Sugar-derived 2-S-substituted-2H-pyran-3(6H)-ones: Synthesis and reactivity

Article abstract of DOI:10.1016/j.carres.2005.05.024

A practical procedure for the preparation of chiral 2-S-substituted-2H- pyran-3(6H)-ones is described. According to the reaction conditions, 1,5-anhydro-2,3,4-tri-O-acetyl-d-threo-pent-1-enitol (1) reacted with thiophenol under Lewis acid catalysis to aff

Full text of DOI:10.1016/j.carres.2005.05.024

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2104–2110
Sugar-derived 2-S-substituted-2H-pyran-3(6H)-ones:
synthesis and reactivity
Christian A. Iriarte Capaccio and Oscar Varela*
CIHIDECAR-CONICET, Departamento de Quı´mica Orga´nica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabello´n II, 1428, Buenos Aires, Argentina
Received 5 February 2005; accepted 30 May 2005
Available online 18 July 2005
Abstract—A practical procedure for the preparation of chiral 2-S-substituted-2H-pyran-3(6H)-ones is described. According to the
reaction conditions, 1,5-anhydro-2,3,4-tri-O-acetyl-D-threo-pent-1-enitol (1) reacted with thiophenol under Lewis acid catalysis to
afford the polysubstitution product 1,5-anhydro-2,3,4-tri-S-phenyl-2,3,4-trithio-D,L-threo-pent-1-enitol (2) or phenyl 2,4-di-O-acet-
yl-3-deoxy-1-thio-a- and b-D-glycero-pent-2-enopyranoside (3 and 4, respectively). The iodine-promoted addition of thiophenol or
a-toluenethiol to 1 gave (2S)-2-phenylthio-2H-pyran-3(6H)-one (5) or its 2-benzylthio analogue 6, but these products showed low
enantiomeric excesses (ee ꢀ40–60%). However, dihydropyranone 5 with high optical purity (ee >94%) was successfully obtained by
treatment of 4 with iodine in acetonitrile. On the other hand, it was established that the benzylthio group of 5 exerts high stereo-
control in reduction and cycloaddition reactions performed on the a,b-unsaturated carbonyl system.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Dihydropyranone; Glycosylations; Iodine; Lewis acids; Thiols
1. Introduction
which took place with high stereocontrol similar to other
addition reactions involving their a,b-unsaturated car-
bonyl system.4,6 They have been also employed as Mi-
chael acceptors of thiols in the synthesis of glycosides
of 3-deoxy-4-thiopyranosid-2-uloses and 3-deoxy-4-thio-
pentopyranosides.7 The presence of a thioglycoside func-
tionality in the last compounds would facilitate the
activation of the anomeric center for the synthesis of
disaccharides of thio sugars.3 Therefore, we report here
the preparation of 2-S-substituted-2H-pyran-3(6H)-ones
as precursors of thioglycosides of 4-thiopentopyrano-
sides. Also, we describe the synthesis of carbocyclic
derivatives by Diels–Alder cycloadditions to these
pyranones, and the stereochemical outcome of the addi-
tion reactions was studied.
Sugar-derived dihydropyranones are useful intermedi-
ates in the synthesis of natural products and biologically
active molecules.1 The usefulness of the dihydropyra-
nones as versatile building blocks relies on the reactivity
of the a,b-unsaturated carbonyl system present in their
molecules, to which a variety of well-known reactions
may be applied. These reactions are usually highly dia-
stereoselective due to the presence of the stereocenters
located in the pyranone ring.1d,e
Furthermore, thioglycosides are known to be inhibi-
tors of glycosylhydrolases,2 and have been employed
as glycosyl donors in oligosaccharide synthesis.3
Recently, we have described practical and large-scale
procedures for the synthesis of 2-alkoxy-2H-pyran-
3(6H)-ones from pentoses.4,5 Such pyranones proved to
be active dienophiles in Diels–Alder cycloadditions,
2. Results and discussion
Treatment of 1,5-anhydro-2,3,4-tri-O-acetyl-D-threo-
pent-1-enitol (2-acetoxy-3,4-di-O-acetyl-D-xylal, 1) with
*
Corresponding author. Tel.: +54 11 4576 3346; fax: +54 11 4576
3352; e-mail: varela@qo.fcen.uba.ar
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.05.024

C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 340 (2005) 2104–2110
2105
PhS
O
SPh
PhS
SnCl4, PhSH
CH2Cl2, -18 °C, 10 min
2 (D,L)
.
Et2O BF3, CH2Cl2,
-18 °C, 40 min
.
