Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

Article abstract of DOI:10.3762/bjoc.7.128

Diglycose derivatives, consisting of two monosaccharides linked at non-anomeric positions by a bridging nitrogen atom, have been synthesised. Conversion of one of the precursor monosaccharide coupling components into an unsaturated derivative enhances its

Full text of DOI:10.3762/bjoc.7.128

Amine-linked diglycosides: Synthesis facilitated by
the enhanced reactivity of allylic electrophiles,
and glycosidase inhibition assays
Ian Cumpstey*1,2, Jens Frigell1, Elias Pershagen1, Tashfeen Akhtar1,
Elena Moreno-Clavijo3, Inmaculada Robina3, Dominic S. Alonzi4
and Terry D. Butters4
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1115–1123.
1Department of Organic Chemistry, The Arrhenius Laboratory,
Stockholm University, 106 91 Stockholm, Sweden, 2Institut de Chimie
des Substances Naturelles, Centre National de la Recherche
Scientifique, 91198 Gif-sur-Yvette CEDEX, France, 3Department of
Organic Chemistry, Faculty of Chemistry, University of Seville, Prof.
García González, 1, 41012 Seville, Spain and 4Glycobiology Institute,
Department of Biochemistry, Oxford University, South Parks Road,
Oxford, OX1 3QU, England
doi:10.3762/bjoc.7.128
Received: 26 April 2011
Accepted: 25 July 2011
Published: 16 August 2011
Associate Editor: S. Flitsch
© 2011 Cumpstey et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Ian Cumpstey* - ian.cumpstey@sjc.oxon.org
* Corresponding author
Keywords:
amination; glycomimetics; glycosidases; Mitsunobu;
pseudodisaccharides
Abstract
Diglycose derivatives, consisting of two monosaccharides linked at non-anomeric positions by a bridging nitrogen atom, have been
synthesised. Conversion of one of the precursor monosaccharide coupling components into an unsaturated derivative enhances its
electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsatu-
rated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A
palladium-catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino-pseudodisaccharide as
the major product, along with other minor products. Derivatisation of the C=C double bond in pseudodisaccharides allowed the for-
mation of Man(N4–6)Glc and Man(N4–6)Man diglycosides. The amine-linked diglycosides were found to show weak glycosidase
inhibitory activity.
Introduction
We have been interested in synthesising molecules consisting of diglycoses (or neodisaccharides), are linked by ether, amine,
two monosaccharides linked by formal condensation without thioether, selenoether, etc., bridges, and so are presumably more
using the anomeric position [1]. Such molecules, termed stable to hydrolysis by acid or glycosidases than (glycosidic)
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Beilstein J. Org. Chem. 2011, 7, 1115–1123.
disaccharides. Diglycoses have many features in common with Bearing in mind the limitations discovered in our earlier work,
disaccharides, with a similar general appearance, size, and func- we planned to enhance the reactivity of the electrophilic compo-
tional group pattern, i.e., polyhydroxylation with potentially nent in our coupling reactions by converting a carbohydrate into
hydrophobic areas above and below the ring plane. Synthetic an unsaturated derivative with an allylic alcohol as leaving
structures of this type have been known since the 1960s [2,3], group [16]. After the coupling reaction, dihydroxylation of the
and have attracted sporadic attention since then, often in the C=C double bond would restore the carbohydrate structure
context of proposed carbohydrate or disaccharide mimicry. Last (Scheme 1) [17]. As well as Mitsunobu chemistry [18], the
year, we reported that neutral ether- and thioether-linked allylic nature of the electrophile opens up the way for transition-
diglycose derivatives can interact with lectins with affinities metal-catalysed allylic amination reactions [19-21] as a possible
similar to those of strongly binding disaccharide ligands [4]. In coupling method. We report our investigations into this area in
the related carbasugar series, Ogawa et al. have shown that this paper.
pseudodisaccharides with a bridging nitrogen atom bind more
strongly to glycosidases than do the corresponding ether or
thioether derivatives [5]. It follows that amine-linked diglycose
derivatives may act as glycosidase inhibitors. We set about the
synthesis of some compounds of this type to test this hypoth-
esis.
