Aminolysis of glycal-derived allyl epoxides and activated aziridines. Effects of the absence of coordination processes on the regio- and stereoselectivity

Article abstract of DOI:10.1016/j.tet.2009.11.059

The addition of primary and secondary aliphatic amines to glycal-derived allyl epoxides is completely 1,2-regio- and anti-stereoselective, whereas mixtures of the corresponding anti-1,2- [3-N-(substituted-amino) glycals] and anti-1,4-addition products (N-glycosyl amines) are obtained with N-(mesyl)-aziridines. In this way, structural moieties, otherwise difficult to synthesize, are obtained by means of a very simple protocol. The regio- and stereoselectivity observed with epoxides is the consequence of an isomerization process, whereas the result obtained with aziridines is explained by the absence of an effective substrate-nucleophile (amine) coordination.

Full text of DOI:10.1016/j.tet.2009.11.059

Tetrahedron 66 (2010) 689–697
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Aminolysis of glycal-derived allyl epoxides and activated aziridines. Effects of
the absence of coordination processes on the regio- and stereoselectivity
*
Valeria Di Bussolo , Lorenzo Checchia, Maria Rosaria Romano, Lucilla Favero,
*
Mauro Pineschi, Paolo Crotti
`
Dipartimento di Scienze Farmaceutiche, sede Chimica Bioorganica e Biofarmacia, Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of primary and secondary aliphatic amines to glycal-derived allyl epoxides is completely
1,2-regio- and anti-stereoselective, whereas mixtures of the corresponding anti-1,2- [3–N-(substituted-
amino) glycals] and anti-1,4-addition products (N-glycosyl amines) are obtained with N-(mesyl)-azir-
idines. In this way, structural moieties, otherwise difficult to synthesize, are obtained by means of a very
simple protocol. The regio- and stereoselectivity observed with epoxides is the consequence of an
isomerization process, whereas the result obtained with aziridines is explained by the absence of an
effective substrate–nucleophile (amine) coordination.
Received 9 August 2009
Received in revised form
22 October 2009
Accepted 12 November 2009
Available online 17 November 2009
Keywords:
Glycals
Ó 2009 Elsevier Ltd. All rights reserved.
Allyl epoxides
Allyl aziridines
Aminolysis
1. Introduction
exclusively at the C(3) allylic carbon in an anti fashion (route c in 1–3a
and route d in 1–3b
),9 with the formation of the corresponding anti-
Recently, we found that the glycal-derived allyl epoxides 1
and 2b and N-(mesyl)-aziridines 3a and 3b are very efficient and
a,1b,2a,
1,2-addition products (the so-called non-coordination products),6,10
never observed with coordinating O-nucleophiles.1,8
stereoselective glycosyl donors(Scheme 1).1–3 Actually, theregio- and
stereoselectivity of the glycosylation of O-nucleophiles, such as
alcohols, partially protected monosaccharides and alcoholate species,
turned out to be closely related to the ability of the O-nucleophile
(R2OM, M¼H, or a metal, Scheme 1) to coordinate the oxirane oxygen
or aziridine nitrogen by means of a hydrogen bond (alcohols) or
through the metal (metal alcoholate) (structures 4 and 5, Scheme 1).
Inthepresenceofsuchacoordinationandifthenucleophileispresent
to a very reduced extent (3 equiv) (protocol B reaction conditions),4,5
the corresponding syn-1,4-addition products (the so-called
coordination products),6 whose configuration is the same as the
The results obtained with alcohols prompted us to investigate
the regio- and stereoselective behavior of epoxides 1,2
a,b, and
aziridines 3 toward N-nucleophiles, such as amines. The aim
a,b
was to find a simple protocol for the regio- and stereoselective
introduction of an N-(substituted-amino) group on the glycal
system of these allyl heterocycles. This would lead to 3-deoxy-3-(N-
substituted-amino) glycals 6 (1,2-addition products) and/or 2,3-
unsaturated-N-glycosyl amines
epoxides 1,2 and the corresponding 4-deoxy-4-(N-mesyl-
amino)-derivatives 8 and 9 from aziridines 3 (Scheme 2).
7 (1,4-addition products) from
a,b,
a,b
N-glycosyl amines structurally related to 7 and 9 (1,4-addition
products) are important as intermediates for the synthesis of gly-
coproteins and glycoconjugates and as constituents of natural
products,11,12 whereas glycals structurally related to 6 and 8 (1,2-
addition products) are desirable compounds as intermediates for
the synthesis of products of pharmaceutical interest.13
startingepoxideoraziridine, are exclusivelyobtained:
from epoxides 1,2 , and aziridine 3 (route a) and
from epoxides 1,2 , and aziridine 3
a
b
-O-glycosides
-O-glycosides
a
a
b
b
(route b), in a new, uncatalyzed,
directly substrate-dependent, stereospecific glycosylation process.7,8
In contrast, when non-coordinating O-nucleophiles (R2OY, Y¼non-
coordinating counterion, Scheme 1), such as tetrabutylammonium
trimethylsilanolate (TBAþMe3SiOꢀ) and tetrabutylammonium
methoxide (TBAOMe) are used, the nucleophilic attack occurs
2. Results and discussion
The reactions of epoxides 1,2a,b, and aziridines 3a,b with pri-
mary and secondary aliphatic amines turned out to be particularly
interesting, not only because they furnish a simple protocol for the
synthesis of the corresponding 1,4- and/or 1,2-addition products
* Corresponding authors. Tel.: þ39 0502219690; fax: þ39 0502219660.
E-mail addresses: valeriadb@farm.unipi.it (V. Di Bussolo), crotti@farm.unipi.it
(P. Crotti).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.059

690
V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
R1
HX
O
anti-1,2-addition product
(non-coordination product)
OR2
route c
R2
R1
O
c
Y
R1
OR2
R1
O
R1
HX
O
O
R2OM
or
route a
O
1
3
δ+
α
R2OY
X
X
X
(α')
α
4
(α")
a
α-O-glycoside
1-3α
M
O
1, X= O, R1 = CH2OBn
R2
2, X = O, R1 = Me
substrate-nucleophile
coordination
3, X = N-Ms, R1 = CH2OBn
syn-1,4-addition product
(coordination product)
M= H or a metal
Y = non-coordinating
counterion
R2
δ+
M
OR2
O
R1
O
X
R1
O
R1
R2OM
or
route b
b
O
β
HX
β-O-glycoside
R2OY
3
1
5 (β')
route d
O
X
β
1-3β
R2
d
O
Y
R1
HX
anti-1,2-addition product
(non-coordination product)
OR2
Scheme 1.
anti-1,2-addition products, (3
deoxy-3-(N-substitued-amino)-glycals (27–29, Table 2), from 1,2
and 1,2 , respectively, characterized by the presence of a trans 3,4-
(N-substituted-amino)-alcohol moiety. While the regiochemical
behavior is the same, the reactivity of - and -epoxides is
decidedly different: epoxides 1,2 show a good reactivity and afford
a satisfactory yield of the corresponding anti-1,2-addition products
with different types of amines (Table 1), whereas epoxides 1,2
a, 4b)–(16–26, Table 1) and (3b, 4a)-3-
1,2-addition product
1,4-addition product
R1 NR2R3
HX
b
R1
HX
O
O
R1
O
a
NHR2R3
+
a
b
X
NR2R3
b
X = O, R1= CH2OBn, Me
1-3α,β
X = O, NMs
R1= CH2OBn, Me
6
7
X = NMs, R1= CH2OBn
8
9
a
R2 = H, alkyl group; R3 = alkyl group
with the opposite configuration show a reactivity unexpectedly
limited to few amines (Table 2).
Scheme 2.
The finding, in some cases (entries 6–8, Table 1 and entry 1,
Table 2), of small amounts of the corresponding 1,4-addition prod-
ucts in the crude reaction mixture (1H NMR spectroscopy) could be
an indication of the presence of an isomerization process control-
ling the final result of the addition reaction. In fact, appropriate
experiments carried out by stopping the reaction at different times
(30 s,1, 5, and 30 min) clearly indicated that the aminolysis reaction
(Tables 1–4), but also because they have revealed some significant
differences in the reactivity and the regio- and stereochemical
behavior of these allyl heterocycles with respect to that previously
observed with alcohols.1
With aziridines 3a and 3b and whenever the boiling point of the
amine made it possible, the reactions were carried out both by
using the amine as the solvent, that is in the presence of a large
amount of nucleophile (protocol A), and by adding the amine only in
a reduced amount (3 equiv) to a benzene solution of the aziridine
of epoxides 1,2a,b is under thermodynamic control and the final
anti-1,2-addition product, the only reaction product in each case
obtained, is the consequence of an isomerization process by the
corresponding 1,4-addition product (apparently a mixture of
b
a- and
(protocol B).4 With epoxides 1
a
,b
and 2
a,
b, protocol A reaction
-anomers, 1H NMR spectroscopy), the primary (kinetic) reaction
conditions were effective for the formation of the corresponding
addition products, whereas the reactions carried out under protocol
B turned out to be sluggish, and complex reaction mixtures were
usually obtained. However, no catalyst was added in any case to the
reaction mixture in order to promote the addition reaction.
