Michael addition of thiols to sugar enones. Synthesis of 3-deoxy-4-thiohexopyranosid-2-uloses as key precursors of 3-deoxy- and C-2 branched-chain 4-thiosugars

Article abstract of DOI:10.1071/CH01200

Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) were readily prepared by the tin(IV) chloride-promoted glycosylation of glycal (1). The enone system of (2) and (3) underwent a highly diastereoselective Michae

Full text of DOI:10.1071/CH01200

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Aust. J. Chem. 2002, 55, 155–160
Michael Addition of Thiols to Sugar Enones. Synthesis of
3-Deoxy-4-thiohexopyranosid-2-uloses as Key Precursors of
3-Deoxy- and C-2 Branched-Chain 4-Thiosugars
María Laura UhrigA and Oscar VarelaA,B
A CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires. Pabellón II, Ciudad Universitaria, 1428, Buenos Aires, Argentina.
B Author to whom correspondence should be addressed (e-mail: varela@qo.fcen.uba.ar).
Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α-D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) were readily
prepared by the tin(IV) chloride-promoted glycosylation of glycal (1). The enone system of (2) and (3) underwent
a highly diastereoselective Michael addition of thiols (ethanethiol, propane-2-thiol, and benzenemethanethiol) to
afford the sulfur-containing hexopyranosid-2-ulose derivatives (4a–c) and (5a–c) in good yields. Sodium
borohydride reduction of the carbonyl functionalities of (4b,c) and (5b) led to the corresponding
3-deoxy-4-thiohexopyranosides having the D-xylo (6b), (6c), and (8b) or the D-lyxo (7b), (7c), and (8c)
configuration. Standard acetylation of these compounds gave the corresponding per-O-acetyl derivatives (10b),
(10c), and (12b) and (11b), (11c), and (13b), useful for confirming all the previous configurational assignments by
1
means of their H and 13C nuclear magnetic resonance spectra. Furthermore the 2-ulose (5b) proved to be a key
intermediate for the synthesis of C-2 branched-chain 4-thiopyranosides, such as (16). The latter was synthesized by
a good yielding ammonium acetate-catalysed Knoevenagel-type condensation of malononitrile with (5b).
Manuscript received: 12 December 2001.
Final version: 22 February 2002.
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Introduction
1-thio-D-allopyranoses to levoglucosenone or by the SN2´
substitution of such a nucleophile to an appropriate
derivative of the enone.[12,13]
In connection with our project on the synthesis of sugar
enones[14,15] and their use as chiral templates for the
synthesis of varied molecules,[16–20] we report here the
conjugated addition of thiols to the 3-en-2-ulose derived
from D-galactose, through its 2-acetoxy glycal derivative (1).
Sugar enones are convenient pyranoid chiral building blocks
for the synthesis of natural products.[1] Their usefulness
arises from the fact that they have a reduced number of
hydroxyl functionalities and stereocenters in comparison to
their parent monosaccharides, and they possess olefinic and
carbonylic unsaturations to which a variety of reactions may
be directly applied.[2] The most popular of the sugar enones,
The
resulting
3-deoxy-4-thiohexapyranosid-2-ulose
levoglucosenone
(1,6-anhydro-3,4-dideoxy-β-D-glycero-
underwent a Knoevenagel-type condensation to afford C-2
branched-chain thiosugars.
hex-3-enopyranos-2-ulose) has been employed as a chiral
precursor of non-carbohydrate natural products.[3,4] Also,
rare sugars have been obtained by highly diastereoselective
Michael additions to levoglucosenone.[5–8] In particular,
conjugated additions of thiols to this enone afforded
4-thiohexopyranos-2-uloses.[6,9,10] Such highly modified
thiosugars have been recently employed as starting materials
for the construction of push–pull derivatives which are
precursors of annellated pyranosides.[10,11] Furthermore,
thiooligosaccharides, the sulfur analogues of naturally
occurring oligosaccharides, have been prepared and used in
glycotherapy and in studies concerning the mechanism of
action of hydrolytic enzymes. The glycosidic linkage was
constructed by the Michael addition of protected
Results and Discussion
2,3,4,6-Tetra-O-acetyl-1,5-anhydro-D-lyxo-hex-1-enitol (1)
was readily prepared by the 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU)-promoted elimination of hydrogen
bromide from the acylated glycosyl bromide derived from
penta-O-acetyl-D-galactose.[15] Glycal (1) reacted highly
diastereoselectively with benzyl alcohol or propan-2-ol in
the presence of tin(IV) chloride to give the α anomers of the
corresponding hex-3-enopyranosid-2-uloses (2) and (3). The
1H nuclear magnetic resosnance (NMR) spectrum of (2) was
similar to that of (3),[14] and they suggested that such enones
© CSIRO 2002
10.1071/CH01200
0004-9425/02/010155

156
M. L. Uhrig and O. Varela
0
adopt a preferred axial, E (D) conformation. Thus, the J4,5
(1.8 Hz) coupling constant indicated the almost
perpendicular disposition of H6 to the plane of the 0E
envelope, and the long-range coupling between H3 and H5
(2.6 Hz) agreed with the relative magnitude predicted by the
Garbisch equation for such an atomic arrangement.[21] The
0E conformation is stabilized by the anomeric effect, which
is probably intensified by the carbonyl group next to the
anomeric center, as 2-alkoxydihydropyran-3-ones showed an
enhanced axial preference for the alkoxy group.[22]
Furthermore, molecular mechanics calculations for sugar
enolones structurally related to (2) and (3), revealed that the
conformer with an axial alkoxy or acyloxy anomeric
coupled protons. For the analogs (4a) and (4c), such a
coupling was observed only as a broadening of the H1 and
H3´ signals. All these data were in agreement with a chair
conformation (4C1) for (4a–c) distorted due to the
2-carbonyl. This conformation is stabilized by the equatorial
disposition of the bulky acetoxymethyl group at C5 and by
the anomeric effect which, as in the enuloses, should be more
intense due to the carbonyl functionality adjacent to the
anomeric center.[22] The same threo configuration and ring
conformation were found for compounds (5a–c), the
thiosugars derived from (3).
The high diastereoselectivity for the 1,4-addition of thiols
to the enone system of (2) and (3) may be explained taking
into account the steric hindrance of the axial anomeric
substituent, which induces the attack to C4 from the opposite
side.
