Ring-opening reactions of aziridines fused to a conformationally locked tetrahydropyran ring

Article abstract of DOI:10.1002/ejoc.200900762

1,6-Anhydro-2,3,4-trideoxy-2,3-(tosylepimino)-β-D-hexopyranoses 1 and 2 underwent aziridine ring-opening reactions with halides and other heteroatom-centered nucleophiles. Ribo-epimine 1 provided trans-diaxial and cis products. The lyxo-epimine 2 gave tra

Full text of DOI:10.1002/ejoc.200900762

FULL PAPER
DOI: 10.1002/ejoc.200900762
Ring-Opening Reactions of Aziridines Fused to a Conformationally Locked
Tetrahydropyran Ring
[a]
[b]
[c]
[a]
[d]
ˇ
ˇ
ˇ
ˇˇ
ˇ
Jindrich Karban,* Jirí Kroutil, Milos Budesínský, Jan Sýkora, and Ivana Císarová
Dedicated to Professor Jan Schraml on the occasion of his 70th birthday
Keywords: Aziridines / Regioselectivity / Carbohydrates / Nitrogen heterocycles / Cleavage reactions
1,6-Anhydro-2,3,4-trideoxy-2,3-(tosylepimino)-β-
D
-hexopyr-
cleavage versus base cleavage) and the nucleophile (hard
nucleophiles versus soft ones). These results have been ra-
tionalized by assuming that both SN2 and borderline SN2
cleavage mechanisms are operative.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
anoses 1 and 2 underwent aziridine ring-opening reactions
with halides and other heteroatom-centered nucleophiles.
Ribo-epimine 1 provided trans-diaxial and cis products. The
lyxo-epimine 2 gave trans-diaxial and trans-diequatorial
products, depending upon the reaction conditions (acid
ogy to similar oxiranes, we may expect that the simulta-
neous intervention of steric and electronic effects will play
a significant role too.[12–17]
Introduction
Aziridines have found widespread use as synthetic inter-
mediates in organic synthesis.[1–10] Their synthetic value is
based predominantly upon their ability to undergo stereose-
lective ring-opening reactions. To facilitate nucleophilic ring
opening, aziridines need to be activated by N-substitution
with a strongly electron-withdrawing group such as an al-
kane/arenesulfonyl, acyl or alkoxycarbonyl group. Alterna-
tively, Lewis-acid coordination, N-protonation or quar-
ternization can be also used to enhance the reactivity of
aziridines.
As predicted by the Fürst–Plattner rule, the preferential
formation of the trans-diaxial stereoisomer is often ob-
served.[11,18] The applicability of the Fürst–Plattner rule to
the carbohydrate aziridines is, however, limited to cleavage
reactions following the SN2 mechanistic pathway. Moreover,
the rule can be successfully applied only to aziridines that
are fused to a six-membered ring with a fixed conforma-
tion.[11]
The unusual formation of trans-diequatorial isomers has
also been observed[19–22] and rationalized by the postulation
of an equilibrium between the unreacted aziridine and the
trans-diaxial product.[19] To produce trans-diequatorial,
ring-cleavage product the epimine probably reacts either
through a twist conformation of the tetrahydropyran ring
or through an ionic SN1 mechanism.
The stereoselectivity of the ring-opening reactions is usu-
ally determined by inversion of configuration at the at-
tacked carbon, whereas regioselectivity presents a more
complex issue, particularly for carbohydrate-based azirid-
ines (epimines). Aziridines fused to a hexopyranose unit
show regioselectivity dependent primarily upon the six-
membered-ring conformation[11] (steric effect), but in anal-
Recently, we have published articles describing the reac-
tivity of N-substituted epimines of 1,6-anhydro-β--hexop-
yranoses towards heteroatom-centered nucleophiles.[19,23–25]
In this paper, we have extended the ring-cleavage reactions
of epimines to 4-deoxy-derivatives of 1,6-anhydro-β--hex-
opyranoses in order to obtain deeper insight into the
mechanisms actually involved in the aziridine cleavage. We
have performed a series of nucleophilic ring-opening reac-
tions on N-tosylaziridines 1 and 2 (Scheme 1) with selected
nucleophiles. The tetrahydropyran ring of 1 and 2 is confor-
mationally locked by the 1,6-anhydro bridge[26] and asym-
metrically substituted (acetal oxygen versus hydrogen
atoms) at the carbon atoms adjacent to the aziridine ring.
This enabled us to assess the influence of the electron-with-
[a] Institute of Chemical Process Fundamentals of the
ASCR, v. v. i.,
Rozvojová 135, 165 02 Praha 6, Czech Republic
Fax: +420-220920661
E-mail: karban@icpf.cas.cz
[b] Department of Organic and Nuclear Chemistry,
Charles University in Prague,
Albertov 6, 128 43 Praha 2, Czech Republic
[c] Institute of Organic Chemistry and Biochemistry of the
ASCR, v.v.i.,
Flemingovo nám. 2, 166 10 Praha 6, Czech Republic
[d] Center of Molecular and Crystal Structures, Faculty of Science,
Charles University,
Hlavova 2030, 128 40 Praha 2, Czech Republic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900762.
Eur. J. Org. Chem. 2009, 6399–6406
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6399

J. Karban, J. Kroutil, M. Budeˇsˇínský, J. Sýkora, I. Císarˇová
We also obtained unsaturated tosylamino derivative 5 as
FULL PAPER
drawing properties of the acetal functionality in combina-
tion with steric effects on the regioisomeric outcome of the a single product by the action of tBuOK upon 1 in THF
reaction. In addition, aziridine cleavage of 1 and 2 should (Table 1, Entry 11). The isomerization of 1 into 5 began
provide various selectively substituted 2- or 3-amino-4-de- with hydrogen abstraction from C-4, and the hydrogen had
oxyhexopyranoses, which are valuable chiral synthons.
to be trans with respect to the aziridine.[23] We can explain
the formation of 5 as a side product in the reaction with
Bu4NX by hydrogen abstraction from 1 by the strongly ba-
sic tosylamide anion formed during the cleavage.
