Stereoselective synthesis of 2,3-unsaturated 1,6-oligosaccharides by means of a glycal-derived allyl epoxide and N-nosyl aziridine

Article abstract of DOI:10.1021/ol800793f

(Chemical Equation Presented) β-D-threo- and 4-deoxy-4-amino-α- D-erythro-hex-2-enopyranosyl di- (n = 0) and trisaccharides (n = 1) of types A and B were synthetized by means of a reiterative, completely stereoselective glycosylation process which makes u

Full text of DOI:10.1021/ol800793f

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2493-2496
Stereoselective Synthesis of
2,3-Unsaturated 1,6-Oligosaccharides by
Means of a Glycal-Derived Allyl Epoxide
and N-Nosyl Aziridine†
Valeria Di Bussolo, Lorenzo Checchia, Maria Rosaria Romano, Mauro Pineschi,
and Paolo Crotti*
Dipartimento di Chimica Bioorganica e Biofarmacia, UniVersita` di Pisa,
Via Bonanno 33, I-56126 Pisa, Italy
crotti@farm.unipi.it
Received April 7, 2008
ABSTRACT
ꢀ-D-threo- and 4-deoxy-4-amino-r-D-erythro-hex-2-enopyranosyl di- (n ) 0) and trisaccharides (n ) 1) of types A and B were synthetized by
means of a reiterative, completely stereoselective glycosylation process which makes use of the D-galactal-derived allyl epoxide 1ꢀ and
D-allal-derived allyl N-nosyl aziridine 2r, respectively.
Besides being present in many natural, biologically active
compounds (antibiotics, antitumor agents, and cardiac gly-
cosides), oligosaccharides are often found as components of
glycoproteins and glycolipids which are important in cell
surface recognition and cellular interactions and as blood
group determinants and tumor-associated antigens.1 The
interest in these carbohydrates has stimulated the develop-
ment of several solution- and solid-phase protocols for the
synthesis of fully oxygenated natural oligosaccharides.1,2 By
way of contrast, less attention has been given to the synthesis
of unsaturated oligosaccharides.3 In this framework, the
presence of the double bond, which allows further function-
alization, makes 2,3-unsaturated oligosaccharides very in-
teresting systems for the construction, not only of fully
Recently, we found that the reaction of the diastereoiso-
meric D-galactal- and D-allal-derived allyl epoxides 1r4a and
1ꢀ4b,c and N-nosyl aziridines 2r and 2ꢀ5a with O-nucleo-
philes, such as alcohols and partially protected monosac-
charides (3-4 equiv), led to the corresponding R-O-
glycosides from 1r and 2r and ꢀ-O-glycosides from 1ꢀ and
2ꢀ in a new uncatalyzed substrate-dependent stereospecific
glycosylation process (1,4-addition process). The close cor-
respondence found between the configuration of the glycosides
obtained and that of the starting heterocycle was rationalized
by the occurrence of a coordination between the O-nucleophile
and the oxirane oxygen or aziridine nitrogen in the form of a
hydrogen bond, as shown in 3r′′ and 4ꢀ′ (Scheme 1).6,7
3a
oxygenated, but also of deoxy and dideoxy sugars.
(4) (a) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti,
P. J. Org. Chem. 2004, 69, 7383. (b) Di Bussolo, V.; Caselli, M.; Romano,
M. R.; Pineschi, M.; Crotti, P. J. Org. Chem. 2004, 69, 8702. (c) Di Bussolo,
V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett. 2003, 5, 2173.
† Dedicated to the memory of Professor Bruno Macchia (1933-2008).
(1) (a) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000, and references
therein. (b) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046.
(2) (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. 1996,
35, 1380. (b) Nicolaou, K. C.; Wissinger, N.; Pastor, J.; DeRoose, F. J. Am.
(5) (a) Di Bussolo, V.; Romano, M. R.; Pineschi, M.; Crotti, P.
Tetrahedron 2007, 63, 2482. See also: (b) Di Bussolo, V.; Romano, M. R.;
Pineschi, M.; Crotti, P. Org. Lett. 2005, 7, 1299. (c) Di Bussolo, V.; Favero,
L.; Romano, M. R.; Pineschi, M.; Crotti, P. J. Org. Chem. 2006, 71, 1696.
(6) A theoretical conformational study carried out on simplified structur-
ally related models has indicated that epoxide 1r7 and aziridine 2r
(unpublished results) exist as an equilibrium mixture of the corresponding
conformers r′ and r′′, whereas the diastereoisomeric epoxide 1ꢀ7and
aziridine 2ꢀ5c exist only as the corresponding conformer ꢀ′ (Scheme 1).
Chem. Soc. 1997, 119, 449, and references therein
.
(3) For recent, effective synthesis of this kind of carbohydrates, see:
(a) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126,
3428. (b) McDonald, F. E.; Zhu, H. Y. H. J. Am. Chem. Soc. 1998, 120,
4246.
10.1021/ol800793f CCC: $40.75
Published on Web 05/22/2008
2008 American Chemical Society

