-talo configured C1-substituted ethers with a free OH-group at the C2 position. Inversion of configuration
at C2 by an oxidation–reduction sequence gave the α-galacto configured carbahexofuranose C1 ethers. A carbadisaccharide corres-
ponding to the Galf(α1→3)Manp substructure from Apodus deciduus galactomannan was synthesised to exemplify the method.
Introduction
Galactofuranose is found in nature as a component of glycocon- β-galactofuranosides and the substrate for galactofuranosyl-
jugates in many microorganisms [1,2]. Galactofuranosides with transferases is UDP-galactofuranose, which has an α configur-
the α configuration are rather less common than their β-linked ation [1,2]. Modified, hydrolytically stable analogues of
anomers, from which they are distinguished by their 13C C1 galactofuranosides could find application in the design and syn-
chemical shifts (α, 103.8 ppm; β, 109.9 ppm for the methyl thesis of potential inhibitors of the enzymes involved in the
glycosides) [3], and 3J1,2 1H,1H coupling constants (α, 4 Hz; β, biosynthesis of galactofuranose-containing glycoconjugates.
2 Hz) [4]. Nevertheless, α-galactofuranosides occur as compo-
nents of a number of oligosaccharides, including plant polysac- We have recently developed what appears to be a general route
charides [5], fungal cell wall polysaccharides [6], glycolipids towards carbasugar analogues of β-galactofuranosides [9]. In
from thermophilic bacteria [7] and glycosphingolipids from our approach, alcohol nucleophiles attack an α-galacto carba-
marine sponge (agelagalastatin) [8]. Moreover, the precursor to sugar 1,2-epoxide 1 (Figure 1) under Lewis acidic conditions
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with excellent regioselectivity for attack at C1. The regio- neutral or base-catalysed conditions [14]. Carbon C2 bears a β
selectivity may be rationalised by steric and electronic argu- electron-withdrawing group (the C3 benzyl ether), whereas C1
ments: C1 is more accessible than C2 due to the absence of a does not. Hence, from an electronic point of view, SN2 reac-
neighbouring bulky group, the C3 benzyl ether. C1 is more tions should be more favourable at C1 than at C2. The same
electrophilic than C2; it is better able to sustain partial positive concept is a major factor in explaining the generally low re-
charge under Lewis acid coordination due to the absence of a activity of carbohydrates (at non-anomeric positions) in SN2
neighbouring electron-withdrawing group, the C3 benzyl ether. reactions. Carbapyranose 1,2-epoxides with α-gluco 3 and
α-galacto configurations did not give such good results. With
amine nucleophiles, attack was often unregioselective [15]:
attack at C1 (favoured sterically and electronically) leads to
stereoelectronically unfavourable [11] 1,2-trans-diequatorial
opening. This nucleophilic dilemma presumably accounts for
the poor regioselectivity and yields of such reactions. With
alcohol nucleophiles, no coupling products were observed with
either α-gluco or α-galacto carbapyranose 1,2-epoxides [16].
We considered the reactivity of a diastereomeric epoxide to the
α-galacto carbafuranose epoxide 1, i.e., a β-talo epoxide 4, in
nucleophilic ring-opening reactions. The same steric and elec-
tronic arguments on regioselectivity would predict attack at C1
in the β-talo 1,2-epoxide 4. In 5-membered rings, nucleophilic
Figure 1: Structures of carbapyranose and carbafuranose 1,2-epox-
ides.
attack at either carbon of an epoxide (with an envelope con-
formation) would result in a product with a twist-boat con-
formation, meaning that there was no great difference in energy
Ogawa has extensively used epoxide-opening reactions as a between the two regioisomers as was the case in the
coupling method to access N- and O-linked pseudodisaccha- 6-membered ring series, irrespective of the preferred envelope
rides based on carbapyranoses [10]. The epoxides were opened conformation of the epoxide, and that stereoelectronic effects
by amines in uncatalysed reactions, or by alcohols under Lewis are thus likely to be much less relevant for the more flexible
acidic, but more usually basic, conditions. An important general cyclopentane derivatives. One factor that could speak against
feature of epoxide opening in 6-membered rings is the ten- good regioselectivity in this case would be the fact that the
dency for trans-diaxial ring opening [11]. The existing α-talo product has a 2,3-cis and 1,4-cis substituent pattern,
substituents on the cyclohexane ring favour one of the two which could lead to some strain in the transition state, whereas
possible half-chair conformations (4H5 for 1 and 2). The prin- β-galacto derivatives have an all trans substituent pattern.
ciple of microscopic reversibility requires an antiperiplanar rela-
tionship between the nucleophile and the epoxide oxygen in the Should the epoxide-opening reaction proceed to give the α-talo
product immediately after reaction. From a given half-chair configured C1-substituted products, then this could offer a route
conformation of the epoxide, nucleophilic attack results in to α-configured galactofuranoside pseudodisaccharides via a
either a chair (with the substituents trans-diaxial) or a skew- subsequent epimerisation of the unprotected C2 alcohol, analog-
boat conformation, which must rearrange to give the diequato- ous to the α-manno to α-gluco epimerisation route developed by
rial product. As the skew-boat is a higher energy conformation, Ogawa in the six-membered ring series [17]. In this paper we
this situation is disfavoured from a stereoelectronic point of report our results on the synthesis of carbasugar analogues of
view.