The reactions of 1,6-anhydro-2,3,4-trideoxy-2,3-(tosylep-
imino)-β--lyxo-hexopyranose (2) are summarized in
Table 2. trans-Diequatorial products formed by nucleophilic
attack at C-3 predominated over trans-diaxial products in
all reactions except for that with Bu4NI and BnSH, in
which case opening at C-2 prevailed (Table 2, Entries 6 and
9). Solely trans-diequatorial products 6a–c formed in the
reaction with haloacids in EtOH, along with minor trans-
diequatorial solvolytic product 6h (Table 2, Entries 1–3). We
also obtained this trans-diequatorial ethoxy derivative (6h)
upon reaction with EtOH under sulfuric-acid catalysis
(Table 2, Entry 11), whereas we obtained both regioisomers
6h and 7h (Table 2, Entry 12) with sodium ethanolate. The
unreacted epimine 2, isolated after the workup of 6c
(Table 2, Entry 3), probably arose from back-cyclization,
despite the trans-diequatorial disposition of the reacting
groups. A similar aziridine closure has been observed for
a trans-diequatorial azido tosylate upon reaction with
LiAlH4.[27] The regioselectivity of the cleavage of epimine 2
contrasts with that of the cleavage of 4-O-benzyl-1,6-an-
hydro-2,3-(tosylepimino)-2,3-dideoxy-β--mannopyranose,
which provided only trans-diaxial stereoisomers upon reac-
tion with the same nucleophiles.[19]
Scheme 1.
Results and Discussion
The reactions of 1,6-anhydro-2,3,4-trideoxy-2,3-(tosylep-
imino)-β--ribo-hexopyranose (1) provided solely the trans-
diaxial products 3a–g upon reaction with haloacids, azide,
benzylamine, phenylmethanethiol and benzyl alcoholate
(see Table 1, Entries 1–7). Only reactions with tetrabutylam-
monium halides (Table 1, Entries 8–10) gave a mixture of
products 3, 4 and 5. We could not be separate product 3b
from 4b or 3c from 4c (Nu = Br and I, respectively, Table 1,
Entries 9 and 10) by column chromatography, and we deter-
mined their structures and ratios by NMR only. For Nu =
Cl (Table 1, Entry 8), we estimated the composition of the
mixture by GC/MS because 3a, 4a, 5 and unreacted 1 were
completely inseparable by column chromatography. We
could not properly identify 4a in the mixture by NMR, and
we tentatively assigned its structure by analogy with 4b and
4c.
Table 1. The product distribution for reactions of 1 with nucleophiles.
Entry
Nu
Reagent
Solvent
Reaction
Product yield [%]
time/temperature
3, trans-diaxial
4, cis
5
1
2
3
4
5
6
7
8
Cl
Br
I
N3
BnNH
BnS
BnO
Cl
Br
I
HCl
HBr
HI
NaN3
EtOH
EtOH
EtOH
24 h/room temp.
12 h/room temp.
3 h/room temp.
3a
3b
3c
3d
3e
3f
3g
3a
3b
3c
–
80
70
63
82
88
94
72
–
–
–
–
–
–
–
4a
4b
4c
–
–
–
–
–
–
–
–
5
5
5
5
–
–
–
–
–
–
–
–
–
–
–
–
MeOCH2CH2OH/H2O 2.5 h/110 °C
–
MeOH
BnOH
BnNH2
BnSH/MeONa
BnONa
Bu4NCl, NH4Cl toluene
Bu4NBr, NH4Br toluene
3 h/140 °C
3 h/70 °C
7 h/105 °C
20 h/reflux
4 h/reflux
62[a]
15[b]
7[c]
–
9[a]
39[b]
67[c]
–
4[a]
18
16
52
9
10
11
Bu4NI, NH4I
tBuOK
toluene
THF
1.5 h/reflux
18 h/room temp.
tBuO
[a] 3a, 4a and 5 were inseparable by column chromatography; the total yield of 90% including 15% of regenerated 1 was determined by
GC/MS, and the structure of 4a was assigned tentatively by analogy with 4b and 4c. [b] Compounds 3b and 4b were inseparable by
column chromatography, and the product distribution was determined by NMR. [c] Compounds 3c and 4c were inseparable by column
chromatography, and the product distribution was determined by NMR spectroscopy.
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Ring-Opening Reactions of Aziridines
Table 2. The product distribution for reactions of 2 with nucleophiles.
Entry
Nu
Reagent
Solvent
Reaction
time/temperature
Product yield [%]
6, trans-diequatorial
7, trans-diaxial
1
2
3
4
5
6
7
8
Cl
Br
I
Cl
Br
I
N3
BnNH
BnS
BnO
EtO
EtO
HCl
HBr
HI
Bu4NCl, NH4Cl
Bu4NBr, NH4Br
Bu4NI, NH4I
NaN3
BnNH2
BnSH/MeONa
BnONa
EtOH
EtOH
EtOH
toluene
toluene
toluene
iPrOH/H2O
–
MeOH
BnOH
EtOH
EtOH
21 h/50 °C
6 h/50 °C
6 h/50 °C
6 h/reflux
6 h/reflux
10 h/reflux
14 h/reflux
3.5 h/140 °C
18 h/50 °C
25 h/120 °C
14 d/room temp.
12 h/reflux
6a
6b
6c
6a
6b
6c
6d
6e
6f
66 (+ 27% 6h)
–
–
–
–
–
–
82 (+ 12% 6h)
60 (+ 7% 6h)[a]
80
61
31
83
55
35
46
78
47
7a
7b
7c
7d
7e
7f
7g
–
10[b]
25
61
17
25
59
36
–
9
10
11
12
6g
6h
6h
EtOH/H2SO4
EtONa
7h
47
[a] 23% of unreacted 2 was isolated after workup. [b] Compound 7a contained 2% of unreacted 2 after workup.
Scheme 2.
To interpret these results, we propose three possible reac-
tion pathways for the aziridine cleavage of epimines 1 and
2 (see Scheme 2 for epimine 2 and Scheme 3 for epimine 1).
Scheme 3.
Pathway 1: SN2 cleavage with the tetrahydropyran ring
in approximately a half-chair conformation in the transition
state. This is energetically the most favored cleavage pattern substituents. This pathway can produce either diaxial or di-
and produces trans-diaxial isomers.
equatorial isomers.
