Systematic study on free radical hydrothiolation of unsaturated monosaccharide derivatives with exo- and endocyclic double bonds

Article abstract of DOI:10.1039/c3ob40547h

Exo- and endocyclic double bonds of glycals and terminal double bonds of enoses were reacted with various thiols by irradiation with UV light in the presence of a cleavable photoinitiator. The photoinduced radical-mediated hydrothiolation reactions showed highly varying overall conversions depending not only on the substitution pattern and electron-density of the double bond but also on the nature and substitution pattern of the thiol partner. Out of the applied thiols thiophenol, producing the highly stabilized thiyl radical, exhibited the lowest reactivity toward each type of alkene. In most cases, the hydrothiolations took place with full regio- and stereoselectivities. Successful addition of 1,2:3,4-di-O-isopropylidene-6-thio-α-d-galactopyranose to a 2,3-unsaturated N-acetylneuraminic acid derivative, providing a (3 → 6)-S-linked pseudodisaccharide, demonstrated that the endocyclic double bond of Neu5Ac-2-ene, bearing an electron-withdrawing substituent, shows sufficient reactivity in the photoinduced thiol-ene coupling reaction.

Full text of DOI:10.1039/c3ob40547h

Organic &
Biomolecular Chemistry
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PAPER
Systematic study on free radical hydrothiolation of
unsaturated monosaccharide derivatives with exo- and
endocyclic double bonds†
Cite this: Org. Biomol. Chem., 2013, 11,
5339
László Lázár,a Magdolna Csávás,b Ádám Hadházi,b Mihály Herczeg,a,c
Marietta Tóth,c László Somsák,c Terézia Barna,d Pál Herczeghb and Anikó Borbás*a,b
Exo- and endocyclic double bonds of glycals and terminal double bonds of enoses were reacted with
various thiols by irradiation with UV light in the presence of a cleavable photoinitiator. The photoinduced
radical-mediated hydrothiolation reactions showed highly varying overall conversions depending not
only on the substitution pattern and electron-density of the double bond but also on the nature and
substitution pattern of the thiol partner. Out of the applied thiols thiophenol, producing the highly
stabilized thiyl radical, exhibited the lowest reactivity toward each type of alkene. In most cases, the
hydrothiolations took place with full regio- and stereoselectivities. Successful addition of 1,2 : 3,4-di-O-iso-
propylidene-6-thio-α-D-galactopyranose to a 2,3-unsaturated N-acetylneuraminic acid derivative, provid-
ing a (3 → 6)-S-linked pseudodisaccharide, demonstrated that the endocyclic double bond of Neu5Ac-2-
ene, bearing an electron-withdrawing substituent, shows sufficient reactivity in the photoinduced thiol–
ene coupling reaction.
Received 19th March 2013,
Accepted 25th June 2013
DOI: 10.1039/c3ob40547h
www.rsc.org/obc
of 1-thioglycoses across the terminal double bonds of alkenyl
tags of dendritic or polymeric scaffolds. Carbohydrates
Introduction
Over the last decade, the photoinduced thiol–ene coupling, equipped with alkenyl auxiliaries have been used also as the
free-radical addition of a thiol to a nonactivated carbon– ene reactants in the thio-click strategy to afford alkyl-tethered
carbon double bond, has been recognised as a robust ligation glycosyl-cysteines10 or glycopeptides,11 β-cyclodextrin-based
tool possessing many of the attributes of click chemistry.1,2 saccharide clusters12 and sucrose-containing polymers.13 Thio-
The great synthetic potential of the reaction has been amply linked mimics of α(2 → 3) and α(2 → 6)-linked sialosides were
demonstrated in the areas of polymer chemistry and material also prepared by photoinduced hydrothiolation of 6-O-allyl or
sciences for network formation,3 dendrimer synthesis,4 and 3-O-allyl substituted galactose derivatives with the 2-thiosialic
polymer functionalization.5
acid.14
The carbohydrate skeleton itself with an exo- or endocyclic
The photoinduced thiol–ene coupling was also applied as a
metal-free click process for S-glycoconjugation producing double bond has scarcely been applied as the ene partner,
glycodendrimers,6 calix[4]arene-based glycoclusters,7 S-linked with only three articles published until now.15–17 Dondoni and
protein glycoconjugates8 as well as thioglucoside-containing co-workers were the first to exploit the thiol–ene reaction for
micellar structures appropriate for controlled drug delivery.9 the synthesis of S-disaccharides by reacting sugar thiols with
In these approaches thioglycosylation occurred by the addition exo- and endoglycals.15,16 They found that hydrothiolation of
the exocyclic double bond of hex-5-enopyranoside and pent-4-
enofuranoside derivatives with 1-thioglycoses afforded S-di-
aResearch Group for Carbohydrates, University of Debrecen, PO Box 94, H-4010
saccharides with high yields and diastereoselectivites of up to
Debrecen, Hungary. Fax: +3652 512914
bDepartment of Pharmaceutical Chemistry, Medical and Health Science Center,
99%.15 Addition of 1-thioglycoses across the endocyclic double
bond of glycals showed regioselectivity but a lack of stereo-
University of Debrecen, PO Box 70, H-4010 Debrecen, Hungary.
