Stereoselective uncatalyzed synthesis of 2,3-unsaturated-4-N-substituted- β-O-glycosides by means of a new D-galactal-derived N-(mesyl)-aziridine

Article abstract of DOI:10.1021/jo051877p

The reaction of the new D-galactal-derived allylic aziridine 1β with O-nucleophiles (alcohols and monosaccharides) affords, in a high to complete β-stereoselectivity, the corresponding 2,3-unsaturated-β-O-glycosides bearing a β-N-functionality at C(4).

Full text of DOI:10.1021/jo051877p

SCHEME 1
Stereoselective Uncatalyzed Synthesis of
2,3-Unsaturated-4-N-substituted-â-O-glycosides by
Means of a New D-Galactal-Derived
N-(Mesyl)-aziridine†
Valeria Di Bussolo, Maria Rosaria Romano, Lucilla Favero,
Mauro Pineschi, and Paolo Crotti*
process, giving rise to exclusive R-stereoselectivity. Through
the use of this methodology, a nitrogen functionality was regio-
and stereoselectively introduced at the C(4)-carbon of a
pseudoglycal system (Scheme 1).3
Dipartimento di Chimica Bioorganica e Biofarmacia,
UniVersita` di Pisa, Via Bonanno 33, 56126 Pisa, Italy
crotti@farm.unipi.it
To evaluate the synthetic utility of this new class of activated
allylic aziridines and to check whether the stereoselectivity
observed in the glycosylation of alcohols and monosaccharides
is substrate-dependent, the diastereoisomeric activated D-galac-
tal-derived allylic aziridine 1â4 was synthesized and its regio-
and stereochemical behavior in nucleophilic addition reactions
with O-nucleophiles was examined.
ReceiVed September 7, 2005
The stereoselective synthesis of aziridine 1â started from the
previously described glycal-derived allylic epoxide 3r (Scheme
2).6 The nucleophilic ring opening of epoxide 3r with tetra-
methylguanidine azide (TMGA) afforded in a completely regio-
selective and highly stereoselective way the trans-azido alcohol
5 in a 90:10 mixture with the cis diastereoisomer 6. Azido
alcohol 5 was separated by flash chromatography and reduced
by the SnCl2/PhSH/NEt3 protocol7 in MeCN to yield the trans-
â-amino alcohol 7, which was not purified, but directly protected
with MsCl in pyridine to give the trans-N,O-dimesylate 2â, the
stable precursor of allylic aziridine 1â. Base-catalyzed (t-BuOK)
cyclization of 2â affords aziridine 1â, which is consequently
reacted immediately in situ with a nucleophile.8 Alternatively,
the necessary trans-azido alcohol 5 was prepared from the more
readily available diastereoisomeric allylic epoxide 3â.5 The
addition reaction of TMSN3 to epoxide 3â at -20 °C afforded
in excellent regio- and stereoselective control the cis-azido
alcohol 8, which was oxidized by PCC using microwaves to
the azido ketone 9.9 The reduction of 9 with LiAlH4 at -20 °C
afforded a 20:80 mixture of the starting cis-azido alcohol 8 and
the desired trans-azido alcohol 5, which was then separated pure
by flash chromatography (Scheme 3).10
The reaction of the new D-galactal-derived allylic aziridine
1â with O-nucleophiles (alcohols and monosaccharides)
affords, in a high to complete â-stereoselectivity, the
corresponding 2,3-unsaturated-â-O-glycosides bearing a â-N-
functionality at C(4).
Aminosugars1 are an important class of monosaccharides,
widely distributed in nature, and some of them constitute the
essential part of highly effective aminoglycoside antibiotics with
antiviral and anticancer activity.2 Glycal-derived activated allylic
aziridines can be valuable synthetic intermediates for the regio-
and stereoselective synthesis of 4-amino-derived-2,3-unsaturated
glycosides, assuming that a selective glycosylation process (a
conjugated addition) could occur under nucleophilic addition
reaction conditions. Recently, we synthesized and studied the
nucleophilic addition reactions of O-nucleophiles to the N-
(mesyl)-aziridine 1r, a newly activated D-allal-derived allylic
aziridine (Scheme 1).3,4 The glycosylation of alcohols and
monosaccharides with 1r, obtained by base-catalyzed cycliza-
tion of the corresponding stable precursor, the N,O-dimesylate
2r,5 led to the corresponding 2,3-unsaturated-O-glycosides and
disaccharides through a completely regioselective 1,4-addition
(5) (a) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett.