Scheme 4. Stereoselective Synthesis of Trisaccharide 5
Scheme 1. Stereoselective Addition of O-Nucleophiles to Allyl
Epoxides 1r and 1ꢀ and Allyl N-Nosyl Aziridines 2r and 2ꢀ
We saw the possibility of adapting the new glycosylation
process found with epoxides 1r and 1ꢀ and aziridines 2r
and 2ꢀ, in a reiterative version for the stereoselective
synthesis of 2,3-unsaturated-1,6-oligosaccharides of type A,
by using a type 1 epoxide, and the corresponding 4-deoxy-
4-amino-substituted oligosaccharides of type B, by using a
type 2 aziridine (Scheme 2). This possibility was checked
Scheme 2. 2,3-Unsaturated-1,6-oligosaccharides (A and B)
R-linked-4-deoxy-4-amino-D-erythro-hex-2-enopyranosyl-
1,6-trisaccharide 6 (Schemes 5 and 6).
Scheme 5. Glycosyl Donor and Glycosyl Acceptor for the
Synthesis of Trisaccharide 6
by preparing the type A ꢀ-linked-D-threo-hex-2-enopyrano-
syl-1,6-trisaccharide 5 (Schemes 3 and 4) and the type B
Scheme 3
.
Glycosyl Donor and Glycosyl Acceptor for the
Synthesis of Trisaccharide 5
For the synthesis of trisaccharide 5, epoxide 1ꢀ was taken
as the initial glycosyl donor and primary alcohol 7 as the
permanent glycosyl acceptor. Alcohol 7 was prepared
(7) Crotti, P.; Di Bussolo, V.; Pomelli, C. S.; Favero, L. Theor. Chem.
Acc., submitted.
2494
Org. Lett., Vol. 10, No. 12, 2008