selectivity, furnishing the stereoisomeric 1-deoxy-S-disacchar-
ides in about 1 : 1 ratios.16
The incorporation of 2-acetoxy-glycals and 2,3-unsaturated
glycosides within the thiol–ene coupling strategy was reported
for the first time by our group.17 We have shown that reactions
between 2-acetoxy-D-glucal and a range of thiols including
E-mail: borbas.aniko@pharm.unideb.hu; Fax: +3652 512914
cDepartment of Organic Chemistry, University of Debrecen, PO Box 20, H-4010
Debrecen, Hungary
dDepartment of Genetics and Applied Microbiology, University of Debrecen, 4032
Debrecen, Hungary
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob40547h
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amino acid, peptide, and sugar thiols gave 1,2-cis-α-S-gluco-
Hydrothiolation of 2-acetoxy glycal 1 with thiols 2c–2h took
conjugates and S-disaccharides with full regio- and stereoselec- place with full regio- and stereoselectivities affording the
tivities in good to excellent yields. Addition of 1-thioglycoses corresponding α-D-1-thioglycosides, but with various conver-
to a 2,3-unsaturated glycoside (Ferrier glycal) was found sions. Phenylmethanethiol 2c showed low reactivity toward 1
to proceed also with high selectivity offering easy access to affording the hydrothiolation product 3c with 22% yield. Simi-
3-deoxy-S-disaccharides.17
larly, addition of (4-methoxyphenyl)methanethiol 2d across
Regarding the great potential of hydrothiolation of the the double bond of compound 1 proceeded with low conver-
easily available glycals in the synthesis of thioglycosides, sion furnishing 3d only with 10%. The possible explanation
which are especially valuable glycoside mimics, further for the low conversions observed could be the stability of the
exploration and exploitation of the reaction can be foreseen. thiyl radicals generated from 2c and 2d, which favours rather
Here we present a systematic study of the reactivity of the acetyl- the backward than the forward reaction in the reversible thiyl
ated and benzylated derivatives of 2-hydroxy-D-glucal towards a addition step.21
range of thiols in the photoinduced thiol–ene coupling reaction,
Reaction of 2-methylpropane-2-thiol with glycal 1 gave the
in comparison to the reactivity of saccharides bearing an exo- α-thioglucoside 3e with 25% isolated yield. The low conversion
methylene moiety. Free radical hydrothiolation of the endocyc- might be the result of either the stability of the thiyl radical or
lic double bond of sialic acid glycal is also shown.
a steric congestion between the 2-acetoxy moiety and the bulky
tert-butyl group, both anchored to the α-side of the sugar ring
in the intermediate C-2 radical.
The significantly different conversion in the reaction of 1
with 2,3-di-O-acetyl-1-thioglycerol 2f22 compared to that with
Results and discussion
To study the scope of the hydrothiolation reaction of unsatu- acetonide-protected 1-thioglycerol 2g23 highlights that the con-
rated monosaccharides, 2-acetoxy-3,4,6-tri-O-acetyl-D-glucal 118 version of the reactants in the radical-mediated hydrothiola-
was reacted with thiols 2b–h applying the optimized con- tion reaction can be tuned by the substitution pattern of the
ditions established in our recent work for the synthesis of thiol. While thiol 2f possessing electron withdrawing substitu-
3a.17 Thus, the reactions were carried out in toluene at room ents afforded 3f in 67% yield, the acetal-protecting group of 2g
temperature with a 2 : 1 thiol : ene ratio by irradiation at λmax proved to be disadvantageous during addition across the endo-
365 nm for 3 × 15 min in the presence of 2,2-dimethoxy- cyclic double bond of 1 furnishing product 3g with a yield of
2-phenylacetophenone (DPAP) (3 × 0.1 equiv.) as the cleavable only 31%.
photoinitiator1a (Table 1). In the case of ethanethiol and
Recently, Dondoni and co-workers have reported that
2-methylpropane-2-thiol, a higher thiol–ene ratio was applied photoinduced hydrothiolation of the terminal double bond of
because of the volatility of the reagents. When the reaction a galactose derived alkene with peracetylated 1-thioglucose
showed low conversion after 45 min, further portions of thiol afforded the corresponding S-disaccharide in 81% isolated
and initiator were added and the irradiation was continued yield; however, an attempted reaction of 2,3,4,6-tetra-O-benzyl-
(Scheme 1).19
1-thio-β-D-glucopyranose with the same alkene failed, and only
Unexpectedly, thiophenol did not react with compound 1. decomposition occurred.15 These results support our finding
Our attempts to elicit a reaction between 1 and 2b by applying that in the thiol–ene coupling the reactivity of a given thiol is
high excess of thiol, increasing the amount of DPAP, and strongly influenced by the substituents.
prolongation of the irradiation time were unsuccessful.
Finally, the sodium sulfonatoethyl mercaptan 2h (Mesna),
Aromatic thiols are better chain transfer reagents in free- used as a detoxifying adjuvant in cancer chemotherapy, was
radical additions than aliphatic thiols, since in the former reacted with 1. We were pleased to find that compound 2h
case the energy required to break the S–H bond is lowered by added readily across the endocyclic double bond of 1 in MeOH
the resonance stabilization of the thiyl radical formed.20 This and gave 3h in good yield. To the best of our knowledge, this
fact seems to be in contradiction to the observed reactivities of is the first example of using a salt as the thiol partner in the
ethanethiol and thiophenol towards compound 1. We assume photoinduced hydrothiolation reaction.