2003, 5, 2173. (b) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi,
M.; Crotti, P. J. Org. Chem. 2004, 69, 8702.
(6) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti, P.
J. Org. Chem. 2004, 69, 7383.
(7) Bartra, M.; Romea, P.; Urpi, F.; Vilarrasa, J. Tetrahedron 1990, 46,
587.
† Dedicated to the memory of Professor Giancarlo Berti.
(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. (c) Bernfield, M.;
Gotte, M.; Park, P. W.; Reizes, O.; Fitzgerald, M. L.; Lincecum, J.; Zako,
M. Annu. ReV. Biochem. 1999, 68, 729. (d) Dwek, R. A. Chem. ReV. 1996,
96, 683.
(2) (a) Kotra, L. P.; Mobashery, S. Curr. Org. Chem. 2001, 5, 193. (b)
Michael, K.; Tor, Y. Chem.-Eur. J. 1998, 4, 2091. (c) Sears, P.; Wong,
C.-H. Angew. Chem., Int. Ed. 1999, 38, 2301.
(3) Di Bussolo, V.; Romano, M. R.; Pineschi, M.; Crotti, P. Org. Lett.
2005, 7, 1299.
(4) On the basis of the absolute configuration of the corresponding C(3)
and C(4) aziridine carbons, aziridines 1r and 1â are considered to be derived
from D-allal and D-galactal, respectively, which present the same absolute
configuration at the same carbons.
(8) Aziridine 1â turned out to be particularly reactive and unstable: the
1H NMR spectrum of the reaction mixture obtained by treatment of a
solution of dimesylate 2â in C6D6 with a dried alkaline resin (MP-carbonate)
showed the presence of only a limited amount (15%) of aziridine 1â,
together with products deriving from its extensive decomposition. The use
in this experiment of t-BuOK (1 equiv) as the base led to a complex reaction
mixture containing glycoside 13â (10-15%), the product of the addition
of t-BuOH, formed in the reaction mixture, to the in situ formed aziridine
1â.
(9) The same reaction carried out under standard conditions turned out
to be extremely sluggish, to the point that after 36 h at room temperature,
the starting azido alcohol 8 was still present (20%). Longer reaction times
led only to complex reaction mixtures.
(10) Other reduction protocols (LiAlH4 room temperature, 0 °C, -78
°C, and NaBH4-EtOH) turned out to be decidedly less stereoselective
toward the desired trans-azido alcohol 5.
10.1021/jo051877p CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/19/2006
1696
J. Org. Chem. 2006, 71, 1696-1699

SCHEME 2
SCHEME 3
selectivity drastically driven toward the anomer (â) having the
same configuration (â) as the starting aziridine. The nature of
the O-nucleophile determines only the extent of the generally
observed â-stereoselectivity. In this framework, whereas MeOH
shows only a moderate â-stereoselectivity (â-anomer/R-anomer
) 85:15), showing an inverted behavior with respect to the same
reaction carried out under protocol A, EtOH leads to an almost
exclusive â-stereoselectivity (95%), and a complete â-stereo-
selectivity (>99% of the corresponding â-anomer turned out
to be present in the crude reaction product) was observed with
those O-nucleophiles such as i-PrOH, t-BuOH, dihydrocholes-
terol, diacetone-D-glucose, and 1,2;3,4-diisopropyliden-D-ga-
lactopyranose, which are characterized by an increasing steric
demand around the nucleophilic center (entries 1-8, Table 1).