substituent (0E) was favored by 21 kJ mol– over its
1
equatorial (E0) counterpart.[22]
The carbonyl group of the 4-thio-α-D-threo-hexo-
pyranosid-2-uloses (4b,c) and (5b) was reduced with sodium
borohydride in order to obtain the corresponding
4-thioglycosides (Scheme 1). When applied to (4b), this
reaction led to the epimeric mixture (6b)/(7b). Compounds
(4c) and (5b) gave [(6c) and (7c)] and [(8b) and (9b)],
respectively. The epimers exhibited markedly different
polarities by thin-layer chromatography (TLC), and they
could be readily separated by column chromatography. In
each case, the 1H NMR spectrum of the less polar compound
showed a broad singlet for H1, which suggested a
diequatorial disposition of H1 and H2, and hence an
α-D-lyxo configuration for (7b,c) and (9b). However, no
other coupling constants could be measured to confirm this
assignment, as the H2 signal appeared as a broad singlet and
the H3 and H3´ signals were overlapped as a rather narrow
multiplet. Similar difficulties were encountered for the
elucidation of the structure of the more polar isomers. In
their 1H NMR spectra, the H2 signal appeared in a complex
region, and the H3 and H3´ signals were overlapped with the
singlet of the methyl group of the acetate. As before, from
the resonance of H1 only, which gave a doublet having J1,2
≈ 3.7 Hz, an α-D-xylo configuration was proposed for (6b,c)
and (8b). These assignments were confirmed from the NMR
spectra of the acetylated derivatives. Thus, acetylation of
(7b,c) and (9b) under standard conditions afforded the
corresponding 2-O-acetyl derivatives (11b,c) and (13b),
OAc
O
R1S
OAc
O
AcO
AcO
OAc
O
R1SH
Et3N
ROH
SnCl4
OR
OR
OAc
O
O
(4a) R = PhCH2, R1 = Et
(1)
(2) R = PhCH2
(3) R = Me2CH
(4b) R = PhCH2, R1 = Me2CH
(4c) R = PhCH2, R1 = PhCH2
(5a) R = Me2CH, R1 = Et
(5b) R = Me2CH, R1 = Me2CH
(5c) R = Me2CH, R1 = PhCH2
OAc
R1S
R1S
OAc
R2
O
R2
(4b)
(4c)
(5b)
Ac2O
O
NaBH4
MeOH
R3
R3
C5H5N
OR
OR
R
R1
R2 R3
R
R1
R2 R3
(10b) PhCH2, Me2CH, H, OAc
(11b) PhCH2, Me2CH, OAc, H
(10c) PhCH2, PhCH2, H, OAc
(11c) PhCH2, PhCH2, OAc, H
(12b) Me2CH, Me2CH, H, OAc
(13b) Me2CH, Me2CH, OAc, H
(6b) PhCH2, Me2CH, H, OH
(7b) PhCH2, Me2CH, OH, H
(6c) PhCH2, PhCH2, H, OH
(7c) PhCH2, PhCH2, OH, H
(8b) Me2CH, Me2CH, H, OH
(9b) Me2CH, Me2CH, OH, H
Scheme 1
The enuloses (2) and (3) underwent Michael addition of
thiols to afford sulfur-containing carbohydrate derivatives,
which were readily isolated in high yields (Scheme 1). Thus,
the triethylamine-catalysed addition of thiols (ethanethiol,
propane-2-thiol, and benzenemethanethiol) to (2) con-
sistently produced the respective 4-thiohexopyrano-
sid-2-ulose derivatives (4a–c). The configuration of the
1
respectively. Their H NMR spectra showed small coupling
constant values between H2 and H3/H3´, consistent with an
equatorial disposition of H2 and H4, with the C–H2 and
C–H4 bonds bisecting the angle formed by H3–C–H3´.
Therefore, an α-D-lyxo configuration was established. In
contrast, the J values for compounds (10b,c) and (12b)
indicated that the C–H2 bond lies out of such an angle (J2,3
≈ 12 Hz), and the acetoxy group at C2 is equatorially
orientated, in agreement with an α-D-xylo configuration
(Scheme 1).
The configurational assignments were also confirmed by
means of the 13C NMR spectra of the ulosides and their
reduction products. Compounds (4a–c) and (5a–c) showed
similar chemical shifts for the resonances of C3 and C4, as
the former is deshielded by the effect of the vicinal carbonyl
1
stereocenter at C4 was readily deduced from the H NMR
spectra of (4a–c). For all the compounds the H3 and H3´
signals appeared as double doublets, each having small
coupling constant values with H4 (J3,4 4.8, J3´,4 ≈ 2.0 Hz).
This fact indicates that the C4–H bond bisects the angle
formed by the methylene protons at C3. Furthermore, the H4
signal was a narrow multiplet, as expected from the small
couplings with H3, H3´, and also with H5. In particular, the
J4,5 could be measured for (4b), and its value (2.2 Hz) was
consistent with an equatorial and axial disposition for H4
and H5, respectively. Interestingly, the 1H NMR spectrum of
(4b) also showed a long-range coupling between H1 and H3´
(J1,3´ 1.1 Hz), indicating a diequatorial orientation for the

Michael Addition of Thiols to Sugar Enones
157
group, and the latter is protected by the sulfur substituent.[23]
However, these signals could be readily differentiated by
means of distortionless enhancement by polarization transfer
(DEPT) experiments.[24] As expected, the reduction of the
carbonyl group produced a strong upfield shifting for the C3
signal in compounds (6b,c), (7b,c), (8b), and (9b) compared
with the same resonances in their respective precursor
enuloses (4b), (4c), and (5b). In agreement with the
spectroscopic pattern displayed by methyl 3-deoxyhexo-
pyranosides having a D-xylo and D-lyxo configuration,[25] the
C1 and C3 resonances of the thiosugar derivatives with a
D-xylo configuration, (6b), (6c), and (8b), were shifted
upfield and downfield, respectively, in comparison to the
same signals of the corresponding D-lyxo analogues, (7b),
(7c), and (9b).
However, under similar conditions, compound (14) gave
only poor yields (ca. 25%) of (15), and a considerable
amount of starting material remained unreactive. Therefore,
the reaction was conducted using other catalysts. From the
varied basic reagents employed for Knoevenagel-type
condensations,[27] we found that ammonium acetate in
ethanol (pH ≈ 7.8) efficiently promoted the conversion of
(14) into (15), which was isolated in ca. 65% yield
1
(Scheme 2). The H NMR spectrum of (15) presented a
nicely separated pattern of signals, even for the two coupled
methylene groups in the molecule, and admitted a first order
analysis. Furthermore, the 13C NMR spectrum of (15),
showed the resonances of the carbons of two CN groups, and
the C2 signal appeared strongly deshielded (ca. 170 ppm),
whereas the signal of the sp2 carbon adjacent to both nitrile
groups was unusually shifted upfield (84.3 ppm), as reported
for similar adducts.[10]
The diastereoselectivity in the reduction of (4b,c) and
(5b) was determined by the average integral of
1
distinguishable signals in the H NMR spectrum of each
The ammonium acetate-promoted condensation of (5b)
with malononitrile was conducted under the reaction
conditions optimized for (14). This way the adduct (16) was
obtained in 72% yield, after purification by flash
chromatography (Scheme 2). The 13C NMR spectrum of
(16), similar to that of (15), also showed the signal of the
strongly deshielded (ca. 170 ppm, C2) and shielded (86.9
ppm, C(CN)2) vinylic carbons, and the signal of the carbon
bonded to sulfur at high fields (44.3 ppm), confirming the
structure of this adduct. It is interesting to note that the
chromatographic purification of (16) should be rapidly
accomplished (flash chromatography) as prolonged contact
of the compound with the silica gel produces the
β-elimination of the thiol to give the diunsaturated derivative
(17) (Scheme 2) as by-product. The structure of (17) was
mixture of epimers. The ratio of D-xylo [(6b,c) and (8b)] to
D-lyxo [(7b,c) and (9b)] isomers was approximately 2:1. The
major products (6b,c) and (8b) resulted from the attack of the
hydride from the face of the molecule opposite to that
hindered by the anomeric substituent. High stereocontrol has
been observed for the hydride-addition to the carbonyl
vicinal to the anomeric centre.[17,26] However, as the
2-ulosides (4b,c) and (5b) also possess an axially oriented
thioalkyl (or thiobenzyl) group at C4 both sides of the
carbonyl plane are hindered, resulting in a lower selectivity.