that the resolution of this contradiction lies in the reversibility
In our earlier experiments, depending on the solubility of
of the reaction. The reactivity of the olefin partner in a thiol– the reactants, toluene, toluene–MeOH or MeOH have been
ene free-radical chain reaction is dependent on the extent of used as the solvents for the thiol–ene couplings. Toluene has
substitution. Terminal alkenes are found to be the most reac- proven to be a good solvent for the apolar thiols; however, low
tive, while internal 1,2-disubstituted alkenes exhibit much efficiency of the reaction has been observed in toluene–MeOH
lower overall reaction rates. The reduced rates and conversions or MeOH with some polar thiols. In those cases, significantly
observed for 1,2-disubstituted enes are a result of the reversi- enhanced yields could be reached by changing the toluene–
bility of the addition of the thiyl radical across the internal MeOH systems to DMF–water.17 Here, we decided to study how
double bond.1,20 In this case the reversible equilibrium in the the solvent affects the reaction when low conversion was
addition step depicted in Scheme 2 is shifted backward by the observed in toluene. Thus, the reaction of 2-acetoxy glycal 1
high stability of the aromatic thiyl radical causing a complete and thiol 2c was carried out in different solvents with a thiol–
lack of reaction between 1 and thiophenol.
ene ratio of 2 : 1, irradiating at λmax 365 nm for 3 × 15 min
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Table 1 Free radical addition of thiols to 2-acetoxy glycal 1
Thiol
Thiol : ene ratio
Product
Yielda (%)
81
15 : 1
50 : 1
4 : 1
22c
10c
4 : 1
15 : 1
25c
2 : 1
2 : 1
67
31c
2 : 1
64d
a Yield of isolated compounds after 3 × 15 min irradiation under Ar, using 3 × 0.1 equiv. of DPAP. b 6 × 15 min irradiation, 6 × 0.1 equiv. of DPAP.
c 4 × 15 min irradiation, unreacted 1 was recovered with 55–60%. d The reaction was carried out in abs. MeOH.
(Table 2). Unfortunately, the conversion of glycal 1 remained attempted to elicit a reaction between glycal 1 and thiophenol
below 25% in all runs, as established by 1H NMR analysis. The by changing the solvent to methanol, dichloromethane or
same yields were obtained for product 3c in toluene, methanol DMF–water, but without any success.
and dichloromethane, while switching to DMF, some drop in
Next, we decided to study the photoinduced hydrothiolation
conversion was observed. Interestingly, a 1 : 1 mixture of DMF reactions of the benzylated 2-hydroxyglycal 4.24 It is known
and water was a better solvent than pure DMF, but was not that the overall reaction rate of the thiol–ene reaction is
superior to toluene, methanol or dichloromethane. We also directly related to the electron density on the ene: for a given
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To our delight, when glycal 4 was reacted with thiophenol,
a fair conversion of 4 was observed after 45 min irradiation
affording the α-glucoside 5b in a yield of 21%. Applying higher
excess of thiol or longer exposure to UV light did not give rise
to a noticeable increase of the conversion. Despite the moder-
ate yield, this reaction clearly demonstrates that the highly
stable thiophenyl radical can be trapped by an internal double
bond of sufficient electron-density and the equilibrium of the
thiyl addition can be forced toward the irreversible hydrogen
abstraction step to give the final addition product.
Reaction of 2-methylpropane-2-thiol with 4 gave α-thio-
glucoside 5e with 40% isolated yield. The good conversion of 4
with 2e revealed that rather the stability of the thiyl radical
than steric hindrance had caused the low reactivity of 2e
towards the acetoxy-glycal 1. Previously, we have found that
reaction between 1 and 1-thioglycerol 2i showed very low con-
version of the glycal when either toluene–MeOH or MeOH was
used as the solvent, furnishing the corresponding α-thiogluco-
side in only 15–17% yield.17 As we expected, thiol 2i reacted
more readily with the more electron-rich double bond of 4 pro-
viding product 5i in 46% yield.
Finally, S-disaccharide 5j was prepared by the reaction
between 4 and the sterically hindered di-O-isopropylidenated
sugar thiol 2j.28 Despite complete conversion of the glycal
observed, the isolated yield of 5j was only 59% because
decomposition also occurred due to lability of the benzyl-pro-
tecting groups under the conditions of the radical addition.29
Thereafter, we studied the photoinduced hydrothiolation
reactions of glycal 6 with ethanethiol and thiophenol under
the optimized conditions (Scheme 3). In this case, addition of
thiophenol across the endocyclic double bond of 6 failed,
revealing again the lack of reactivity of the resonance stabilized
Scheme 1 Sequential thiyl-addition and hydrogen abstraction steps during a
thiol–ene coupling, and the mechanism for the initiation with the cleavable
photoinitiator 2,2-dimethoxy-2-phenylacetophenone (DPAP).
Scheme 2 Reversible addition of the thiyl radical to the endocyclic double
bond of 1.
aromatic thiyl radical towards
a relatively electron-poor
internal double bond. Reaction between glycal 6 and etha-
nethiol showed almost complete conversion after 45 min
affording a mixture of the axially and equatorially linked
2-ethylthio derivatives 7 and 8 and thioglycoside 9 in a ratio of
∼5 : 3 : 1.30,31
Because of the poor selectivity, which was also reported by
Dondoni and co-workers,16,32 and the difficulty of separation
of the diastereoisomers formed, hydrothiolation of glycal 6
was not examined further.