In our initial investigations into this area [6] we found that the
installation of amine linkages between primary–primary
carbons of monosaccharides was relatively straightforward; this
was achieved by Mitsunobu coupling between carbohydrate C-6
alcohols and carbohydrate C-6 sulfonamides. Primary–second-
ary linkages were more difficult to synthesise; attempted
Mitsunobu coupling failed, but we synthesised such amines by
epoxide-opening. We did not achieve the formation of sec–sec
linked secondary amines. The synthesis of a sec–sec amine-
linked diglycoside structure by epoxide-opening was reported
by Coxon [7], its formation being achieved in low yield (25%)
under rather harsh conditions (autoclave, 140 °C), while a
Scheme 1: The concept of using allylic reactivity enhancement to facil-
itate diglycoside synthesis.
similar epoxide-opening reaction starting from a rather more
complex substrate has been used to synthesise a pseudohexasac-
charide in very low yield (12%) [8]. Kroutil et al. reported the
synthesis of a number of aminated amine-linked sec–sec struc- There is extensive coverage in the literature of the derivatisa-
tures by aziridine-opening reactions (ionic liquid, 120 °C) [9]. tion of primary carbohydrate alcohols by Mitsunobu type reac-
Primary–sec amine-linked structures have been synthesised by tions [22]. Reports of Mitsunobu reactions of secondary alco-
Thiem et al., through a reductive amination strategy [10,11].
hols in fully functionalized carbohydrates are much scarcer.
Rather, reports exist of failed attempts at Mitsunobu reactions
In contrast, related structures containing an amine linkage of secondary carbohydrate alcohols [23] or the selective func-
between a carbohydrate ring carbon (i.e., a secondary position) tionalisation of primary carbohydrate alcohols in the presence
and C-1 of either a (C-5a methylene) carbasugar or a C5=C5a of secondary alcohols [24]. Some examples of successful reac-
unsaturated carbasugar, are relatively common [12]. There are tions do exist, though, for oxygen, nitrogen and sulfur nucleo-
two possible contributing factors to this: First, these classes of philes [25-28]. Unsaturated carbohydrates, similar to those
carbasugar or valienamine structures have been more widely described here, have also been reported to undergo Mitsunobu
studied, possibly due to their presence in natural products and reaction with simple, non-carbohydrate nucleophiles [29,30].
well known biological activities as glycosidase inhibitors [13]; The palladium-catalysed allylic amination reaction on unsatu-
second, electrophiles that are either lacking a bulky and elec- rated pyranose rings was pioneered thirty years ago by Hanna
tron-withdrawing substituent at one beta position [14] (making and Baer [19,20], and has more recently been reinvestigated
them less carbohydrate-like), or that are allylic [15], would tend with rather simple nitrogen nucleophiles [30,31]. Carbohydrate
to be intrinsically more reactive than similar carbohydrate elec- amines have been used as nucleophiles in allylic amination by
trophiles, thus facilitating the coupling reaction.
Shing to form valienamine pseudodisaccharides [21].
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Beilstein J. Org. Chem. 2011, 7, 1115–1123.
Results and Discussion
Assignment of the NMR spectra of the coupling products 10–15
The synthesis of the 2,3-unsaturated erythro carbohydrate by the usual 2D methods (COSY, HSQC) gave an unam-
derivative 1 was carried out from triacetyl glucal essentially biguous indication that, in all cases, the nitrogen nucleophile
according to the literature procedure [30]. The threo alcohol 2 had attacked C-4, as judged by an upfield shifted 13C signal,
has been previously synthesised by Mitsunobu inversion of the and that the unsaturated bond was between C-2 and C-3. Hence
erythro alcohol 1 [30]. We synthesised 2 from triacetyl galactal these reactions proceeded with essentially complete regioselec-
3 by an analogous route to that used for the erythro alcohol 1 tivity, with no SN2’ products arising from attack at C-2 being
(Scheme 2). We found that the choice of Lewis acid used in the seen. The coupling reactions were stereospecific: The nucle-
Ferrier reaction of 3 with ethanol was critical for a satisfactory ophile 6 coupled with the threo alcohol 2 to give the coupling
yield of the unsaturated glycoside 4 to be achieved; phospho- product as a single diastereomer 13; but 6 also coupled with the
molybdic acid [32] gave the product (α:β, 8:1) in 63% yield. diastereomeric erythro alcohol 1 to give a different product 10,
Deacetylation of 4 and regioselective silylation of the primary again as a single diastereomer. This is consistent with an SN2
alcohol gave the threo allylic alcohol 2. The sulfonamide pathway with inversion of configuration, which is as expected
nucleophiles 6, 7 and 9 were prepared from the corresponding for Mitsunobu reactions. The same was true of the other sulfon-
amines 5 [33] and 8 [34], as described previously [6], with only amide nucleophiles, 7 and 9. Moreover, the erythro configur-
one equivalent of the sulfonylating agent so as to avoid bis- ation of coupling product 15 was proved by the large value of
sulfonamide formation.