SCHEME 4
The great tendency of aziridine 1â, and in general of three-
membered heterocycles (epoxides and aziridines) derived from
glycals, to give 1,4-addition products with O-nucleophiles3,5,6
is further demonstrated by the reaction of aziridine 1â with
AcONa in DMF, that is to say, under conditions that should
reasonably favor a typical SN2 process. Actually, the corre-
sponding â-acetyl glycoside, the acetate 18â, turned out to be
clearly the main addition reaction product (92%) with only a
small amount of the expected 1,2-addition product, the trans-
mesylamino acetate 22 (8%) (entry 11, Table 1, and Scheme
5). In the same way, the reaction of aziridine 1â with a
nucleophile such as MeONa afforded a crude reaction mixture
containing both anti-1,2 and â-1,4-addition products in a 60:40
ratio (entry 12, Table 1). A selective 1,2-addition process was
obtained only by making use of two reagents recently prepared
in our laboratory in which the appropriate O-nucleophile is the
counterion of the noncoordinating tetrabutylammonium cation
(Bu4N+). In this way, the treatment of a solution of aziridine
1â with tetrabutylammonium methoxide (TBAOMe)5b and
tetrabutylammonium trimethylsilanolate (TBAOSiMe3)5b af-
forded exclusively the corresponding trans-methoxy- (19) and
trans-hydroxymesylamino derivative (21), respectively, in a
complete 1,2-regio- and anti-stereoselective fashion (entries 9
and 10, Table 1, and Scheme 5). Acetylation of 21 afforded
acetate 22, thus confirming the structure and stereochemistry
of the minor product previously obtained in the reaction of
aziridine 1â with AcONa.
The glycosylation of simple alcohols (MeOH, EtOH, i-PrOH,
t-BuOH) by the in situ formed allylic aziridine 1â (t-BuOK
cyclization of dimesylate 2â), carried out in the alcohol itself
as the solvent (protocol A), turned out to be completely 1,4-
regioselective, with a stereochemical behavior (the R/â anomeric
ratio) not only largely dependent on the alcohol used, but also
decidedly different from that observed with aziridine 1r and
related allylic oxiranes 3r and 3â in the same experimental
conditions.3,5,6 In fact, with both MeOH and EtOH a practically
identical 31:69 â/R selectivity was observed, indicating, for the
first time, the same stereochemical behavior for these two
alcohols and, more notably, a stereoselectivity (R, in the present
case) opposite to the configuration (â, in the present case) of
the intermediate reactive heterocycle, the aziridine 1â, in the
present case. Only in the case of the more sterically demanding
i-PrOH was the usual selectivity, even if inferior to expectations
(60%), favoring the anomer (â) configurationally homogeneous
with the configuration (â) of the aziridine obtained, to the point
that with t-BuOH a complete â-stereoselectivity was observed
(Scheme 4). In the case of the reactions carried out with MeOH,
EtOH, and i-PrOH, the corresponding pair of R- and â-glyco-
sides were separated and independently characterized.11
Because we were interested in the use of not only simple
alcohols but also more complex alcohols, phenol, and monosac-
charides toward a more general preparation of 4-N-substituted-
O-glycosides, the addition reaction was repeated by treating a
benzene solution of aziridine 1â with only a small amount of
nucleophile (3-4 equiv) (protocol B, Table 1). Under these
conditions, with the only exclusion of phenol, the addition
reactions are completely 1,4-regioselective and show a stereo-
(11) The R-configuration of glycosides 10-12r and 14r and the
â-configuration of glycosides 10-17â were established by comparison of
the chemical shift of the anomeric proton in both R- and â-anomers, which
indicates, in accordance with previously reported data, that the value for
H-1 in the R-anomer is upfield with respect to the value for the H-1 proton
in the corresponding â-anomer.12,13 The â-configuration of glycosyl acetate
18â was established by comparison of the chemical shift of the anomeric
proton (δ 5.79) with literature data for the same proton in structurally related
glycosyl acetates (around δ 5.75-5.91 for â-anomer and δ 6.07-6.35 for
the corresponding R-anomer).14
J. Org. Chem, Vol. 71, No. 4, 2006 1697

TABLE 1. Regio- and Stereoselectivity of the Addition Reaction of O-Nucleophiles to the in Situ Formed N-(Mesyl)-aziridine 1â under
Protocol Ba
a Protocol B: benzene, THF or DMF as the solvent, ROH ) 3-4 equiv. b Crude product. c Purified product (flash chromatography or preparative TLC).