through a simple procedure starting from tri-O-acetyl-D-
glucal (8), as shown in Scheme 3.8
The reaction of epoxide 1ꢀ (prepared in situ by base-
catalyzed cyclization of trans-hydroxy mesylate 14)4b with
alcohol 7 afforded, with complete ꢀ-stereoselectivity, the
ꢀ-O-glycoside 15, which was acetylated (15-Ac) then depro-
as the initial glycosyl donor and 1,3-diol 21 (prepared from
the THP-derivative 13), as the permanent glycosyl acceptor
(Scheme 5).
The synthesis of trisaccharide 6 is conceptually similar to
that of trisaccharide 5. In this case, all the glycosylation steps
are R-stereoselective because the initial and the intermediate
glycosyl donors are R-aziridines (Scheme 6).
The reaction of aziridine 2r [prepared in situ by base-
catalyzed (K2CO3) cyclization of the stable trans-N-nosyl-
O-mesylate 26]5a with diol 21 afforded the O-glycoside 27
with complete regioselectivity (exclusive attack by the
primary alcoholic functionality of 21) and R-stereoselectivity.
O-Glycoside 27 was transformed (MsCl/Py) into the trans-
N-nosyl-O-mesylate 28, which was cyclized under basic
conditions to the intermediate R-aziridine 29, the new
glycosyl donor. The reaction of 29 with diol 21 introduces
the third fragment, still with complete regio- and R-stereo-
selectivity, to give R-O-glycoside 30, which was converted
(MsCl/Py) into the trans-N-nosyl-O-mesylate 31. The treat-
ment of 31 with i-PrOH in the presence of K2CO3 afforded,
through the intermediate R-aziridine 32, the N-nosyl-
substituted trisaccharide 33, as the corresponding isopropyl
R-O-glycoside (Scheme 6).11 Deprotection of the N-nosyl-
protected 33 by the PhSH/K2CO3 protocol5a afforded the
desired free amino group-containing trisaccharide 6 in 25%
overall yield (six steps) (Scheme 6).
Scheme 6. Stereoselective Synthesis of Trisaccharide 6
Alternatively, the protocols described in Schemes 4 and
6 could be directed toward the synthesis of the corresponding
disaccharides (equations a and b, Scheme 7). For this
Scheme 7. Synthesis of Disaccharides 34 and 36 (eqs a and b)
tected (TBAF/THF) to give the trans-hydroxy mesylate 16-
Ac. Base-catalyzed cyclization of 16-Ac, followed by
reaction of the intermediate allyl epoxide 17-Ac (the new
glycosyl donor) with alcohol 7 introduces the third fragment,
still with complete ꢀ-stereoselectivity, to give the ꢀ-O-
glycoside 18-Ac, which was acetylated (18-diAc). Depro-
tection of 18-diAc (TBAF/THF) led to the trans-hydroxy
mesylate 19-diAc which, on treatment with t-BuOH in the
presence of t-BuOK, afforded, through the formation of the
intermediate allyl epoxide 20-diAc, the trisaccharide 5-diA-
cas the corresponding tert-butyl ꢀ-O-glycoside.9 Final saponi-
fication of the diacetyl derivative 5-diAc afforded trisaccharide
5 in 33% overall yield (seven steps) (Scheme 4).10
Trisaccharide 5 was also prepared without acetylating the
synthetic intermediates, but the quality of the crude product
of each step and the overall yield [17% (five steps)] were
lower (see Scheme 9, Supporting Information).
For the synthesis of trisaccharide 6, aziridine 2r was taken
purpose, it was sufficient to subject trans-hydroxy mesylate
16, obtained by deprotection (TBAF/THF) of ꢀ-O-glycoside
15, and trans N-nosyl-O-mesylate 28 to the t-BuOH/t-BuOK
and i-PrOH/K2CO3 protocol, respectively, in order to obtain,
(8) For the preparation of 3,4-di-O-acetyl-D-glucal (9), see: Di Bussolo,
V.; Favero, L.; Macchia, F.; Pineschi, M.; Crotti, P. Tetrahedron 2002, 58,
6069.
(9) t-BuOH was chosen for the formation of the final O-glycoside
because, when this alcohol was used as the solvent, a completely
ꢀ-stereoselective O-glycosylation process was obtained, as in the corre-
sponding monomer, epoxide 1ꢀ.4b
(11) i-PrOH was chosen for the formation of the final O-glycoside,
because when this alcohol was used as the solvent, a completely R-
stereoselective O-glycosylation process was obtained, as in the corresponding
monomer, aziridine 2r.5a
(10) Trisaccharide 5 was fully characterized also as the corresponding
triacetyl derivative 5-triAc (Scheme 4).
Org. Lett., Vol. 10, No. 12, 2008
2495