α-galactofuranosides by this route.
Carbapyranose 1,2-epoxides with the β-manno configuration 2 Some related work in the form of ring opening of carbapentafu-
(Figure 1) were opened efficiently with attack at C1 (sterically ranose 1,2-epoxides has been reported in the area of carbanucle-
and electronically favoured) to give 1,2-trans-diaxial [11] oside chemistry. Indeed, various α-ribo configured carbasugar
carba-α-mannose derivatives with both oxygen [12] and epoxides, which have the same configuration around the carbo-
nitrogen [13] nucleophiles. The electronic argument must be cyclic ring as the β-talo epoxide 4, were opened by nitrogen
reformulated slightly in the absence of a Lewis acid. The locali- nucleophiles (nucleobases [18] or azide [19,20]) with generally
sation of electrons onto the leaving group (the epoxide oxygen) good regioselectivity for attack at C1. The only precedent for
is necessary as the transition state is approached also under attack at such carbapentafuranose epoxides with an oxygen
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Beilstein J. Org. Chem. 2010, 6, 1127–1131.
nucleophile would appear to be the acid-mediated attack of the direct formation of the required epoxide 4, presumably by
water on an α-xylo configured epoxide, again with apparently cleavage of the C1 benzoate to the alcoholate (with retention of
good regioselectivity for attack at C1 [21].
configuration) followed by intramolecular displacement of the
C2 tosylate (with inversion of configuration). We synthesised
the same epoxide 4 (78%) by treatment of isolated 3,5,6-tri-O-
Results and Discussion
Our synthesis of the β-talo 1,2-epoxide began from the benzyl-2-O-(toluene-4-sulfonyl)-4a-carba-β-D-galactofuranose
β-galacto 1,2-diol 5 [22]. We needed to regioselectively trans- [9] with sodium hydride in DMF.
form OH-2 into a leaving group that could then undergo
intramolecular displacement by O-1. The OH-1 hydroxyl group We investigated ring-opening of the epoxide 4 by alcohol
appears to be more nucleophilic than OH-2 in 5 [9]; a benzoate nucleophiles under Lewis acidic conditions as used in the
protecting group was introduced at O-1 using a tin acetal diastereomeric series [9]. With excess ethanol (10 equiv), we
method [23] to give the monobenzoate 6 with enhanced regio- obtained the C1 ethyl ether 8 as the major product (90%) along
selectivity (Scheme 1). Only very small amounts (<5%) of the with a small amount (4%) of the regioisomer (Scheme 2). The
regioisomer were observed and were not isolated in a pure regiochemistry was proved by acetylation of the free alcohols.
form. The free OH-2 could then be converted to its tosylate 7. The major product 8 gave a C2 acetate 9, as shown by the
Treatment of this diester 7 with sodium methoxide resulted in downfield shift of H2 in the 1H NMR spectrum, indicating
nucleophilic attack at C1 during the epoxide-opening step to
give an α-talo configured product. The minor product gave a C1
acetate on acetylation, indicating attack at C2 in the epoxide
opening and formation of a β-galacto product.
We then examined a secondary carbohydrate alcohol as the
nucleophile. The mannose OH-3 nucleophile 10 [24] would
lead to a structure corresponding to a Galf(α1→3)Manp disac-
charide substructure from the galactomannan from the fungus
Apodus deciduus [6]. Here also, the epoxide 4 underwent ring
opening with very good regioselectivity in favour of the
C1-substituted (α-talo) product 11, which was isolated in 57%
yield and characterised as its C2 acetate 12. The regioisomeric
C2-substituted (β-galacto) product was not detected in the
epoxide-opening reaction. In this reaction, a by-product 13 was
Scheme 1: (i) Bu2SnO, MeOH, 70 °C; (ii) BzCl, toluene, 82%; (iii)
TsCl, py, 50 °C, 86%; (iv) NaOMe, MeOH, 81%.
also formed, which was characterised as its acetate 14 and
assigned the structure given in Figure 2a.