Reactivity of thiophenol towards terminal double bonds of
monosaccharides was studied next by applying compounds
10,33 1234 and 1435 as the ene partners (Table 4). The reactions
were carried out in toluene with a 2 : 1 thiol : ene ratio. Hydro-
Table 2 Reaction of 2-acetoxy glycal 1 with thiol 2c in different solvents
Entry 1 : 2ca ratio DPAP (%) Solvent
Conv.b (%) 3cc (%)
1
2
3
4
5
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
3 × 10
3 × 10
3 × 10
3 × 10
3 × 10
Toluene
MeOH
CH2Cl2
DMF
DMF–H2O
(1 : 1)
22
24
23
16
23
19
19
19
14
18
a Reactions were performed with 0.1 mmol of 1 in 2 mL of solvent.
b Reacted glycal determined using 1H NMR analysis of the crude
mixture. c Isolated yield.
thiol, electron-rich enes react much more rapidly than elec- thiolation of the galactose derived alkene 10 afforded the
tron-poor ones.1,20 Compound 4, possessing a more electron- addition product 11 in 46% yield. Reaction of 3-exomethylene-
rich double bond than that of 1, was expected to show higher glucofuranose derivative 12 with thiophenol showed a slightly
conversions with the thiols which exhibited low reactivity lower efficiency but full selectivity furnishing compound 13 as
towards compound 1. Hydrothiolation of 4 with ethanethiol a single diastereoisomer in 32% yield.
went to completion rapidly and with full selectivity to give the
We were pleased to find that in the reaction of exoglycal 14
expected α-thioglucoside 5a in 71% yield (Table 3). The slight with thiophenol almost complete conversion of the glycal
decrease of the yield compared to that of 3a was a result of the occurred after 45 min providing the C-glycosyl derivative 15
lability of the benzyl-type protecting groups under radical stereoselectively, in high yield. The exclusive formation of the
mediated hydrothiolation reaction.25–27
β-glycoside 15 can be explained by the preferred axial attack on
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Table 3 Free radical addition of thiols to 2-benzyloxy glycal 4
Thiol
Thiol : ene ratio
Product
Yielda (%)
71
15 : 1
2 : 1
21
40
15 : 1
2 : 1
2 : 1
46b
59
a Yield of isolated compounds after 3 × 15 min irradiation under Ar, using 3 × 0.1 equiv. of DPAP. b The reaction was carried out in abs. MeOH.
propensity for suffering oxidation upon standing in air,
especially in the presence of ethyl acetate. When the crude 15
was chromatographed with an ethyl acetate-containing eluent,
besides the hydrothiolation product 15, a significant amount
of the sulfoxide derivative 15b (8%) was also isolated. There-
fore, ethyl acetate was avoided during work-up and purification
of 15 and 16.
Finally, we tested the applicability of the 2,3-unsaturated
N-acetylneuraminic acid (Neu5Ac-2-ene) derivative 17,37 an
Scheme 3 Reagents and conditions: (a) 15 equiv. of EtSH, toluene, 3 × 15 min
intermediate in the synthesis of the influenza neuraminidase
irradiation, 3 × 0.1 equiv. of DPAP; (b) 50 equiv. of PhSH toluene, 6 × 15 min
inhibitor Relenza, to the thiol–ene coupling reaction. We envi-
irradiation, 6 × 0.1 equiv. of DPAP.
sioned the synthesis of an S-linked mimetic of the natural
α(2 → 6)-linked sialyl-galactoside structure by hydrothiolation
the D-glucopyranosyl radical.36 Then, the reactivity of 14 of 17 with 1,2: 3,4-di-O-isopropylidene-6-thio-α-D-galacto-
toward ethanethiol was also tested. A fast and complete reac- pyranose 18.38 Previously, thiol 18 was applied successfully to
tion was observed to afford the β-configured 16 in 93% yield. It hydrothiolation of the 2-acetoxy-glycal 1 to afford the corres-
is important to note that sulfides 15 and 16 had a great ponding S-disaccharide in 69% yield.17 In the present case,
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Table 4 Hydrothiolations of terminal double bonds in monosaccharide
derivatives
Alkene
Thiol
PhSH
Product
Yielda (%)
46
PhSH
PhSH
32
74b
61c
Scheme 4 Reagents and conditions: 2 equiv. of 18, 5 × 15 min irradiation,
5 × 0.1 equiv. of DPAP, 23% for 19; unreacted 17 was recovered in 35% yield.
analogues of the biorelevant N-acetylneuraminic acid glyco-
8c
sides,40 is worthy of further investigation.
EtSH
93d
Conclusions
Photoinduced radical-mediated hydrothiolation of acetyl or
benzyl-protected endoglycals and monosaccharides bearing an
exocyclic double bond at C1-, C3- or C6-position with a range
of thiols was studied. In most cases, the thiol–ene coupling
reactions took place with full regio- and stereoselectivities;
however, the conversions highly varied. We assume that the
overall conversion of a given ene substantially depends on the
stability of the thiyl radical, most probably due to the revers-
ible nature of the radical addition step. The highly resonance
stabilized thiophenyl radical proved to be especially useful for
testing the reactivity of the different enes in the thiol–ene
coupling reactions. An attempted reaction between thiophenol
and either 2-acetoxy-3,4,6-tri-O-acetyl-D-glucal 1 or 3,4,6-tri-O-
acetyl-D-glucal 6 failed even by applying 50 equivalents of the
thiol. This hydrothiolation agent displayed moderate reactivity
towards both the electron-rich internal double bond of the
benzylated 2-hydroxy-glycal 4, and the electron-poor terminal
double bonds of exoglycals 10 and 12 furnishing the final pro-
ducts in 21–46% yields. The reaction of thiophenol and exo-
glycal 14 afforded the corresponding β-C-glycoside in 74% yield.