OAc
O
OAc
O
CH2(CN)2
NH4OAc
H2/Pd
OPri
OPri
OAc
O
O
C
1
established on the basis of its H NMR spectrum, which
NC CN
(15)
(14)
OPri
showed the resonances of the two vinylic protons (H3 and
H4, J4,5 10.1 Hz) and the absence of the signals of the
isopropylthio group. The 13C NMR spectrum of (17) was in
agreement with the proposed structure.
O
(3)
PriS
PriS
OAc
O
OAc
O
CH2(CN)2
NH4OAc
OPri
OPri
O
C
NC CN
(5b)
(16)
Conclusions
OAc
O
In summary, the procedure described here constitutes a direct
route for the synthesis of 3-deoxy-4-thiohexopyrano-
sid-2-uloses, key intermediates for the preparation of
3-deoxy-4-thiosugar derivatives having the D-xylo and
D-lyxo configuration. Such 4-thiouloses are also convenient
precursors of C-2 branched-chain 4-thiosugars.
OPri
C
NC CN
(17)
Scheme 2
Experimental
The carbonyl group of the 4-thiohexopyranosid-2-ulose
glycosides (4a–c) and (5a–c) can react with compounds
having an active methylene group to generate a C–C
bond.[27] This procedure would constitute a ready access to
C-2 branched-chain 4-thiosugars. For optimizing the
conditions of this Knoevenagel-type condensation, the
3,4-dideoxyhexopyranosid-2-ulose (14) was prepared by
catalytic hydrogenation of (3).[17] Malononitrile was selected
as the methylene-active compound and aluminum oxide as
catalyst, as this has been successfully employed for
condensations with derivatives of levoglucosenone.[10]
General
Solvents were reagent grade and in most cases were dried prior to use
according to standard procedures. Melting points (m.p.) were
determined with a Fisher–Johns apparatus and are uncorrected.
Analytical thin-layer chromatography (TLC) was performed on 0.2 mm
silica gel 60 F254 (Merck) aluminum supported plates. Visualization of
the spots was effected by exposure to UV light or charring with a
solution of 5% sulfuric acid, in EtOH containing 0.5% p-anisaldehyde.
Column chromatography was performed with silica gel 60 (230–400
mesh, Merck). Optical rotations were measured with a Perkin–Elmer
343 digital polarimeter at 25°C, for solutions in CHCl3. Nuclear
magnetic resonances (NMR) were recorded on a Bruker AC 200 or on

158
M. L. Uhrig and O. Varela
a Bruker AMX 500 machine, in CDCl3 solutions with tetramethylsilane
as an internal standard. The signals from the 13C NMR spectra were
assigned by DEPT experiments. Fast atom bombardment (FAB) mass
spectrometry was conducted by LANAIS-EMAR (Buenos Aires,
Argentina) using a ZAB-VSEQ mass spectrometer, Cs+ gun accelerated
at 35 eV. Glycerol was employed as matrix and as standard for
calibration.
3.68, 2 × d, J 13.5 Hz, PhCH2S; 3.18, m, H4; 3.10, dd, J3,4 4.8, J3,3´ 14.6
Hz, H3; 2.67, dd, J3´,4 1.6 Hz, H3´; 2.03, s, CH3CO. 13C NMR (50.3
MHz) δ 199.0 (C2); 170.3 (CH3CO); 137.3, 136.4, 128.8, 128.6, 128.5,
128.2, 127.4 (C aromatic); 98.2 (C1); 69.8 (PhCH2O); 69.0 (C5); 64.4
(C6); 44.4 (C4); 42.3 (C3); 34.9 (PhCH2S); 20.7 (CH3CO).
2-Propyl
6-O-acetyl–3-deoxy-4-S-ethyl-4-thio-α-D-threo-hexo-
pyranosid-2-ulose (5a). Yield 72%; [α]D +79.0 (c, 1.0) (Found: C,
54.0; H, 7.9; S, 11.1%. C13H22O5S requires C, 53.8; H, 7.7; S, 11.0%).
1H NMR (200 MHz) δ 4.72, m, H1, H5; 4.33, dd, J5,6 5.1, J6,6´ 11,7 Hz,
H6; 4.26, dd J5,6´ 7.3 Hz, H6´; 4.00, septet, J 6.2 Hz, Me2CHO; 3.34,
m, J4,5 1.8 Hz, H4; 3.15, dd J3,4 4.9, J3,3´ 15.0 Hz, H3; 2.67, dd, J3´,4 2.0
Hz, H3´; 2.54, m, CH3CH2S; 2.05, s, CH3CO; 1.26, 1.16, 2 d, J 6.2 Hz,
(CH3)2CHO; 1.22, t, J 7.3 Hz, CH3CH2S. 13C NMR (50.3 MHz) δ
199.5 (C2); 170.5 (CH3CO); 97.9 (C1); 71.6 (Me2CHO); 68.8 (C5);
64.8 (C6); 45.6 (C4); 42.8 (C3); 25.0 (CH3CH2S); 23.2, 21.7
((CH3)2CHO); 20.7 (CH3CO); 14.6 (CH3CH2S).
Benzyl 6-O-Acetyl-3,4-dideoxy-α-D-glycero-hex-3-
enopyranosid-2-ulose (2)
A solution of glycal (1)[14,15] (2.00 g, 6.0 mmol) and benzyl alcohol
(1.25 mL, 12.1 mmol) in dry CH2Cl2 (100 mL) was cooled to –20°C
(ice-salt bath) and SnCl4 (0.84 mL, 7.2 mmol) was added. The mixture
was stirred at that temperature for 3 h and then was allowed to reach
room temperature. Upon dilution with CH2Cl2 the solution was washed
twice with saturated aqueous NaHCO3, and then with brine. The
organic extract was dried (MgSO4) and concentrated. The residue was
column chromatographed with hexane/EtOAc 10:1, to afford syrupy
(2) (1.26 g, 76% yield). [α]D +34.1 (c, 1.0). (Found: C, 64.9; H, 6.1%.
C15H16O5 requires C, 65.2; H, 5.8%). 1H NMR (200 MHz) (200 MHz)
δ 7.36, br s, 5 × ArH; 6.94, dd, J3,4 10.6, J4,5 1.8 Hz, H4; 6.18, dd, J3,5
2.6 Hz, H3; 5.00, br s, H1; 4.83, 4.73, 2 × d, J 11.1 Hz, PhCH2O; 4.70,
m, H5; 4.35, dd, J5,6 5.4, J6,6´ 11.7 Hz, H6; 4.21, dd, J5,6´ 4.4 Hz, H6´;
2.10, s, CH3CO. 13C NMR (50.3 MHz) δ 188.1 (C2); 170.6 (CH3CO);
147.1 (C4); 136.5, 128.5, 128.1, 128.0 (C aromatic); 126.3 (C3); 97.0
(C1); 71.1 (PhCH2O); 66.9 (C5); 64.5 (C6); 20.7 (CH3CO).
