Synthesis of 2-deoxyglycopyranosyl thioureas from glycals

Article abstract of DOI:10.1055/s-1999-3632

The reaction of glycals with phenylselenenyl chloride followed by treatment with KNCS lead to 2-deoxy-2-phenylselenoglycopyranosyl isotiocyanates which were further transformed into 2-deoxyglycopyranosyl thioureas.

Full text of DOI:10.1055/s-1999-3632

PAPER
2049
Synthesis of 2-Deoxyglycopyranosyl Thioureas from Glycals
Clara Uriel, Francisco Santoyo-González*
Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
Fax+34(958)243186; E-mail: fsantoyo@goliat.ugr.es
Received 11 June 1999; revised 16 September 1999
We now report the synthesis of 2-deoxy-2-phenylsele-
noglycopyranosyl isothiocyanates and their transforma-
tion into 2-deoxyglycopyranosyl thioureas from glycals.
Tri-O-acetyl-D-glucal (1) and -galactal (2) were chosen as
starting materials. Reaction of 1 with phenylselenenyl
chloride was followed by in situ addition of silica support-
ed KSCN using ether as solvent. The trans addition com-
pounds 3 (a-D-manno) and 4 (b-D-gluco) were isolated in
29 and 33% yield, respectively. However, when 2 was
used only the stereoisomer with a-D-talo configuration 5
was obtained in 40% yield. The assignment of the product
Abstract: The reaction of glycals with phenylselenenyl chloride
followed by treatment with KNCS lead to 2-deoxy-2-phenylseleno-
glycopyranosyl isotiocyanates which were further transformed into
2-deoxyglycopyranosyl thioureas.
Key words: glycals, 2-deoxysugars, thioureas, isothiocyanates,
phenylselenenyl chloride
Sugar isothiocyanates are versatile synthetic intermedi-
ates in carbohydrate chemistry. By exploiting the strong
electrophilic character of the NCS group, a wide variety of
other functional groups can be accessed which, in turn,
may be subjected to other transformations. The synthesis,
chemistry and preparative applications of sugar isothiocy-
anates have been previously reviewed.1,2 Glycals are also
very versatile intermediates, especially in the synthesis of
2-deoxyglycosides, and different reports have exhaustive-
ly covered their synthetic applications.3-8 In particular, the
reactions of glycals with electrophilic sulfur and selenium
reagents have been studied9-17 and the factors controlling
the stereoselectivity course of the reactions elucidated.14
By application of these reactions, the introduction of ni-
trogen in the anomeric position was achieved using phe-
nylselenenyl azide18 or phenylselenenyl chloride followed
by N-glycosidation with bis(trimethylsilyl)uracil19 allow-
ing the synthesis of 2-deoxyglycosyl azides and 2’-de-
oxypyranosyl nucleosides, respectively.
3
stereochemistry was based on vicinal proton JH,H and
geminal heteronuclear 1JC1,H1 coupling constants (see Ta-
ble 2 and 3). Typically, H-1 for the b-gluco product 4 ap-
peared at d = 4.67 as a doublet (J1,2 = 10.0 Hz), with H-2
appearing at d = 3.15 as a triplet (J1,2 ªJ2,3). In the case of
the a-manno (3) and a-talo (5) isothiocyanates H-1 ap-
peared at d = 5.82 and 5.88 as a doublet (J1,2 = 1.7 and 1.3
Hz), respectively, and H-2 appeared at d = 3.98 and 3.60
as a doublet of doublets (J2,3 = 4.4 Hz).
In agreement with these assignations is the observed
1JC1,H1 values that for the a-glycosylpyranosyl isothiocy-
anates 3 and 5 (with an equatorial H-1) are higher (ª177
Hz) that in the case of the b-isothiocyanate 4 (with an ax-
ial H-1) (163.4 Hz). This is in accordance with the known
rule that correlates the values of the heteronuclear cou-
1
pling constant JC1,H1 and the anomeric configuration21
that is of special value in the case of the manno series. A
literature survey regarding the value of this constant for
glycosyl isothiocyanates indicates that this data is only
available in two cases, namely, compounds 12 and 13
having an a-anomeric configuration.22 In order to have
more data, the 1JC1,H1 coupling constant of other glycopy-
ranosyl isothiocyanates were measured. An analysis of the
results obtained (see Scheme 3) corroborate the tendency
of the a-anomers to have higher values (>170 Hz) for this
constant than the b-anomers (<170 Hz).
In this domain we have described20 the application of gly-
cals as glycosyl isothiocyanate precursors and reported a
very convenient route for the simultaneous introduction of
the iodo and isothiocyanate functionalities in a sugar mol-
ecule. Electrophilic addition of iodine(I) thiocyanate, gen-
erated in situ from silica supported KSCN and iodine, to
the double bond leads exclusively to trans-2-deoxy-2-io-
doglycopyranosyl isothiocyanates. The methodology is
relevant for its efficiency, good stereoselectivity and sim-
plicity.
2-Deoxy-2-phenylselenoglycopyranosyl thioureas 6-8
were now prepared in high yield by reaction of com-
Scheme 1
Synthesis 1999, No. 12, 2049–2052 ISSN 0039-7881 © Thieme Stuttgart · New York

