LETTER
▌2271
lIemtterproved Synthesis of 6-Azido-6-deoxy- and 6,6′-Diazido-dideoxy-
α,α-trehaloses
Synthesis of α,α-Trehalose Derivatives
a
b,c
b
b
a
b
Mina R. Narouz, Sameh E. Soliman, Rafik W. Bassily, Ramadan I. El-Sokkary, Adel Z. Nasr, Mina A. Nashed*
a
Department of Chemistry, Faculty of Science, Damanhour University, Damanhour, Beheira, Egypt
b
Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia, PO Box 426, Alexandria 21321, Egypt
Fax +203(487)0564; E-mail: mina4na@yahoo.com
c
NIDDK, LBC, National Institutes of Health, Bethesda, MD 20892-0815, USA
Received: 14.07.2013; Accepted after revision: 22.08.2013
quired chromatography; however, the unchanged starting
Abstract: An efficient synthesis of 6-azido-6-deoxy and 6,6′-diaz-
material 1, and any over-hydrolyzed product could be re-
ido-dideoxy-α,α-trehalose derivatives was achieved by reaction of
covered for recycling.
trifluoromethanesulfonic anhydride with partially trimethylsilylat-
ed heptakis- and hexakis-O-(trimethylsilyl)-α,α-trehalose in the
presence of pyridine and 4-(N,N-dimethylamino)pyridine. Dis-
placement with azide and desilylation afforded the title compounds,
ed trehaloses. Hence, acylation of the 6,6′-OH groups of 2
which represent potential precursors for the corresponding 6-ami-
no- and 6,6′-diamino-trehaloses.
The hexakis-O-(trimethylsilyl)-α,α-trehalose 2, thus ob-
tained, permitted the synthesis of symmetrically substitut-
with trifluoromethanesulfonic anhydride (triflic anhy-
dride) gave 6,6′-ditriflate derivative 4 in almost quantita-
Key words: carbohydrate chemistry, regioselectivity, azides, pro-
12
tive yield. Reaction of the latter compound with sodium
azide in N,N-dimethylformamide in the presence of dicy-
clopentano-15-crown-5 at ambient temperature gave 6-
azido-6-deoxy-2,3,4-tri-O-(trimethylsilyl)-α-D-glucopy-
ranosyl-(1→1)-6-azido-6-deoxy-2,3,4-tri-O-(trimethylsi-
lyl)-α-D-glucopyranoside (5).13 The combination of
triflate as the leaving group and azide as the nucleophile,
in the presence of crown ether, provided an excellent yield
of the displacement product 5.
tecting groups
In a previous communication, we reported the synthesis of
trehalose esters of corynomycolic acid, the simplest of the
mycolic acids, for studies of trehalose-mycoloyl transfer-
1
,2
ase. We also reported the synthesis of a gluco-galacto
3
,4
analogue of trehalose for the same purpose. Trehalos-
amines have been isolated from microorganisms and been
synthesized and found to have antimicrobial activity,5
,6
Desilylation of 5 afforded crystalline 6,6′-diazido-dide-
1
4
oxy-α,α-trehalose 6 in 65% overall yield from 2. The
and several groups of investigators have recently reported
1
characterization of 6 was based on H NMR spectroscopic
the syntheses of 6-amino- and 6,6′-diamino-α,α-treha-
7
–9
analysis; irradiation of the 5,5′-H resonance at δ = 3.94–
lose. In the present study, we describe a convenient syn-
thesis of 6-azido- and 6,6′-diazido-α,α-trehalose
compounds in which we have used the triflate derivatives
of the partially trimethylsilylated-α,α-trehaloses, displac-
ing the trifluoromethanesulfonate group by azide in the
presence of a crown ether in N,N-dimethylformamide at
room temperature.
3
.90 ppm simplified the triplet at δ = 3.40 ppm to a dou-
blet (J = 9.5 Hz, H-4,4′) and simplified the double double
doublet at δ = 3.56 ppm into a double doublet (H-6 ,6′ ),
a,b
a,b
indicating a symmetrical structure for which the 1,1-H
signal was observed as a doublet with a small coupling
constant (J = 4.0 Hz).
Acetylation of 6 afforded hexa-acetyl derivative 7 in al-
As shown in Scheme 1, partially protected trehalose de-
rivatives 2 and 3 were obtained from the known
most quantitative yield. The structure of 7 was again con-
1
firmed by
H
NMR spectroscopy, indicating
a
2
,3,4,6,2′,3′,4′,6′-octakis-O-(trimethylsilyl)-α,α-trehalose
1
,10
symmetrical structure for which the signal of the 1,1′-H
appeared as a doublet with a small coupling constant
(
1) by controlled alkaline hydrolysis. The 2,3,4,2′,3′,4′-
hexakis-O-(trimethylsilyl)-α,α-trehalose 2 was obtained
from 1 as described by Toubiana et al. [methanolic K CO
(
J = 4.0 Hz) at δ = 5.34 ppm and the ring protons, except
2
3
1
0
for (6 ,6′ -H) were shifted downfield. Irradiation of the
solution for 2 h at 0 °C]. This hexakis ester 2 was isolat-
a,b
a,b
11
H-2,2′ resonance at δ = 5.09 ppm simplified the triplet at
δ = 5.48 ppm to a doublet with a large coupling (H-3,3′),
and collapsed the doublet at δ = 5.34 ppm to a singlet (H-
ed by direct crystallization in excellent yield (90%). On
the other hand, 2,3,4,2′,3′,4′,6′-heptakis-O-(trimethylsi-
lyl)-α,α-trehalose 3 was prepared from 1 following the
method developed by Anderson et al. [methanolic K CO
1
,1′). Irradiation of the H-4,4′ resonance at δ = 5.00 ppm
2
3
1
collapsed the triplet at δ = 5.48 ppm to a doublet (H-3,3′)
and simplified the multiplet at δ = 4.12–3.99 ppm (H-
solution for ca. 20 min at 0–4 °C]. The yield of 3 was
limited by the symmetry of its precursor, but a better than
expected value of 65% was achieved. Isolation of 3 re-
5
,5′).
In an analogous manner, heptakis-O-(trimethylsilyl)-α,α-
trehalose 3 was also converted into 6′-triflate 8, which, on
SYNLETT 2013, 24, 2271–2273
Advanced online publication: 23.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
treatment with sodium azide, afforded 6′-azido-6′-deoxy-
DOI: 10.1055/s-0033-1339843; Art ID: ST-2013-D0650-L
Georg Thieme Verlag Stuttgart · New York
12,13
α,α-trehalose derivative 9.
Desilylation of 9 afforded
©
Narouz, Mina R.