2-Propyl
6-O-Acetyl-3-deoxy-4-S-(2-propyl)-4-thio-α-D-threo-
hexopyranosid-2-ulose (5b). Yield 77%; m.p. 38°C (from hexane).
[α]D +69.6 (c, 1.0) (Found: C, 55.1; H, 8.1; S, 10.6%. C14H24O5S
requires C, 55.2; H, 8.0; S, 10.5%). 1H NMR (200 MHz) δ 4.73, m, H1
and H5; 4.34, dd, J5,6 5.1, J6,6´ 11.5 Hz, H6; 4.26, dd, J5,6´ 6.9 Hz, H6´;
4.00, septet, J 6.2 Hz, Me2CHO; 3.40, m, J4,5 1.8 Hz, H4; 3.17, dd, J3,4
4.7, J3,3´ 14.6 Hz, H3; 2.90, septet, J 6.7 Hz, Me2CHS; 2.65, ddd, J3´,4
2.9, J1,3´ ≈ 1.0 Hz, H3´; 2.07, s, CH3CO; 1.28–1.15, m, (CH3)2CHO and
(CH3)2CHS. 13C NMR (50.3 MHz) δ 199.5 (C2); 170.6 (CH3CO); 98.0
(C1); 71.6 (Me2CHO); 68.9 (C5); 64.9 (C6); 44.7 (C4); 43.6 (C3); 34.4
(Me2CHS); 23.7, 23.5, 23.3, 21.8, 20.8 ((CH3)2CHO, (CH3)2CHS, and
CH3CO).
General Procedure for the Preparation of 6-O-Acetyl-4-S-alkyl- (or
Benzyl-)3-deoxy-4-thio-α-D-threo-hexopyranosid-2-ulose
Glycosides (4a–c) and (5a–c)
2-Propyl 6-O-acetyl-4-S-benzyl-3-deoxy-4-thio-α-D-threo-hexo-
pyranosid-2-ulose (5c). Yield 86%; m.p. 74–75°C (from hexane).
[α]D –16.4 (c, 1.0) (Found: C, 61.5; H, 6.9; S, 9.5%. C18H24O5S
requires C, 61.3; H, 6.9; S, 9.1%). 1H NMR (200 MHz) δ 7.30, br s, 5
× ArH; 4.75, br s, H1; 4.67, m, H5; 4.32, dd, J5,6 7.1, J6,6´ 11.7 Hz, H6;
4.13, dd, J5,6´ 5.1 Hz, H6´; 4.00, septet, J 6.2 Hz, Me2CHO; 3.80, 3.66,
2 × d, J 13.6 Hz, PhCH2S; 3.15, m, J4,5 1.8 Hz, H4; 3.08, dd, J3,4 4.8,
J3,3´ 14.3 Hz, H3; 2.64, br d, J3´4 J1,3´ 1 Hz, H3´; 2.00, s, CH3CO;
1.25, 1.17, 2 × d, J 6.2 Hz, (CH3)2CHO. 13C NMR (50.3 MHz) δ 199.5
(C2); 170.5 (CH3CO); 137.4, 128.9, 127.4 (C aromatic); 98.0 (C1);
71.6 (Me2CHO); 68.7 (C5); 64.6 (C6); 44.6 (C4); 42.2 (C3); 34.9
(PhCH2S); 23.2, 21.8, 20.7 ((CH3)2CHO, CH3CO).
To a solution of the enulose (2) or (3) [14] (1.0 mmol) in CH2Cl2 (2.0
mL), placed in a thick-walled glass tube, were added the thiol (1.5
mmol) and a catalytic amount of triethylamine (ca. 2% of the mass of
(2) or (3)). After bubbling nitrogen through the solution, the glass tube
was sealed and heated in a sand bath to 50°C for 5 h. The reaction
mixture was then concentrated, and the residue was purified by column
chromatography (hexane/EtOAc, 11:1) to afford the Michael-addition
products (4a–c) and (5a–c). In many cases unreacted (2) or (3) were
recovered from the column.
Benzyl
6-O-acetyl-3-deoxy-4-S-ethyl-4-thio-α-D-threo-hexo-
pyranosid-2-ulose (4a). Yield: 70%; m.p. 77–78°C (from hexane).
[α]D +88.4 (c, 0.9) (Found: C, 60.6; H, 6.9; S, 9.0%. C17H22O5S
requires, C, 60.3; H, 6.6; S, 9.5%). 1H NMR (200 MHz) δ 7.37, br s, 5
× ArH; 4.82, 4.35, 2 × d, J 11.3 Hz, PhCH2O; 4.76, br s, H1; 4.73, m,
H5; 4.35, d, J 6.2 Hz, H6 and H6´; 3.40, m, H4; 3.20, dd, J3,4 4.8, J3,3´
15.0 Hz, H3; 2.74, dd J3´,4 1.8 Hz, H3´; 2.57, m, CH3CH2S; 2.12, s,
CH3CO; 1.24, t, J 7.3 Hz, CH3CH2S. 13C NMR (50.3 MHz) δ 199.1
(C2); 170.4 (CH3CO); 136.4, 128.5, 128.2 (C aromatic); 98.2 (C1);
69.8 (PhCH2O); 69.1 (C5); 64.8 (C6); 45.4 (C4); 42.9 (C3); 25.0
(CH3CH2S); 20.8 (CH3CO); 14.7 (CH3CH2S).
General Procedure for the Reduction of the Hexopyranosid-2-uloses
(4b,c) and (5b)
Synthesis of 6-O-Acetyl-4-S-alkyl- (or Benzyl-)3-deoxy-4-thio-
α-D-xylo-Hexopyranosides (6b,c) and (8b), and their α-D-lyxo
Analogues (7b,c) and (9b)
To a solution of the hexopyranosid-2-uloses (4b,c) or (5b) (1 mmol) in
dry methanol (8 mL) was added sodium borohydride (1.0 mmol). The
mixture was stirred at room temperature for 30–40 min, until TLC
(hexane/EtOAc, 2:1) showed complete consumption of the starting
material. The solution was neutralized by addition of Dowex 50W (H+
form) resin; then was filtered and concentrated. The residue was
dissolved in methanol and concentrated in order to remove boric acid.
The procedure was repeated four times and the resulting syrup was
purified by column chromatography with mixtures of increasing
polarity of hexane/EtOAc (from 10:1 to 8:1). Thus, the following
products were obtained (RF values in hexane/EtOAc, 2:1 are reported).
Benzyl 6-O-acetyl-3-deoxy-4-S-(2-propyl)-4-thio-α-D-threo-hexo-
pyranosid-2-ulose (4b). Yield: 64%; [α]D +80.8 (c, 1.0) (Found: C,
61.6; H, 6.9; S, 8.7%. C18H24O5S requires C, 61.3; H, 6.9; S, 9.1%). 1H
NMR (200 MHz) δ 7.36, br s, 5 × ArH; 4.82, 4.60, 2 × d, J 11.3 Hz,
PhCH2O; 4.76, br s, H1; 4.73, m, H5; 4.33, d, J 6.3 Hz, H6 and H6´;
3.43, ddd, J3,4 4.8, J3´,4 2.5, J4,5 2.2 Hz, H4; 3.21, dd, J3,3´ 15.0 Hz, H3;
2.92, septet, J 6.6 Hz, Me2CHS; 2.71, ddd, J1,3´ 1.1 Hz, H3´; 2.12, s,
CH3CO; 1.27, d, J 6.3 Hz, (CH3)2CHS. 13C NMR (50.3 MHz) δ 199.1
(C2); 170.5 (CH3CO); 136.4, 128.5, 128.2 (C aromatic); 98.2 (C1);
69.8 (PhCH2O); 69.2 (C5); 64.8 (C6); 44.4 (C4); 43.6 (C3); 34.4
(Me2CHS); 23.7, 23.5 ((CH3)2CHS); 20.9 (CH3CO).