2050
C. Uriel, F. Santoyo-González
PAPER
Table 1 Experimental Yields and Physical Data for Compounds 3–
8 and 11
Prod- Yield mp (ºC) [a]D (c,
IR
MS
uct
(%)
CHCl3)a
n (cm-1) m/z
3
29
119–120 +130 (0.9) 2036,
_b
_b
2109,
1741
4
5
6
33
40
96–97
– 37 (0.6) 2037,
1747
syrup
+238 (1.2) 2007,
1749
CI: 429
[M – NCS]+
Scheme 3
100
77–78 + 67 (0.3) 3551,
_b
_b
3414,
1746,
1618,
1233
to high yields by treatment of 6-8 with tributyltin hydride
in the presence of a catalytic amount of AIBN. An alter-
native route starting from 2-deoxy-2-iodoglycopyranosyl
isothiocyanates was previously described for the synthe-
sis of compounds 9 and 10.20
7
8
93
92
+ 14 (0.4) 3418,
3332,
1749,
1619,
1231
Mps were determined with a Reichert hotplate microscope and are
uncorrected. Solutions were dried (Na2SO4) before concentration
under diminished pressure. NMR spectra were obtained with a
Bruker AM-300 spectrometer. Elemental analyses were performed
with a Perkin-Elmer analyzer 240C. MS data (m/z) were obtained
by the chemical ionization mode using methane as the ionizing gas
with a Fisons VG Platform II instrument and molecular weights
were obtained with a Fisons VG Autospec-Q instrument. Specific
optical rotations were measured with a Perkin-Elmer Polarimeter
141. TLC and column chromatography were performed on precoat-
ed silica gel plates (Merck 60 F245) and on Kieselgel 60 (Merck
230−400 mesh), respectively. All the evaporations were carried out
under diminished pressure at 40 ºC.
100
syrup
+ 59 (2)
3320,
3204,
1746,
1244
FAB+:
C19H24N2O7SeS
Calcd for [M +
Na]+ 527.0367.
Found 527.0365
913
80
73
1013
11
100
162–164 – 32 (1)
3427,
3358,
1740,
1714,
1556
_b
3,4,6-Tri-O-acetyl-2-deoxy-2-phenylselenoglycopyranosyl
Isothiocyanates 3-5. General Procedure
a Recorded at 23°C.
A mixture of the corresponding peracetylated glycal 1 or 2 (1 mmol)
and phenylselenyl chloride (2 mmol) in anhyd Et2O (6 mL) was
stirred at r.t. under Ar and light protected. After 45 min KSCN (8
mmol) supported on silica [prepared by rotatory evaporation of an
aqueous solution of KSCN (1.5 mmol) with silica gel (Merck 60) (3
mmol.g−1) followed by drying] was added and the reaction was
stirred for an additional 12 h. Et2O was then removed in vacuo to
b Satisfactory microanalyses obtained: C, ±0.45; H, ±0.31; N, ±0.27;
S, ±0.42. Exception, 7: C +0.51.
pounds 3-5 with an excess of ammonia at 0 ºC. 2-Deoxy-
glycopyranosyl thioureas 9-11 were then accessed in good
Scheme 2
Synthesis 1999, No. 12, 2049–2052 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Deoxyglycopyranosyl Thioureas from Glycals
2051
Table 2 1H NMR Chemical Shifts (d), Multiplicity and Coupling Constants (J, Hz) for Compounds 3–8 and 11
Prod- H-1
uct
H-2
H-3
H-4
H-5
H-6
H-6’
Others
3a
5.82 d
(1.7)
3.98 dd
(4.4, 1.8)
5.34 dd
(9.6, 4.4)
5.43 t
(9.6)
4.11 m
4.21 m
7.56, 7.32 (2 m, C6H5)
2.14 ,2.08, 1.81 (3 s, OCOCH3)
4a
4.67 d
(10.0)
3.15 dd
5.12 dd
4.99 t
3.54 ddd
(10.0, 4.8,
2.2)
4.22 dd
(12.4, 4.8) (12.4, 2.2)
4.06 dd
7.70, 7.40 (2 m, C6H5)
(10.9, 10.2) (11.1, 9.1) (9.5)
5a
6a
5.88 d
(1.3)
3.60 dd
(4.3, 1.6)
5.40 m
4.38 m
4.22 dd
4.15 dd
7.54, 7.33 (2 m, C6H5)
(11.4, 5.9) (11.4, 7.0) 2.22 , 2.13, 2.08 (3 s, OCOCH3)
5.50 br s
6.20 br s
5.50 m
3.91 dd
(4.3, 2.7)
5.23 dd
(8.6, 4.3)
5.33 t
(8.6)
4.08 ddd
4.26 dd 4.17 dd 7.60, 7.32 (2 m, C6H5)
(8.6, 6.3, 2.5) (12.3, 6.3) (12.3, 2.5) 7.04, 6.65 (2 br s, NH, NH2), 2.10 ,
2.07, 1.82 (3 s, OCOCH3)
6b
7a
3.88 m
5.35 dd
(8.7,4.2)
5.21 t
(8.9)
3.88 m
8.86 (d, J = 8.8 Hz, NH) 7.57, 7.30
(2 m, C6H5), 2.02 , 2.01, 1.66 (3 s,
OCOCH3)
3.44 t
(4.4)
5.31 m
5.39 m
5.44 br s
4.96 t
4.30 m
4.41 dd
4.17 dd
7.70 (br s, NH), 7.59, 7.35
(11.4, 8.2) (11.4, 3.8) (2 m, C6H5), 6.49 (br s, NH2), 2.18,
2.15, 2.07 (3 s, OCOCH3)
7
6.05 m
3.59 t
(4.3)
5.20 br s
4.20–4.03 m
3.61 m
8.58 (d, J = 8.1 Hz, NH), 7.58, 7.30
(2 m, C6H5), 6.49 (br s, NH2), 2.08,
1.98 (3 s, OCOCH3)
8a
3.11 br t
(10.5)
5.16 dd
(10.9, 9.0) (9.5)
4.22 dd
(12.5, 5.2) (11.9)
4.06 br d
7.69, 7.38 (2 m, C6H5), 7.13 (br s,
NH), 6.50 (br s, NH2), 2.11 , 2.04,
2.03 (3 s, OCOCH3)
8b
5.28 br s
4.28 dd
3.43 t
(10.5)
4.76 t
(9.6)
5.08 dd
3.71 ddd
(10.9, 9.1) (10.0, 4.6,
2.6)
4.15 dd
3.95 dd
8.19 (d, J = 9.8 Hz, NH), 7.58, 7.30
(12.3, 4.6) (12.3, 3.6) (2 m, C6H5), 7.25 (br s, NH2), 2.11 ,
2.04, 2.03 (3 s, OCOCH3)
11b
3.76 ddd
5.07 ddd
(11.2, 9.6,
5.2)
4.93 t
(9.7)
3.76 ddd
(9.7, 4.6, 2.2)
4.08 m
7.65 (br s, NH), 6.68 (br s, NH),
1.95, 1.90, 1.81 (3 s, OCOCH3)
(11.2, 5.2) (9.7, 4.6,
2.2)
2.40 m
a CDCI3 as solvent
b DMSO-d6 as solvent
give a crude product that was purified by column chromatography
(Et2O-hexane 1:1)
Acknowledgement
We thank Dirección General de Enseñanza Superior for financial
support (PB95-1207), Dr. Sergio Castillón (University of Tarrago-
na, Spain) for comments to the work and Dr. Ali Haidour for the
realisation of the NMR spectra.
N-(3’,4’,6’-Tri-O-acetyl-2’-deoxy-2’-phenylselenoglycopyrano-
syl) Thioureas 6-8. General Procedure
Anhydrous NH3 was bubbled through a solution of the correspond-
ing glycosyl isothiocyanate 3-5 (1 mmol) in anhyd benzene (25 mL)
cooled with an ice-water bath. After 10 min. the mixture was
warmed at r.t. and the solvent removed in vacuo to give a crude
product that was purified by column chromatography (Et2O fol-
lowed by EtOAc).
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Synthesis 1999, No. 12, 2049–2052 ISSN 0039-7881 © Thieme Stuttgart · New York