through the intermediate formation of the allyl ꢀ-epoxide
17 and allyl R-aziridine 29, disaccharide 34 as tert-butyl ꢀ-O-
glycoside (from 16) and disaccharide 35 as isopropyl R-O-
glycoside (from 28).9,11 Deprotection of 35 by the usual
protocol (PhSH/K2CO3) afforded the free amino group-
containing disaccharide 36.
Scheme 8. Synthesis of Disaccharide 41
The method here described for the synthesis of 2,3-
unsaturated-1,6-oligosaccharides (trisaccharides 5 and 6 and
disaccharides 34 and 36) appears to be very efficient with
regard to the complete stereo- and regioselectivity observed
in each glycosylation step and nice with regard to the overall
yield (25-33% for six to seven steps). Moreover, it is
interesting to note that the two protocols described for the
construction of this class of oligosaccharides, one based on
the D-galactal-derived allyl epoxide 1ꢀ and the other based
on the D-allal-derived allyl aziridine 2r, can reasonably be
mixed to give 1,6-oligosaccharides containing alternating
-OH and -NH2 groups at C(4), in which the stereoselec-
tivity (R or ꢀ) of each glycosylation process is simply
determined by the configuration (R or ꢀ) of the starting and
intermediate allyl epoxide or aziridine system.4,5 This point
is nicely demonstrated by the synthesis of disaccharide 41.
In this case, aziridine 2r was reacted with alcohol 7 (the
glycosyl acceptor previously used for the synthesis of
disaccharide 34 and trisaccharide 5) affording the new
O-glycoside 37, with complete R-stereoselectivity. By means
of the usual protocol (TBAF/THF), R-O-glycoside 37 was
transformed into the trans-hydroxy mesylate 38, which, on
treatment with t-BuOH in the presence of t-BuOK, afforded,
through the intermediate formation of ꢀ-epoxide 39, disac-
charide 40 as the corresponding tert-butyl ꢀ-O-glycoside
(Scheme 8).9 Deprotection of 40 by the PhSH/K2CO3
protocol afforded the corresponding free amino group-
containing disaccharide 41 in 30% overall yield (four steps).
The synthetic value and utility of our protocol for the
construction of 2,3-unsaturated-1,6-oligosaccharides such as
5, 6, 34, 36, and 41 is also confirmed by the observation
that little is present in the literature on this subject. Actually,
4-amino-substituted-2,3-unsaturated-1,6-oligosaccharides such
as trisaccharide 6, the corresponding disaccharide 36 and the
“mixed” disaccharide 41 are not present at all, at the moment,
in literature, whereas, as regards 2,3-unsaturated-1,6-oli-
gosaccharides such as the ꢀ-linked (threo configuration)
trisaccharide 5 and the corresponding disaccharide 34, there
is only a recent paper by O’Doherty reporting the synthesis
of structurally related R-linked (erythro configuration) di-
and trisaccharides.3a
Studies are in progress in order to identify conditions for
the stereo- and/or regioselective functionalization of the
double bond present in disaccharides 34, 36, and 41,
trisaccharides 5 and 6, and the corresponding monosaccha-
rides.12
Acknowledgment. This work was supported by the
University of Pisa and MIUR, Roma. We thank Prof.
Gabriele Renzi (Universita` di Camerino) for the determina-
tion of the molecular weight of oligosaccharides 5, 5-triAc,
6, 34, and 36. P.C. gratefully acknowledges Merck Research
Laboratories for the generous financial support deriving from
the 2005 ADP Chemistry Award.
Supporting Information Available: Experimental details
and spectral and analytical data for all reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800793F
(12) The choice of the 6-OBn protecting group on the terminal
unsaturated unit of type A and B oligosaccharides was based on the
assumption that its removal should occur only after functionalization of
the double bond. Moreover, in type B oligosaccharides the cleavage of the
benzyl ether should be carried out on the corresponding N-acetyl derivatives,
rather than on the free amino group-containing compounds.
2496
Org. Lett., Vol. 10, No. 12, 2008