Benzyl 6-O-Acetyl-3-deoxy-4-S-(2-propyl)-4-thio-α-D-xylo- and
α-D-lyxo-Hexopyranoside (6b) and (7b), Respectively
Compound (6b) (RF 0.38) was isolated in 42% yield; m.p. 100°C (from
hexane). [α]D +84.0 (c, 0.4) (Found: C, 61.4; H, 7.5; S, 9.1%.
Benzyl
6-O-acetyl-4-S-benzyl-3-deoxy-4-thio-α-D-threo-hexo-
1
pyranosid-2-ulose (4c). Yield 88%; m.p. 67–68°C (from hexane).
[α]D –5.5 (c, 1.0) (Found: C, 66.2; H, 6.2; S, 7.8%. C22H24O5S requires
C, 66.0; H, 6.0; S, 8.0%). 1H NMR (200 MHz) δ 7.36, 7.28, 2 × br s, 10
ArH; 4.80, 4.61, 2 × d, J 11.3 Hz, PhCH2O; 4.77, br s, H1; 4.68, m, H5;
4.29, dd, J5,6 6.9, J6,6´ 11.3 Hz, H6; 4.16, dd, J5,6´ 5.5 Hz, H6´; 3.81,
C18H26O5S requires C, 61.0; H, 7.4; S, 9.0%). H NMR (200 MHz) δ
7.38, br s, 5 × ArH; 4.94, d, J1,2 3.7 Hz, H1; 4.79, 4.52, 2 × d, J 11.3 Hz,
PhCH2O; 4.33–4.06, m, H2, H5, H6, and H6´; 3.04, br s, H4; 2.91,
septet, J 6.6 Hz, Me2CHS; 2.14, m, H3 and H3´, CH3CO; 1.28, 1.26,
2 × d, J 6.6 Hz, (CH3)2CHS. 13C NMR (50.3 MHz) δ 170.6 (CH3CO);

Michael Addition of Thiols to Sugar Enones
159
137.0, 128.5, 128.1, 128.0 (C aromatic); 97.2 (C1); 69.3 (PhCH2O);
68.4 (C5); 65.5 (C6); 64.8 (C2); 42.6 (C4); 35.3 (Me2CHS); 35.0 (C3);
23.6, 23.5 ((CH3)2CHS); 20.8 (CH3CO).
Benzyl 2,6-Di-O-acetyl-3-deoxy-4-S-(2-propyl)-4-thio-α-D-xylo- and
α-D-lyxo-Hexopyranoside (10b) and (11b), Respectively
Compound (10b) gave m.p. 64–65°C (from heptane). [α]D +108.5 (c,
0.79) (Found: [M+1]+ 397 (FAB). C20H28O6S requires: [M+1]+ 397).
1H NMR (200 MHz) δ 7.35, br s, 5 × ArH; 5.24, ddd, J1,2 3.6, J2,3 12.1,
J2,3´ 4.7 Hz, H2; 5.05, d, H1; 4.76, 4.54, 2 × d, J 12.1 Hz, PhCH2O; 4.33,
ddd, J4,5 2.6, J5,6 4.4, J5,6´ 7.5 Hz, H5; 4.25, dd, J6,6´ 11.3 Hz, H6; 4.20,
dd, H6´; 3.09, br s, H4; 2.92, septet, J 6.6 Hz, Me2CH; 2.36, ddd, J3,4
3.7, J3,3´ 12.4 Hz, H3; 2.10, m, H3´; 2.08, 2.03, 2 × s, CH3CO; 1.28,
1.26, 2 × d, J 6.6 Hz, (CH3)2CHS. 13C NMR (50.3 MHz) δ 170.4, 170.0
(CH3CO); 138.0, 128.5, 127.9 (C aromatic); 94.9 (C1); 69.1
(PhCH2O); 68.4, 67.6 (C2 and C5); 65.4 (C6); 42.6, 35.4 (C4 and
Me2CHS); 31.0 (C3); 23.7, 21.1, 20.9 ((CH3)2CS and CH3CO).
Compound (11b) gave m.p. 58–59°C (from hexane). [α]D +120.2
(c, 0.7) (Found: [M+1]+ 397 (FAB). C20H28O6S requires [M+1]+ 397).
1H NMR (200 MHz) δ 7.35, br s, 5 × ArH; 4.83, br s, J1,2 ≈ 1 Hz, H1;
4.75, br dd, J2,3 4.7, J2,3´ 2.9 Hz, H2; 4.74, 4.53, 2 × d, J 11.7 Hz,
PhCH2O; 4.40–4.27, m, H5, H6, and H6´; 2.88, br s, H4; 2.81, septet,
J 6.6 Hz, Me2CHS; 2.44, ddd, J3,4 3.5, J3,3´ 15.3 Hz, H3; 2.24, dt, J3´,4
≈ 2.5 Hz, H3´; 2.11, 2.06, 2 × s, CH3CO; 1.32, 1.22, 2 × d, J 6.6 Hz,
(CH3)2CHS. 13C NMR (50.3 MHz) δ 170.4, 170.3 (CH3CO); 136.8,
128.5, 128.1 (C aromatic); 96.4 (C1); 68.8 (PhCH2O); 68.6, 67.6 (C2
and C5); 65.3 (C6); 38.8, 36.5 (C4 and Me2CHS); 30.6 (C3); 23.8, 23.2,
((CH3)2CS); 21.4, 20.8 (CH3CO).
Compound (7b) (RF 0.51) was obtained in 26% yield; it gave [α]D
+75.0 (c, 1.2) (Found: C, 61.1; H, 7.3; S, 9.3%. C18H26O5S requires C,
61.0; H, 7.4; S, 9.0%). 1H NMR (200 MHz) δ 7.37, br s, 5 × ArH; 4.92,
br s, H1; 4.76, 4.52, 2 × d, J 11.7 Hz, PhCH2O; 4.40, ddd, J4,5 2.4, J5,6
≈ J5,6´ 6.0 Hz, H5; 4.29, bd, H6 and H6´; 3.73, br s, H2; 3.06, septet, J
6.7 Hz, Me2CHS; 3.02, br d, H4; 2.28, m, H3 and H3´; 2.07, s, CH3CO;
1.30, 1.29, 2 × d, J 6.7 Hz, (CH3)2CHS. 13C NMR (50.3 MHz) δ 170.7
(CH3CO); 137.1, 128.5, 128.0, 127.9 (C aromatic); 100.0 (C1); 68.8
(PhCH2O); 68.3, 67.2 (C2, C5); 65.6 (C6); 38.5 (C4); 34.0 (Me2CHS);
29.6 (C3); 23.3, 23.2 ((CH3)2CHS); 20.8 (CH3CO).