Pathway 2: SN2 cleavage with the tetrahydropyran ring
Pathway 3 favors nucleophilic attack at C-3 for both -
in the energetically less-favored twist conformation in the lyxo and -ribo epimines. The C-2 attack is disfavored be-
transition state, which produces trans-diequatorial isomers cause the transition state is destabilized by the inductive
(from the point of view of the product configuration, this electron-withdrawing effect of the acetal group. Accord-
cleavage is frequently termed as trans-diequatorial cleav- ingly, lyxo-epimine 2 should afford the trans-diaxial prod-
age).
ucts 7 in accordance with the Fürst–Plattner rule (pathway
Pathway 3: Cleavage with a partially heterolyzed C–N 1) and the trans-diequatorial products 6 by pathway 3 (see
aziridine bond (borderline SN2), with the regioisomeric out- Scheme 2). In support of this explanation are two other ob-
come determined by the electronic effects of the adjacent servations. First, epimine 2 gave no C-2 trans-diaxial prod-
Eur. J. Org. Chem. 2009, 6399–6406
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Karban, J. Kroutil, M. Budeˇsˇínský, J. Sýkora, I. Císarˇová
FULL PAPER
ucts under acidic conditions (reaction with HX or EtOH/ the position of the N-tosyl group by observing the J value
H2SO4). Acidic conditions favor the opening that proceeds of 8–10 Hz for the coupling of its NH proton to either H-
through the more stable, partially carbocationic species 2 (in 3a–6h) or H-3 (in 7a–7h). Small values of J for the
formed by protonation. Second, under non-acidic condi- equatorial H-2 and H-3 protons (J2,1 = 1.7–2.3, J2,3 = 1.3–
tions, soft nucleophiles afforded more trans-diaxial product 2.2, J3,4ax = 4.0–7.2 and J3,4eq = 1.2–2.3 Hz) in 3a–3g and
in comparison with hard nucleophiles and vice versa. For 7a–7h indicated the 2,3-trans-diaxial position of the substit-
example, 2 gave 61% and 31% of C-2 and C-3 products, uents. The long-range couplings (J1,3, J2,4 and J3,5) further
respectively, upon reaction with Bu4NI but 10% and 80%, supported the equatorial position of H-2 and H-3 in these
respectively, upon reaction with Bu4NCl (Table 2, Entries 6 compounds. On the other hand, large values of J2,3 (8.7–
and 4). Similarly, the C-2 product/C-3 product ratio in- 10.3 Hz) and J3,4ax (10.4–12.2 Hz) indicated 2,3-trans-di-
–
creased on going from N3 to BnSH upon reaction of 2 equatorial substitution in 6a–6h. In 2,3-cis substituted 4b,c,
with the corresponding reagents (Table 2, Entries 7–9).
the observed J3,4ax (12.7–13.2 Hz) and J2,3 (ca. 5 Hz) re-
Soft nucleophiles are known[28] to exhibit more SN2 be- quired the axial H-3 and equatorial H-2 and, therefore, 2-
havior and greater sensitivity to steric effects than hard nu- axial-3-equatorial configuration of substituents. The dif-
cleophiles, in which case charge control and electrostatic in- ferent electronegativities of the substituents at C-2 or C-3
teractions prevail. Consequently, under non-acidic condi- (Cl, Br, I, N3, NBn, SBn or OBn) were obviously the main
3
tions, the SN2 mechanism is favored upon reaction of 2 with cause of the variations of JH,H inside each group of com-
soft nucleophiles, giving rise predominantly to the C-2 pounds with the same configuration of substituents; slight
1
product (7) by pathway 1, and the borderline SN2 mecha- differences in the C4 conformation of the pyranose ring
nism (pathway 3) is favored with hard nucleophiles, giving contributed to these results minimally. The coupling con-
C-3 products (6). Under acidic conditions, the carbo- stants J5,6en (0.16–1.5 Hz) and J5,6ex (4.1–5.1 Hz) observed
cationic species reacts quickly with any nucleophile present throughout the whole series of 3a–7h agreed approximately
5
(either soft or hard) at C-3. Reactions with BnO– and EtO– with an E (in the atom sequence of C-1–O-2–C-6–C-5–O-
(Table 2, Entries 10 and 12) appear to be exceptions with a 1) conformation of the five-membered dioxolane ring. The
1
significant amount of trans-diaxial products isolated.
-CH= signals in the H (δ = 5.40 and 6.10 ppm) and 13C
The trans-diequatorial products 6 from lyxo-epimine 2 (δ = 124.02 and 131.04 ppm) NMR spectra indicated the
can also arise by reaction pathway 2. Under the given con- presence of a double bond in 5.
ditions, we cannot distinguish pathway 3 (borderline SN2
In order to confirm the NMR assignment, we prepared
cleavage) from pathway 2 (SN2 cleavage through a twist a single crystal of 1, 2, 3g, 3f, 4c, 5, 6a and 7c and submitted
conformation) by product analysis. The cleavage through them to X-ray crystallography. These compounds are repre-
the twist conformation, however, seems less likely, owing to sentatives of each configuration discussed in this work. The
the conformational rigidity of the tricyclic skeleton.[26]
results of the structural analysis verified the NMR assign-
The ribo-epimine 1 gave almost exclusively C-3 trans-di- ment, and we assigned unequivocally the remaining deriva-
1
axial products 3. The unusual formation of C-3 cis-products tives on the basis of H chemical shifts and spin-spin cou-
4a–c in the reaction of 1 with NBu4X/NH4X most probably pling patterns characteristic for each configuration.
resulted from a consecutive halogen-exchange reaction with
The conformational analysis showed that the six-mem-
primarily formed trans-diaxial products 3. In agreement bered pyranose ring of the 4-deoxy-2,3-epimines 1 and 2
with this explanation is an increasing amount of 4 going adopted the envelope conformation E6 (in the atom se-
from X = Cl to X = I. An alternative explanation by cis quence of C-1–C-2–C-3–C-4–C-5–O-1), thus falling in the
opening of aziridine is extremely unlikely. An attempt to range of other known 2,3-epimines (Figure 1).[26] The open-
verify the halogen exchange by a direct halogen-exchange ing of the aziridine relieved the strain of the pyranose ring,
reaction from 3b (Nu = Br) failed, because under the reac- and the resulting structures adopted conformations close to
tion conditions, 3b is in equilibrium with aziridine 1. The
suggested reactions pathways for the ring cleavage of 1 are
depicted in Scheme 3. Pathways 1 and 3 give the same trans-
diaxial product, because steric and electronic effects are
synergic. The SN2 mechanism through a twist conformation
(pathway 2) is not involved, because we isolated no trans-
diequatorial product.
