Novel glycosylidene-spiro-heterocycles from unprecedented solvent incorporation in Koenigs-Knorr-like reactions of C-(1-bromo-1-deoxy-β-D-glycopyranosyl)formamides

Article abstract of DOI:10.1039/a900082h

The title compounds give glycopyranosylidene-spiro-dioxolanes 3 and 4 in acetone and C-(1-methylsulfanylmethoxy-α-D-glycopyranosyl)formamides 5 in DMSO in the presence of Ag₂CO₃ and AgF, respectively.

Full text of DOI:10.1039/a900082h

Novel glycosylidene-spiro-heterocycles from unprecedented solvent
incorporation in Koenigs–Knorr-like reactions of
C-(1-bromo-1-deoxy-b-d-glycopyranosyl)formamides
¯
László Somsák,* László Kovács, Viktor Gyóllai and Erzsébet Osz
Department of Organic Chemistry, Lajos Kossuth University, Debrecen, POB 20, H-4010 Hungary.
E-mail: somsak@tigris.klte.hu
Received (in Liverpool, UK) 4th January 1999, Accepted 22nd February 1999
The title compounds give glycopyranosylidene-spiro-dioxo-
lanes 3 and 4 in acetone and C-(1-methylsulfanylmethoxy-a-
d-glycopyranosyl)formamides 5 in DMSO in the presence of
Ag2CO3 and AgF, respectively.
Based on the experimental data available at present we think
that formation of these derivatives of novel structure can most
probably be explained by participation of the solvents used. The
first step probably common for each transformation may be the
generation of a glycosylium ion destabilized by the electron-
withdrawing CONH2 substituent. This intermediate can com-
As part of an ongoing program to synthesize new anomerically
bifunctional monosaccharide derivatives1–3 as glycomimetics
and their precursors we have investigated the reactions of
acetylated C-(1-bromo-1-deoxy-b-d-glycopyranosyl)forma-
mides (1a3 and 1b4) with nucleophiles under Koenigs–Knorr
conditions.5 While reaction of 1a,b with 1 equiv. of water in
DMSO in the presence of Ag2O (Scheme 1) gave the expected
hydroxyformamide derivatives 2a,b in a crystalline state6 [2a:
85%, mp 177–179 °C, [a]D +36 (CHCl3, c 1.03); 2b: 89%, mp
143–144 °C, [a]D +53 (CHCl3, c 1.0)], a similar transformation
of 1b in acetone7 produced the spiro compound 3b in addition
to 2b (ratio ~ 1:1 by 1H NMR spectroscopy). Using dry
acetone with Ag2CO3 gave 3a,b [3a: 78%, mp 165–167 °C,
[a]D +21 (CHCl3, c 1.0); 3b: 71%, mp 155–157 °C, [a]D +31
(CHCl3, c 1.0)] and small amounts of 4a,b [4a: 6%, syrup, [a]D
+39, (CHCl3, c 2.06); 4b: 4%, syrup, [a]D +57, (CHCl3, c 1.06)]
and 2a,b ( ~ 5% for each) after chromatographic separation.
Carrying out the reaction in dry DMSO with AgF the