SPh
Et2O BF3, PhSH
O
AcO
CH2Cl2, -18 °C, 15 sec
AcO
O
+
O
AcO
or I2, PhSH, PhMe
SPh
SR
AcO
OAc
OAc
AcO
4
3
1
I2, PhSH,
CH3CN
I2, RSH, CH3CN
O
O
5 R = Ph
6 R = CH2Ph
Scheme 1.
thiophenol in the presence of tin(IV) chloride as catalyst,
under the conditions employed for the synthesis of 2-
alkoxy-2H-pyran-3(6H)-ones,4 afforded the 2,3,4-tri-S-
phenyl-2,3,4-trithio-D,L-threo-pent-1-enitol (2) instead
rangement,9 the 2,3-unsaturated derivatives as kinetic
products. At equilibrium, 2-unsubstituted glycals react
with thiols to give 3-thio-substituted glycals as major
products,9,10 whereas 1 leads to 2. It was also deter-
mined that treatment of 4 with Et2OÆBF3 yielded 2, un-
der the same conditions employed in the glycosylation
but in the absence of thiophenol. Together with 2 the
formation of degradation products having Rf = 0 (prob-
ably a polymeric material) was detected by TLC. The
efficiency of the conversion of 2 into 4 was relatively
high (23% or 70% of theoretical), and no other phenyl-
thio substituted derivatives from 1 were isolated. This
result indicated that, under Lewis acid catalysis, the
dihydropyranones could not be obtained because the
intermediate pent-2-enopyranoside rapidly reacts releas-
ing thiophenol, which is captured by an unsaturated
intermediate (probably the enone 5, see later) to afford
2.
of the expected 2-phenylthio dihydropyranone
5
(Scheme 1). The 1H NMR spectrum of the reaction mix-
ture showed, together with 2, the presence of pyranone 5
as a minor byproduct, but the other diastereoisomers of
2 were not detected. Compound 2 was isolated by col-
umn chromatography in 57% yield. The integral of the
1
aromatic signals (15 protons) in the H NMR spectrum
of 2 indicated that this is a product of polysubstitution,
in which all the acetoxy groups of 1 have been replaced
by phenylthio. The small values for J3,4 (<1 Hz), J4,5 and
0
J4,5 were indicative of a trans disposition between H-3
5
and H-4 in the preferred H4 (D) conformation found
for structurally related glycal derivatives.4,8 The fact
that 2 is optically inactive in contrast to its analogue
1, which shows
a
large optical rotation value
As the previous Lewis acid-promoted additions to 1
did not produce the desired dihydropyranone 5, a differ-
ent type of catalyst was tested. Iodine and electrophilic
iodine-releasing agents have been used for the anomeric
activation of glycals,11 and we have found that alkyl 2-
enopyranosides and 2-alkoxy-2H-pyran-3(6H)-ones
were the major products in the N-iodosuccinimide- and
iodine-mediated additions of alcohols to glycals.12 The
iodine-promoted glycosylations of 1 with thiophenol
and x-toluenethiol in acetonitrile (room temperature,
40 min) gave good yields (>63%) of the respective dihy-
dropyranones 5 and 6. To establish the enantiomeric
excess (ee) of these enones, NMR experiments were
conducted using a chiral lanthanide shift reagent
([a]D ꢁ272.3),4 suggests that 2 is a racemic product.
To prevent the formation of 2, the glycosylation of 1
with thiophenol catalyzed by a weaker Lewis acid was
attempted. When the reaction was conducted with
Et2OÆBF3 for a short time (15 s) the pent-2-enopyrano-
sides 3 and 4 were obtained as main products (65%
yield). The longer reaction times led to variable ratios
of 3 and 4, and the formation of increasing amounts
of polysubstituted 2 (the presence of 5 was also detected
in the reaction mixtures). In this case, the behavior of
glycal 1 is similar to that of analogous nonsubstituted
glycals at C-2, which react with alcohols or thiols in
the presence of a Lewis acid to give, via a Ferrier rear-

2106
C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 340 (2005) 2104–2110
SR
SR
AcO
O
O
AcO
O
O
AcO
H
SR
+
AcO
AcO
AcO
OCOMe
RSH
O
1
3 (α)
4 (β)
5
RSH
SR
RSH
RS
PhS
SR
O
O
O
O
SR
SPh
PhS
RS
RS
+OH2
+OH2
SR
RSH
2 (D,L)
(D,L)
Scheme 2.