Structures and Configurations
We determined the structures of products 3a–7h mainly
from 1H and 13C NMR spectra. We measured the 2D-PFG-
H,H-COSY and 2D-H,C-PFG-HSQC spectra for the struc-
1
tural assignment of H and 13C signals (see the Supporting
Information for NMR spectroscopic data). We determined Figure 1. Projection of the ring-puckering parameters.
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Eur. J. Org. Chem. 2009, 6399–6406

Ring-Opening Reactions of Aziridines
1C4. The ring-puckering parameters[29] of measured com-
pounds are available in the Supporting Information, and
their polar projection[30] is shown in Figure 1.
7.7 mmol) in dichloromethane (1.5 mL) was added dropwise to a
solution of 1,6-anhydro-2,3,4-trideoxy-2,3-epimino-β--ribo-
hexopyranose[27] (890 mg, 7.0 mmol) and pyridine (1.5 mL,
18.6 mmol) in dichloromethane (10 mL) under cooling (–15 °C)
and stirring. Stirring and cooling continued for 30 min until the
unreacted epimine was consumed (TLC in ethyl acetate). The reac-
tion mixture was washed with cold water (ca. 0 °C), cold aq. HCl
(2%) and cold water, dried and concentrated. Chromatography on
silica gel (65 g) in ethyl acetate afforded 1 (1.365 g, 69%); m.p. 158–
159.5 °C, [α]2D5 = 0 (c = 0.2, CHCl3). C13H15NO4S (281.33): calcd.
C 55.50, H 5.37, N 4.98, S 11.40; found C 55.39, H 5.14, H 4.80,
S 11.26.
Conclusions
N-Tosylated aziridines with asymmetrical, vicinal substi-
tution fused to a tetrahydropyran ring, whose conformation
was locked by a 1,6-anhydro bridge, were shown to undergo
ring cleavage with heteroatom-centered nucleophiles under
appropriate conditions. The regioisomeric outcome de-
pended primarily upon the configuration of the tricyclic
skeleton but, to a significant degree, also upon the reaction
conditions and the type of nucleophile. For -lyxo-epimine
2, the regioselectivity was controlled by electronic effects
under acidic conditions or with hard nucleophiles, giving
rise to predominantly C-3 cleavage products; whereas, un-
der basic conditions with soft nucleophiles, C-2 cleavage
products predominantly formed, in agreement with the
Fürst–Plattner rule. -ribo-Epimine 1 reacted at C-3 in all
cases in accordance with the Fürst–Plattner rule. The ring-
opening products represent 4-deoxy 2,3-disubstituted
amino pyranoses, possessing a defined configuration and
can serve as valuable intermediates for additional transfor-
mation. Further investigation into the aziridine cleavage
mechanism is currently under way.
1,6-Anhydro-2,3,4-trideoxy-2,3-(tosylepimino)-β-D-lyxo-hexopyr-
anose (2): A solution of 4-toluenesulfonyl chloride (1.257 mg,
6.59 mmol) in dichloromethane (5 mL) was added dropwise to 1,6-
anhydro-2,3,4-trideoxy-2,3-epimino-β--lyxo-hexopyranose[27] (762
mg, 6.0 mmol), pyridine (0.63 mL, 7.82 mmol) and triethylamine
(1.67 mL, 12.0 mmol) in dichloromethane (10 mL) under cooling
(–15 °C) and stirring. Stirring and cooling continued for 30 min
until the unreacted epimine was consumed (TLC in S2). The reac-
tion mixture was poured into ice. The common workup followed
by chromatography (50 g) in ethyl acetate/hexane (2:1) afforded 2
(1.248 g, 74%); m.p. 153–154.5 °C (sublimated, ethyl acetate/hep-
tane), [α]2D5 = –36 (c = 0.23, CHCl3). C13H15NO4S (281.33): calcd.
C 55.50, H 5.37, N 4.98, S 11.40; found C 55.79, H 5.32, N 4.97,
S 11.03.
Reactions of 1 with Halo Acids: A mixture of the epimine 1 (100 mg,
0.355 mmol), EtOH (10 mL) and hydrohalogenic acid (3.41–
3.62 mmol) was stirred for a given time at r.t. until 1 was consumed
(TLC in S1). The reaction mixture was poured into ice, and the
crystalline precipitate was filtered off to afford the cleavage prod-
uct. An attempt to isolate products 3b and 3c by solvent extraction
with dichloromethane led to partial back-closure to epimine 1 ac-
cording to TLC.
Experimental Section
General: The optical rotations were measured on an Autopol III
(Rudolph Research, Flanders, NJ) polarimeter at 25 °C. The 1H
and 13C NMR spectra were measured with a Varian UNITY-500
instrument (1H at 500 MHz and 13C at 125.7 MHz) in CDCl3
HCl: Reaction with HCl (35%, 320 µL, 3.62 mmol) for 24 h gave
1,6-anhydro-3-chloro-2,3,4-trideoxy-2-(tosylamino)-β--xylo-hexo-
pyranose (3a, 90 mg, 80%); m.p. 158.5–161 °C (sublimated), [α]2D5
= –69 (c = 0.25, CHCl3). C13H16ClNO4S (317.79): calcd. C 49.13,
H 5.07, N 4.41, S 10.09, Cl 11.16; found C 49.23, H 5.12, N 4.23,
S 9.79, Cl 11.00.
