Stereoselective synthesis of 4-(N-mesylamino)-2,3-unsaturated-α-O- glycosides via a new glycal-derived vinyl α-N-(mesyl)-aziridine

Article abstract of DOI:10.1021/ol050053r

(Chemical Equation Presented) N-Mesyl aziridine 7α, a new activated vinyl aziridine derived from D-glucal, has been synthesized by cyclization of trans-N,O-dimesylate 6 with t-BuOK in anhydrous benzene. The reaction of 7α with alcohols, phenol, and monosa

Full text of DOI:10.1021/ol050053r

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1299-1302
Stereoselective Synthesis of
4-(N-Mesylamino)-2,3-unsaturated-
r
-O-glycosides via a New
Glycal-Derived Vinyl
r
-N-(Mesyl)-aziridine
Valeria Di Bussolo, 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 January 11, 2005
ABSTRACT
N-Mesyl aziridine 7
t-BuOK in anhydrous benzene. The reaction of 7
4-N-(mesylamino)-2,3-unsaturated-O-glycosides and disaccharides through a completely regioselective 1,4-addition process that proceeds with
high or complete -stereoselectivity.
r
, a new activated vinyl aziridine derived from
D-glucal, has been synthesized by cyclization of trans-N,O-dimesylate 6 with
r
with alcohols, phenol, and monosaccharides (O-nucleophiles) leads to the corresponding
r
Alkyl O-glycosides having differently functionalized amino
groups in different positions (aminosugars) are an important
category of modified carbohydrate units present in numerous
oligosaccharides and glycoconjugates.1 Furthermore, ami-
nosugars are important as essential components of bacterial
capsular polysaccharides and as structural elements of
aminoglycoside antibiotics with antiviral and antitumor
activity.2 In consideration of the biological importance of
natural products containing aminosugars,3 the development
of efficient synthetic routes to these carbohydrates is an
attractive goal.
In this framework, our interest has been directed toward
the stereoselective introduction of a nitrogen functionality
at the C(4) carbon of a glycal system with simultaneous
glycosylation to give 2,3,4-trideoxy-4-N-(substituted-amino)-
hex-2-enopyranosides as valuable, nitrogen-containing, syn-
thetic intermediates since the unsaturation allows further
functionalization. Few methods have been reported to date
for the synthesis of these synthetically useful compounds:
the most convenient of these involves an allyl cyanate-to-
isocyanate rearrangement of hex-3-enopyranosides and a
palladium-catalyzed allylic substitution by secondary amines
of suitable hex-2-enopyranosides.4
Recently, we disclosed a new glycosylation process based
on the regioselective 1,4-addition of O-nucleophiles (alco-
hols) and C-nucleophiles (lithium alkyls) to diastereoisomeric
vinyl oxiranes 1â (a and b) and 1R derived from 6-O-
(benzyl)- (2a), 6-(O-trityl)-D-glucal (2b), and 6-O-(benzyl)-
D-gulal (3), respectively. Corresponding 2,3-unsaturated R-O-
and C-glycosides (from 1R) and â-O- and C-glycosides (from
1â) were obtained in a stereospecific way, whose configur-
ation turned out to depend only on the configuration (R or
â) of the starting epoxide (Scheme 1).5 The observation that
in this process the C(4)-OH group of addition products comes
from the intermediate epoxide led us to pursue the prospect
(1) (a) Banoub, J.; Boullanger, P.; Lafont, D. Chem. ReV. 1992, 92, 1167.
(b) van den Bos, L J.; Code´e, J. D. C.; van Boom, J. H.; Overkleeft, H. S.;
van der Marel, G. A. Org. Biomol. Chem. 2003, 1, 4160.
(2) (a) Wang, Y.; Kalka-Moll, W. M.; Roehrl, M. H.; Kasper, D. L. Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 13478. (b) Choi, Y.-H.; Roehrl, M. H.;
Kasper, D. L.; Wang, J. Y. Biochemistry 2002, 41, 15144. (c) Sears, P.;
Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300.
(4) (a) Ichikawa, Y.; Kobayashi, C.; Isobe, M. J. Chem. Soc., Perkin
Trans. 1 1996, 377. (b) Ichikawa, Y.; Kobayashi, C.; Isobe, M. Synlett 1994,
919 and references therein. (c) de Brito, T. M. B.; da Silva, L. P.; Siqueira,
V. L.; Srivastava, R. M. J. Carbohydr. Chem. 1999, 18, 609.
(3) Knapp, S. Chem. Soc. ReV. 1999, 28, 61.
10.1021/ol050053r CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/26/2005