(ytterbium tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate]).13 Such experiments indicated that 5
and 6 were obtained with rather low and nonreproduc-
ible enantiopurities (ee ranging from 40% to 60%, for dif-
ferent preparations conducted under practically identical
conditions). On the other hand, the large negative value
of their optical rotations ([a]D between ꢁ170 and ꢁ270)
suggested that the enantiomer in excess in 5 and 6 had the
S configuration at the C-2 stereocenter.4 The formation
of the dihydropyranone should involve a second allylic
rearrangement in 3 or 4. This type of rearrangement
was shown to be promoted by the anhydrous hydrogen
iodide generated by oxidation of the thiol by iodine.14
We observed that the solvent had a remarkable influ-
ence on the rate of the rearrangements that led to the
dihydropyranone under iodine-catalyzed conditions.
The reaction conducted in acetonitrile and dichloro-
methane showed by TLC faster disappearance of the
starting glycal than additions performed in carbon tetra-
chloride or toluene. In the last solvent, the second Fer-
rier rearrangement was slow enough to allow the
isolation of the 2-enopyranosides 3 and 4. In acetoni-
trile, even at very short times (10–60 s), were obtained
mixtures of 2-enopyranosides 3 and 4 along with the
dihydropyranone 5. It is noteworthy that the observed
ratios of 3 and 4 were variable, and they do not correlate
with the enantiomeric composition of 5, obtained after
longer reaction times. Moreover, treatment of the b-
pent-2-enopyranoside 4 with iodine in acetonitrile led
to 5, and this product showed a large negative optical
rotation ([a]D ꢁ433.6) and high optical purity in favor
of the S enantiomer (ee >94%). The same reaction when
applied to a mixture of 3 and 4 (2.4:1) led also to 5, hav-
ing a small excess (ee >2%) of the enantiomer with S
configuration. This result suggests that during the rear-
rangement that leads to 5, the equilibrium between the
2-enopyranosides is shifted toward the b isomer 4.
Moreover, the enone 5 converts rapidly into racemic 2
on treatment with thiophenol–Et2OÆBF3.
A general mechanism for the acid-catalyzed thiogly-
cosylation of 1, which accounts for the formation of
the main products under different conditions, is depicted
in Scheme 2. The enopyranosides 3 and 4 are the pri-
mary products formed via a Ferrier rearrangement, un-
der smooth reaction conditions (catalysis with Et2OÆBF3
during short times or with iodine in nonpolar solvents).
Attack of the thiol to the vinylic acetoxy group in 3 or 4
promotes a second allylic rearrangement to the dihydro-
pyranone 5.12 This rearrangement is efficiently catalyzed
by iodine in polar solvents, whereas it occurs slowly in
nonpolar solvents, and 3 and 4 can be isolated. Proba-
bly, the polar solvent is able to stabilize the intermediate
ionic species by solvation, facilitating the reaction. Dur-
ing this rearrangement equilibration between 3 and 4
takes place, 4 being the favored isomer. The enopyrano-
side 4 is expected to be more stable than 3, as it is stabi-
lized by the anomeric effect (as 3) and additionally by
the axially oriented acetoxy group (ꢀallylic effectꢁ). From
the precursor 5, the successive additions of the thiol to
the carbonyl and double bonds of the intermediates
would lead to 2 as the final product. The fact that opti-
cally active 5 afforded racemic 2, under Et2OÆBF3 catal-
ysis, suggests that isomerization of the stereocenter of
the enone takes place during the rearrangements. As
shown in the scheme, the configuration of C-2 in 5
would determine the stereochemical course of the addi-
tions of thiol that leads to 2. Furthermore, as the pro-
posed disubstituted intermediates were not detected in
the reaction mixture, it suggests that these species are
unstable with respect to the trisubstituted 2.
In order to compare the level of stereocontrol exerted
by the benzylthio group of the pyranone with respect to
the benzyloxy group of the respective analogues,4 we
conducted reduction and cycloaddition reactions to the
enone system of 6. Thus, the sodium borohydride reduc-
tion of the carbonyl group of 6 was highly facially selec-
tive to give the alcohol 7, the product formed by attack
of the hydride from the a face15 of the pyranone

C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 340 (2005) 2104–2110
2107
SBn
O
.
NaBH4, CeCl3 7 H2O,
OH
MeOH, 0 °C
7
SBn
O
SBn
1
2
O
3
SBn
O
H
6
8a
8
4a
H
+
O
, Lewis acid
4
H
5
H
O
7
O
6
9
8
Scheme 3.
(Scheme 3). This selectivity was even higher than that
observed for the 2-benzyloxy analogue of 6,4 as 7 was
the only diastereomer detected in the NMR spectra of
the crude reaction mixture.
In summary, we have described a procedure for the
synthesis of 2-S-substituted-2H-pyran-3(6H)-ones start-
ing from the readily accessible 2-acetoxy-3,4-di-O-acet-
yl-D-xylal. Dihydropyranone 5, having high enantio-
meric purity, could be obtained by treatment of the
pent-2-enopyranoside 4 with iodine in acetonitrile. On
the other hand, reduction of the carbonyl system of
dihydropyranone 6, as well as cycloaddition to the dou-
ble bond, was highly diastereoselective due to the stereo-
control exerted by the C-2 stereocenter.