1
(TMS was an internal reference for H, and the chloroform signal
at δ = 77.0 ppm was an internal reference for 13C) at 25 °C. GC/
MS analyses were carried out with a Hewlett–Packard HP 6890 gas
chromatograph equipped with a DB-5MS column (30 mϫ250 µm
ϫ0.25 µm) and with a Hewlett–Packard HP 5973 mass-selective
detector. TLC was carried out with Merck DC Alufolien with Kie-
segel F254 and the following solvent systems: S1 = hexane/ethyl ace-
tate (1:1) and S2 = dichloromethane/acetone (20:1); spots were de-
tected with an anisaldehyde solution in H2SO4. UV detection at
254 nm was also used where appropriate. Column chromatography
was performed with silica gel 60 (70–230 mesh, Merck), and the
amount of silica gel is given in parentheses. The solvents were evap-
orated with a vacuum rotary evaporator at less than 40 °C. Anhy-
drous sodium sulfate was used to dry solutions during workup. The
term “common workup” refers to extraction with dichloromethane
followed by drying and concentration under reduced pressure. Tol-
uene and diethyl ether were dried with sodium, methanol with mag-
nesium, THF was dried with LiAlH4 and absolute EtOH was of
commercial grade (for synthesis, Merck). Ammonium halides were
sublimed at 300 °C under water-aspirator vacuum, and tetraalk-
ylammonium halides were purchased from Aldrich and used as
supplied. Both ammonium halides and tetraalkylammonium ha-
lides were thoroughly pulverized immediately before use. All other
chemicals were of reagent grade and were used without purifica-
tion.
HBr: Reaction with HBr (46%, 400 µL, 3.41 mmol) for 12 h gave
1,6-anhydro-3-bromo-2,3,4-trideoxy-2-(tosylamino)-β--xylo-hexo-
pyranose (3b, 90 mg, 70%); m.p. 145–147.5 °C (decomposed),
[α]2D5 = –58 (c = 0.22, CHCl3). C13H16BrNO4S (362.25): calcd. C
43.10, H 4.45, N 3.87, S 8.85, Br 22.06; found C 43.22, H 4.45, N
3.69, S 8.59, Br 21.94.
HI: Reaction with HI (57%, 465 µL, 3.52 mmol) for 3 h (the reac-
tion mixture was decolorized with a few drops of aq. sodium thio-
sulfate before workup) gave 1,6-anhydro-3-iodo-2,3,4-trideoxy-2-
(tosylamino)-β--xylo-hexopyranose (3c, 92 mg, 63%); m.p. 102–
105 °C (sublimated), [α]2D5 = –31 (c = 0.23, CHCl3). C13H16INO4S
(409.24): calcd. C 38.15, H 3.94, N 3.42, I 31.01; found C 38.53, H
3.97, N 3.17, I 31.21.
Reactions of 1 with Bu4NX + NH4X
X = Cl: A mixture of the epimine 1 (118 mg, 0.42 mmol), Bu4NCl
(232 mg, 0.83 mmol) NH4Cl (304 mg, 5.68 mmol) and molecular
sieves (4 Å) was refluxed in toluene (10 mL) for 20 h. The reaction
mixture was then diluted with dichloromethane, filtered and con-
centrated. Chromatography (25 g) in dichloromethane/acetone
1,6-Anhydro-2,3,4-trideoxy-2,3-(tosylepimino)-β-
anose (1): A solution of 4-toluenesulfonyl chloride (1.468 mg,
D
-ribo-hexopyr- (10:1) gave 117 mg (ca. 90%) of a mixture inseparable by column
chromatography, whose composition was estimated by GC/MS by
Eur. J. Org. Chem. 2009, 6399–6406
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6403

J. Karban, J. Kroutil, M. Budeˇsˇínský, J. Sýkora, I. Císarˇová
FULL PAPER
means of comparison with authentic samples: 70% of 3a, 15% of
the unreacted 1, 4% of the unsaturated tosylamino derivative 5 (see
below) and 10% of an unidentified compound, probably chloride
4a; the percentages in Table 1 are recalculated as yields from 1.
NMR analysis of the mixture confirmed this composition.
Reaction of 1 with Benzyl Alcohol: Sodium benzyl alcoholate
(1.22  in benzyl alcohol, 0.7 mL, 0.85 mmol) was added to a mix-
ture of the epimine 1 (100 mg, 0.355 mmol) and benzyl alcohol
(2 mL), and the resulting solution was stirred for 7 h at 105 °C. The
reaction mixture was diluted with water and neutralized with aq.
Crystallization from anhydrous EtOH afforded 3a (63 mg, 47%) in HCl (5%). The common workup afforded 1,6-anhydro-3-O-benzyl-
1
approximately 90% purity according to H NMR and GC/MS.
2,4-dideoxy-2-(tosylamino)-β--xylo-hexopyranose (3g, 100 mg,
72%); m.p. 174–176 °C (methanol/water), [α]2D5 = –103 (c = 0.21,
CHCl3). C20H23NO5S (389.47): calcd. C 61.68, H 5.95, N 3.60, S
8.23; found C 61.45, H 5.93, N 3.55, S 8.53.
X = Br: A mixture of the epimine 1 (100 mg, 0.355 mmol), Bu4NBr
(226 mg, 0.70 mmol) and NH4Br (171 mg, 1.75 mmol) was refluxed
in dry toluene (10 mL) for 4 h. The reaction mixture was worked
up as described above for X = Cl. Chromatography (13 g) in hep-
tane/ethyl acetate (12:5) gave: 1) 70 mg (54%) of an inseparable
mixture of 1,6-anhydro-3-bromo-2,3,4-trideoxy-2-(tosylamino)-β-
-ribo-hexopyranose (4b) and 1,6-anhydro-3-bromo-2,3,4-trideoxy-
2-(tosylamino)-β--xylo-hexopyranose (3b) in a 72:28 ratio (deter-
Reaction of 1 with Potassium tert-Butoxide: A solution of the epim-
ine 1 (100 mg, 0.355 mmol) in THF (5 mL) was added to a suspen-
sion of potassium tert-butoxide (400 mg, 3.56 mmol) in THF
(5 mL), and the resulting mixture was stirred for 18 h at r.t. The
reaction mixture was worked up as described above for 3g.
Chromatography (10 g) in S1 gave 1,6-anhydro-2,3,4-trideoxy-2-
(tosylamino)-β--erythro-hex-2-enopyranose (5, 52 mg, 52%); m.p.
180–184 °C (acetone/heptane), [α]2D5 = –131 (c = 0.20, CHCl3).