The uncatalyzed reactions of epoxides 1a,b and 2a,b with
primary and secondary aliphatic amines (protocol A) are completely
regioselective, with the exclusive formation of the corresponding
product. Unfortunately, due to their rapid isomerization and
instability under any chromatographic conditions attempted, the
1,4-addition products could not be isolated (Tables 1 and 2).
The corresponding reactions of aziridines 3a and 3b, carried out
under both protocol A and B,4 are not regioselective, and lead to
mixtures of the corresponding 1,2- and 1,4-addition products.14
Accurate 1H NMR spectroscopy analysis indicated that the 1,2-ad-
dition product in each case obtained is the corresponding trans

V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
691
Table 1
Regio- and stereoselectivity of the addition reactions of primary and secondary aliphatic amines to epoxides 1
b
and 2
b
(protocol A)a
1,4-addition product
anti-1,2-addition product
R1
O
R1
O
R1
HO
O
NR2R3
R1
HO
O
t-BuOK
R2R3NH
MsO
O
NR2R3
OH
10
R1= CH2OBn
R1= Me
16-26
1β
2β
11
Entry
1
Epoxide
Amine
Time (h)
0.5
Addition product (%)
Yieldb
%
1
b
16 (>99%)
R1¼CH2OBn, R2¼Pr, R3¼H
92(72)
NH2
2
3
1
1
b
b
0.5
0.5
17 (>99%)
18 (>99%)
R1¼CH2OBn, R2¼Bu, R3¼H
R1¼CH2OBn, R2¼Allyl, R3¼H
85(51)
90(62)
NH2
NH2
4
5
6
1
1
1
b
b
b
Et2NH
Me2NH
i-PrNH2
1.0
0.5
1.0
19 (>99%)
20 (>99%)
21 (95%)c
R1¼CH2OBn, R2¼R3¼Et
R1¼CH2OBn, R2¼R3¼Me
R1¼CH2OBn, R2¼i-Pr, R3¼H
88(53)
98(75)
89(58)
7
1
b
0.5
22 (95%)c
R1¼CH2OBn, R2¼C6H11, R3¼H
89(70)
NH2
8
9
1
2
b
b
0.5
0.5
23 (92%)c
R1¼CH2OBn, R2¼C3H5, R3¼H
R1¼Me, R2¼Pr, R3¼H
79(48)
90(69)
NH2
NH2
Me2NH
Et2NH
24 (>99%)
10
11
2
2
b
b
0.5
1.0
25 (>99%)
26 (>99%)
R1¼R2¼R3¼Me
89
85(69)
R1¼Me, R2¼R3¼Et
a
Protocol A: amine as the solvent/nucleophile.
Yields calculated on the crude reaction product (yields calculated after purification by flash chromatography or preparative TLC).
A certain amount (5–8%) of the corresponding 1,4-addition products was present.
b
c
derivative,
substituted-amino)-4-(N-mesylamino)-glycals (46–53) (anti-1,2-
addition products) from 3 and 3 , respectively, (Tables 3 and 4).
The determination of the structure of the only 1,4-addition
product (N-glycosyl amine), in each case obtained in a mixture with
(3
b
,4
a
)-(30–37)
and
(3
a
,4
b
)-3,4-dideoxy-3-(N-
the corresponding anomeric syn-1,4-addition products, having the
same configuration as the starting aziridine (coordination products,
a
b
Scheme 1),6 as constantly found in the reactions of aziridines 3
a
and 3b
with alcohols (directly substrate-dependent selectivity)1d,e
are completely absent under all the aminolysis reaction conditions
the corresponding anti-1,2-addition product, led to
a
really
tried (protocol A and B).4 Moreover, the reaction outcome with
unexpected result: the configuration of the anomeric C(1) carbon is
aziridines 3a and 3b turned out to be insensitive to the reaction
opposite to that of the starting aziridine. In this way, only 2,3-un-
conditions, and almost the same result was obtained under both
protocol A and B (entries 1–4, 7, 8, 10–13, Table 3 and entries 1, 2, 6
and 7, Table 4).
On standing in solution for several hours or days, the anti-1,4-
addition products obtained in the aminolysis reactions of aziridines
saturated-
corresponding 2,3-unsaturated-
aziridine 3 (anti-1,4-addition products) were selectively obtained.
b
-N-glycosyl amines 38b–45b
from aziridine 3
a
and only
a
-N-glycosyl amines 54
a
–61 from
a
b
To the best of our knowledge, this result appears to be the first
example of a completely anti-stereoselective and inversely substrate-
dependent N-glycosylation process of amines.12,13,15 Significantly,
3a
and 3
b slowly, and partially, isomerize to the corresponding
regioisomeric anti-1,2-addition products, already present in the
Table 2
Regio- and stereoselectivity of the addition reactions of primary and secondary aliphatic amines to epoxides 1
a
and 2
a
(protocol A)a
1,4-addition product
anti-1,2-addition product
R1
HO
O
NR2R3
R1
HO
O
R1
O
R1
O
t-BuOK
R2R3NH
MsO
O
NR2R3
OH
12 R1= CH2OBn
27-29
1α
2α
13 R1= Me
Entry
1
Epoxide
Amine
Time (h)
0.5
Addition product (%)
Yieldb
%
27 (95%)c
R1¼CH2OBn, R2¼Pr, R3¼H
82(51)
NH2
1
a
2
3
1
2
a
a
Me2NH
Me2NH
0.5
0.5
28 (>99%)
29 (>99%)
R1¼CH2OBn, R2¼R3¼Me
96(64)
88(63)
R1¼R2¼R3¼Me
a
Protocol A: amine as the solvent/nucleophile.
Yields calculated on the crude reaction product (yields calculated after purification by flash chromatography or preparative TLC).
A certain amount (5%) of the corresponding 1,4-addition products was present.
b
c

692
V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
Table 3
Regio- and stereoselectivity of the addition reactions of primary and secondary aliphatic amines to N-mesyl aziridine 3
a
(protocol A and B)
anti-1,2-addition product
anti-1,4-addition product
NR2R3
O
O
O
O
BnO
BnO
MsO
BnO
BnO
MsHN
t-BuOK
R2R3NH
MsHN
NR2R3
N
NHMs
14
Ms
3α
38β-45β
30-37
Entry
Amine
Protocola
Time (h)
anti-1,2
Addition product(s) (%)
anti-1,4
Yieldb
%
1
2
3
4
A
B
A
B
1
30 (30%)
30 (26%)
31 (20%)
31 (14%)
R2¼Pr, R3¼H
R2¼Pr, R3¼H
R2¼allyl, R3¼H
R2¼allyl, R3¼H
38
b
b
b
b
(70%)
(74%)
(80%)
(86%)
89
92
89
70
NH2
NH2
NH2
NH2
3
38
39
39
0.5
3
5
6
7
8
PhCH2NH2
i-PrNH2
t-Bu-NH2
t-Bu-NH2
Me2NH
Et2NH
Et2NH
Piperidine
Piperidine
B
A
A
B
A
A
B
A
B
3
32 (15%)
33 (15%)
34 (10%)
34 (10%)
35 (63%)
36 (47%)
36 (42%)
37 (43%)
37 (40%)
R2¼PhCH2, R3¼H
R2¼i-Pr, R3¼H
R2¼t-Bu, R3¼H
R2¼t-Bu, R3¼H
R2¼R3¼Me
40
41
42
42
43
44
44
45
45
b
b
b
b
b
b
b
b
b
(85%)
(85%)
(90%)
(90%)
(37%)
(53%)
(58%)
(57%)
(60%)
97
93
83
84
98
98
91
92
82
0.5
0.5
3
0.5
0.5
3
9
10
11
12
13
R2¼R3¼Et
R2¼R3¼Et
0.5
3
R2¼R3¼c-C5H10
R2¼R3¼c-C5H10
a
A¼Protocol A: amine as the solvent/nucleophile; B¼Protocol B: amine (3 equiv) in anhydrous benzene as the solvent.