N-mesyl aziridine 7R. As in the case of the corresponding
epoxides 1R and 1â, aziridine 7R was not stable enough to
be isolated and could only be obtained in situ by base-
catalyzed (t-BuOK) cyclization of N,O-dimesylate 6.9 How-
Scheme 1. Stereospecific R- and â-O-Glycosylation and
C-Glycosidation by Epoxides 1R and 1â, Respectively
1
ever, appropriate H NMR (200 MHz) experiments carried
out on the sample prepared by adding t-BuOK to a C6D6
solution of 6 at 5 °C clearly showed that, within 10 min,
vinyl aziridine 7R was present in the reaction mixture
together with an almost equivalent amount of the unreacted
precursor 6 (50% conversion).10 The evidence for aziridine
formation prompted us to determine the best protocol in order
to accomplish an efficient one-pot glycosylation process
using this new glycal donor.
In the optimized procedure, t-BuOK (1 equiv) was added
at room temperature to a solution of trans-N,O-dimesylate
6 in anhydrous benzene containing MeOH (4 equiv) (protocol
A). A regioselective SN2′ reaction was obtained with clean
formation of the corresponding 4-N-(mesylamino)-2,3-
unsaturated-R-O-methyl glycoside 8R (entry 1, Table 1) with
a high R-stereoselectivity (93%). Under this protocol, the
intermediate vinyl aziridine 7R does not decompose but
immediately reacts with the nucleophile (MeOH) present in
the reaction mixture.11
of achieving an analogous nitrogen transfer to the C(4)
position via a corresponding activated aziridine intermediate.
In this preliminary approach to the chemistry of glycal-
derived aziridines, the readily accessible N-mesyl R-aziridine
7R (Scheme 2) turned out to be appropriate in order to check
Scheme 2. Stereoselective Synthesis of N,O-Dimesylate 6 and
in Situ Cyclization to N-Mesyl Aziridine 7R
(6) Actually, the N-acetyl-O-mesyl deivative 6-Ac corresponding to N,O-
dimesylate 6 (Scheme 2) was initially prepared as a suitable precursor of
the N-acetyl aziridine (7R-Ac) corresponding to 7R and examined in addition
reaction with alcohols.
Unfortunately, 6-Ac turned out to be completely unreactive with alcohols
under protocol B (see text) and was entirely recovered from the reaction
mixture. 1,4-Addition products derived from the corresponding aziridine
7R-Ac were obtained, even if in an unsatisfactory yield, only when 6-Ac
was left to react under protocol A (see text) only with MeOH and EtOH.
(7) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti, P.
J. Org. Chem. 2004, 69, 8702.
(8) Bartra, M.; Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron 1990, 46,
587.
(9) For reviews on aziridine chemistry, see: (a) McCoull, W.; Davis, F.
A. Synthesis 2000, 1347. (b) Osborn, H. M. I.; Sweeney, J. Tetrahedron:
Asymmetry 1997, 8, 1693. (c) Tanner, D. Angew. Chem., Int. Ed. 1994, 33,
599. For synthesis of activated vinylaziridines, see: (d) Arini, L. G.; Sinclair,
A.; Szeto, P.; Stockman, R. A. Tetrahedron Lett. 2004, 45, 1589. (e) Morton,
D.; Pearson, D.; Field, R. A.; Stockman, R. A. Org. Lett. 2004, 6, 2377. (f)
Liao, W.-W.; Deng, X.-M.; Tang, Y. Chem. Commun. 2004, 1516. (g) Ibuka,
T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga, T.;
Nakai, K.; Tamamura, H.; Fujii, N. J. Org. Chem. 1997, 62, 999. (h) Åhman,
T.; Jarevång, T.; Somfai, P. J. Org. Chem. 1996, 61, 8148 and references
therein. For synthetic applications and ring-opening reactions of sugar
aziridines, see: (i) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving,
E.; Scheinmann, F. Org. Lett. 2003, 5, 2927. (j) Charon, D.; Mondange,
M.; Pons, J.-F.; Le Blay, K.; Chaby, R. Bioorg. Med. Chem. 1998, 6, 755.
(k) Ali, Y.; Richardson, A. C.; Gibbs, C. F.; Hough, L. Carbohydr. Res.
1968, 7, 255. (l) Gibbs, C. F.; Hough, L.; Richardson, A. C. Carbohydr.
Res. 1965, 1, 290. (m) Guthrie, R. D.; Murphy, D. J. Chem. Soc. 1965,
3828. (n) Buss, D. H.; Hough, L.; Richardson, A. C. J. Chem. Soc. 1965,
2736.
the chemical behavior of this new class of activated aziri-
dines. We now report the stereoselective synthesis of the
glycal-derived, activated aziridine 7R, starting from vinyl
â-epoxide 1aâ (Scheme 2), and the corresponding regio- and
stereochemical behavior in nucleophilic addition reactions
with alcohols (O-nucleophiles).6
As previously reported,7 the reaction of epoxide 1aâ with
the noncoordinating tetramethylguanidinazide (TMGA) in
MeCN proceeds in a completely 1,2-regioselective and anti-
stereoselective way to afford the trans-azido alcohol 4 as
the only reaction product (Scheme 2). The reduction of 4
with SnCl2 in MeCN in the presence of PhSH/Et3N led to
trans-â-amino alcohol 5,8 which was protected on both the
amino and alcoholic groups with MsCl in Py to give the
trans-N,O-dimesylate 6, the ultimate precursor of vinyl
(10) Prolonged reaction times (1 h) at 5 °C afforded a 7:3 mixture of
vinyl aziridine 7R and tert-butyl R-O-glycoside 11R (Table 1) derived from
1,4-addition to aziridine 7R of t-BuOH formed in the reaction mixture by
deprotonation-cyclization of N,O-dimesylate 6 by t-BuOK.
(5) (a) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett.
2002, 4, 3695. (b) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P.
Org. Lett. 2003, 5, 2173. (c) Di Bussolo, V.; Caselli, M.; Romano, M. R.;
Pineschi, M.; Crotti, P. J. Org. Chem. 2004, 69, 7383.
(11) If MeOH is not initially present in the reaction mixture but is added
only after 15 min of stirring of the starting solution of N,O-dimesylate 6 in
the presence of t-BuOK, tert-butyl R-O-glycoside 11R turned out to be the
only product present in the crude reaction mixture (1H NMR).
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Org. Lett., Vol. 7, No. 7, 2005