Benzyl 6-O-Acetyl-4-S-benzyl-3-deoxy-4-thio-α-D-xylo- and
α-D-lyxo-Hexopyranoside (6c) and (7c), Respectively
Compound (6c) was obtained in 49% yield (RF 0.32); m.p. 80–81°C
(from hexane). [α]D +24.0 (c, 0.9) (Found: C, 65.9; H, 6.7; S, 7.9%
1
C22H26O5S requires C, 65.7; H, 6.5; S, 8.0%). H NMR (200 MHz) δ
7.36, 7.30, 2 × br s, 10 × ArH; 4.92, d, J1,2 3.7 Hz, H1; 4.76, 4.51, 2 ×
d, J 11.3 Hz, PhCH2); 4.24–3.97, m, H2, H5, H6, and H6´; 3.77, 3.69,
2 × d, J 13.9 Hz, PhCH2S; 2.84, br s, H4; 2.08, ddd, J 3.2, 5.5, 13.2 Hz,
H3; 2.01, s, CH3CO; 1.92, m, H3´. 13C NMR (50.3 MHz) δ 170.6
(CH3CO); 137.1, 136,8, 128.8, 128.7, 128.5, 128.1, 128.0, 127.9, 127.4
(C aromatic); 97.3 (C1); 69.3, 68.3, 65.1, 64.7 (C2, C5, C6, and
PhCH2O); 42.7 (C4); 35.9, 33.6 (PhCH2S and C3); 20.8 (CH3CO).
Compound (7c) (RF 0.44, yield 22%) gave m.p. 57°C (from hexane).
[α]D –1.0 (c, 1.0) (Found: C, 65.5; H, 6.5; S, 7.8%. C22H26O5S requires
C, 65.7; H, 6.5; S, 8.0%). 1H NMR (200 MHz) δ 7.34, 7.30, 2 × br s, 10
× ArH; 4.92, br s, H1; 4.73, 4.51, 2 × d, J 11.3 Hz, PhCH2O; 4.38–4.21,
m, H2, H5, and H6; 4.11, dd, J5,6´ 3.7, J6,6´ 10.6 Hz, H6´; 3.88, 3.78, 2
× d, J 13.9 Hz, PhCH2S; 3.70, br s, H2; 2.77, br s, H4; 2.23, m, H3 and
H3´; 2.00, s, CH3CO. 13C NMR (50.3 MHz) d 170.6 (CH3CO); 137.1,
136,8, 128.8, 128.7, 128.5, 128.1, 128.0, 127.9, 127.4 (C aromatic);
99.1 (C1); 68.9 (PhCH2O); 68.0, 67.2 (C2 and C5); 65.2 (C6); 38.4
(C4); 34.5 (PhCH2S); 28.7 (C3); 20.7 (CH3CO).
Benzyl 2,6-Di-O-acetyl-4-S-(benzyl)-3-deoxy-4-thio-α-D-xylo- and
α-D-lyxo-Hexopyranoside (10c) and (11c), Respectively
Compound (10c) gave [α]D +26.6 (c, 0.7). (Found: [M+1]+ 445 (FAB).
1
C24H28O6S requires [M+1]+ 445). H NMR (500 MHz) δ 7.35, 7.31,
2 × br s, 10 × ArH; 5.26, ddd, J1,2 3.7, J2,3 12.0, J2,3´ 4.5 Hz, H2; 5.04,
d, H1; 4.72, 4.51, 2 d, J 11.9 Hz, PhCH2O; 4.24, ddd, J4,5 2.4, J5,6 7.3,
J5,6´ 4.8 Hz, H5; 4.16, dd, J6,6´ 11.4 Hz, H6; 4.04, dd, H6´; 3.77, 3.70, 2
× d, J 13.9 Hz, PhCH2S; 2.91, br s, H4; 2.23, ddd, J3,4 3.7, J3,3´ 12.4 Hz,
H3; 2.05, 2.00, 2 × s, CH3CO and H3´. 13C NMR (50.3 MHz) δ 170.5,
170.2 (CH3CO); 137.8, 137.3, 128.9, 128.5, 128.3, 127.8, 127.2 (C
aromatic); 94.9 (C1); 69.1, 68.1, 67.4 (C2, C5, and PhCH2O); 65.0
(C6); 42.7 (C4); 35.7, 29.4 (C3 and PhCH2S); 20.9, 20.7 (CH3CO).
Compound (11c) gave m.p. 93–94°C (from heptane). [α]D +133.3
(c, 0.3). (Found: [M+1]+ 445 (FAB). C24H28O6S requires [M+1]+ 445).
1H NMR (500 MHz) δ 7.32, m, 10 × ArH; 4.81, br s, J1,2 ≈ 1 Hz, H1;
4.72, 4.51, 2 × d, J 11.6 Hz, PhCH2O; 4.71, m, H2; 4.40, dd, J5,6 7.3,
J6,6´ 11.2 Hz, H6; 4.29, ddd, J4,5 2.5, J5,6´ 4.9, H5; 4.17, dd, H6´; 3.72,
3.67, 2 × d, J 13.5 Hz, PhCH2S; 2.74, m, H4; 2.31, ddd, J2,3 4.8, J3,4 3.7,
J3,3´ 15.1 Hz, H3; 2.14, br dt, J2,3´ 3.3, J3´,4 2.3 Hz, H3´; 2.08, 2.06, 2 ×
s, CH3CO. 13C NMR (50.3 MHz) δ 170.5, 170.2 (CH3CO); 137.9,
137.2, 128.9, 128.6, 128.5, 128.1, 128.0 127.2 (C aromatic); 96.5 (C1);
68.9, 68.5, 67.5 (C2, C5, and PhCH2O); 65.2 (C6); 39.5 (C4); 38.0,
30.0 (C3 and PhCH2S); 21.4, 20.9 (CH3CO).
2-Propyl 6-O-Acetyl-3-deoxy-4-S-(2-propyl)-4-thio-α-D-xylo- and
α-D-lyxo-Hexopyranoside (8b) and (9b), Respectively
Compound (8b) (RF 0.45, yield 55%) gave m.p. 68°C (from heptane).
[α]D +91.8 (c, 0.8) (Found: C, 55.0; H, 8.4; S, 10.1%. C14H26O5S
requires C, 54.9; H, 8.6; S, 10.5%). 1H NMR (200 MHz) δ 4.90, d, J1,2
4.0 Hz, H1; 4.27–4.18, m, H5, H6, and H6´; 4.08–3.88, m, H2,
Me2CHO; 3.00, br s, H4; 2.90, septet, Me2CHS; 2.18–1.93, m, H3 and
H3´; 2.05, s, CH3CO; 1.30–1.17, m, (CH3)2CHO and (CH3)2CHS. 13
C
NMR (50.3 MHz) δ 170.7 (CH3CO); 96.9 (C1); 70.7, 68.3, 64.5 (C2,
C5, and Me2CHO); 65.6 (C6); 42.7 (C4); 35.4 (Me2CHS); 35.1 (C3);
23.8, 23.7, 23.3, 22.0, 20.8 ((CH3)2CHO, (CH3)2CHS, and CH3CO).