b
Yields calculated on the crude reaction product.
reaction mixture. Experiments appropriately carried out by
reducing the reaction time (10 s) have demonstrated that the
corresponding anti-1,2-addition products. As a consequence, a high
anti-1,4-stereoselectivity (70–90%) is observed in the reactions of
addition reactions of amines to aziridines 3
a
and 3
b
, as reported in
aziridine 3a with primary amines (n-PrNH2, allylamine, i-PrNH2,
Tables 3 and 4, are under kinetic control.16
t-BuNH2, BnNH2), whereas secondary amines (dimethylamine,
diethylamine, and piperidine) show little or no regioselectivity
(Table 3). Accordingly, in the case of the diastereoisomeric aziridine
Even if the aminolysis reactions of 3a and 3b are not regiose-
lective, there is a clear difference in the anti-1,2-addition product/
anti-1,4-addition product distribution from the two aziridines: from
3b, whereas primary amines show a poor regioselectivity, sec-
aziridine 3
N-(substituted-amino)-glycals, are largely or exclusively obtained
(55–99%), whereas from aziridine 3 , the anti-1,4-addition products,
the corresponding -N-glycosyl amines, are the main reaction
b
, the anti-1,2-addition products, the corresponding
ondary amines determined a complete anti-1,2-addition process,
with the exclusive formation of the corresponding anti-1,2-addition
products (Table 4).
a
b
On the whole, the present protocol, which uses N-mesyl azir-
products (57–90%) (Tables 3 and 4). In this framework, the less
nucleophilic primary amines turned out to favor the formation of
the corresponding anti-1,4-addition products, whereas the more
nucleophilic secondary amines showed a clear tendency toward the
idines 3a and 3b, makes possible the simple stereoselective
construction of a vicinal trans-3,4- (as found in the anti-1,2-addition
products) or distal trans-1,4-di-(N-substituted-amino) functionality
(as found in the anti-1,4-addition products) in
a glycal and
Table 4
Regio- and stereoselectivity of the addition reactions of primary and secondary aliphatic amines to N-mesyl aziridine 3
b
(protocol A and B)
anti-1,2-addition product
anti-1,4-addition product
NR2R3
O
O
O
O
BnO
BnO
MsO
BnO
MsHN
BnO
MsHN
t-BuOK
R2R3NH
N
NHMs
15
NR2R3
Ms
3β
46-53
54α-61α
Entry
Amine
Protocola
Time (h)
anti-1,2
Addition product(s) (%)
anti-1,4
Yieldb
%
NH2
NH2
NH2
1
2
3
A
B
A
1
3
1
46 (70%)
46 (74%)
47 (56%)
R2¼Pr, R3¼H
R2¼Pr, R3¼H
R2¼allyl, R3¼H
54
54
55
a
a
a
(30%)
(26%)
(44%)
91
84
87
4
5
6
7
8
9
10
PhCH2NH2
i-PrNH2
t-Bu-NH2
t-Bu-NH2
Me2NH
B
A
A
B
A
A
A
3
1
1
3
1
1
1
48 (62%)
49 (64%)
50 (50%)
50 (55%)
51 (>99%)
52 (>99%)
53 (96%)
R2¼PhCH2, R3¼H
R2¼i-Pr, R3¼H
R2¼t-Bu, R3¼H
R2¼t-Bu, R3¼H
R2¼R3¼Me
56
57
58
58
59
60
61
a
a
a
a
a
a
a
(38%)
(36%)
(50%)
(45%)
(<1%)
(<1%)
(4%)
89
95
89
70
96(72)
88(61)
91(65)
Et2NH
R2¼R3¼Et
Piperidine
R2¼R3¼c-C5H10
a
A¼Protocol A: amine as the solvent/nucleophile; B¼Protocol B: amine (3 equiv) in anhydrous benzene, as the solvent.
b
Yields calculated on the crude product (yields calculated after purification by flash chromatography).

V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
693
pseudoglycal system, respectively. In this way, the corresponding
(3 ,4 )- and (1 ,4 )- (from aziridine 3 ) and (3 ,4 )- and (1 , 4 )-
di-(N-substituted-amino) sub-structural moieties (from 3 ) of
interest for the synthesis of biologically active compounds can be
stereoselectively synthesized (Tables 3 and 4).11–13
aziridine 3
a
) necessarily arise by a corresponding amine attack on
b
a
b
a
a
a
b
a
b
b
aziridine 3
a
through conformer a02 (route c, Scheme 3), but an 1,3-
diaxial interaction between the C(5)–C(6) bond and the direction of
the nucleophilic attack is present in the opening process. This
interaction could be responsible for the reduced amount of anti-1,2-
addition products found in the case of aziridine 3
As for the anti-1,4-addition products, the N-glycosyl amines 38
and 54 –61 obtained from aziridines 3 and 3 , respectively,
a (vide infra).
b–
3. Discussion
45b
a
a
a
b
steric repulsion between the N-mesyl substituted aziridine ring and
the attacking nucleophile could be responsible for the conjugated
nucleophilic addition to C(1) on the face opposite to that bearing
The behavior of epoxides 1,2a,b in the reactions with amines
under protocol A is similar to that observed in the corresponding
reactions with alcohols under the same conditions, and the differ-
ent result derives from the decidedly different stability of the pri-
mary reaction product. Actually, in both aminolysis and alcoholysis,
mixtures of syn- and anti-1,4-addition products are kinetically
obtained, but in the case of the alcoholysis, the 1,4-addition prod-
ucts, the corresponding alkyl O-glycosides are stable and constitute
the final reaction products,1a–c,8 whereas in the aminolysis, an
isomerization process occurs on the initially formed 1,4-addition
products and the corresponding, more stable, anti-1,2-addition
products are the final reaction products (Tables 1 and 2).15
the aziridine ring (Scheme 3). In aziridine 3b, amine attack on C(1)
in an anti fashion occurs through the only existing conformer 3b01e
and is favorably pseudoaxial (route g, Scheme 3), whereas in azir-
idine 3
a
, the corresponding attack can occur in both conformers 3a0
and 3a00 present at the equilibrium in an almost 1:1 ratio.2 In 3a0
,
the conjugated anti-attack is pseudoaxial (route e, Scheme 3), but it
suffers from 1,3-diaxial interaction with the axial C(5)-C(6) bond,
whereas in conformer 3
pseudoequatorial attack (route f, Scheme 3). As a consequence, in 3
both anti-1,2- and anti-1,4-addition process are favored, whereas in
aziridine 3 , due to the possible presence of an 1,3-diaxial
a
00 no strain is present in the corresponding
b
,
The results obtained in the aminolysis of N-mesyl aziridines
a
3
a
,
b
are primarily consistent with the absence of any type of
coordination between the nucleophile (amine) and the aziridine
nitrogen of In these conditions, only anti-addition
interaction, only the pseudoequatorial anti-1,4-addition process
through conformer 3a00 is favored. All this could determine the
3a,b.
prevalence of anti-1,4-addition products in 3a and, considering that
processes, made possible also by the marked nucleophilicity of
the amine, can occur, and, as a consequence, only products (non-
coordination products)6 deriving from a direct, non-coordinated
attack of the nucleophile, in an anti fashion, on the reactive sites
[C(1) and C(3)] of the allylic system can consequently be found:
anti-1,4-addition products by nucleophilic attack on C(1) and anti-
1,2-addition products by corresponding attack on allylic C(3)
carbon (Scheme 3).
in the absence of any coordinating and/or steric factors the C(3)
allylic carbon should be the preferred reactive terminus,1 the
prevalence of anti-1,2-addition products in 3
different distribution of products observed in the aminolysis of
N-mesyl aziridines 3
and 3b 17,18
The behavior of aziridines 3
b, thus justifying the
a
.
a
and 3b in the reactions with
amines under protocol A and protocol B is decidedly different from
R2
R2
H
H
R3
N
N
R3
BnO
6
c
OBn
f
e
5
O
NR2R3
routes e,f
O
O
1
O
BnO
BnO
MsHN
route c
1
NHR2R3
Ms
NHR2R3
MsHN
3
N
α
α
3 '
3
"
NR2R3
N
Ms
β
38β-45
30-37
1° amines (90-70%)
2° amines (60-37%)
1° amines (10-30%)
2° amines (40-63%)
anti-1,2-addition product
(non-coordination product)
anti-1,4-addition product
(non-coordination product)
Ms
N
O
NR2R3
route g
OBn
O
O
BnO
BnO
route d
NHR2R3
NHR2R3
1
MsHN
NR2R3
46-53
MsHN
3
3β'
g
d
54α -61α
1° amines (26-50%)
1° amines (74-50%)
N
H
R2
R3
2° amines (4 - 1%)
2° amines (96-99%)
Scheme 3.