idene-R-D-glucofuranose (diacetone D-glucose), and 1,2;3,4-
di-O-isopropylidene-R-D-galactopyranose (entries 4 and 6-8,
Table 1), were glycosylated with good yields. The corre-
sponding 4-N-(mesylamino)-2,3-unsaturated-R-glycosides
(9R-13R) and disaccharides (14R and 15R) were obtained
with complete 1,4-regioselectivity and high (93-95%, in the
case of 9R, 10R, and 12R) or complete R-stereoselectivity
(in the case of 11R and 13R-15R) (Table 1).
Table 1. Glycosylation of Alcohols and Phenol by the in
Situ-Formed Vinyl Aziridine 7R (Protocol A)
In the case of MeOH, EtOH, i-PrOH, and t-BuOH, the
addition reaction was repeated using the alcohol itself as the
solvent (protocol B). Under these conditions, the glycosyl-
ation reaction was still completely 1,4-regioselective, but the
R/â anomeric ratio depended on the alcohol used. For
example, the low R-stereoselectivity observed with the less
hindered MeOH (R/â ) 60/40) increased on passing to the
progressively more hindered EtOH (R/â ) 75/25) and
i-PrOH (R/â ) 93:7). Only in the case of the encumbered
t-BuOH was complete R-stereoselectivity observed (Scheme
3).
Scheme 3. Glycosylation of Simple Alcohols by the in
Situ-Formed Vinyl Aziridine 7R (Protocol B)
Due to the substantial amount of â-anomer present, the
reactions carried out in MeOH and EtOH under protocol B
required the separation by preparative TLC of the R- (8R
and 9R) and â-glycosides (8â and 9â) whose relative
structure and configuration were independently determined
by appropriate NOE experiments carried out on the respective
H-1 and H-5 protons. This allowed us to assign the
R-configuration to the major or only O-glycoside present,
not only in these (MeOH and EtOH) but also in all other
addition reactions (entries 3-8, Table 1).12
(12) Contrary to what was observed in the R- and â-O-glycosides derived
from epoxides 1R and 1â, respectively, the chemical shift of the anomeric
a In all cases, the corresponding â-anomer was detected (1H NMR):
entries 1-3 (7%), entry 5 (5%), and entries 4 and 6-8 (less than 1%).
b Purified product (flash chromatography or preparative TLC).
1
proton H-1 in the H NMR spectra of the diastereoisomeric pairs 8R and
8â and 9R and 9â is not useful for assigning the relative R- and
â-configuration of anomers. However, the chemical shift of the singlet
corresponding to the methyl group of the MeSO2NH- group in the 1H
NMR spectrum of both 8â and 9â (δ 2.95) is more downfield than that in
the corresponding anomers 8R and 9R (δ 2.88). As a consequence, the
observed value of the chemical shift of the mesyl group for the main or
almost unique addition product, typically around δ 2.87-2.90, together with
the observation of the constant presence of a slightly downfield singlet signal
around δ 2.95-2.98 in the crude addition reaction mixture corresponding
to entries 3-8, Table 1, reasonably due to the corresponding â-anomer
(5-7% in entries 3 and 5, and less than 1% in entries 4 and 6-8, Table 1)
made it possible to assign the R-configuration to the main, or almost unique
product, in each addition reaction.
To verify the scope of this glycosylation method, a number
of glycosyl acceptors were employed in coupling reactions
with the intermediate aziridine 7R (Table 1). Under the
described protocol (protocol A), simple primary (EtOH) and
secondary alcohols (i-PrOH) and phenol (entries 2, 3, and
5, Table 1), as well as more hindered O-nucleophiles such
as t-BuOH, (+)-dihydrocholesterol, 1,2;5,6-di-O-isopropyl-
Org. Lett., Vol. 7, No. 7, 2005
1301