Scheme 2: (i) ROH, BF3.OEt2, CH2Cl2, RT; 8, 90%; 11, 57%; (ii) Ac2O, py; 9, >99%; 12, 91%; (iii) (COCl)2, DMSO, CH2Cl2, −60 °C, then Et3N, RT;
15, 88%; 16, 68%; (iv) L-selectride, THF, 0 °C; 17, 78%; 18, 66%.
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Beilstein J. Org. Chem. 2010, 6, 1127–1131.
Figure 2: a) Structures of 13 and 14; b) observed NOEs consistent with structure 14; c) observed NOEs inconsistent with structure 14x.
The 1H NMR spectrum of the by-product 13 showed the pres- J 11 Hz in the 1H NMR spectrum, which is consistent with a
ence of only two sets of characteristic signals for benzyl ethers, diaxial coupling to H5 as seen in structure 14, but not in 14x.
indicating that the third benzyl ether protecting group had been
lost. The mass spectrum showed a peak at m/z 363, consistent Hence, compound 13 presumably arose from debenzylative
with a bicyclic system. Acetylation with acetic anhydride and cycloetherification by attack of O-6 on C1, C1 being the most
pyridine gave a monoacetate 14 according to NMR spec- electrophilic carbon in both inter- and intramolecular epoxide-
troscopy and mass spectrometry (m/z 405).
opening reactions.
We deduced the structure of the monoacetate 14 using NMR To achieve the inversion of stereochemistry at C2 of the α-talo
spectroscopy, including HSQC, HMBC and NOESY experi- carbasugars, our best results were obtained using an
ments. The C1/H1, C2/H2 and C3/H3 pairings could not be oxidation–reduction approach. Attempted SN2 reactions
easily distinguished due to the presence of some long-range (Mitsunobu reaction or sulfonate displacement) gave inferior
couplings and correlations in the COSY spectra. One of these results. Hence the C2 alcohols 8 and 11 were oxidised under
three carbons bore an acetate, as seen from the downfield shift Swern conditions to give the ketones 15 and 16. Reduction of
of the corresponding proton. The second bore a benzyl ether, as ketone group in ethyl ether 15 with sodium borohydride gave a
shown by the PhCH2→C cross-peaks in the HMBC spectrum. rather poor diastereoselectivity. However, using L-selectride
The third was linked to C6 by an ether, as seen from the excellent selectivity for the formation of the required α-galacto
H6’→C cross-peak in the HMBC spectrum. The HMBC spec- carbasugar 17 (78% isolated) was observed; the α-talo product
trum also revealed that O-5 was still benzyl-ether-protected; 8 was also formed, but not in sufficient quantity that it could be
hence, the benzyl ether was lost from O-6, presumably isolated in a pure state. The pseudodisaccharide ketone 16 was
following nucleophilic attack by O-6 on either C1 or C2 of the also then reduced with L-selectride, again very good diastereo-
epoxide. The large difference in chemical shift between H6 selectivity for the α-galacto configured carbasugar 18 was
(3.15 ppm) and H6’ (3.90 ppm) is consistent with C6 being part observed.
of a rigid cyclic structure, rather than exocyclic.
Conclusion
The answer to the question of whether attack occurred at C1 or Complementing our approach to β-configured O-linked galacto-
C2 required information from NOESY experiments. Attack at furanosides by epoxide ring opening, the corresponding α-com-
C1 would have led to 14, whereas attack at C2 would have led pounds can be made by an indirect route: Opening of a β-talo
to 14x. The strongest support for the proposed structure was the configured epoxide followed by C2 epimerisation. The very
NOE observed (Figure 2b) between H1 (if attack occurred at good regioselectivity in the epoxide-opening reaction indicates
C1) and H4a and H4a’, which is consistent with structure 14; that steric and/or electronic effects favouring attack at C1 over
this would correspond to an NOE (Figure 2c) between H2 (if C2 are more important than other factors; the difference in effi-
attack occurred at C2) and H4a and H4a’, which is not consis- ciency of the “up” (β-manno) and “down” (α-gluco) carbapyra-
tent with structure 14x. No NOE was seen between the nose 1,2-epoxides in coupling reactions was not observed in the
acetylated H (H1 or H2) and H4a or H4a’: This supports struc- carbafuranose series. It is possible that this strategy for pseudo-
ture 14 and essentially excludes the alternative structure 14x. disaccharide formation by epoxide ring opening in the (α and β)
Finally, an NOE was observed between H6 (but not H6’) and carbagalactofuranose series could be extended to the pseu-
the acetylated H (H1 or H2), which allowed the C6 protons to doenantiomeric (β and α) carbaarabinofuranose series [25],
be distinguished. H6 appeared as an apparent triplet with which represent similarly relevant biological targets [26].
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Supporting information features experimental section and
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Supporting Information File 1
Experimental and NMR data.
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