Considering the conformational equilibrium present in azir-
idines 3
b2 and the stereoelectronic factors related to the prefer-
ential trans-diaxial ring opening of three-membered heterocycles,
the anti-1,2-addition products 46–53 (from aziridines 3 ) arise by
that observed in the corresponding reactions with alcohols under
the same conditions: only 1,4-addition products, with a consistent
prevalence (protocol A) or unique presence (protocol B) of the
corresponding syn-1,4-addition product (coordination product)6
from the reactions with alcohols (Scheme 1)1d,e and mixtures of
anti-1,2- and anti-1,4-addition products (non-coordination
products)6 from the reaction with amines (Scheme 3).
a
,
b
amine pseudoaxial attack on the allylic C(3) carbon of aziridine 3b,
reacting in its corresponding unique conformer b01e (route d,
Scheme 3). Likewise, anti-1,2-addition products 30–37 (from

694
V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
The reason for such a decidedly different behavior in apparently
corresponding trans 4-hydroxy-3-(N-substituted-amino) glycals
(anti-1,2-addition products). On the contrary, the aminolysis
reactions of the structurally related N-mesyl aziridines 3a and 3b
are under kinetic control and lead to mixtures of the corresponding
trans 3,4-di-(N-substituted-amino) glycals (anti-1,2-addition prod-
ucts) and N-glycosyl amines having a configuration opposite to that
of the starting aziridine (anti-1,4-addition products). The composi-
similar reactions can be found in a combination of the two above-
mentioned factors: the different nucleophilicity of amines with
respect to alcohols, and the different efficiency of the aziridine
nitrogen-nucleophile coordination (hydrogen bond) in the case of
alcohols and amines. As shown for simplicity in Scheme 4 only for
aziridine 3b, these two factors make the direct attack on the C(3)
carbon (route d) particularly favored in the case of amines, which
are characterized by a high nucleophilicity and a possibly reduced
efficiency of the coordination with the aziridine nitrogen, to the
point that the coordination pathway (route b0) is not observed at all,
and the anti-1,2-addition process (route d) is the largely observed
reaction pathway. With the less nucleophilic alcohols, no direct,
uncatalyzed attack on the allylic C(3) carbon (route d0) can rea-
sonably take place. In these conditions, only a nucleophilic attack
on C(1), largely promoted by the efficient oxirane oxygen–alcohol
coordination, in the form of a hydrogen bond, is possible. In this
tion of the aminolysis reaction mixtures of aziridines 3a and 3b
depends exclusively of the aziridine and the amine (primary or
secondary) and the results obtained have been explained by the
nucleophilicity of amines and their reduced ability to form a hy-
drogen bond with the aziridine nitrogen. When compared with the
corresponding results obtained in the alcoholysis, the aminolysis of
aziridines 3a and 3b probably constitutes the best demonstration
of how the presence or the absence of a substrate–nucleophile
coordination effect can direct the regio- and stereoselectivity of the
nucleophilic addition reactions in these glycal-derived allyl het-
erocyclic systems.
way, the poorly nucleophilic alcohol is brought on the
b face and
practically ‘activated’ for a -directed attack on the nearby C(1)
b
Theoretical, computational studies are in due progress in our
laboratory in order to have, if possible, a more complete ration-
alization of the regio- and stereochemical behavior of these in-
carbon, in a sort of intramolecular, entropically favored, reaction
pathway (route b, Scheme 4).19
O
BnO
N
Ms
less
more
3β
effective
NHR2R3
effective
R1OH
R3
syn 1,4-addition product
anti-1,2-addition product
δ+
R1
δ+
H
Ms
H
Ms
R2
O
N
N
N
OR1
O
OBn
OBn
O
O
route b
b'
route d
b
BnO
BnO
O
not
observed
3
3
1
1
MsHN
MsHN
not
NR2R3
d'
observed
d
3β'
3β'
coordination
product
O
non-coordination
product
H
H
R2
N
R1
R3
(more nucleophilic)
(less nucleophilic)
Scheme 4.
4. Structures and configurations
teresting glycal-derived allyl oxiranes 1,2
a,b and N-mesyl
aziridines 3 in nucleophilic addition reactions.
a,b
The regioisomeric 1,2- or 1,4-addition product structure of the
products obtained in the aminolysis of epoxides 1,2 and azir-
idines 3 was simply determined on the basis of the chemical
shift of the corresponding vinyl protons in 1H NMR spectra of the
addition compounds obtained [ 6.58–6.35 (1H) and 4.60–4.99 (1H)
in 1,2-addition products and 5.82–6.15 (2H) in 1,4-addition prod-
ucts]. Moreover, 1,4-addition products also show the presence of the
anomeric H(1) proton at 4.73–5.30. The trans configuration in the
anti-1,2-addition products obtained in the reactions of epoxides
1,2 and aziridines 3 was demonstrated by means of appro-
priate NOE experiments. As for the anti-1,4-addition products (N-
glycosyl amines) obtained in the reactions of aziridines 3 the
(from aziridine 3 ) and configuration (from aziridine 3 ) were
a,b
6. Experimental
6.1. General
a,b
d
d
All reactions were performed in a flame-dried modified Schlenk
(Kjeldahl shape) flasks fitted with a glass stopper or rubber septa
under a positive pressure of argon. Flash column chromatography
was performed employing 230–400 mesh silica gel (Macherey–
Nagel). Analytical TLCs were performed on Alugram SIL G/UV254
silica gel sheets (Macherey–Nagel) with detection by 0.5% phos-
phomolybdic acid solution in 95% EtOH. Benzene, toluene, Et2O,
and THF were distilled from sodium/benzophenone. Epoxides
d
a
,
b
a,b
a,b
a
a
b
b
determined on the basis of the presence of NOE between anomeric
H(1) and the methyl group of the methansulfonylamino group on
C(4) and on the observation that the chemical shift of anomeric
1,2a,b and N-mesyl aziridines 3a,b were prepared by cyclization
under basic conditions (t-BuOK) of the corresponding stable pre-
cursors, trans hydroxy mesylates 10–131a–c and trans N,O-dimesy-
lates 141d and 15,1e as previously described.
H(1) in the
a series is constantly at a lower field than in the b series,
in accordance with literature data.12b,c,20
6.2. Reactions of epoxides 1a,1b,2a and 2b with amines under
5. Conclusions
protocol A reaction conditions
The addition reactions of primary and secondary aliphatic
amines to glycal-derived allyl epoxides 1 and 2 are under
thermodynamic control and lead to the exclusive formation of the
6.2.1. Reaction of epoxide 1b with PrNH2 (protocol A). Typical Pro-
cedure. A solution of trans hydroxy mesylate 10 (0.035 g, 0.11 mmol)
in PrNH2 (2.2 mL) was treated with t-BuOK (0.012 g, 0.11 mmol,
a
,
b
a
,b