The results obtained indicate that in the case of aziridine
7R there is a close relationship between the configuration
(R) of the three-membered heterocycle (the aziridine ring)
and the largely predominant or exclusive direction (R) of
the O-glycosylation process, as previously observed for the
corresponding epoxide 1R in related addition reactions.5c
The occurrence of an effective coordination (hydrogen
bond) between the aziridine nitrogen and the O-nucleophile
(ROH) as shown in structure 16 (Scheme 4) can reasonably
Within this rationalization, it is interesting to note that the
R/â stereoselectivity observed under protocol B with vinyl
R-aziridine 7R (from R/â ) 60/40 in MeOH to R/â ) 75/25
in EtOH, and R/â ) 93/7 in i-PrOH, Scheme 4) is smaller
than that observed with the corresponding R-epoxide 1R
under the same O-glycosylating conditions (from R/â ) 81/
19 in MeOH to R/â ) 93/7 in EtOH and complete
R-stereoselectivity in i-PrOH).5c Reasonably, the inductive
and conjugative electron-withdrawing effect of the mesyl
group makes the lone pair of the aziridine nitrogen of 7R
less available for hydrogen bonding than the oxirane oxygen
lone pair of epoxide 1R,13 thus making, in the case of
aziridine 7R, the â-directed attack by a noncoordinated
nucleophile molecule (ROH) more competitive (route b,
Scheme 4).
Scheme 4. Rationalization of the 1,4-Regio- and
R-Stereoselective Addition of Alcohols to Aziridine 7R
Studies are under way in order to evaluate the regio- and
stereochemical behavior of aziridine 7R with other nucleo-
philes, such as C-, N-, and S-nucleophiles.
Acknowledgment. This work was supported by the
University of Pisa and MIUR, Roma. P.C. gratefully
acknowledges Merck Research Laboratories for the generous
financial support derived from the 2002 ADP Chemistry
Award.
rationalize the results. In this way, the nucleophile alcohol
(ROH) is brought onto the R-face of the aziridine system
and is suitably arranged for an entropically favored R-directed
nucleophilic attack on the C(1) carbon of the unsaturated
system, via pseudoaxial attack (route a, Scheme 4). Con-
versely, a â-directed attack on C(1) (route b, Scheme 4),
which corresponds to a less favored pseudoequatorial attack,
by a free, noncoordinated O-nucleophile (ROH) should
reasonably be less active, particularly in conditions where a
small amount of the nucleophile is present (protocol A), as
experimentally observed (Table 1 and Scheme 4).
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.
OL050053R
(13) Overberger, C. G.; Tobkes, M. J. Polym. Sci. 1964, 2, 2481.
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Org. Lett., Vol. 7, No. 7, 2005