C13H15NO4S (281.33): calcd. C 55.50, H 5.37, N 4.98, S 11.40;
found C 55.46, H 5.37, N 4.89, S 11.02.
1
mined by H NMR); the percentages in Table 1 were recalculated
as yields from 1, 2) 18 mg (18%) of 1,6-anhydro-2,3,4-trideoxy-2-
(tosylamino)-β--erythro-hex-2-enopyranose (5), and 3) 13 mg of
an unresolved mixture of 4b, 3b and 5.
X = I: A mixture of epimine 1 (100 mg, 0.355 mmol), Bu4NI
(259 mg, 0.70 mmol) and NH4I (254 mg, 1.75 mmol) was refluxed
in dry toluene (10 mL) for 1.5 h. The reaction mixture was then
concentrated to ca. 1 mL, diluted with ethyl acetate, washed with
aq. sodium thiosulfate and concentrated. Chromatography (13 g)
in heptane/ethyl acetate (2:1) gave: 1) 108 mg (74%) of a mixture
of 1,6-anhydro-3-iodo-2,3,4-trideoxy-2-(tosylamino)-β--ribo-hexo-
pyranose (4c) and 1,6-anhydro-3-iodo-2,3,4-trideoxy-2-(tosylam-
Reactions of 2 with Halo Acids: A mixture of the epimine 2 (100 mg,
0.355 mmol), EtOH (10 mL) and hydrohalogenic acid (320 µL,
3.41–3.62 mmol) was stirred at 50 °C for a given time until 2 was
consumed (TLC in S1). The reaction mixture was diluted with
brine, and the common workup followed by column chromatog-
raphy afforded the ring-cleavage products.
HCl: Reaction with HCl (35%, 320 µL, 3.62 mmol) for 21 h.
Chromatography (10 g) afforded: 1) 1,6-anhydro-3-chloro-2,3,4-tri-
deoxy-2-(tosylamino)-β--arabino-hexopyranose (6a, 75 mg, 66%);
1
ino)-β--xylo-hexopyranose (3c) in a 91:9 ratio (determined by H
NMR); recrystallization gave 4c [15 mg, 10%, m.p. 179–182 °C
(ethyl acetate/heptane) for X-ray analysis], 2) 16 mg (16%) of 1,6-
anhydro-2,3,4-trideoxy-2-(tosylamino)-β--erythro-hex-2-enopyr-
anose (5), and 3) 15 mg of an unresolved mixture of 4c, 3c and 5.
m.p. 174–176 °C (EtOH), [α]2D5
= –107 (c = 0.21, CHCl3),
C13H16ClNO4S (317.79): calcd. C 49.13, H 5.07, N 4.41, Cl 11.16;
found C 48.99, H 5.00, N 4.27, Cl 11.07 and 2) 1,6-anhydro-3-
O-ethyl-2,4-dideoxy-2-(tosylamino)-β--arabino-hexopyranose (6h,
31 mg, 27%), identical to 6h prepared by the ethanolysis of 2.
Reaction of 1 with Azide: A mixture of the epimine 1 (100 mg,
0.355 mmol), sodium azide (100 mg, 1.54 mmol), 2-methoxy-
ethanol (5 mL) and water (1 mL) was stirred for 2.5 h at 110 °C
until 1 was consumed (TLC in S1). The reaction mixture was di-
luted with water, and the common workup afforded 1,6-anhydro-
3-azido-2,3,4-trideoxy-2-(tosylamino)-β--xylo-hexopyranose (3d,
94 mg, 82%); m.p. 114–116 °C (ethyl acetate/heptane), [α]2D5 = –96
(c = 0.21, CHCl3). C13H16N4O4S (324.36): calcd. C 48.14, H 4.97,
N 17.27, S 9.88; found C 48.05, H 4.95, N 17.13, S 9.96.
HBr: Reaction with HBr (46%, 400 µL, 3.41 mmol) for 6 h.
Chromatography (20 g) afforded: 1) 1,6-anhydro-3-bromo-2,3,4-tri-
deoxy-2-(tosylamino)-β--arabino-hexopyranose
(6b,
106 mg,
82%); m.p. 170–172 °C (EtOH), [α]2D5 = –104 (c = 0.21, CHCl3);
C15H22BrNO5S (408.31, M + EtOH): calcd. C 44.12, H 5.43, N
3.43, S 7.85; found C 43.81, H 5.47, N 3.37, S 7.60; HRMS: calcd.
for C13H17BrNO4S [M + H]+ 362.0056; found 362.0057 and 2) 1,6-
anhydro-3-O-ethyl-2,4-dideoxy-2-(tosylamino)-β--arabino-hexo-
pyranose (6h, 14 mg, 12%), identical to 6h prepared by the etha-
nolysis of 2.
Reaction of 1 with Benzylamine: A solution of the epimine 1
(100 mg, 0.355 mmol) in benzylamine (600 µL, 5.69 mmol) was
stirred for 3 h at 140 °C. The reaction mixture was then poured
into ice, and the resulting crystalline precipitate was filtered off to
afford 1,6-anhydro-3-benzylamino-2,3,4-trideoxy-2-(tosylamino)-
β--xylo-hexopyranose (3e, 121 mg, 88%); m.p. 161–163 °C, [α]2D5
= –67 (c = 0.24, CHCl3). C20H24N2O4S (388.49): calcd. C 61.83, H
6.23, N 7.21, S 8.25; found C 62.31, H 6.21, N 7.11, S 8.40. HRMS:
calcd. for C20H25N2O4S [M + H]+ 389.1529; found 389.1513.
HI: Reaction with HI (57%, 470 µL, 3.56 mmol) for 6 h. The reac-
tion mixture was decolorized by the addition of aq. sodium thiosul-
fate before workup. Chromatography (20 g) afforded: 1) the epim-
ine 2 (23 mg, 23%), formed by aziridine back-closure during
workup according to TLC, 2) 1,6-anhydro-3-iodo-2,3,4-trideoxy-2-
(tosylamino)-β--arabino-hexopyranose (6c, 88 mg, 60%); m.p.