V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
695
1 equiv) and the reaction mixture was stirred 30 min at room
temperature. Dilution with Et2O and evaporation of the washed
(saturated aqueous NaCl) organic solution afforded a crude product
(0.028 g, 92% yield) consisting of practically pure 3-deoxy-3-(N-
5H), 6.58 (d,1H, J¼6.2 Hz), 4.99 (dt,1H, J¼6.2, 2.0 Hz), 4.76–4.81 (m,
1H), 4.61 (d, 1H, J¼11.8 Hz), 4.56 (d, 1H, J¼11.8 Hz), 4.53–4.64 (m,
1H), 4.18–4.29 (m, 1H), 3.61–3.87 (m, 2H), 2.79–2.84 (m, 1H), 2.98
d 146.9, 137.4, 128.7, 128.1, 99.9, 75.2, 73.8,
70.3, 67.8, 61.7, 38.3. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N,
5.32. Found: C, 68.22; H, 8.16; N, 5.57.
(s, 6H). 13C NMR (CDCl3)
propylamino)-
to flash chromatography. Elution with a 9:1 CH2Cl2/MeOH mix-
ture afforded 6-O-(benzyl)-3-deoxy-3-(N-propylamino)- -gulal (16)
(0.022 g, 72% yield), pure as a liquid: Rf¼0.23 (9:1 CH2Cl2/MeOH); IR
(neat) 7.26–
3462, 1645, 1454, 1244, 1097 cmꢀ1. 1H NMR (CDCl3)
D
-gulal derivative 16 (1H NMR), which was subjected
D
6.2.5. Reaction of epoxide 2b with PrNH2 (protocol A). Following the
n
d
typical procedure, the treatment of a solution of trans hydroxy
mesylate 11 (0.050 g, 0.24 mmol) in PrNH2 (3.3 mL) with t-BuOK
(0.027 g, 0.24 mmol) afforded, after 30 min at room temperature,
a crude product consisting of 3,6-dideoxy-3-(N-propylamino)-D-
gulal derivative 24 (0.037 g, 90% yield), which was subjected to
7.39 (m, 5H), 6.52 (d, 1H, J¼6.1 Hz), 4.84 (ddd, 1H, J¼6.1, 5.0, 1.6 Hz),
4.66 (d, 1H, J¼11.9 Hz), 4.58 (d, 1H, J¼11.9 Hz), 3.95–4.04 (t, 1H,
J¼4.0 Hz), 3.78–3.94 (m, 3H), 2.88–2.99 (m, 1H), 2.57–2.73 (m, 2H),
1.88–2.20 (m, 2H, OH and NH), 1.58 (six lines, 2H, J¼7.3 Hz), 0.90 (t,
3H, J¼7.3 Hz). 13C NMR
d
145.2, 137.6, 128.7, 128.1, 128.0, 100.0, 74.1,
flash chromatography. Elution with a 1:1 hexane/AcOEt mixture
72.1, 71.4, 69.0, 54.5, 49.4, 23.5, 11.9. Anal. Calcd for C16H23NO3: C,
69.29; H, 8.36; N, 5.05. Found: C, 69.12; H, 8.20; N, 5.25.
afforded pure 3,6-dideoxy-3-(N-propylamino)-
69% yield), pure as a liquid: Rf¼0.33 (1:1 hexane/AcOEt); IR (neat)
3459, 1649, 1451, 1236, 1095 cmꢀ1 1H NMR (CDCl3)
6.44 (d, 1H,
D-gulal (24) (0.028 g,
n
.
d
6.2.2. Reaction of epoxide 1
b
with Me2NH (protocol A). Following
J¼6.1 Hz), 4.85–4.95 (m, 1H), 4.81 (ddd, 1H, J¼6.1, 4.7, 1.5 Hz), 4.02
(q, 1H, J¼6.3 Hz), 3.48–3.55 (m, 1H), 2.90–2.97 (m, 1H), 2.66–2.77
(m, 1H), 2.54–2.65 (m, 1H), 1.48 (sextet, 2H, J¼7.3 Hz), 1.34 (d, 3H,
the typical procedure, the treatment of a solution of trans hydroxy
mesylate 10 (0.041 g, 0.13 mmol) in Me2NH (2.5 mL) with t-BuOK
(0.015 g, 0.13 mmol) afforded, after 30 min at room temperature,
a crude product (0.034 g, 98% yield) consisting of practically pure 3-
J¼6.5 Hz), 0.91 (t, 3H, J¼7.3 Hz). 13C NMR (CDCl3)
d 143.6, 100.0,
70.2, 70.1, 55.1, 46.7, 23.8, 16.7, 11.5. Anal. Calcd for C9H16NO2: C,
63.13; H, 10.01; N, 8.18. Found: C, 63.45; H, 9.70; N, 8.31.
deoxy-3-(N,N-dimethylamino)-D
-gulal derivative 20 (1H NMR),
which was subjected to flash chromatography. Elution with
a 3:7:0.3 hexane/AcOEt/MeOH mixture afforded 6-O-(benzyl)-3-
6.2.6. Reaction of epoxide 2b with Et2NH (protocol A). Following the
deoxy-3-(N,N-dimethylamino)-
as a liquid: Rf¼0.29 (3:7:0.3 hexane/AcOEt/MeOH); IR (neat)
1655, 1462, 1377, 1095 cmꢀ1. 1H NMR (CDCl3)
7.24–7.40 (m, 5H),
D
-gulal (20) (0.025 g, 75% yield), pure
typical procedure, the treatment of a solution of trans hydroxy
mesylate 11 (0.030 g, 0.14 mmol) in Et2NH (2 mL) with t-BuOK
(0.016 g, 0.14 mmol) afforded, after 1 h at room temperature,
n
3331,
d
6.55 (dd,1H, J¼6.3, 0.6 Hz), 4.72 (ddd, 1H, J¼6.3, 4.9, 1.7 Hz), 4.64 (d,
1H, J¼12.0 Hz), 4.57 (d, 1H, J¼12.0 Hz), 4.02 (t, 1H, J¼4.3 Hz), 3.91–
3.95 (m, 1H), 3.86 (dd, 1H, J¼10.5, 3.5 Hz) 3.79 (dd, 1H, J¼10.5,
a crude product consisting of 3,6-dideoxy-3-(N,N-diethylamino)-D-
gulal derivative 26 (0.022 g, 85% yield), which was subjected to
flash chromatography. Elution with a 1:1 hexane/AcOEt mixture
5.1 Hz), 2.47–2.56 (m, 1H), 2.30 (s, 6H). 13C NMR (CDCl3)
d
145.1,
afforded pure 3,6-dideoxy-3-(N,N-diethylamino)-
(0.018 g, 69% yield), pure as a liquid: Rf¼0.44 (1:1 hexane/AcOEt); IR
(neat) 6.37
3559, 1648, 1456, 1229, 1094 cmꢀ1. 1H NMR (CDCl3)
D-gulal (26)
137.7, 128.7, 128.0, 127.9, 98.7, 73.9, 73.1, 71.0, 67.1, 62.1, 42.9. Anal.
Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.67; H,
8.32; N, 5.13.
n
d
(dd, 1H, J¼6.3, 1.6 Hz), 4.64 (dd, 1H, J¼6.2, 3.7 Hz), 4.20 (dd, 1H,
J¼6.4, 2.8 Hz), 3.58–3.65 (m, 1H), 2.99–3.06 (m, 1H), 2.41–2.83 (m,
4H), 1.30 (d, 3H, J¼6.6 Hz), 1.03 (t, 6H, J¼7.2 Hz). 13C NMR (CDCl3)
6.2.3. Reaction of epoxide 1a with PrNH2 (protocol A). Following the
typical procedure, the treatment of a solution of trans hydroxy
mesylate 12 (0.035 g, 0.11 mmol) in PrNH2 (2 mL) with t-BuOK
(0.012 g, 0.11 mmol) afforded, after 1 h at room temperature,
a crude product (0.025 g, 82% yield) consisting of a 95:5 mixture of
d 144.6, 99.2, 71.7, 68.2, 58.2, 44.0, 29.8, 13.6. Anal. Calcd for
C10H19NO2: C, 64.83; H, 10.34; N, 7.56. Found: C, 64.90; H, 10.29; N,
7.43.
3-deoxy-3-(N-propylamino)-
D
-glucal derivative 27 and corre-
6.2.7. Reaction of epoxide 2a with Me2NH (protocol A). Following
sponding 1,4-addition products (1H NMR), which was subjected to
flash chromatography. Elution with a 9:1 CH2Cl2/MeOH mixture,
containing Et3N (0.1%) afforded 6-O-(benzyl)-3-deoxy-3-(N-propy-
the typical procedure, the treatment of a solution of trans hydroxy
mesylate 13 (0.050 g, 0.24 mmol) in Me2NH (3.3 mL) with t-BuOK
(0.027 g, 0.24 mmol) afforded, after 30 min at room temperature,
a crude product (0.033 g, 88% yield) consisting of N,N-dimethyla-
mino-derivative 29 and unreacted starting material, which was
subjected to preparative TLC (an 1:1 hexane/AcOEt mixture was
used as the eluent). Extraction of the slower more intense band
lamino)-
(9:1 CH2Cl2/MeOH); IR (neat)
1H NMR (CDCl3)
D-glucal (27) (0.016 g, 51% yield), pure as a liquid: Rf¼0.40
n
3329, 1651, 1454, 1234, 1097 cmꢀ1
.
d
7.20–7.42 (m, 5H), 6.38 (dd,1H, J¼6.1,1.8 Hz), 4.76
(dd, 1H, J¼6.1, 1.8 Hz), 4.48–4.71 (m, 2H), 4.65 (d, 1H, J¼12.1 Hz),
4.58 (d, 1H, J¼12.1 Hz), 3.61–4.00 (m, 5H), 2.49–2.83 (m, 2H), 1.55
(sextet, 2H, J¼7.3 Hz), 0.93 (t, 3H, J¼7.3 Hz). 13C NMR (CDCl3)
afforded pure 3,6-dideoxy-3-(N,N-dimethylamino)-
a liquid (0.024 g, 63% yield): Rf¼0.14 (1:1 hexane/AcOEt); IR (neat)
3342,1641,1454,1226,1094 cmꢀ1. 1H NMR (CDCl3)
D
-glucal (29), as
n
d
145.3, 138.0, 128.6, 127.9, 99.4, 77.3, 73.8, 69.6, 58.4, 47.4, 29.8,
d
6.38 (dd, J¼6.2,
18.9, 11.7. Anal. Calcd for C16H23NO3: C, 69.29; H, 8.36; N, 5.05.