With the only exception of these two last reactions, which
are completely 1,2-regio- and anti-stereoselective (see above),
the addition reactions of O-nucleophiles to aziridine 1â, at least
in conditions of a reduced amount of nucleophile present
(protocol B, Table 1), show a complete 1,4-regioselectivity and
a stereoselectivity (â) that appear to be driven by the config-
uration of the aziridine. As in the case of the other previously
examined aziridine and epoxides derived from the glycal
system,3,5,6 the occurrence of a suitable coordination in the form
of a hydrogen bond between the reactive substrate, the aziridine
1â reacting in the only stable conformation 1â′,15 and the
O-nucleophile appears to be adequate to rationalize the observed
results. In this way, the nucleophile is advantageously brought
to the â face of the aziridine system and is well-disposed for
(13) In the case of the reaction of aziridine 1â with t-BuOH, (+)-
dihydrocholesterol, diacetone-D-glucose, and 1,2;3,4-di-O-isopropylidene-
R-D-galactopyranose (protocol B), a signal could be detected at δ 5.06,
4.99-5.03, 5.13-5.17, 4.99-5.03 in the 1H NMR spectrum of the respective
crude reaction mixture, reasonably due to the corresponding isomeric
R-anomer 13r, 15-17r (less than 1%), respectively.
(14) (a) Horton, D.; Hughes, J. B.; Jewell, J. S.; Philips, K, D.; Turner,
W. N. J. Org. Chem. 1967, 32, 1073. (b) Liu, F.-W.; Zhang, Y.-B.; Liu,
H.-M.; Song, X.-P. Cabohydr. Res. 2005, 304, 489. (c) Vaghefi, M. M.;
Bernacki, R. J.; Dalley, N. K.; Wilson, B. E.; Robins, R. K. J. Med. Chem.
1987, 30, 1383. (d) Capon, B.; Lee, Y. J. Org. Chem. 1991, 56, 4428.
(12) Achmatowicz, O., Jr.; Bielski, R. Carbohydr. Res. 1977, 55, 165.
1698 J. Org. Chem., Vol. 71, No. 4, 2006

SCHEME 5
O-nucleophile that partially escapes this rationalization, and an
unusual mixture of all the three possible addition products (the
corresponding R-anomer 14r, â-anomer 14â, and anti-1,2-
adduct 20) was unexpectedly obtained under protocol B reaction
conditions (entry 5, Table 1).18
A comparison of the results obtained with D-galactal-derived
aziridine 1â with previously studied D-allal-derived aziridine
1r in their reactions with O-nucleophiles, under protocol B,
indicates that, in these glycal-derived vinyl aziridine systems,
the configuration â or R of the aziridine ring and the related
coordination effects are responsible for the complete or almost
complete â- or R-stereoselectivity, respectively, observed in the
completely regioselective conjugate addition of O-nucleo-
philes.19
Studies are in progress to examine the chemical behavior of
this new class of activated aziridines with nucleophiles other
than O-nucleophiles, such as C-, N-, and S-nucleophiles.
SCHEME 6
Experimental Section
Reaction of Aziridine 1â with MeOH in Anhydrous Benzene.
Typical Procedure (Protocol B). A solution of trans-N,O-
dimesylate 2â (0.034 g, 0.086 mmol) in anhydrous benzene (1 mL)
was treated with t-BuOK (0.010 g, 0.086 mmol, 1 equiv) in the
presence of MeOH (0.014 mL, 0.34 mmol, 4 equiv), and the
reaction mixture was stirred at room temperature for 2 h. The
solution was partitioned between Et2O (8 mL) and brine (3 mL),
and the aqueous layer was further extracted with Et2O (2 × 5 mL).