Compound (9b) (RF 0.51, yield 27%) gave m.p. 41–42°C (on
standing in the refrigerator). [α]D +71.1 (c, 0.9). (Found: C, 55.0; H,
8.8; S, 10.3%. C14H26O5S requires C, 54.9; H, 8.6; S, 10.5%). 1H NMR
(200 MHz) δ 4.89, br s, H1; 4.38, ddd, J4,5 2.3, J5,6 4.8, J5,6´ 7.2 Hz, H5;
4.26, br d, H6 and H6´; 3.96, septet, J 6.1 Hz, Me2CHO; 3.60, br s, H2;
3.06, septet, J 6.7 Hz, Me2CHS; 3.00, br s, H4; 2.21, m, H3 and H3´;
2.06, s, CH3CO; 1.30, 1.28, 2 × d, J 6.7 Hz, (CH3)2CHS; 1.21, 1.16, 2
× d, J 6.1 Hz, (CH3)2CHO. 13C NMR (50.3 MHz) δ 170.7 (CH3CO);
99.2 (C1); 69.3, 68.3, 68.0 (C2, C5, and Me2CHO); 65.6 (C6); 38.9
(C4); 34.2 (Me2CHS); 29.9 (C3); 23.3, 23.2, 21.6, 20.8, ((CH3)2CHO,
(CH3)2CHS, and CH3CO).
2-Propyl 2,6-Di-O-acetyl-3-deoxy-4-S-(2-propyl)-4-thio-α-D-xylo-
and α-D-lyxo-Hexopyranoside: (12b) and (13b), Respectively
Compound (12b) gave [α]D +92.3 (c, 0.8) (Found: [M+1]+ 349 (FAB).
C16H28O6S requires [M+1]+ 349). 1H NMR (500 MHz) δ 5.16, ddd, J1,2
3.6, J2,3 12.1, J2,3´ 4.6 Hz, H2; 5.08, d, H1; 4.33, ddd, J4,5 2.5, J5,6 4.5,
J5,6´ 7.5 Hz, H5; 4.25, dd, J6,6´ 11.4 Hz, H6; 4.18, dd, H6´; 3.89, septet,
J 6.1 Hz, Me2CHO; 3.07, br s, H4; 2.92, septet, J 6.7 Hz, Me2CHS;
2.31, ddd, J3,4 3.7, J3,3´ 12.4 Hz, H3; 2.05, br s, CH3CO and H3´; 1.29,
1.26, 2 × d, J 6.7 Hz (CH3)2CHS; 1.24, 1.13, 2 × d, J 6.1 Hz
(CH3)2CHO. 13C NMR (50.3 MHz) δ 170.2 (CH3CO); 94.4 (C1); 70.4,
68.0, 67.7 (C2, C5, and Me2CHO); 65.5 C6, 42.7 (C4); 35.3
(Me2CHS); 31.0 (C3); 23.6, 23.1, 21.7, 20.9, 20.7 ((CH3)2CHO,
(CH3)2CHS, and CH3CO).
Acetylation of (6b,c), (7b,c), (8b), and (9b)
The glycosides (20 mg, 0.05–0.07 mmol) were acetylated with acetic
anhydride (1 mL) in pyridine (1 mL) at room temperature for 16 h. The
residue obtained upon concentration at reduced pressure was purified
through a short column of silica gel (hexane/EtOAc, 12:1) to afford the
corresponding 2-acetyl derivatives (10b,c), (11b,c), (12b), and (13b) in
almost quantitative yields. These products showed the following
properties.
Compound (13b) gave m.p. 70°C (from heptane). [α]D +117.5 (c
0.85) (Found: [M+1]+ 349 (FAB). C16H28O6S requires [M+1]+ 349).
1H NMR (200 MHz) δ 4.83, br s, J1,2 ≈ 1Hz, H1; 4.65, dd, J2,3 5.1, J2,3´
3.3 Hz, H2; 4.37–4.26, m, H5, H6, and H6´; 3.95, septet, J 6.2 Hz,
Me2CHO; 2.87, m, H4; 2.81, septet, J 6.6 Hz, Me2CHS; 2.41, ddd, J3,4
3.7, J3,3´ 15.0 Hz, H3; 2.20, dt, J3´,4 2.3 Hz, H3´; 2.12, 2.06, 2 × s,
CH3CO; 1.26, 1.21, 2 × d, J 6.6 Hz, (CH3)2CHS; 1.22, 1.15, 2 × d, J 6.2

160
M. L. Uhrig and O. Varela
Hz, (CH3)2CHO. 13C NMR. (50.3 MHz) δ 170.7, 170.4 (CH3CO); 95.7
(C1); 69.7, 68.4, 68.3 (C2, C5, and Me2CHO); 65.2 (C6); 39.0, 36.5
(C4 and Me2CHS); 30.6 (C3); 23.8, 23.2, 23.1 ((CH3)2CH); 21.5, 20.8
(CH3CO).
109.8 (CN); 93.2 (C1); 72.3, 67.1 (C5 and Me2HCO); 64.3 (C6); 23.2,
21.5 ((CH3)2HCO); 20.8 (CH3CO).
Acknowledgments
2-Propyl 6-O-Acetyl-2-(dicyanomethylene)-2,3,4-trideoxy-α-D-
threo-hexopyranoside (15)
Financial support from the University of Buenos Aires
(Project X108) is gratefully acknowledged. We thank Lic.
Marta Marcote (UMYMFOR-CONICET-University of
Buenos Aires) for the elemental analyses.
To a solution of compound (14)17 (65 mg, 0.28 mmol) in dry
tetrahydrofuran (THF, 1 mL) was added malononitrile (28 mg, 0.42
mmol) and alumina (Merck, Type II-III, 100 mg). The mixture was
stirred at room temperature for 16 h, filtered and the residue washed
with THF. Concentration of the solution and washing liquids gave a
syrup, which was chromatographed (hexane/EtOAc, 12:1) to afford
compound (15) (19 mg, 25% yield), which crystallized upon standing;
m.p. 58°C. [α]D +143.7 (c, 0.9) (Found: C, 60.2; H, 6.7%. C14H18N2O4
requires C, 60.4; H, 6.5%). 1H NMR (200 MHz) δ 5.62, br s, H1; 4.34,
ddt, J4,5 2.6, J5,6 4.7, J4´,5 11.9 Hz, H5; 4.11, d, H6 and H6´; 4.07, septet,
J 6.2 Hz, Me2HCO; 3.00, ddd, J3,4 2.9, J3,4´ 5.1, J3,3´ 15.3 Hz, H3 (eq);
2.86, ddd, J3´,4 5.5, J3´,4´ 12.4 Hz, H3´ (ax); 2.09, s, CH3CO; 1.97, dddd,
J4,4´ 13.1 Hz, H4 (eq); 1.72, dddd, J4´,5 11.9 Hz, H4´ (ax); 1.28, 1.24, 2
× d, J 6.2 Hz, (CH3)2CO. 13C NMR (50.3 MHz) δ 173.4, 170.6 (C2 and
CH3CO); 110.6, 109.9 (CN); 93.8 (C1); 84.3 (C(CN)2); 71.5, 66.5 (C5
and Me2CHO); 65.3 (C6); 28.2, 27.6 (C3 and C4); 23.1, 21.6
((CH3)2CHO); 20.6 (CH3CO).