methylsulfanylmethoxyformamides 5a,b [5a: 11%, syrup, [a]D
+21 (CHCl3, c 1.03); 5b: 15%, mp 155–156 °C, [a]D +29
(CHCl3, c 1.07)] could be isolated as minor products over 2a,b.
Experiments with 2a showed that this compound was un-
changed after one day when dissolved in acetone or DMSO
either in the absence or presence of Ag2CO3 or AgF,
respectively.
OAc
OAc
AcO
AcO
AcO
O
O
CONH2
CONH2
OH
AcO
AcO
AcO
Br
1a,b
2a,b
-AgBr
AgX
i
O
+
CONH2
OAc
ii
iii
O
O
+
C
CH3
CH3
O
O
S+
AcO
H2N
AcO
CH3
C
C
CH3
•
H2N
O
O
•
–H+
O
O
+
O–
CH2
Structure elucidation† of 3–5 was performed by NMR
(Tables 1 and 2) and MS measurements. Incorporation of
acetone in 3 and 4 was indicated by a molecular ion (m/z 431,
M+ for each) and by two methyl singlets. The presence of one
exchangable proton belonging to an sp2-hybridized nitrogen as
shown by 15N/1H HSQC experiments, and carbon resonances
indicative of an imino ether moiety (C-10) as well as for an
acetal carbon (C-8) are in accordance with the cyclic stuctures.
For each derivative the vicinal proton–proton couplings showed
that the sugar rings existed in the 4C1 conformation. The
configuration of the spiro carbons was established by the three
bond heteronuclear coupling between H-5 and C-10, indicating
antiperiplanar arrangement for the nuclei involved in the given
conformation (see Scheme 1). This was corroborated by the
characteristic downfield shifts of the sugar protons cis to C-10
(H-2 and H-4 in 3a,b, H-5 in 4a,b) following a rule established
recently for glycopyranosylidene-spiro-hydantoin derivatives.2
This effect, which is a further indirect proof of the spirocyclic
structure, is attributed to the shielding anisotropy contribution
of the CNNH bond which occupies a fixed position with respect
to the sugar ring.
O
CH3
CH3
S
AcO
C
AcO
C
C
CH3
O
H2N
H2N
O
+
–H+
SCH3
CH2
O
AcO
AcO
AcO
AcO
6
H
H
O 1
5
O
2
3
4
2
5
O7
6
1
CH3
CH3
AcO
AcO
4
3
AcO
HN
AcO
10
CONH2
O9
3a,b
5a,b
+
+
2a,b
OAc
AcO
AcO
O
NH
O
a
b
D-gluco
D-galacto
AcO
O
CH3
H3C
4a,b
Compounds 5 had a fragment ion (m/z 407, [M 2 CONH2]+
for each) and characteristic resonances for a CONH2 group and
a OCH2SCH3 moiety. The anomeric configurations followed
Scheme 1 Reagents and conditions: i, AgX = Ag2O (1 equiv.), DMSO,
H2O (1 equiv.), 3 h, room temp.; ii, AgX = Ag2CO3 (1 equiv.), dry acetone,
18 h, room temp., N2; iii, AgX = AgF (1.5 equiv.), dry DMSO, 0.5 h, room
temp.
3
from the JH-2,CONH couplings indicating the trans-diaxial
2
relationship of the two nuclei in the 4C1 conformation.
Chem. Commun., 1999, 591–592
591