Found: C, 69.09; H, 8.51; N, 5.40.
2.0 Hz), 4.66 (dd, J¼6.2, 1.8 Hz), 4.07–4.19 (m, 1H), 3.32–3.43 (m,
1H), 3.15–3.24 (m, 1H), 2.24 (s, 6H), 1.36 (d, 3H, J¼6.3 Hz). 13C NMR
d
147.6, 99.8, 79.2, 70.8, 60.2, 44.1, 39.5, 16.5. Anal. Calcd for
6.2.4. Reaction of epoxide 1
a
with Me2NH (protocol A). Following
C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.46, H, 9.55; N, 8.72.
the typical procedure, the treatment of a solution of trans hydroxy
mesylate 12 (0.035 g, 0.11 mmol) in Me2NH (2 mL) with t-BuOK
(0.012 g, 0.11 mmol) afforded, after 30 min at room temperature,
a crude product (0.028 g, 96% yield) consisting of practically pure 3-
6.3. Reactions of aziridines 3
protocol A reaction conditions
a and 3b with amines under
deoxy-3-(N,N-dimethylamino)-
D
-glucal derivative 28 (1H NMR),
6.3.1. Reaction of aziridine 3
a with PrNH2 (protocol A). Typical
which was subjected to flash chromatography. Elution with
procedure. solution of trans N,O-dimesylate 14 (0.031 g,
A
a 3:7:0.3 hexane/AcOEt/MeOH mixture afforded 6-O-(benzyl)-3-
0.080 mmol) in PrNH2 (1.6 mL) was treated with t-BuOK (0.009 g,
0.080 mmol, 1 equiv) and the reaction mixture was stirred at room
temperature until the TLC analysis showed the complete disap-
pearance of the starting material (1 h). Evaporation of the solvent
deoxy-3-(N,N-dimethylamino)-
pure as a liquid: Rf¼0.53 (3:7:0.3 hexane/AcOEt/MeOH); IR (neat)
3387, 1645, 1361, 1224, 1098 cmꢀ1. 1H NMR (CDCl3)
7.18–7.45 (m,
D-glucal (28) (0.019 g, 64% yield),
n
d

696
V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
afforded a crude product (0.025 g, 89% yield) consisting of a 70:30
mixture of -N-glycosyl amine 38 and 3,4-dideoxy-3,4-di-(N-
substituted-amino)-
-glucal derivative 30 (1H NMR), which was
subjected to flash chromatography. Elution with an 8:2 CH2Cl2/
J¼6.1, 5.3, 1.7 Hz), 4.61 (d, 1H, J¼11.9 Hz), 4.54 (d, 1H, J¼11.9 Hz),
4.60 (d, 1H, J¼3.8 Hz, NH), 4.22–4.32 (m, 1H), 3.65–3.78 (m, 3H),
2.91 (s, 3H), 2.53–2.59 (m, 1H), 2.34 (s, 6H). 13C NMR (CDCl3)
b
b
D
d
145.5, 137.7, 128.7, 128.2, 128.1, 99.1, 73.9, 72.0, 68.9, 62.2, 49.8,
acetone mixture afforded pure 38
(0.005 g, 16% yield).
b
(0.013 g, 46% yield) and 30
43.0. 41.9. Anal. Calcd for C16H24N2O4S: C, 56.45; H, 7.11; N, 8.23.
Found: C, 56.40; H, 7.45; N, 8.16.
6.3.1.1. N-(Propyl)-[6-O-(benzyl)-2,3,4-trideoxy-4-(N-mesyl-
amino)- -erithro-hex-2-enopyranosyl]-amine (38 ). A liquid:
Rf¼0.31 (8:2 CH2Cl2/acetone); IR (neat) 3558, 3360, 1653, 1319,
1101 cmꢀ1. 1H NMR (CDCl3)
7.27–7.39 (m, 5H), 5.96–6.03 (m, 1H),
6.4. Reactions of aziridines 3
protocol B reaction conditions
a and 3b with amines under
b
-D
b
n
d
6.4.1. Reaction of aziridine 3
a with BnNH2 (protocol B). Typical
5.93 (dt, 1H, J¼6.2, 1.7 Hz), 5.22–5.26 (m, 1H), 4.58 (d, 1H,
J¼11.7 Hz), 4.56 (d, 1H, J¼11.7 Hz), 4.46–4.62 (m, 2H), 4.00–4.08 (m,
1H), 3.60 (d, 2H, J¼5.4 Hz), 2.94–3.15 (m, 2H), 2.76 (s, 3H), 2.59–
2.85 (m, 1H), 1.47 (q, 2H, J¼7.3 Hz), 0.91 (t, 3H, J¼7.3 Hz). 13C NMR
procedure. solution of trans N,O-dimesylate 14 (0.030 g,
A
0.077 mmol) in anhydrous benzene (1 mL) was treated with t-
BuOK (0.009 g, 0.080 mmol) in the presence of BnNH2 (0.025 mL,
0.23 mmol, 3 equiv) and the resulting reaction mixture was stirred
at room temperature until the TLC analysis showed the complete
disappearance of the starting material and the formation of
a product (3 h). Dilution with Et2O and evaporation of the washed
(saturated aqueous NaCl) organic solution afforded a crude product
(CDCl3)
d 137.9, 130.4, 129.4, 128.7, 128.1, 80.8, 72.0, 71.4, 69.1, 47.1,
35.9, 29.8, 23.5, 11.9. Anal. Calcd for C17H26N2O4S: C, 57.60; H, 7.39;
N, 7.90. Found: C, 57.45; H, 7.23; N, 7.81.
6.3.1.2. 6-O-(Benzyl)-3,4-dideoxy-4-(N-mesylamino)-3-(N-pro-
(0.030 g, 97% yield) consisting of an 85:15 mixture of
amine 40 and the corresponding regioisomeric 3,4-dideoxy-
3,4-di-(N-substituted-amino)-
-glucal derivative 32 (1H NMR)
b-N-glycosyl
pylamino)-
D-glucal (30). A liquid: Rf¼0.15 (8:2 CH2Cl2/acetone); IR
b
(neat)
n
3560, 3345, 1650, 1320, 1098 cmꢀ1. 1H NMR (CDCl3)
d
7.27–
D
7.39 (m, 5H), 6.40 (dd, 1H, J¼6.1, 1.6 Hz), 4.85 (dd, 1H, J¼6.1, 2.6 Hz),
4.60 (s, 2H), 3.95–4.05 (m, 1H), 3.84–3.90 (m, 2H), 3.53 (t, 1H,
J¼8.1 Hz), 3.11–3.19 (m, 1H), 3.13 (s, 3H), 2.66–2.76 (m, 1H), 2.44–
2.54 (m, 1H), 1.48 (q, 2H, J¼7.4 Hz), 0.92 (t, 3H, J¼7.4 Hz). 13C NMR
(Table 3), which was subjected to flash chromatography. Elution
with an 5:3:2 CH2Cl2/hexane/AcOEt mixture afforded pure N-
(benzyl)-[6-O-(benzyl)-2,3,4-trideoxy-4-(N-mesylamino)-
hex-2-enopyranosyl]amine (40 ), pure as a liquid (0.019 g, 62%
yield): Rf¼0.23 (5:3:2 CH2Cl2/hexane/AcOEt); IR (neat) 3451, 3325,
1647, 1320, 1099 cmꢀ1 1H NMR (CDCl3)
7.15–7.44 (m, 10H), 6.00
b-D-erithro-
b
d
144.0, 137.9, 128.6, 127.9, 102.0, 78.8, 77.3, 69.8, 57.0, 53.6, 48.3,
n
42.2, 23.6, 12.0 Anal. Calcd for C17H26N2O4S: C, 57.60; H, 7.39; N,
7.90. Found: C, 57.72; H, 7.50; N, 8.01.
.