As 2-alkoxydihydropyranones derived from pentoses
have been shown to be reactive dienophiles in Diels–Al-
der cycloadditions to afford synthetically useful carbocy-
clic and polycyclic systems,4,6 cycloadditions to 6 were
conducted. The influence of the benzylthio substituent
on C-2 of this pyranone on the stereochemistry of the
reaction was established and compared with that of
the benzyloxy group in the 2-benzyloxy analogue of 6.
The Diels–Alder cycloaddition of 2,3-dimethylbutadiene
to 6, under Et2OÆBF3 catalysis, was highly diastereo-
facially selective. Cycloadduct 8, the product of addition
of the diene from the a face, was the only isolated prod-
uct. The 1H NMR spectra of the crude reaction mixture
showed only traces of other products, and a diastereo-
meric ratio 8:9 higher than 50:1. On the other hand, the
Diels–Alder reaction under chelating SnCl4 catalysis16,17
showed the formation of 8 and 9 in a 1:1.9 ratio. Again in
this case the selectivity in favor of the a-addition product
was higher than that observed for the 2-benzyloxy ana-
logue.4 These results seem to indicate that the benzylthio
group at C-2, bulkier than the benzyloxy substituent, hin-
ders the b face of the pyranone more efficiently. The
structures of 8 and 9 were established on the basis of their
NMR spectra and confirmed by 2D COSY NMR exper-
iments. They were also in excellent agreement with data
already reported for related systems.4,18 In the 1H
3. Experimental
3.1. General methods
Melting points are uncorrected. Optical rotations were
measured at 25 ꢁC. Column-chromatographic separa-
tions were performed with silica gel 60, 240–400 mesh.
Analytical TLC was conducted on silica gel 60 F254 pre-
coated plates (0.2 mm). Visualization of the spots was
effected by exposure to UV light and charring with a
solution of 5% H2SO4 in EtOH, containing 0.5% p-anis-
aldehyde. Solvents were reagent grade and, in most
cases, were dried and distilled prior to use according
to the standard procedures. The identity of the protons
1
in the H NMR spectra of the products was confirmed
by 2D COSY NMR experiments; and for the assign-
ment of the signals in the 13C NMR spectra, DEPT
experiments were conducted.
0
NMR spectrum of 8, the small J1,8a (2.3 Hz) and J1 ,8a
(1.7 Hz) values indicated that the C–H-8a bond bisects
the dihedral angle of the H-1–C–H-10 group, and the
J4a,8a (5.3 Hz) value was consistent with a gauche axial–
equatorial disposition for H-4a and H-8a. The relatively
3.2. 1,5-Anhydro-2,3,4-tri-S-phenyl-2,3,4-trithio-D,L-
threo-pent-1-enitol (2)
3.2.1. By SnCl4-promoted addition of thiophenol to 1,5-
anhydro-2,3,4-tri-O-acetyl-D-threo-pent-1-enitol (2-acet-
0
large J1,8a (6.3 Hz) and J1 ,8a (4.6 Hz) values in the spec-
trum of 9 suggested an axial disposition for H-8a, and
the J4a,8a (5.9 Hz) value was compatible with an equato-
rial–axial relationship for H-4a and H-8a. These data
showed that the cyclohexene ring is cis-fused to the pyra-
none from the a face in 8 and from the b-face in 9.
oxy-3,4-di-O-acetyl-D-xylal, 1).
A
solution of 14
(122 mg, 0.47 mmol) and thiophenol (100 lL, 0.98
mmol) in anhydrous CH2Cl2 (5 mL) was cooled to
ꢁ18 ꢁC, and SnCl4 (72 lL, 0.61 mmol) was added under
argon. The mixture was stirred for 10 min and then

2108
C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 340 (2005) 2104–2110
diluted with CH2Cl2. This solution was washed with
saturated (satd) aqueous (aq) NaHCO3, dried (MgSO4),
and concentrated. The resulting crude syrupy product
showed (1H NMR) the presence of 2 and the pyranone
5 (ratio 7:1) as main products. The syrup was purified
by flash chromatography (70:1 hexane–EtOAc) to give
oily 2 (111 mg, 57%); [a]D 0.0 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3): d 7.51–6.92 (m, 15H, H-aro-
matic), 7.06 (br s, 1H, H-1), 4.63 (dd, 1H, J4,5 = 2.2 Hz,
From further fractions of the column was isolated
crystalline 4 (136 mg, 42%); mp 62 ꢁC; [a]D ꢁ23.2 (c
1
1.0, CHCl3); H NMR (500 MHz, CDCl3) d 7.51–7.26
(m, 5H, H-aromatic), 5.87 (br d, 1H, J3,4 = 5.8 Hz,
H-3), 5.82 (br s, 1H, H-1), 5.25 (dd, 1H, J4,5 = 2.7 Hz,
0
H-4), 4.43 (dd, 1H, J5,5 = 13.2 Hz, H-5ax), 3.93 (br d,
1H, H-50eq), 2.20, 2.09 (2s, 6H, 2 CH3CO); 13C NMR
(50.3 MHz, CDCl3): d 170.4, 167.8 (CH3CO), 148.9
(C-2), 131.3, 129.0, 127.5 (C-aromatic), 112.5 (C-3),
83.0 (C-1), 64.8 (C-4), 61.6 (C-5), 21.0 (·2) (CH3CO).