References
[1] F.W. Lichtenthaler, Natural Product Chemistry (Ed.
Atta-ur-Rahman) 1989, p. 227 (Springer: Heidelberg).
[2] B. Becker, J. Carbohydr. Chem. 2000, 19, 253.
[3] M. Mori, T. Chuman, K. Kato, Carbohydr. Res. 1984, 129, 73.
[4] H. Isobe, N. Fukami, T. Nishikawa, T. Goto, Heterocycles 1987,
25, 521.
[5] Z. J. Witczak, R. Chhabra, J. Chojnacki, Tetrahedron Lett. 1997,
38, 2215.
[6] F. Shafizadeh, R. H. Fourneaux, T. T. Stevenson, Carbohydr. Res.
1979, 71, 169.
[7] F. Shafizadeh, D. D. Ward, D. Pang, Carbohydr. Res. 1982, 102,
217.
Alternatively, compound (15) was prepared according to the
following procedure: Malononitrile (28 mg, 0.42 mmol) and compound
(14) (50 mg, 0.22 mmol) were dissolved in 6 × 10–3M ammonium
acetate in ethanol (0,5 mL). The solution was stirred at room
temperature for 16 h, until TLC showed a main spot (RF 0.42;
hexane/EtOAc, 3:1), faster moving than the starting (14) (RF 0.26). The
solution was concentrated and the residue purified by column
chromatography (hexane/EtOAc, 10:1) to afford (15) (39 mg, 65%),
which showed the same physical and spectroscopic properties reported
above.
[8] R. Blattner, D. M. Page, J. Carbohydr. Chem. 1994, 13, 27.
[9] M. G. Essig, Carbohydr. Res. 1986, 156, 225.
[10] M. Gómez, J. Quincoces, B. Kuhla, K. Peseke, H. Reinke, J.
Carbohydr. Chem. 1999, 18, 57.
[11] M. Gómez, J. Quincoces, K. Peseke, M. Michalik, H. Reinke, J.
Carbohydr. Chem. 1999, 18, 851.
[12] Z. J. Witczak, R. Chhabra, H. Chen, X.-Q. Xie, Carbohydr. Res.
1997, 301, 167.
[13] J. Kroutil, M. Cerný, T. Trnka, M. Budesínsky, Carbohydr. Res.
2001, 334, 153.
[14] G. De Fina, O. Varela, R. M. de Lederkremer, Synthesis, 1988,
891.
[15] O. Varela, G. De Fina, R. M. de Lederkremer, Carbohydr. Res.
1987, 165, 187.
[16] O. Varela, G. De Fina, R. M. de Lederkremer, J. Chem. Res.,
Synop. 1990, 262.
[17] O. Varela, G. De Fina, R. M. de Lederkremer, Carbohydr. Res.
1993, 246, 371.
[18] C. Di Nardo, O. Varela, R. M. de Lederkremer, R. Baggio, D.
Vega, M. T. Garland, Carbohydr. Res. 1995, 269, 99.
[19] P. A. Zunszain, O Varela, Tetrahedron: Asymmetry 1998, 9, 1269.
[20] C. Iriarte Capaccio, O. Varela, Tetrahedron: Asymmetry 2000, 11,
4945.
[21] E. W. Garbisch, J. Am. Chem. Soc. 1964, 86, 5561.
[22] W. G. Dauben, B. A. Kowalczyk, F. W. Lichtenthaler, J. Org.
Chem. 1990, 55, 2391.
2-Propyl 6-O-Acetyl-2-(dicyanomethylene)-2,3-dideoxy-4-S-(2-
propyl)-4-thio-α-D-threo-hexopyranoside (16)
The ammonium acetate-promoted condensation, already described for
(14), was followed. Starting from compound (5b) (74 mg, 0.22 mmol)
and malononitrile (32 mg, 0.48 mmol) the reaction was conducted for
16 h. TLC showed a major product (RF 0.65, chloroform) less polar than
(5b) (RF 0.50). Upon concentration of the reaction mixture, the residue
was purified by flash chromatography with dichloromethane.
Compound (16) (60 mg, 72%) was isolated from the first fractions of
the column. [α]D +103.0 (c, 0.9) (Found: C, 57.6; H, 6.7; S, 8.9%.
C17H24N2O4S requires C, 57.9; H, 6.9; S, 9.1%). 1H NMR (200 MHz)
δ 5.58, br s, H1; 4.58, ddd, J4,5 1.8, J5,6 5.1, J5,6´ 6.9 Hz, H5; 4.27, dd,
J6,6´ 11.7 Hz, H6; 4.20, dd, H6´; 4.07, septet, J 6.2 Hz, Me2HCO; 3.25,
m, H4; 3.19, t, J3,4 ≈ J3´,4 3.6 Hz, H3 and H3´; 2.95, septet, J 6.6 Hz,
Me2HCS; 2.07, s, CH3CO; 1.27, m, (CH3)2HCO and (CH3)2HCS). 13
C
NMR (50.3 MHz) δ 170.6, 170.4 (C2, CH3CO); 110.7, 109.7 (CN);
93.8 (C1); 86.9 (C(CN)2); 71.8, 69.1 (C5 and Me2HCO); 64.7 (C6);
44.3 (C4); 36.6 (C3); 35.2 (Me2HCS); 23.7, 23.4, 23.1, 21.7
((CH3)2HCO and (CH3)2HCS); 20.7 (CH3CO).
[23] E. Breitmaier, W. Voelter Carbon-13 NMR Spectroscopy, 3rd
Edition 1987, pp. 281, 234 and 256 (VCH: Weinheim, Germany).
[24] (a) D. M. Doddrell, D. T. Pegg, M. R. Bendall, J. Magn. Res.
1982, 48, 323; (b) J. Chem. Phys. 1982, 77, 2745.
[25] K. Bock, C. Pederson, Adv. Carbohydr. Chem. Biochem. 1983,
41, 27.
[26] F. W. Lichtenthaler, S. Nishiyama, P. Köhler, H. J. Linder,
Carbohydr. Res. 1985, 136, 13.
[27] F. S. Prout, V. D. Beaucaire, G. P. Dyrkacz, W. M. Koppes, R. E.
Kuznicki, T. A. Marlewski, J. J. Pienkowski, J. M. Puda, J. Org.
Chem. 1973, 38, 1512.
Further fractions from the column afforded 2-propyl
6-O-acetyl-2-(dicyanomethylene)-2,3,4-trideoxy-α-D-glycero-hex-3-e
nopyranoside (17) (10 mg). 1H NMR (200 MHz) δ 6.85, dd, J3,4 10.1,
J4,5 2.4 Hz, H4; 6.70, dd, J3,5 1.7 Hz, H3; 5.76, br s, H1; 4.73, m, H5;
4.37, dd, J5,6 5.5, J6,6´ 11.7 Hz, H6; 4.24, dd, J5,6´ 4.7 Hz, H6´; 4.13, q,
J 7.3 Hz, Me2HCO; 2.05, s, CH3CO, 1.28, d, J 7.3 Hz, (CH3)2HCO. 13
C
NMR (50.3 MHz) δ 170.6 (CH3CO); 143.4 (C4); 122.4 (C3); 110.7,