d
(dd, 1H, J¼6.2, 0.8 Hz), 5.93 (dt, 1H, J¼6.2, 1.5 Hz), 5.30 (s, 1H), 4.58
(d, 1H, J¼11.9 Hz), 4.55 (d, 1H, J¼11.9 Hz), 4.46–4.51 (m, 1H), 4.03–
4.12 (m, 1H), 3.86 (s, 2H), 3.57–3.64 (m, 2H), 2.76 (s, 3H), 2.09–2.52
6.3.2. Reaction of aziridine 3
b with PrNH2 (protocol A). Following
the typical procedure, the treatment of a solution of trans N,O-
dimesylate 15 (0.023 g, 0.060 mmol) in PrNH2 (1.2 mL) with t-BuOK
(0.007 g, 0.060 mmol) afforded, after 1 h at room temperature,
a crude product (0.019 g, 91% yield) consisting of a 30:70 mixture of
(br s, 2H). 13C NMR (CDCl3)
d 144.1, 140.1, 137.8, 130.5, 129.3, 128.6,
128.4, 128.0, 127.3, 127.2, 80.8, 73.7, 71.9, 71.4, 49.1, 46.5, 41.7. Anal.
Calcd for C21H26N2O4S: C, 62.66; H, 6.51; N, 6.96. Found: C, 62.69; H,
6.16; N, 7.15.
the corresponding
(N-substituted-amino)-
a
-N-glycosyl amine 54
a
and 3,4-dideoxy-3,4-di-
Even if not recovered from the flash chromatography, the
presence of the corresponding regioisomeric 3,4-dideoxy-3,4-di-
D
-gulal derivative 46 (1H NMR), which was
subjected to flash chromatography. Elution with a 4:6 hexane/
acetone mixture afforded 6-O-(benzyl)-3,4-dideoxy-4-(N-mesyl-
(N-substituted-amino)-D-glucal derivative 32 as a reaction product,
was firmly established by 1H NMR examination of the crude re-
amino)-3-(N-propylamino)-
a liquid: Rf¼0.36 (4:6 hexane/acetone); IR (neat)
1261, 1093 cmꢀ1. 1H NMR (CDCl3)
7.22–7.39 (m, 5H), 6.48 (d, 1H,
D-gulal (46) (0.010 g, 49% yield), pure as
action mixture: 32, 1H NMR
1H, J¼6.2, 2.5), 3.04 (s, 3H).
d
6.42 (dd, 1H, J¼6.2, 1.4 Hz), 4.88 (dd,
n
3488, 3360,1643,
d
J¼6.3 Hz), 4.75–4.89 (m, 1H), 4.47–4.62 (m, 2H), 4.58 (s, 2H), 4.18–
4.33 (m, 1H), 3.54–3.80 (m, 3H), 2.99–3.13 (m, 2H), 2.90 (s, 3H), 2.68
(t, 1H, J¼7.0 Hz), 1.48 (q, 2H, J¼7.4), 0.91 (t, 3H, J¼7.4 Hz). 13C NMR
6.4.2. Reaction of aziridine 3b with BnNH2 (protocol B). Following
the above described typical procedure, the treatment of a solution
of trans N,O-dimesylate 15 (0.030 g, 0.077 mmol) in anhydrous
benzene (1 mL) with t-BuOK (0.009 g, 0.080 mmol) in the presence
of BnNH2 (0.025 mL, 0.23 mmol, 3 equiv) afforded, after 3 h stirring
at room temperature, a crude product (0.028 g, 89% yield) con-
(CDCl3)
d 145.4, 137.5, 128.7, 128.0, 100.9, 73.8, 71.1, 69.1, 54.7, 49.4,
29.8, 23.6, 11.8. Anal. Calcd for C17H26N2O4S: C, 57.60; H, 7.39; N,
7.90. Found: C, 57.53; H, 7.44; N, 8.06.
Even if not recovered from the flash chromatography, the
sisting of a 38:62 mixture of
corresponding regioisomeric 3,4-dideoxy-3,4-di-(N-substituted-
amino)- -gulal derivative 48, which was subjected to flash
chromatography. Elution with 5:3:2 CH2Cl2/hexane/AcOEt
mixture afforded N-(benzyl)-[6-O-(benzyl)-2,3,4-trideoxy-4-(N-
mesylamino)- -threo-hex-2-enopyranosyl]amine (56 ), pure as
a-N-glycosyl amine 56a and the
presence of the regioisomeric
product, was firmly established by 1H NMR examination of the
crude reaction mixture: 54 5.89 (s, 2H), 5.30 (s, 1H, H-
, 1H NMR
1), 2.74 (s, 3H), 0.90 (t, 3H, J¼7.4 Hz).
a-N-glycosyl amine 54a, as a reaction
D
a
d
a
a-
D
a
6.3.3. Reaction of aziridine 3 with Me2NH (protocol A). Following
b
a liquid (0.008 g, 25% yield): Rf¼0.25 (5:3:2 CH2Cl2/hexane/AcOEt);
the typical procedure, the treatment of a solution of trans N,O-
dimesylate 15 (0.031 g, 0.080 mmol) in Me2NH (1.6 mL) with
t-BuOK (0.009 g, 0.080 mmol) afforded, after 1 h at room temper-
ature, a crude product (0.026 g, 96% yield) essentially consisting of
IR
n
(neat) 3487, 3302, 1645, 1319, 1104 cmꢀ1
.
1H NMR (CDCl3)
d
7.20–7.41 (m, 10H), 5.92 (s, 2H), 5.36 (s, 1H), 4.63 (d, 1H,
J¼11.7 Hz), 4.54 (d, 1H, J¼11.7 Hz), 4.54–4.62 (m, 1H), 3.91 (s, 2H),
3.57–3.74 (m, 2H), 3.77–3.85 (m, 1H), 2.75 (s, 3H), 2.01–2.09 (br s,
3,4-dideoxy-3,4-di-(N-substituted-amino)-
D
-gulal derivative 51
2H). 13C NMR (CDCl3)
d 145.6, 139.2, 138.4, 130.3, 129.7, 128.8, 128.1,
(1H NMR), which was subjected to flash chromatography. Elution
with a 1:1 CH2Cl2/AcOEt mixture containing Et3N (0.1%) afforded 6-
O-(benzyl)-3,4-dideoxy-4-(N-mesylamino)-3-(N,N-dimethylamino)-
127.9, 127.4, 127.2, 82.7, 74.1, 72.3, 70.1, 48.2, 45.4, 41.9. Anal. Calcd
for C21H26N2O4S: C, 62.66; H, 6.51; N, 6.96. Found: C, 62.27; H, 6.39;
N, 6.57.
D
-gulal (51) (0.019 g, 72% yield), pure as a liquid: Rf¼0.20 (1:1
CH2Cl2/AcOEt); IR (neat)
3283, 1643, 1323, 1098 cmꢀ1 1H NMR
(CDCl3)
7.23–7.42 (m, 5H), 6.52 (d, 1H, J¼6.1 Hz), 4.73 (ddd, 1H,
Even if not recovered from the flash chromatography, the
presence of the corresponding regioisomeric 3,4-dideoxy-3,4-di-
(N-substituted-amino)-D-gulal derivative 48 as a reaction product,
n
.
d

V. Di Bussolo et al. / Tetrahedron 66 (2010) 689–697
697
was firmly established by 1H NMR examination of the crude re-
8. With simple alcohols (MeOH, EtOH, i-PrOH. t-BuOH), the reactions of epoxides
1,2a,b and aziridines 3a,b were repeated using the alcohol/nucleophile as the
action mixture: 48, 1H NMR
J¼6.3, 1.8), 3.02 (s, 3H).
d
6.48 (d, 1H, J¼6.3 Hz), 4.79 (dt, 1H,
solvent (protocol A reaction conditions).4 In these conditions, the addition
reactions were still completely 1,4-regioselective, but not completely stereo-
selective and mixtures of the corresponding anomeric alkyl
a-O- and b-O-
glycosides were obtained with increasing amount of the corresponding
coordination product on passing from MeOH to EtOH and i-PrOH. With the more
sterically hindered and less nucleophilic t-BuOH, a completely regio- and
stereoselective reaction toward the corresponding coordination product was
observed.1
Acknowledgements
`
This work was supported by the Universita di Pisa and MIUR
0
`
(Ministero dell Istruzione, della Universita e della Ricerca), Roma.