Anal. Calcd for C15H16O5S: C, 58.43; H, 5.23; S,
10.40. Found: C, 58.85; H, 5.16; S, 10.27.
0
0
0
J5,5 = 11.5 Hz, H-5), 4.28 (dt, 1H, J3,5 ꢀ J4,5 ꢀ 2.1 Hz,
H-50), 3.61 (m, 1H, H-3), 3.54 (td, 1H, H-4); 13C NMR
(125 MHz, CDCl3): d 152.7 (C-1), 132.4, 131.6, 129.2,
129.1, 128.9, 128.6, 127.5, 127.2, 126.2 (C-aromatic,
C-2), 64.5 (C-5), 49.0, 47.8 (C-3,4). Anal. Calcd for
C23H20OS3: C, 67.61; H, 4.93; S, 23.54. Found: C,
67.97; H, 4.70; S, 23.19.
1
The H NMR spectra of the crude reaction mixture
showed a 1.8:1 ratio for 4:3. Signals of low intensity
due to dihydropyranone 5 were also detected. Longer
reaction times afforded mixtures having variable ratios
of 3 and 4, and increasing amounts of polysubstituted 2.
3.2.2. By Et2OÆBF3-promoted conversion of 4 into 2.
A
solution of 4 (142 mg, 0.46 mmol) in anhydrous CH2Cl2
(5.4 mL) was cooled to ꢁ18 ꢁC, and Et2OÆBF3 (74 lL,
0.59 mmol) was added under argon. The mixture was
stirred for 40 min, when TLC showed no remaining
starting material and the formation of a main com-
pound having the same mobility as 2 and decomposition
products (Rf = 0) were observed. The reaction mixture
was diluted with CH2Cl2, washed with satd aq
NaHCO3, dried (MgSO4) and concentrated. The residue
was subjected to flash chromatography to afford 2
(43 mg, 23%); [a]D 0.0 (c 1.0, CHCl3).
3.3.2. By iodine-promoted addition of thiophenol to 1.
A
solution of 1 (156 mg, 0.60 mmol) and thiophenol (70 lL,
0.69 mmol) in dry toluene (5 mL) was treated in the dark
with iodine (37 mg, 0.15 mmol, added in two equal
portions over a period of 20 min) at room temperature
for 40 min. After the usual workup for iodine reactions,
the residue was subjected to flash chromatography
(30:1 hexane–EtOAc) to afford three products: the dihy-
dropyranone 5 (3 mg, 2%) and the pent-2-enopyrano-
sides a (3, 18 mg, 10%) and b (4, 81 mg, 43%).
Compounds 3 and 4 showed the same physical and spec-
1
troscopic properties as those already described. The H
3.3. Phenyl 2,4-di-O-acetyl-3-deoxy-1-thio-a- and b-D-
glycero-pent-2-enopyranoside (3 and 4, respectively)
NMR of the crude mixture showed a 21:4:1 ratio of 4:3:5.