In this case the highly reactive electron-rich terminal double
bond of 14 captured the thiyl radical and, therefore, forced the
equilibrium of the thiyl radical addition step towards the hydro-
gen abstraction step affording the product in high yield.
a Yield of isolated compounds after 3 × 15 min irradiation under Ar,
using 3 × 0.1 equiv. of DPAP and 2 equiv. of thiol. b Purified using
column chromatography in 98 : 2 CH2Cl2–acetone. c Column
chromatography of the reaction mixture of 15 in 75 : 25 n-hexane–
EtOAc. d 15 min irradiation, 0.1 equiv. of DPAP, 5 equiv. of EtSH.
reaction of 17 and the galactose-6-thiol derivative 18 led to
∼50–60% consumption of the glycal, estimated by tlc,39 and
resulted in a mixture of stereoisomers from which only the
main product 19 could be isolated in 23% yield (Scheme 4).
The low conversion could be a result of the lower electron-
density of the double bond in Neu5Ac-2-ene possessing the
electron-withdrawing carboxyl moiety. The equatorial orien-
tation of the C-1 group and the axial orientation of the
S-linkage were evidenced by crosspeaks between H-3 and both
H-2 and H-4 hydrogens of the sialyl residue appeared in the
ROESY spectrum of 19.
The formation of the pseudodisaccharide 19 as the main
product can be explained by the preferred attack on the less
substituted carbon at the less hindered side in the thiyl radical
addition step and the preferred axial attack on the C-2 radical
in the hydrogen abstraction step. Despite the moderate yield,
the approach allowing a simple one-step transformation of the
easily available 17 into 2-S-linked sialomimetics, stable
Successful hydrothiolation of a 2,3-unsaturated N-acetyl-
neuraminic acid derivative revealed that the endocyclic double
bond of Neu5Ac-2-ene, bearing an electron-withdrawing substitu-
ent, exhibits sufficient reactivity in thiol–ene coupling reaction.
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Photoinduced addition of thiol 2c to 2-acetoxy glycal 1 in
different solvents
Experimental section
General information
To a solution of compound 1 (33.0 mg, 0.10 mmol) in the
given solventc (2 mL), thiol 2c (24 μL, 0.20 mmol) and 2,2-
dimethoxy-2-phenylacetophenone (DPAP, 2.5 mg, 0.01 mmol)
were added. The solution was deoxygenated and irradiated at
room temperature for 15 min. Addition of DPAP and
irradiation were repeated twice more. Then the solution was
concentrated,d and the residue was purified using column
chromatography.e
Ethanethiol, 2-methylpropane-2-thiol, thiophenol, phenyl-
methanethiol,
(4-methoxyphenyl)methanethiol,
sodium
2-mercaptoethanesulfonate and 1-thioglycerol were purchased
from Sigma Aldrich Chemical Co. Optical rotations were
measured at room temperature with a Perkin-Elmer 241 auto-
matic polarimeter. TLC was performed on Kieselgel 60 F254
(Merck) with detection by immersing into 5% ethanolic sulfu-
ric acid solution followed by heating. Column chromatography
was performed on Silica Gel 60 (Merck 0.063–0.200 mm).
Organic solutions were dried over MgSO4, and concentrated
cToluene, MeOH, CH2Cl2, DMF and DMF–H2O, 1 : 1, were
applied as the solvents.
dWhen DMF–H2O, 1 : 1, was used as the solvent, the residue
coevaporated twice with toluene.
1
under vacuum. The H (360, 400 and 500 MHz) and 13C NMR
(90.54, 100.28 and 125.76 MHz) spectra were recorded with
Bruker DRX-360, Bruker DRX-400 and Bruker Avance II 500
spectrometers. Chemical shifts are referenced to Me4Si or DSS
(0.00 ppm for 1H) and to the residual solvent signals (CDCl3:
77.00 ppm, CD3OD: 49.15 ppm, DMSO-d6: 39.52 ppm for 13C).
The coupling constant values (J) are given in Hz. Elemental ana-
lyses (C, H, S, N) were performed using an Elementar Vario
MicroCube instrument. The photocatalytic reactions were
carried out at room temperature by irradiation with a Hg-lamp
with a borosilicate vessel giving maximum emission at 365 nm.
eBefore purification, the 1H NMR spectrum of the crude
product was recorded.
Phenylmethyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-glucopyranoside
(3c)
Compound 1 (330 mg, 1.00 mmol) and phenylmethanethiol
(2c 2 × 235 μL, 4.00 mmol) were reacted according to general
method B using 4 irradiation cycles. The crude product was
purified using column chromatography (97 : 3 CH2Cl2–
acetone) to give 3c (106 mg, 22%) as a syrup. [α]2D2 +211.5
(c 0.68 in MeOH), (lit.41 [α]D +190); Rf 0.30 (97 : 3 CH2Cl2–
acetone). Elemental analysis: found: C, 54.6; H, 5.7; S, 7.0.
Calc. for C2H26O9S: C, 54.5; H, 5.8; S, 7.1%; 1H NMR
(360 MHz, CDCl3, Me4Si): δ (ppm) 2.01, 2.02, 2.03, 2.10 (12 H,
4 × s, 4 × COCH3), 3.72 (2 H, ABq, J 13.5, SCH2), 3.87 (1 H, dd,
J5,6A 1.8, J6A,B 12.3, 6-HA), 4.24 (1 H, dd, J5,6B 4.6, J6A,B 12.3,
6-HB), 4.36–4.38 (1 H, m, 5-H), 5.00–5.07 (2 H, m, 2-H, 4-H),
5.37 (1 H, t, J 9.7, 3-H), 5.53 (1 H, d, J1,2 5.8, 1-H), 7.19–7.35
(5 H, m, arom.); 13C NMR (90 MHz, CDCl3): δ (ppm) 20.5, 20.5,
20.5, 20.6 (4 × COCH3), 33.9 (SCH2), 61.6 (C-6), 67.6, 68.4, 70.3,
70.5 (C-2, C-3, C-4, C-5), 81.0 (C-1), 127.2, 128.5, 128.7, 137.1
(6 C, arom.), 169.5, 169.5, 169.8, 170.4 (4 × CO).