2052
C. Uriel, F. Santoyo-González
PAPER
Table 3 13C NMR (CDCI3) Data (d and 1JC-1,H-1) for Compounds 3–8 and 10
Product
C-1
C-3,4,5
C-6
C-2
Others
3
85.3
(176.4)
72.1, 70.6,
66.4
61.9
48.4
135.1, 129.6, 128.7 (C6H5), 20.8, 20.7, 20.5 (3 CH3CO)
4
5
85.6
(163.4)
73.2, 71.9,
69.0
61.7
61.6
61.9
61.7
61.9
62.2
48.6
47.3
45.3
44.7
46.2
35.2
142.1 (NCS), 137.1, 129.6, 129.5, 124.2 (C6H5), 20.8, 20.7, 20.6 (3 CH3CO)
134.5, 129.7, 128.6 (C6H5), 20.9, 20.7 (3 CH3CO)
86.8
(177.3)
70.2, 66.6,
65.8
6
82.8
83.6
84.1
80.6
70.5, 70.3,
66.8
184.1 (CS), 134.8, 129.5, 128.5 (C6H5), 20.8, 20.7, 20.3 (3 CH3CO)
184.2 (CS), 134.7, 129.7, 129.2, 128.6 (C6H5), 20.9, 20.8 (3 CH3CO)
184.3 (CS), 137.2, 129.6, 129.5 (C6H5), 20.9, 20.8, 20.7 (3 CH3CO)
183.9 (CS), 21.0, 20.9, 20.7 (3 CH3CO)
7
69.3, 67.4,
66.4
8
73.2, 72.8,
69.5
11
73.6, 70.7,
68.7
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Synthesis 1999, No. 12, 2049–2052 ISSN 0039-7881 © Thieme Stuttgart · New York