the J4,5 coupling constant (9.8 Hz), which can only be explained
by a trans relationship of the 4-H and 5-H protons and a OH5
Mixing equimolar equivalents of the erythro allylic alcohol 1 half-chair conformation. The J4,5 coupling constants for the
and the glucose-6-nosylamide 6 with DIAD and triphenylphos- products assigned as threo were not always well resolved, but in
phine resulted in a smooth coupling reaction to give the pseudo- 12, a smaller coupling constant (ca. 4 Hz) was seen.
disaccharide 10 in high yield (Scheme 3). The alcohol 1 also
underwent similar coupling with the glucose-6-triflamide 7 and Having achieved the coupling, we turned to the refunctionalisa-
the mannose-6-nosylamide 9 under the same Mitsunobu condi- tion of the C=C bond (Scheme 4). Osmium-catalysed dihydrox-
tions to give the respective diglycoside precursors 11 and 12 in ylation of the double bond in erythro configured pseudodisac-
excellent yields. These were the same reaction conditions that charide 13 proceeded to give a single diastereomer of product
had failed to give coupling reactions between a primary alcohol 16. The configuration of the dihydroxylated product 16 was
and a sulfonamide at a secondary carbohydrate position, or a most conveniently assigned after conversion to its diacetate 18,
secondary alcohol and a sulfonamide at a primary carbohydrate which resulted in a downfield shift of the 2-H and 3-H signals
position, in our earlier study [6]. Coupling of this threo alcohol into a clear region of the 1H NMR spectrum, allowing readout
2 with sulfonamide nucleophiles (6, 7 and 9) again gave the of the coupling constants without any signal overlap. The values
protected secondary amines (13–15) in excellent yield. No of J1,2 (1.8 Hz), J2,3 (3.3 Hz), and J3,4 (11.0 Hz) are consistent
difference in the efficiency of the coupling reactions of the with the α-manno configuration, and inconsistent with the alter-
nosylamide 6 and the triflamide 7 was seen with either of the native α-allo configuration. Hence dihydroxylation proceeded
alcohols 1 or 2.
from the opposite side to the two neighbouring substituents (at
Scheme 2: (i) Phosphomolybdic acid, EtOH, MeCN, 0 °C→RT, 63%; (ii) a) NaOMe, MeOH, 87%; b) TBDMSCl, imidazole, DMF, 0 °C→RT, 68%; (iii)
NsCl, Et3N, DMAP, CH2Cl2; 6, 97% [6]; 9, 88%; (iv) Tf2O, Et3N, CH2Cl2, −5 °C, 64% [6].
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Beilstein J. Org. Chem. 2011, 7, 1115–1123.
Scheme 3: (i) DIAD, PPh3, THF, 0 °C→RT; 10, 91%; 11, 88%; 12, 76%; 13, 91%; 14, 91%; 15, 71%.
C-1 and C-4), as expected in a sterically controlled reaction, and NMO, failed to give any reaction. A combination of RuCl3 and
consistent with previous results [35]. The protecting groups NaIO4 produced, after 4 days, a mixture of starting material and
were then removed. First, the TBDMS ether was removed with desilylated material but no oxidised product. Treatment with
acid to give the triol 19. Alternatively, 19 was formed directly mCPBA failed to give an epoxide, and after a week only some
in the dihydroxylation reaction by allowing a longer reaction decomposition of the starting material was seen. Presumably,
time (20 h) after quenching with NaHSO3, leading to a similar the trans relationship between the flanking NNsR and OEt
overall yield (80% from 13). Attempted TBAF deprotection of groups effectively crowds both faces of the olefin, blocking its
the silyl ether in the dihydroxylation product 16 gave only a low reactivity.
yield of the triol 19. Subsequently, the benzyl ethers and nosyl-
amide in 19 were cleaved under Birch reduction conditions to We briefly examined palladium-catalysed allylic amination as a
furnish the free Man(N4–6)Glc diglycoside 21. The other possible coupling procedure. The allylic alcohol in the threo
erythro configured pseudodisaccharide 15 behaved in a similar derivative 2 was converted into its trichloroacetimidate 23 by
way, and we obtained the Man(N4–6)Man diglycoside 22 treatment with trichloroacetonitrile and base. The trichloroacet-
following the same reaction sequence (Scheme 4).
imidate is a leaving group that has the advantage of being easily
and stereospecifically synthesised from the alcohol under basic
However, attempted functionalisation of the C=C double bond conditions. We recently used the trichloroacetimidate as leaving
in the threo configured pseudodisaccharides 10 and 12 under group in palladium catalysed synthesis of carbasugar pseudodis-
the same conditions, or using stoichiometric K2OsO4 with accharides [36]. Treatment of the imidate 23 with an amine
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Beilstein J. Org. Chem. 2011, 7, 1115–1123.