General method A for the photoinduced addition of ethanethiol
and 2-methylpropane-2-thiol to glycals (1, 4, 6 and 14)
To a solution of the starting glycal (1.00 mmol) in dry toluene
(7 mL), ethanethiol or 2-methylpropane-2-thiol (5.00 mmol)
and 2,2-dimethoxy-2-phenylacetophenone (DPAP, 25 mg,
0.10 mmol) were added. The solution was deoxygenated by
argon bubbling and irradiated at room temperature for
15 min. Addition of DPAP and the thiol, deoxygenation and
irradiation were repeated twice more (except for the reaction of
14 and ethanethiol which showed complete conversion of the
glycal after 15 min). Then the solution was concentrated and
the residue was purified using column chromatography.
Unreacted 1 was recovered from the reaction mixture
(182 mg, 55%).
(4-Methoxyphenyl)methyl 2,3,4,6-tetra-O-acetyl-1-thio-
α-D-glucopyranoside (3d)
General method B for the photoinduced addition of thiols to
endo- and exocyclic double bonds of monosaccharide
derivatives
Compound 1 (330 mg, 1.00 mmol) and (4-methoxyphenyl)-
methanethiol (2 × 280 μL, 4.0 mmol) were reacted according to
To a solution of the starting unsaturated monosaccharide general method B using 4 irradiation cycles. The crude
(1.00 mmol) in dry toluenea (7 mL), thiol (2.0–4.0 equiv.) and product was purified using column chromatography (99 : 1
2,2-dimethoxy-2-phenylacetophenone (DPAP, 25 mg, 0.10 CH2Cl2–acetone) to give 3d (49 mg, 10%) as
a syrup.
mmol) were added. The solution was deoxygenated and irra- [α]2D2 +197.1 (c 0.51 in CHCl3); Rf 0.33 (99 : 1 CH2Cl2–acetone).
diated at room temperature for 15 min. Addition of DPAP and Elemental analysis: found: C, 53.9; H, 5.8; S, 6.65. Calc. for
irradiation were repeated twice more. Then the solution was C22H28O10S: C, 54.5; H, 5.8; S, 6.6%; 1H NMR (360 MHz,
concentratedb and the residue was purified using column CDCl3, Me4Si): δ (ppm) 2.00, 2.01, 2.03, 2.10 (12 H, 4 × s, 4 ×
chromatography.
COCH3), 3.67 (2 H, ABq, J 13.4, SCH2), 3.80 (3 H, s, OCH3), 3.96
(1 H, dd, J5,6A 2.0, J6A,B 12.3, 6-HA), 4.24 (1 H, dd, J5,6B 4.6, J6A,B
aIt is indicated when some other solvent was used.
bWhen thiophenol was used as the reagent, the solution 12.3, 6-HB), 4.38–4.41 (1 H, m, 5-H), 4.99–5.06 (2 H, m, 2-H,
was diluted with CH2Cl2, washed with 1 M aq. NaOH, dried 4-H), 5.37 (1 H, t, J 9.8, 3-H), 5.51 (1 H, d, J1,2 5.8, 1-H), 6.83
over MgSO4, concentrated and purified.
(2 H, d, J 8.6, arom.), 7.21(2 H, d, J 8.6, arom.); 13C NMR
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(90 MHz, CDCl3): δ (ppm) 20.6, 20.6, 20.6, 20.7 (4 × COCH3), 50.1; H, 6.35; S, 6.5. Calc. for C20H30O11S: C, 50.2; H, 6.3; S,
33.3 (SCH2), 55.3 (OCH3), 61.9 (C-6), 67.7, 68.6, 70.4, 70.7 (C-2, 6.7%; 1H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 1.35, 1.42,
C-3, C-4, C-5), 81.0 (C-1), 114.0, 129.0, 130.0, 158.9 (6 C, 1.43 (6 H, 3 × s, 2 × CqCH3), 2.02, 2.04, 2.04, 2.07, 2.10 (12 H,
arom.), 169.6, 169.6, 169.9, 170.6 (4 × CO).
5 × br s, 4 × COCH3), 2.57–2.85 (2 H, m), 3.65–3.75 (1 H, m),
Unreacted 1 was recovered from the reaction mixture 4.06–4.10 (2 H, m), 4.22–4.33 (2 H, m), 4.38–4.46 (1 H, m),
(197 mg, 60%).