3.4. (2S)-2-Phenylthio-2H-pyran-3(6H)-one (5)
3.3.1. By Et2OÆBF3-promoted addition of thiophenol to
1. To a solution of 14 (272 mg, 1.05 mmol) and thio-
phenol (107 mL, 1.05 mmol) in anhydrous CH2Cl2
(12 mL), cooled to ꢁ18 ꢁC, was added Et2OÆBF3
(169 lL, 1.35 mmol) under argon. After 15 s of the
addition of the Lewis acid, satd aq NaHCO3 was added
to the cool solution. The mixture was diluted with
CH2Cl2, washed with water, and the organic extract
dried (MgSO4) and concentrated. Flash chromatogra-
phy (30:1 hexane–EtOAc) of the crude product afforded
first compound 3 (75 mg, 23%); [a]D +142.5 (c 1.1,
3.4.1. By iodine-promoted addition of thiophenol to
1. To a solution of 1 (200 mg, 0.77 mmol) and thiophe-
nol (87 lL, 0.85 mmol) in anhydrous acetonitrile (6 mL)
was added iodine (44 mg, 0.17 mmol). The mixture was
stirred in the dark at room temperature for 40 min, and
then diluted with CH2Cl2, washed with a 5:1 (v/v) mix-
ture of satd aq Na2S2O3 and satd aq NaHCO3, dried
(MgSO4) and concentrated. The residue was purified
by flash chromatography (30:1 hexane–EtOAc) to afford
5 (109 mg, 68%). The enantiomeric composition of 5 was
1
1
CHCl3); H NMR (500 MHz, CDCl3): d 7.52–7.25 (m,
determined by H NMR using ytterbium tris[3-(hepta-
5H, H-aromatic), 5.74 (ddd, 1H, J1,3 = 1.1 Hz,
fluoropropylhydroxymethylene)-(+)-camphorate] as a
J3,4 = 3.0 Hz, J3,5 = 0.7 Hz, H-3), 5.70 (dd, 1H,
chiral resolving reagent.4,13 To
a solution of 5
0
J1,4 = 1.8 Hz, H-1), 5.50 (dddd, 1H, J4,5 = 8.0 Hz,
(0.05 mmol) in carbon tetrachloride containing 1% benz-
0
0
J4,5 = 5.9 Hz, H-4), 4.07 (ddd, 1H, J5,5 = 11.4 Hz, H-
5ax), 4.01 (ddd, 1H, H-50eq), 2.19, 2.07 (2s, 6H, 2
CH3CO); 13C NMR (125 MHz, CDCl3): d 170.4,
168.2 (CH3CO), 147.4 (C-2), 134.0, 131.9, 129.0, 127.7
(C-aromatic), 115.4 (C-3), 83.0 (C-1), 65.0 (C-4), 60.9
(C-5), 21.1, 21.0 (CH3CO). Anal. Calcd for
C15H16O5S: C, 58.43; H, 5.23; S, 10.40. Found: C,
58.47; H, 5.31; S, 10.42.
ene-d6 (0.5 mL) was added the ytterbium reagent. Upon
addition of 0.05–0.6 M equiv, the H NMR spectrum
1
showed splitting of the H-2 signal. From the integral
of these signals (3:1 ratio), the enantiomeric composition
(ee >50%) was established for 5. This product had
[a]D ꢁ228.9 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d 7.56–7.30 (m, 5H, H-aromatic), 7.10 (ddd,
0
1H, J4,5 = 10.5 Hz, J5,6 = 1.8 Hz, J5,6 = 4.1 Hz, H-5),

C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 340 (2005) 2104–2110
2109
6.18 (dddd, 1H, J2,4 = 0.4 Hz, J4,6
=
2.7 Hz,
product (Rf = 0.33) and no starting material remaining
(Rf = 0.53). The mixture was diluted with a large excess
of CH2Cl2, washed with satd aq NaCl, dried (NaSO4),
and concentrated. The residue, which showed by 1H
NMR signals of a single product, was purified by flash
chromatography to afford 7 as a syrup (134 mg, 86%,
ee >42%); [a]D ꢁ90.8 (c 1.1, CHCl3); 1H NMR (500
MHz, CDCl3): d 7.35–7.23 (m, 5H, H-aromatic), 5.85,
5.82 (2br d, 2H, J3,4 = 10.7 Hz, H-3,4), 4.81 (d, 1H,
0
J4,6 = 1.6 Hz, H-4), 5.67 (s, 1H, H-2), 4.93 (ddd, 1H,
J6,6 = 19.1 Hz, H-6), 4.34 (ddd, 1H, H-60); 13C NMR
0
(50.3 MHz, CDCl3): d 189.0 (C-3), 148.3 (C-5), 132.8,
132.6, 129.2, 128.1 (C-aromatic), 125.9 (C-4), 88.3 (C-
2), 59.5 (C-6). Anal. Calcd for C11H10O2S: C, 64.05;
H, 4.89; S, 15.55. Found: C, 64.24; H, 4.85; S, 15.82.
Similar yields of 5 were obtained for various prepara-
tions under identical conditions starting from 1. How-
ever, variable enantiomeric excesses (ranging from 40%
to 60%) were obtained for such preparations.