Evaporation of the combined organic extracts afforded a clean crude
product (0.026 g, 92% yield) consisting of a 85:15 mixture of
methyl glycosides 10â and 10r (1H NMR) (see Supporting
Information).
an entropically favored â-directed attack on the nearby C(1)
carbon, as shown in Scheme 6 (route b), which determines the
typical 1,4-regio- and â-stereoselectivity observed.16
Even if favored by the coordination, the pseudoequatorial
nature of this type of nucleophilic attack (route b), together with
the reduced ability of the aziridine nitrogen to give rise to
hydrogen bonds3 and the impossibility for the aziridine 1â to
adopt the alternative conformation 1â′′,15,17 makes the attack
on the C(1) from an external nucleophile through a pseudoaxial
attack (route a) decidedly competitive, particularly in the
presence of a large excess of nucleophile (protocol A), to the
point that with the more nucleophilic MeOH and EtOH, a
stereoselectivity in favor of the R-anomer is observed under
these conditions (Schemes 4 and 6). Phenol is the only
Acknowledgment. This work was supported by the Uni-
versity of Pisa and MIUR (Roma). P.C. gratefully acknowledges
Merck Research Laboratories for the generous financial support
derived from the 2005 ADP Chemistry Award.
Supporting Information Available: General information and
experimental details, spectral and analytical data of all compounds
prepared in this study, and conformational study of aziridine 23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Theoretical conformational studies, in a vacuum and in the presence
of the solvent, carried out for simplicity on the 6-deoxy-N-acetyl aziridine
23, which is structurally related to aziridine 1â, revealed that aziridine 23
exists only in the ring conformation 23′-exo2 with the methyl group
equatorial and with a preference (>98%) for the N-acetyl group in the exo
position (see the Supporting Information). The results obtained with aziridine
23 can reasonably be extended to aziridine 1â and allow us to consider
aziridine 1â as existing only in the corresponding conformation 1â′ (Scheme
6), corresponding to 23′-exo2, as stated in the text.
JO051877P
(18) In addition to the reasonable presence of both R- and â-anomers
14r (15%) and 14â (45%) (see routes a and b, respectively, and discussion
in the text), the unexpected presence of the anti-1,2-adduct 20 (40%) in
this reaction could be attributed to the acidity of phenol, which determines,
in the reaction mixture, a more pronounced protonation of the aziridine
nitrogen with concomitant polarization of the aziridine C(3)-N bond in
the direction of the C(3) allylic carbon. Subsequent nucleophilic attack on
C(3) by a free, noncoordinated PhOH, necessarily occurring in an anti
fashion (route c), leads to the trans-phenoxy sulfonamide 20, as experi-
mentally found.
(16) To check the influence of the chelation ability of K+ on the
â-stereoselective results obtained under protocol B, the reactions with MeOH
and i-PrOH were repeated in benzene in the presence of 18-Crown-6 and
in THF, substituting the t-BuOK with a basic resin (MP-carbonate). The
stereoselective results obtained under these modified protocol B reaction
conditions [10r:10â anomeric ratio ) 22:78 (crown ether) and 20:80 (basic
resin) with MeOH and >99% â-O-glycoside 12â with i-PrOH in both
conditions] may indicate that K+ has little or no influence on the
â-stereoselectivity observed under typical protocol B reaction conditions
[see, for comparison, entries 1 (MeOH) and 3 (i-PrOH), Table 1].
(17) In conformation 1â′′, the corresponding coordination-driven nu-
cleophilic attack on C(1) (route b′) would correspond to a more favored
pseudoaxial attack (Scheme 6).
(19) In accordance with the pseudoaxial or pseudoequatorial nature of
the corresponding coordination-driven nucleophilic attack on C(1), the
R-stereoselectivity previously observed with aziridine 1r under protocol
A3 is larger than the â-stereoselectivity presently obtained with aziridine
1â, under the same conditions.
J. Org. Chem, Vol. 71, No. 4, 2006 1699