5.01–5.08 (2 H, m), 5.34–5.40 (1 H, m), 5.70, 5.75 (1 H, 2 × d,
J 5.7, J 5.8); 13C NMR (90 MHz, CDCl3): δ (ppm) 20.5, 20.6,
20.6 (4 × COCH3), 25.4, 25.5, 26.7, 26.8 (2 × CqCH3), 32.8,
32.9 (SCH2), 61.8, 61.9 (OCH2), 67.7, 67.7, 68.4, 68.5, 70.2,
2-Methylpropane-2-yl 2,3,4,6-tetra-O-acetyl-1-thio-
α-D-glucopyranoside (3e)
Compound 1 (165 mg, 0.500 mmol) and thiol (2e, 3 × 281 μL, 70.5, 74.8, 75.2 (C-2, C-3, C-4, C-5, C-4dioxolane), 68.7 (C-6),
7.50 mmol) were reacted in toluene (5 mL) according to 81.9, 82.7 (C-1), 109.6, 109.7 (Cq), 169.5, 169.7, 169.8, 170.5
general method A using 4 irradiation cycles. The crude (4 × CO).
product was purified using silica gel chromatography in 7 : 3
Unreacted 1 was recovered from the reaction mixture
n-hexane–EtOAc to give 3e (52 mg, 25%) as white needles. Mp (93 mg, 57%).
73–74 °C (from n-hexane–EtOAc) (lit.42 mp 63–65 °C);
Sodium sulfonatoethyl 2,3,4,6-tetra-O-acetyl-1-thio-
α-D-glucopyranoside (3h)
[α]D22 +154.4 (c 0.30 in CHCl3), (lit.42 [α]D +185); Rf 0.60 (6 : 4
n-hexane–EtOAc). Elemental analysis: found: C, 51.6; H, 6.6; S,
7.7. Calc. for C18H28O9S: C, 51.4; H, 6.7; S, 7.6%; 1H NMR Compound 1 (165 mg, 0.500 mmol) and thiol (2h, 164 mg,
(360 MHz, CDCl3, Me4Si): δ (ppm) 1.35 (9 H, s, 3 × SCCH3), 1.00 mmol) were reacted in MeOH (5 mL) according to general
2.02, 2.03, 2.06, 2.07 (12 H, 4 × s, 4 × COCH3), 4.05 (1 H, dd, method B. The crude product was purified using silica gel
J 2.0, J 12.3), 4.30 (1 H, dd, J 4.7, J 12.3), 4.46–4.51 (1 H, m), chromatography in 75 : 25 CH2Cl2–MeOH to give 3h (158 mg,
4.95 (1 H, dd, J 5.9, J 10.5), 5.03 (1 H, t, J 9.7), 5.28 (1 H, t, 64%) as a colourless syrup; [α]2D2 +126.1 (c 0.28 in MeOH);
J 9.9), 5.86 (1 H, d, J1,2 5.9, 1-H); 13C NMR (90 MHz, CDCl3): Rf 0.31 (8 : 2 CH2Cl2–MeOH). Elemental analysis: found: C,
δ (ppm) 20.6, 20.6, 20.6, 20.8 (4 × COCH3), 31.3 (3 × SCCH3), 38.7; H, 5.0; S, 13.4. Calc. for C16H23NaO12S2: C, 38.9; H, 4.7; S,
44.4 (Cq), 61.9 (C-6), 67.6, 68.6, 70.5, 70.8 (C-2, C-3, C-4, C-5), 13.0%; 1H NMR (360 MHz, CDOD3, Me4Si): δ (ppm) 2.00, 2.03,
80.1 (C-1), 169.6, 169.8, 169.9, 170.6 (4 × CO).
2.04, 2.09 (12 H, 4 × s, 4 × CH3), 2.90–3.16 (4 H, m, SCH2,
Unreacted 1 was recovered from the reaction mixture CH2S), 4.12 (1 H, dd, J 1.6, J 12.2), 4.27 (1 H, dd, J 5.9, J 12.2),
(97 mg, 59%).
4.43–4.47 (1 H, m), 4.99–5.07 (2 H, m), 5.30 (1 H, t, J 9.8), 5.75
(1 H, d, J 5.6, 1-H); 13C NMR (90 MHz, CDOD3): δ (ppm) 20.6,
20.6, 20.6, 20.8 (4 × CH3), 26.4 (CH2S), 52.9 (NaO3SCH2), 63.5
(C-6), 69.2, 70.0, 71.6, 71.9 (C-2, C-3, C-4, C-5), 83.7 (C-1),
[(2R,S)-2,3-Di-O-acetoxy]propyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-
glucopyranoside (3f)
Compound 1 (330 mg, 1.00 mmol) and thiol (2f, 384 mg, 171.3, 171.3, 171.5, 172.6 (4 × CO).