0
J1,2 = 3.4 Hz, H-1), 4.35 (d, 1H, J5,5 = 16.2 Hz, H-5),
4.12 (br d, 1H, H-2), 4.06 (dd, 1H, H-50), 3.90, 3.84
(2d, 2H, J = 13.4 Hz, PhCH2S); 13C NMR (50.3 MHz,
CDCl3): d 137.9, 128.9, 128.4, 128.3 (C-aromatic),
127.1, 126.9 (C-3,4), 84.1 (C-1), 64.4 (C-2), 63.7 (C-5),
34.3 (PhCH2S). Anal. Calcd for C12H14O2S: C, 64.83;
H, 6.35; S, 14.42. Found: C, 65.14; H, 6.31; S, 14.57.
3.4.2. By iodine-promoted conversion of 4 into 5.
A
solution of 4 (148 mg, 0.48 mmol) in acetonitrile
(4 mL) was treated in the dark with iodine (27 mg,
0.11 mmol) at room temperature for 25 min. After the
usual workup for iodine reactions, the residue was sub-
jected to flash chromatography (30:1 hexane–EtOAc) to
afford the dihydropyranone 5 (73 mg, 74%) having
[a]D ꢁ433.6 (c 1.0, CHCl3), which corresponded to an
ee >94% (calculated from the 1H NMR spectra recorded
in the presence of the Yb chiral resolving agent).
1
The H NMR spectra of the crude reaction mixture
showed signals of 8 and no other diastereomers.
3.7. Diels–Alder cycloadditions of 2,3-dimethylbutadiene
to 6: synthesis of (3S,4aR,8aS)-3-benzylthio-6,7-
dimethyl-4a,5,8,8a-tetrahydro-1-H-2-benzopyran-4(3H)-
one (8) and (3S,4aS,8aR)-3-benzylthio-6,7-dimethyl-
4a,5,8,8a-tetrahydro-1-H-2-benzopyran-4(3H)-one (9)
The same reaction applied to a mixture of 3 and 4 (2.4:1
ratio, 100 mg, 0.32 mmol) afforded the enone 5 (48 mg,
72%) having [a]D ꢁ11.4 (c 1.0, CHCl3) and ee >2%.
3.7.1. Et2OÆBF3-promoted cycloaddition. A solution of
3.5. (2S)-2-Benzylthio-2H-pyran-3(6H)-one (6)
6 (129 mg, 0.59 mmol, ee >42%) in dry toluene
(1.2 mL) was cooled to ꢁ18 ꢁC and Et2OÆBF3 (74 lL,
0.50 mmol) was added under argon. The vial was sealed
and the mixture was stirred at ꢁ18 ꢁC for 15 min, then
2,3-dimethylbutadiene (113 lL, 1.00 mmol) dissolved
in anhydrous toluene (0.5 mL) was slowly injected into
the solution. When the addition was finished, the mix-
ture was stirred at ꢁ18 ꢁC for 15 min. The reaction mix-
ture was diluted with ethyl ether, washed with satd aq
NaHCO3, dried (MgSO4), and concentrated. The 1H
NMR spectrum of the crude reaction mixture showed
only traces of other products (a diastereomeric ratio
for 8 >50:1). The mixture was subjected to flash chroma-
tography (60:1 hexane–EtOAc) to afford cycloadduct 8
(132 mg, 75%, ee >42%) as a white amorphous solid;
[a]D ꢁ152.4 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3): d 7.34–7.22 (m, 5H, H-aromatic), 5.07 (s, 1H,
Dihydropyranone 6 was prepared following the proce-
dure described for 5 in the previous item. Thus, reaction
of 1 (200 mg, 0.77 mmol) with x-toluenethiol (100 lL,
0.85 mmol) afforded 6 (108 mg, 63%) as an amorphous
yellowish solid. The ee of 6 was established as indicated
for 5. Compound 6 (ee >42%) had [a]D ꢁ179.7 (c 1.2,
1
CHCl3); H NMR (500 MHz, CDCl3): d 7.36–7.24 (m,
5H, H-aromatic), 7.04 (ddd, 1H, J4,5 = 10.5 Hz,
0
J5,6 = 1.8 Hz, J5,6 = 4.0 Hz, H-5), 6.12 (dddd, 1H,
0
J2,4 = 0.5 Hz, J4,6 = 2.7 Hz, J4,6 = 1.6 Hz, H-4), 5.29
0
(br s, 1H, H-2), 4.72 (ddd, 1H, J6,6 = 18.8 Hz, H-6),
4.24 (ddd, 1H, H-60), 3.92, 3.83 (2d, 2H, J = 13.3 Hz,
PhCH2S); 13C NMR (50.3 MHz, CDCl3): d 190.0 (C-
3), 148.0 (C-5), 137.0, 129.0, 128.6, 127.4 (C-aromatic),
125.8 (C-4), 83.4 (C-2), 59.0 (C-6), 34.8 (PhCH2S). Anal.