Scheme 4: (i) K2OsO4, NMO, acetone, H2O; 16, 88%; 17, 73%; (ii) Ac2O, py, 83%; (iii) MeOH, HCl (1 M aq.); 19, 74%; 20, 86%; (iv) Na, NH3 (l),
−78 °C; 21, 78%; 22, 53%.
nucleophile 5 [33] and a palladium catalyst [21] resulted in Three of 24–26 were isomeric, with m/z 734, consistent with
the formation of four products, 24 (44%), 25 (15%), 26 (5%) the expected coupling products, i.e., the allylic amines. The
and 27 (6%), which were assigned the structures given in fourth product had m/z 800, consistent with the carbamate
Scheme 5.
structure 27. The determination of the regiochemistry of the
Scheme 5: (i) Cl3CCN, DBU, CH2Cl2, 99%; (ii) TMPP, Pd(dba)2, 5, Et3N, MeCN, 24, 44%; 25, 15%; 26, 5%; 27, 6%.
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Beilstein J. Org. Chem. 2011, 7, 1115–1123.
unsaturated ring in 24 was complicated by long-range 1H–1H A further characteristic feature that can be used to distinguish
couplings and correlations in the COSY spectrum. It was diffi- 2-amino-3,4-unsaturated-α-threo configured compounds from
cult to distinguish between the C/H-2 and C/H-4 pairs of signals their α-erythro C-2 epimers is the J1,2 coupling constant. Ferrier
due to the presence of a cross-peak between 2-H and 5-H and pointed out that α-threo diastereomers have very small J1,2
the very low intensity of the cross-peaks between 1-H and both coupling constants, i.e., 1-H usually appears as a singlet,
2-H and 4-H, and between 4-H and 5-H. The regiochemistry whereas the α-erythro diastereomers have J1,2 between 3.5–4.5
was established by the presence of correlations between 6-H Hz [44]. In 24, 1-H appeared as a singlet, consistent with our
and C-4 in the HMBC spectrum. Hence, 24 was assigned a assignment of α-threo stereochemistry. The C-4 stereochem-
2-amino-3,4-unsaturated structure.
istry of the two 4-amino derivatives 25 and 26 was assigned on
the basis of the J4,5 vicinal coupling constants. For 25, J4,5 =
The COSY spectrum of 25 was uncomplicated by any such 3.2 Hz, consistent with a 4,5-cis (hence threo) configuration; for
long-range couplings, so the assignment of a 4-amino-2,3- 26, J4,5 = 10.0 Hz, consistent with a 4,5-trans (hence erythro)
unsaturated structure to 25 based on the COSY spectrum was configuration in an OH5 conformation.
straightforward. For 26, the distinction between the C/H-2 and
C/H-4 pairs of signals was based on the strong correlation Hence, the major products 24 and 25 from the palladium-cata-
between 5-H and 4-H, and the absence of any correlation lysed reaction are those with overall retention of configuration
between 5-H and 2-H. Correlations were seen between 1-H and as expected from the double displacement mechanism. Under
each of 2-H, 3-H, and 4-H, although the correlation between these unoptimised reaction conditions though, the palladium-
1-H and 2-H was much more intense than the others. Hence, 26 catalysed reaction was much less regioselective than the
was assigned a 4-amino-2,3-unsaturated structure. The regio- Mitsunobu couplings. Moreover, the major regioisomer in the
chemical assignments for both 25 and 26 were both confirmed palladium-catalysed reaction was the 2-amino sugar, whereas in
by C-4→6-H correlations in the HMBC spectra.
the Mitsunobu reactions, the 4-amino sugars were formed
exclusively. A small amount of stereochemical scrambling of an
Hanna and Baer observed [20] that 2,3-unsaturated-4-amino-α- intermediate π-allyl palladium complex could explain the for-
glycopyranosides have 13C chemical shifts for C-1 in the range mation of 26.