Table 1 Selected NMR data for 3 and 4 (d/ppm, J/Hz)
provide ready access to novel glycopyranosylidene-spiro-
heterocycles 3 and 4 that can be regarded as analogues of sugar
spiro-hydantoin derivatives with important biological effects
(see references in ref. 2) as well as to compounds of type 5 that
can be useful orthogonally protected synthetic intermediates.
The scope and limitations of the reported transformations are
currently being investigated in our laboratory.
This work was supported by the Hungarian Scientific
Research Fund (Grant: OTKA T 19339) and in part by OMFB
(F-7/96, Hungary) and Le Ministe`re des Affaires Étrange`res
(France).
3a
3b
4a
4b
CH3
CH3
NNH
NNH
C-8
1.48, 1.61
27.55, 26.91
197.0
7.51
112.70
1.49, 1.69
1.61, 1.63
1.59, 1.63
27.63, 26.90 27.40, 26.65 27.49, 26.74
198.7
7.42
112.56
160.27
5.6
a
a
7.42
112.60
7.41
112.46
C-10
3JH-5,C-10
160.10
5.4
160.90
161.21
a
a
H-2 (J2,3
H-4 (J3,4
H-5 (J4,5
)
)
)
4.65 (10.2)
6.08 (9.8)
5.33 (10.2)
4.88 (1.1)
6.00 (3.3)
5.58 (10.8)
4.20 (9.5)
5.40 (9.0)
5.53 (9.8)
4.41 (1.4)
5.25 (3.3)
5.74 (11.0)
a Not measured because of insufficient sample quantity.
Notes and references
† Each new compound gave satisfactory elemental analysis. The NMR
spectra were recorded for CDCl3 solutions with reference to internal TMS
Table 2 Selected NMR data for 5
in the 1H, to the solvent signal in the 13C, and to external NH4Cl in the 15
NMR experiments. MS: EI 70 eV.
N
5a
5b
1H
13C
67.95
14.82
168.76
—
1H
13C
1 L. Somsák, E. Sós, Z. Györgydeák, J.-P. Praly and G. Descotes,
Tetrahedron, 1996, 52, 9121.
–OCH2S–
–SCH3
CONH2
4.78, 4.72
2.11
4.93, 4.84
2.11
67.88
14.91
169.21
—
—
—
¯
2 E. Osz, E. Sós, L. Somsák, L. Szilágyi and Z. Dinya, Tetrahedron, 1997,
53, 5813.
6.71, 5.98
5.23 (9.0)
5.82 (9.0)
5.16 (10.0)
—
6.69, 5.69
5.40 (10.6)
5.82 (3.2)
5.47 (1.4)
—
¯
3 E. Osz, L. Somsák, L. Szilágyi, T. Docsa, B. Tóth and P. Gergely,
H-2 (J2,3
H-4 (J3,4
H-5 (J4,5
)
)
)
manuscript in preparation.
—
—
4 L. Kiss and L. Somsák, Carbohydr. Res., 1996, 291, 43.
5 For a general survey on Koenigs–Knorr reactions, see: O. Lockhoff, in
Methoden der Organischen Chemie (Houben-Weyl), ed. H. Hagemann
and D. Klamann, Thieme, Stuttgart, 1992, vol. E14a/3, p. 782.
6 These compounds have already been isolated as syrupy by-products of
the reactions of 1a,b with cyanate or thiocyanate ions in nitromethane
(ref. 2, 3).
7 P. Z. Allen, Methods Carbohydr. Chem., 1962, 1, 372.
8 O. De Lucchi, U. Miotti and G. Modena, Org. React., 1991, 40, 157; D.
Martin and G. Hauthal, Dimethylsulfoxid, Akademie-Verlag, Berlin,
1971, p. 302.
9 For Ritter-like reactions at the anomeric centre of monosaccharide
derivatives, see as leading references: A. A. Pavia, S. N. Ung-Chhun and
J.-L. Durand, J. Org. Chem., 1981, 46, 3158; D. Noort, G. A. van der
Marel, G. J. Mulder and J. H. van Boom, Synlett, 1992, 224.
10 Our observations on the reactions of 1b with nitriles have recently been
presented: V. Gyóllai and L. Somsák, 12th International Conference on
Organic Synthesis, Venezia, Italy, June 28–July 2, 1998, OC-04, p.
25.
3JH-2,CONH
4.6
4.9
2
bine with a nucleophilic molecule present in the reaction
mixture, i.e. water, acetone or DMSO. While deprotonation of
the species obtained after combination of the glycosylium ion
with a water molecule leads to the stable molecule 2, the
alkoxydimethylsulfonium intermediate (from combination with
DMSO) may be deprotonated at one of the methyl groups to
give 5 after a Pummerer-type rearrangement.8 The intermediate
(from combination with acetone) may be stabilized by an attack
of the oxygen of the CONH2 group at the positively charged
carbon. The cyclic structure formed in this step can be
deprotonated at the iminium moiety to result in the spirocyclic
compounds 3 and 4.
To the best of our knowledge similar solvent participation
and incorporation is only known with some nitriles (mainly
acetonitrile) in the sugar series.9,10 These new, simple reactions
Communication 9/00082H
592
Chem. Commun., 1999, 591–592