176–181 °C (EtOH), [α]2D5 = –108 (c = 0.21, CHCl3); C13H16INO4S
(409.24): calcd. C 38.15, H 3.94, N 3.42, S 7.83, I 31.01; found C
38.14, H 3.97, N 3.29, S 7.66, I 30.87, and 3) 1,6-anhydro-3-O-
Reaction of 1 with Phenylmethanethiol: Sodium methoxide (1  in
methanol, 0.3 mL, 0.3 mmol) was added to a solution of the epim-
ine
1 (100 mg, 0.355 mmol) and phenylmethanethiol (80 µL,
ethyl-2,4-dideoxy-2-(tosylamino)-β--arabino-hexopyranose
7 mg, 7%), identical to 6h prepared by the ethanolysis of 2.
(6h,
0.68 mmol) in methanol (5 mL). The resulting solution was stirred
at 70 °C for 3 h and then poured into ice. The crystalline precipitate
was filtered off to afford 1,6-anhydro-3-benzylsulfanyl-2,3,4-trid-
eoxy-2-(tosylamino)-β--xylo-hexopyranose (3f, 135 mg, 94%;
79% after recrystallization); m.p. 202–204 °C (ethyl acetate/meth-
anol), [α]2D5 = –214 (c = 0.22, CHCl3). C20H23NO4S2 (405.54): calcd.
C 59.23, H 5.72, N 3.45, S 15.81; found C 59.27, H 5.70, N 3.43,
S 16.08.
Reactions of 2 with Bu4NX + NH4X
X = Cl: A suspension of the epimine 2 (100 mg, 0.355 mmol),
Bu4NCl (195 mg, 0.70 mmol), NH4Cl (264 mg, 4.93 mmol) and
molecular sieves (4 Å) was refluxed in toluene (10 mL) for 6 h. The
reaction mixture was then diluted with dichloromethane, filtered,
washed with water, and the water was re-extracted with dichloro-
6404
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6399–6406

Ring-Opening Reactions of Aziridines
methane. The combined dichloromethane extracts were dried and
concentrated. The residue was dissolved in dichloromethane/ace-
tone (10:1) and filtered through silica gel (10 g). The filtrate was
concentrated, and chromatography (20 g) in S2 gave: 1) 13 mg of
a mixture of 1,6-anhydro-2-chloro-2,3,4-trideoxy-3-(tosylamino)-β-
-xylo-hexopyranose (7a) and the unreacted epimine 2 in a 82:12
ratio, inseparable by column chromatography, whose composition
was estimated by NMR; the percentage in Table 2 was recalculated
as the yield from 2 and 2) 1,6-anhydro-3-chloro-2,3,4-trideoxy-2-
(tosylamino)-β--arabino-hexopyranose (6a, 90 mg, 80%), identical
to 6a prepared by the reaction of 2 with HCl, described above.
ylmethanethiol (160 µL, 1.36 mmol). The resulting solution was
stirred at 50 °C for 18 h and then poured into ice and neutralized
with aq. HCl (5%). The common workup followed by chromatog-
raphy (20 g) in S2 afforded: 1) 1,6-anhydro-2-benzylsulfanyl-2,3,4-
trideoxy-3-(tosylamino)-β--xylo-hexopyranose (7f, 85 mg, 59%);
m.p. 142–143 °C (EtOH), [α]2D5
= –161 (c = 0.20, CHCl3);
C20H23NO4S2 (405.54): calcd. C 59.23, H 5.72, N 3.45, S 15.81;
found C 59.10, H 5.80, N 3.35, S 15.78 and 2) 1,6-anhydro-
3-benzylsulfanyl-2,3,4-trideoxy-2-(tosylamino)-β--arabino-hexo-
pyranose (6f, 50 mg, 35%); m.p. 186 °C (EtOH), [α]2D5 = –22 (c =
0.20, CHCl3); C20H23NO4S2 (405.54): calcd. C 59.23, H 5.72, N
3.45, S 15.81; found C 59.01, H 5.79, N 3.38, S 15.68.
X = Br: A suspension of the epimine 2 (100 mg, 0.355 mmol),
Bu4NBr (226 mg, 0.70 mmol) and NH4Br (171 mg, 1.75 mmol) was
refluxed in toluene (10 mL) for 6 h. The reaction mixture was then
diluted with ethyl acetate, filtered and concentrated. Chromatog-
raphy (20 g) in S2 gave: 1) 1,6-anhydro-2-bromo-2,3,4-trideoxy-3-
(tosylamino)-β--xylo-hexopyranose (7b, 32 mg, 25%); m.p. 128–
131.5 °C (EtOH), [α]2D5 = +95 (c = 0.20, CHCl3); HRMS: calcd. for
C13H16BrNO4SNa [M + Na]+ 383.9881; found 383.9875 and 2) 1,6-
anhydro-3-bromo-2,3,4-trideoxy-2-(tosylamino)-β--arabino-hexo-
pyranose (6b, 79 mg, 61%), identical to 6b prepared by the reaction
of 2 with HBr.
Reaction of 2 with Benzyl Alcohol: Sodium benzyl alcoholate (1.0 
solution in benzyl alcohol, 1.4 mL, 1.4 mmol) was added to a mix-
ture of the epimine 2 (100 mg, 0.355 mmol) and benzyl alcohol
(1.6 mL), and the resulting solution was stirred for 25 h at 120 °C.
The reaction mixture was diluted with water and neutralized with
aq. HCl (5%). The common workup followed by chromatography
(20 g) in S2 afforded: 1) 1,6-anhydro-2-O-benzyl-3,4-trideoxy-3-
(tosylamino)-β--xylo-hexopyranose (7g, 49 mg, 36%); m.p. 109–
111 °C (EtOH), [α]2D5 = –40 (c = 0.18); C20H23NO5S (389.47): calcd.
C 61.68, H 5.95, N 3.60, S 8.23; found C 61.43, H 6.02, N 3.56, S
7.99 and 2) 1,6-anhydro-3-O-benzyl-2,4-trideoxy-2-(tosylamino)-β-
-arabino-hexopyranose (6g, 64 mg, 46%); m.p. 177–178 °C
(EtOH), [α]D = –46 (c = 0.20); C20H23NO5S (389.47): calcd. C
61.68, H 5.95, N 3.60, S 8.23; found C 61.43, H 6.05, N 3.56, S
8.01.