93.8–94.1 ppm, irrespective of the C-4 configuration. In our
assessment the C-1 chemical shifts for 25 (94.3) and 26 (94.1) Finally, we report the results of assays of the unprotected digly-
are in broad agreement with these values, whereas 24 (98.9) has cosides Man(N4–6)Glc 21 and Man(N4–6)Man 22, along with
a significantly higher shift. However, while a survey of the those we had synthesised earlier [6], viz., Alt(N2–6)Glc 28,
literature reveals that 2-amino-3,4-unsaturated compounds Alt(N2–6)Man 29, Alt(N3–6)Glc 30, Alt(N3–6)Man 31,
with the α-threo configuration (i.e., consistent with 24, Glc(N6–6)Glc 32, and Glc(N6–6)Man 33 (Figure 1), for
as shown) have C-1 shifts in the range 96.7–99.3 ppm (12 inhibitory activity against glycosidases. Screening the com-
examples) [19,30,37-41], the corresponding C-2 epimeric pounds against twelve commercially available glycosidases (see
α-erythro configured structures have C-1 shifts in the Supporting Information File 1) [45,46], we found that none of
range 93.9–95.6 (3 examples) [40,42,43], similar to the 2,3- the compounds had a high inhibitory activity against any of the
unsaturated-4-amino compounds. Therefore, use of 13C C-1 glycosidases when tested at 1 mM inhibitor concentration. The
chemical shift alone as a diagnostic tool for regiochemistry results for those enzymes for which some inhibitory activity
should be avoided.
was seen arising from one or more of the diglycosides, are
Figure 1: Previously synthesised amine-linked diglycosides.
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Beilstein J. Org. Chem. 2011, 7, 1115–1123.
given in Table 1. These diglycosides showed weaker glycosi- tions with C=C double bond migration were not observed. A
dase inhibitory activity than the related N-substituted (monosac- palladium catalysed coupling reaction between an amine and an
charidic) altrosides recently reported by Jenkins et al. [47]. allylic trichloroacetimidate also gave a high yield of a mixture
These results are in accordance with those reported for other of amine-linked pseudodisaccharides, but under the conditions
disaccharide mimetics, such as aza-C-disaccharides, which we used, much lower regioselectivity and diastereoselectivity
showed no significant inhibition towards commercially avail- were seen than in the Mitsunobu reactions. Completion of the
able glycosidases [48].
diglycosides by refunctionalisation of the C=C double bond was
successful for some diastereomers, but not for others. Glycosi-
We also investigated inhibition of α-glucosidase II using the dase inhibitory activity of the compounds synthesised here, and
oligosaccharide Glc2Man7GlcNAc2 as substrate and using the also of structurally related compounds synthesised previously
free oligosaccharide (FOS) assay in cultured cells [49]. The by us, was weak.
Alt(N2–6)Man derivative 29 showed some inhibitory activity,
with IC50 ca. 500 μM. None of the other compounds tested
Supporting Information
inhibited the enzyme at 100 μM concentration.
Supporting Information File 1
Experimental section; copies of 1H and 13C NMR spectra
for new compounds.
Such amine-linked diglycosides have not been shown to have
intrinsic biological activity before. However, the inhibitory
activity, where it exists, is weak for these compounds, and the
nature of the binding and the basis for inhibition is not clear.
α-Glucosidase II cleaves two linkages in nature in the biosyn-
thesis of N-linked glycoproteins: Glc(α1→3)Glc and
Glc(α1→3)Man. The Alt(N2–6)Man structure does not bear an
immediately obvious resemblance to either of these substruc-
tures. Moreover, it has been proposed that a mannose-binding
lectin domain of the α-glucosidase II β-subunit is also impor-
tant for its activity [50], and the possibility that the inhibitor is
actually binding not to the enzyme active site, but to this lectin
domain instead, is not ruled out at present.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-128-S1.pdf]
Supporting Information File 2
1H and 13C NMR spectra of compounds 9–17.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-128-S2.pdf]
Supporting Information File 3
1H and 13C NMR spectra of compounds 18–27.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-128-S3.pdf]
Conclusion
Unsaturated carbohydrate derived electrophiles react readily
with carbohydrate nitrogen nucleophiles to form amine-linked Acknowledgements
pseudodisaccharides. Triflamides and nosylamides were simi- IC acknowledges the support of Vetenskapsrådet (the Swedish
larly effective as nucleophiles in Mitsunobu coupling reactions Research Council). TDB and DSA acknowledge the support of
with allylic alcohols. The Mitsunobu coupling reactions the Glycobiology Institute and Grant No. R01CA125642 from
proceeded with inversion of configuration, and SN2’ type reac- the National Cancer Institute for part of this work.
Table 1: Inhibition of activity of commercially available glycosidases.
Glycosidase
Percentage inhibition at 1 mM inhibitor concentrationa
21
16
NI
15
22
NI
NI
NI
28
NI
19
NI
29
NI
NI
NI
30
NI
NI
NI
31
NI
NI
NI
32
NI
NI
15
33
NI
NI
16
α-L-fucosidase
(bovine kidney)
amyloglucosidase
(Aspergillus niger)
β-mannosidase
(snail)
aNI = no inhibition at 1 mM.
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28.Teodorović, P.; Slättegård, R.; Oscarson, S. Org. Biomol. Chem. 2006,
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