Calcd for C12H12O2S: C, 65.43; H, 5.49; S, 14.56.
Found: C, 65.67; H, 5.51; S, 14.43.
0
H-3), 4.53 (dd, 1H, J1,1 = 11.6 Hz, J1,8a = 2.3 Hz, H-
1), 3.90, 3.81 (2d, 2H, J = 13.3 Hz, PhCH2S), 3.59 (dd,
1H, J1 ,8a = 1.7 Hz, H-10), 3.09 (dd, 1H, J4a,5 = 6.5 Hz,
0
0
0
3.6. S-Benzyl 3,4-dideoxy-1-thio-a-L-glycero-pent-3-eno-
pyranoside (7)
J4a,8a = 5.3 Hz, H-4a), 2.53 (d, 1H, J5,5 = 17.6 Hz,
H-5), 2.35 (m, 1H, H-8a), 2.21 (br dd, 1H,
0
J8a,8 = 11.7 Hz, J8,8 = 17.3 Hz, H-8), 1.96 (br d, 1H,
To a solution of 6 (155 mg, 0.70 mmol, ee >42%) in dry
MeOH (14 mL) was added cerium(III) chloride heptahy-
drate (96 mg, 0.26 mmol).16 The solution was stirred for
5 min at room temperature and then cooled to 0 ꢁC.
Sodium borohydride (29 mg, 0.77 mmol) was added
and the stirring was maintained for 15 min, when TLC
(2:1 hexane–EtOAc) showed formation of a more polar
H-50), 1.83 (br dd, 1H, H-80), 1.62, 1.56 (2 br s, 6H, 2
CH3); 13C NMR (125 MHz, CDCl3):
d
203.7
(C-4), 137.1, 129.1, 128.6, 127.4 (C-aromatic), 123.5,
122.9 (C-6,7), 85.9 (C-3), 64.4 (C-1), 44.4 (C-4a), 36.6
(C-8a), 35.3, 31.4, 28.8 (C-5,8, PhCH2S), 19.1, 18.7
(2CH3). Anal. Calcd for C18H22O2S: C, 71.49; H, 7.33;
S, 10.60. Found: C, 71.63; H, 7.27; S, 10.76.

2110
C. A. Iriarte Capaccio, O. Varela / Carbohydrate Research 340 (2005) 2104–2110
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3.7.2. SnCl4-promoted cycloaddition. The same proce-
dure described for the preceding cycloaddition was fol-
lowed using SnCl4 instead of Et2OÆBF3. Thus, starting
from 6 (150 mg, 0.68 mmol, ee >42%), the reaction pro-
moted by SnCl4 (80 lL, 0.68 mmol) afforded a crude
mixture containing mainly 9 and 8 (1.9:1 ratio, accord-
1
ing to the H NMR spectrum). Column chromatogra-
phy gave adducts 8 (54 mg, 26%, ee >42%) and 9
(101 mg, 49%). Compound 9 (ee >42%) had [a]D ꢁ95.8
1
(c 1.0, CHCl3); H NMR (500 MHz, CDCl3): d 7.35–
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7.22 (m, 5H, H-aromatic), 5.06 (s, 1H, H-3), 4.05 (dd,
0
1H, J1,1 = 11.5 Hz, J1,8a = 6.3 Hz, H-1), 3.89, 3.80 (2
0
d, 2H, J = 13.2 Hz, PhCH2S), 3.82 (dd, 1H, J1 ,8a
=
4.6 Hz, H-10), 2.87 (dd, 1H, J4a,5 ꢀ J4a,8a = 5.9 Hz,
0
0
J4a,5 ꢀ 5.7 Hz, H-4a), 2.56 (br d, 1H, J5,5 = 17.4 Hz,
H-5), 2.52 (m, 1H, H-8a), 2.02 (br s, 2H, H-8,80), 1.96
(dd, 1H, H-50), 1.62, 1.58 (2br s, 6H, 2CH3); 13C
NMR (125 MHz, CDCl3): d 205.3 (C-4), 137.2, 129.2,
128.6, 127.3, 123.2, 122.8 (C-aromatic, C-6,7), 85.2
(C-3), 65.7 (C-1), 45.7 (C-4a), 34.9 (C-8a), 34.6
(PhCH2S), 32.6 (C-8), 29.1 (C-5), 19.0, 18.7 (2CH3).
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addition of the reactive to the (2S)-dihydropyranone ring
took place from the opposite (a) or the same side (b)
respect to the substituent at C-2.
Acknowledgements
This work was supported by grants from the University
of Buenos Aires (Project X059) and from the National
Research Council of Repu´blica Argentina (CONICET,
PIP-2000 Nꢁ 2057). O.V. is a Research Member of
CONICET.
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