X = I: A suspension of the epimine 2 (100 mg, 0.355 mmol), Bu4NI
(259 mg, 0.70 mmol) and NH4I (254 mg, 1.75 mmol) was refluxed
in dry toluene (10 mL) for 10 h. The reaction mixture was decol-
orized by washing it with aq. sodium thiosulfate. The common
workup followed by chromatography (20 g) in S2 afforded: 1) 1,6-
anhydro-2-iodo-2,3,4-trideoxy-3-(tosylamino)-β--xylo-hexopyr-
anose (7c, 88 mg, 61%); m.p. 128–129 °C (EtOH), [α]2D5 = +145 (c
= 0.20, CHCl3); C13H16INO4S (409.24): calcd. C 38.15, H 3.94, N
3.42, S 7.83, I 31.01; found C 38.06, H 3.98, N 3.26, S 7.99, I 30.95
and 2) 1,6-anhydro-3-iodo-2,3,4-trideoxy-2-(tosylamino)-β--ara-
bino-hexopyranose (6c, 45 mg, 31%), identical to 6c prepared by
the reaction of 2 with HI.
Reaction of 2 with EtOH Under Acidic Conditions: A mixture of the
epimine 2 (100 mg, 0.355 mmol), EtOH (10 mL) and concentrated
H2SO4 (50 µL, 0.90 mmol) was stirred at room temperature for 14 d
until the unreacted 2 was consumed (TLC in S2). The reaction mix-
ture was then diluted with water and neutralized with NaHCO3.
The common workup followed by chromatography (20 g) in S1 af-
forded 1,6-anhydro-3-O-ethyl-2,4-trideoxy-2-(tosylamino)-β--ara-
bino-hexopyranose (6h, 91 mg, 78%); m.p. 155 °C (ethyl acetate/
heptane), [α]2D5 = –87 (c = 0.18, CHCl3); C15H21NO5S (327.40):
calcd. C 55.03, H 6.47, N 4.28, S 9.79; found C 54.88, H 6.66, N
3.97, S 9.45.
Reaction of 2 with Azide: A solution of the epimine 2 (100 mg,
0.355 mmol) and sodium azide (100 mg, 1.54 mmol) in 2-propanol
(5 mL) and water (1 mL) was refluxed for 14 h until 2 was con-
sumed (TLC in S2). The reaction mixture was worked up as de-
scribed above for the reaction of 1 with azide. Chromatography
(20 g) in S2 afforded: 1) 1,6-anhydro-2-azido-2,3,4-trideoxy-3-(tosy-
lamino)-β--xylo-hexopyranose (7d, 20 mg, 17%); m.p. 103–
105.5 °C (EtOH); HRMS: calcd. for C13H16N4SO4Na [M + Na]+
347.0790; found 347.0784 and 2) 1,6-anhydro-3-azido-2,3,4-tride-
oxy-2-(tosylamino)-β--arabino-hexopyranose (6d, 95 mg, 83%);
m.p. 136 °C (EtOH); C13H16N4O4S (324.36): calcd. C 48.14, H
4.97, N 17.27, S 9.88; found C 47.93, H 5.04, N 17.14, S 10.22.
Reaction of 2 with EtOH Under Basic Conditions: The epimine 2
(100 mg, 0.355 mmol) was added to a solution of sodium ethan-
olate prepared by the reaction of sodium hydride (229 mg,
9.54 mmol) with anhydrous EtOH (10 mL), and the reaction mix-
ture was refluxed for 12 h until 2 was consumed [TLC in dichloro-
methane/acetone (30:1)]. The reaction mixture was diluted with
water and neutralized with aq. HCl (5%). The common workup
followed by chromatography (20 g) in dichloromethane/acetone
(30:1) afforded: 1) 1,6-anhydro-2-O-ethyl-3,4-trideoxy-3-(tosyl-
amino)-β--xylo-hexopyranose (7h) as a colorless oil (54 mg, 47%);
[α]2D5 = +4 (c = 0.21, CHCl3), HRMS: calcd. for C15H21NSO5Na
[M + Na]+ 350.1033; found 350.1032 and 2) 1,6-anhydro-3-O-ethyl-
2,4-trideoxy-2-(tosylamino)-β--arabino-hexopyranose (6h, 54 mg,
47%), identical to 6h prepared by the reaction of 2 with EtOH
under sulfuric-acid catalysis.
Reaction of 2 with Benzylamine: A solution of the epimine 2
(100 mg, 0.355 mmol) in benzylamine (600 µL, 5.69 mmol) was
stirred for 3.5 h at 140 °C until the epimine 2 was consumed (TLC
in S2). The reaction mixture was poured into ice, and the resulting
precipitate was filtered off and chromatographed (13 g) in S2 to
yield:
1)
1,6-anhydro-2-benzylamino-2,3,4-trideoxy-3-(tosyl-
amino)-β--xylo-hexopyranose (7e, 35 mg, 25%); m.p. 152–154 °C,
[α]2D5 = +22 (c = 0.18, CHCl3); HRMS: calcd. for C20H25N2SO4 [M
Supporting Information (see also the footnote on the first page of
this article): NMR spectroscopic data, crystallographic data, ring
puckering parameters, dihedral angles and ORTEP projections of
the crystal structures.
+
H]+ 389.1530; found 389.1529 and 2) 1,6-anhydro-3-ben-
zylamino-2,3,4-trideoxy-2-(tosylamino)-β--arabino-hexopyranose
(6e, 76 mg, 55%); m.p. 168 –169 °C (EtOH), [α]2D5 = –40 (c = 0.20,
CHCl3); C20H24N2O4S (388.49): calcd. C 61.83, H 6.23, N 7.21, S
8.25; found C 61.67, H 6.31, N 7.14, S 8.34.
Acknowledgments
Reaction of 2 with Phenylmethanethiol: Sodium methoxide (1 
solution in methanol, 0.3 mL, 0.3 mmol) was added to a mixture
of the epimine 2 (100 mg, 0.355 mmol), methanol (5 mL) and phen-
This work was supported by the Grant Agency of the Academy of
Science of the Czech Republic (Grant numbers IAA400720703 and
Eur. J. Org. Chem. 2009, 6399–6406
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6405

J. Karban, J. Kroutil, M. Budeˇsˇínský, J. Sýkora, I. Císarˇová
FULL PAPER
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