9. Routes c and d (Scheme 1) correspond to a preferred trans diaxial opening of
the oxirane ring.
Professor Gloria Uccello-Barretta and Dr. Federica Balzano of the
Dipartimento di Chimica e Chimica Industriale of the University of
Pisa are gratefully acknowledged for NOE experiments. P.C. grate-
fully acknowledges Merck Research Laboratories for the generous
financial support deriving from the 2005 ADP Chemistry Award.
10. Corresponding trans 3,4-diols and 3-methoxy-4-hydroxy derivatives are ob-
tained from epoxides 1,2a, , and corresponding 3-hydroxy- and 3-me-
b 1a–c
thoxy-4-N-mesylamino derivatives are obtained from aziridine 3b1e by their
reaction with TBAþMe3SiOꢀ and TBAOMe, respectively.
11. Norris, P. Curr. Top. Med. Chem. 2008, 8, 101–113 and references therein.
12. (a) Zhang, G.; Shen, J.; Cheng, H.; Zhu, L.; Fang, L.; Luo, S.; Muller, M. T.; Lee, G.
E.; Wei, L.; Du, Y.; Sun, D.; Wang, P. G. J. Med. Chem. 2005, 48, 2600–2611; (b)
Ichikawa, Y.; Hirata, K.; Ohbayashi, M.; Isobe, M. Chem.dEur. J. 2004, 10, 3241–
3251; (c) Gallant, M.; Link, J. T.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 343–
349; (d) Argoudelis, A. D.; Baczynskj, L.; Kuo, M. T.; Laborde, A. L.; Sebek, O. K.;
Truesdell, S. E.; Shilliday, F. B. J. Antibiot. 1987, 40, 750–760; (e) Watanabe, K. A.;
Fox, J. J. Chem. Pharm. Bull. 1973, 21, 2213–2216.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2009.11.059.
13. (a) Lu, Y.; Gervay-Hague, J. Carbohydr. Res. 2007, 342, 1636–1650; (b) Li, J.;
Zheng, M.; Tang, W.; He, P.-L.; Zhu, W.; Li, T,; Zuo, J.-P.; Liu, H.; Jiang, H. Bioorg.
Med. Chem. Lett. 2006, 16, 5009–5013; (c) Liu, K.-G.; Yan, S.; Wu, Y.-L.; Yao, Z.-J.
Org. Lett. 2004, 6, 2269–2272; (d) Masuda, T.; Shibuya, S.; Arai, M.; Yoshida, S.;
Tomozawa, T.; Ohno, A.; Yamashita, M.; Honda, T. Bioorg. Med. Chem. Lett. 2003,
13, 669–673; (e) Sun, X.-L.; Sato, N.; Kai, T.; Furhuata, K. Carbohydr. Res. 2000,
323, 1–6.
References and notes
1. (a) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti, P. J. Org. Chem.
2004, 69, 7383–7386; (b) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi,
M.; Crotti, P. J. Org. Chem. 2004, 69, 8702–8708; (c) Di Bussolo, V.; Favero, L.;
Romano, M. R.; Pineschi, M.; Crotti, P. Tetrahedron 2008, 64, 8188–8201; (d)
DiBussolo, V.; Romano, M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2005, 7, 1299–
1302; (e) Di Bussolo, V.; Favero, L.; Romano, M. R.; Pineschi, M.; Crotti, P. J. Org.
Chem. 2006, 71, 1696–1699.
14. When it was possible, the 1,2- and 1,4-addition products present in the ami-
nolysis reaction mixtures of aziridines 3
a and 3b were separated by flash
chromatography. In other cases, these products, clearly present in the crude
reaction mixtures (1H NMR spectroscopy), could not be recovered pure from
the chromatographic process due to their instability under the separation/
purification conditions or because not separable under the chromatographic
conditions used (flash chromatography or preparative TLC).
2. A theoretical conformational study carried out on epoxides 2
simplified models structurally related to epoxides 1 and 1 and aziridines 3
and 3
has indicated that epoxides 1a3 and 2a3 and aziridine 3
plementary data) exist as an equilibrium mixture (about 65:35 in the case of 1
and 2 and almost 1:1 in the case of 3
a0 and 00, whereas the corresponding diastereoisomeric epoxides 1b3 and 2b3
a and 2b and
a
b
a
,
b
a (see Sup-
15. Ferrier, R. J.; Zubkov, O. A. In Organic Reactions; Overman, L. E., Ed.; John Wiley:
Hoboken, NJ (USA), 2003; Vol. 62, pp 569–736; see, in particular, the ‘2,3-Un-
saturated Glycosyl Azides and N-Glycosides’ paragraph, pp 610–614.
16. The anti-1,2-addition product/anti-1,4-addition product ratio obtained after 10 s
reaction time is identical to that observed after 30 min or 1 h (Tables 3 and 4).
The only difference in the reaction after 10 s is that a consistent amount (70–
75%) of the unreacted stable precursor of the aziridine, the trans N,O-dimesy-
a
a
a
a) of the corresponding conformers
and aziridine 3b1e exist as the corresponding single conformer b0 (Scheme 1).
The unique conformer b0 has the side chain pseudoequatorial as conformer a00
whereas conformer a0 has the side chain pseudoaxial.
,
3. Crotti, P.; Di Bussolo, V.; Pomelli, C. S.; Favero, L. Theor. Chem. Accounts 2009,
122, 245–256.
late 14 (for 3
17. Some model reactions were repeated by using the corresponding N-(nosyl)-
aziridines 3 –Ns and 3 and 3 . The
–Ns18 instead of N-(mesyl)-aziridines 3
regio- and stereoselectivity obtained in these reactions indicated that the be-
havior of N-(nosyl)-aziridines 3 –Ns and 3 –Ns is similar to that of N-(mesyl)-
aziridines 3 and 3 . However, the use of aziridines 3 –Ns and 3 –Ns makes
a) or 15 (for 3b), is still present.
4. Protocol A reaction conditions: the epoxide 1,2
solvent-nucleophile (alcohol or amine). Protocol B reaction conditions: the
epoxide 1,2 or the aziridine 3 in a non-nucleophilic solvent (anhydrous
MeCN or benzene) is treated with the nucleophile (alcohol or amine, 3 equiv).5
5. Epoxides 1,2 and aziridines 3 are not stable and can be prepared only in
a,b or the aziridine 3a,b in the
a
b
a
b
a
,b
a,b
a
b
a
b
a
b
a,
b
a,b
possible the removal of the nosyl residue from the addition product and the
obtainment of the corresponding free amino group-containing product (see
Supplementary data and Ref. 18).
situ by cyclization under basic conditions (t-BuOK) of the corresponding stable
precursor [trans hydroxy mesylates 10–13 for the epoxides (Tables 1 and 2) and
trans N,O-dimesylates 14–15 for the aziridines (Tables 3 and 4)] and made to
react immediately with a nucleophile.1
6. The ‘coordination product’ and ‘non-coordination product’ nomenclature in-
dicates addition products deriving from a nucleophile–substrate (epoxide or
aziridine) coordination or non-coordination process, respectively.1c
7. The nucleophilic attack on C(1) from the same side as the substrate–nucleophile
18. Di Bussolo, V.; Romano, M. R.; Pineschi, M.; Crotti, P. Tetrahedron 2007, 63,
2482–2489.
19. A similar, appropriately modified, rationalization can be applied to aziridine 3a.
20. (a) Zhang, G.; Shen, J.; Cheng, H.; Zhu, L.; Fang, L.; Lou, S.; Mulle, M. T.; Lee, G. E.;
Wei, L.; Du, Y.; Sun, D.; Wang, P. G. J. Med. Chem. 2008, 48, 2600–2611; (b)
´
¨
´
¨
´
´
Somsak, L.; Felfoldi, N.; Konya, B.; Huse, C.; Telepo, K.; Bokor, E.; Czifrak, K.
Carbohydr. Res. 2008, 343, 2083–2093; (c) Das, T. M.; Rao, C. P.; Kolehmainen, E.
Carbohydr. Res. 2001, 334, 261–269.
coordination (route a, a pseudoaxial attack, in 1–3
attack, in 1–3 ) is entropically favored with respect to a corresponding attack
from the opposite side by a non-coordinated nucleophile (Scheme 1).
a and route b, a pseudoequatorial
b