2.00 mmol) were reacted in toluene (7 mL) according to
general method B. The crude product was purified using silica
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-glucopyranoside (5a)
gel chromatography in 6 : 4 n-hexane–EtOAc to give 3f (351 mg, Compound 4 (261 mg, 0.500 mmol) and thiol (2a, 3 × 185 μL,
67%) as a colourless syrup; [α]2D2 +132.5 (c 0.82 in CHCl3); 7.50 mmol) were reacted in toluene (5 mL) according to
Rf 0.32 (6 : 4 n-hexane–EtOAc). Elemental analysis: found: C, general method A. The crude product was purified using silica
48.3; H, 5.85; S, 6.1. Calc. for C21H30O13S: C, 48.3; H, 5.8; S, gel chromatography in 85 : 15 n-hexane–EtOAc to give 5a
6.1%; 1H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 2.02, 2.04, (207 mg, 71%) as white crystals. Mp 86–87 °C (from EtOH),
2.07, 2.09 (18 H, 4 × br s, 6 × CH3), 2.71–2.77 (1 H, m), (lit.43 mp 88–90 °C); [α]2D2 +96.1 (c 0.56 in CHCl3); (lit.43
2.85–2.92 (1 H, m), 4.07–4.14 (2 H, m), 4.28–4.40 (3 H, m), [α]D +108); Rf 0.60 (8 : 2 n-hexane–EtOAc). Elemental analysis:
4.99–5.08 (2 H, m), 5.13–5.22 (1 H, m), 5.28–5.35 (1 H, m), (found: C, 73.9; H, 6.8; S, 5.6. Calc. for C36H40O5S: C, 73.9; H,
1
5.70, 5.75 (1 H, 2 × d, J 5.6, J 5.6); 13C NMR (90 MHz, CDCl3): 6.9; S, 5.5%); H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 1.27
δ (ppm) 20.1, 20.3, 20.3 (6 × CH3), 29.6, 29.8 (SCH2), 61.3, 61.4 (3 H, t, J 7.4, CH3), 2.45–2.63 (2 H, m, CH2), 3.61–3.67 (2 H, m),
(OCH2), 63.1, 63.3 (C-6), 67.4, 67.6, 67.8, 67.9, 69.4, 69.7, 69.9, 3.76 (1 H, dd, J 3.5, J 10.7), 3.81–3.89 (2 H, m), 4.19 (1 H, br d,
70.1, 70.6 (C-2, C-3, C-4, C-5, C-2propyl), 81.8, 82.4 (C-1), 169.0, J 9.7), 4.44, 4.47, 4.60, 4.65, 4.73, 4.76, 4.83, 4.95 (8 × 1 H,
169.1, 169.3, 169.4, 169.6, 169.9 (6 × CO).
8 × d, J 12.1, J 10.6, J 12.1, J 11.8, J 12.2, J 11.0, J 10.8, J 10.8,
4 × CH2Ph), 5.41 (1 H, d, J1,2 4.4, 1-H), 7.12–7.39 (20 H, m,
arom.); 13C NMR (90 MHz, CDCl3): δ (ppm) 14.7 (CH3), 23.6
(CH2), 68.5 (C-6), 70.4, 77.4, 79.4, 82.5, 83.0 (C-1, C-2, C-3, C-4,
[(4R,S)-2,2-Dimethyl-1,3-dioxolane-4-yl]methyl 2,3,4,6-tetra-
O-acetyl-1-thio-α-D-glucopyranoside (3g)
Compound 1 (165 mg, 0.500 mmol) and thiol (2g, 148 mg, C-5), 72.3, 73.4, 74.9, 75.6 (4 × CH2Ph), 127.6–138.7 (24 C, arom.).
1.00 mmol) were reacted in toluene (5 mL) according to
general method B. The crude product was purified using silica
Phenyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-glucopyranoside (5b)
gel chromatography in 97 : 3 CH2Cl2–acetone to give 3g (74 mg, Compound 4 (261 mg, 0.500 mmol) and thiol (2b, 102 μL,
31%) as a colourless syrup; [α]2D2 +141.6 (c 0.43 in CHCl3); 1.00 mmol) were reacted in toluene (5 mL) according to
Rf 0.42 (95 : 5 CH2Cl2–acetone). Elemental analysis: found: C, general method B. The crude product was purified using silica
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gel chromatography in 99 : 1 CH2Cl2–EtOAc to give 5b (67 mg, 1,2:5,6-Di-O-isopropylidene-3-S-(2,3,4,6-tetra-O-benzyl-
21%) as white needles. Mp 77–78 °C (from EtOH) (lit.44 mp α-D-glucopyranosyl)-3-thio-α-D-glucofuranose (5j)
81–82 °C); [α]2D2 +142.7 (c 0.33 in CHCl3), (lit.44 [α]D +154);
Rf 0.58 (8 : 2 n-hexane–EtOAc). Elemental analysis: found: C,
Compound 4 (261 mg, 0.500 mmol) and thiol (2j, 276 mg,
1.00 mmol) were reacted in toluene (5 mL) according to
general method B. The crude product was purified using silica
gel chromatography in 85 : 15 n-hexane–EtOAc to give 5j
76.1; H, 6.5; S, 5.0. Calc. for C40H40O5S: C, 75.9; H, 6.4; S,
5.1%; 1H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 3.61 (1 H, br
d, J 10.2), 3.66–3.72 (1 H, m), 3.77 (1 H, dd, J 3.7, J 10.7),
(235 mg, 59%) as white crystals. Mp 89–90 °C (from EtOH).
3.86–3.93 (2 H, m), 4.33 (1 H, br d, J 9.8), 4.41, 4.49, 4.58, 4.68,
[α]2D2 +89.0 (c 0.73 in CHCl3); Rf 0.32 (85 : 15 n-hexane–EtOAc).
4.76, 4.81, 4.85, 5.00 (8 × 1 H, 8 × d, J 12.0, J 10.8, J 12.0, J 11.7,
Elemental analysis: found: C, 69.0; H, 6.8; S, 3.9. Calc. for
J 11.8, J 10.9, J 10.8, J 10.8, 4 × CH2Ph), 5.64 (1 H, d, J1,2 3.7,
C46H54O10S: C, 69.15; H, 6.8; S, 4.0%; 1H NMR (360 MHz,
1-H), 7.14–7.50 (25 H, m, arom.); 13C NMR (90 MHz, CDCl3):
CDCl3, Me4Si): δ (ppm) 1.24, 1.31, 1.43, 1.50 (12 H, 4 × s, 4 ×
δ (ppm) 68.5 (C-6), 71.1, 77.3, 79.7, 82.5 (C-2, C-3, C-4, C-5),
CH3), 3.58–3.90 (6 H, m), 4.03–4.23 (4 H, m), 4.44–4.49 (2 H,
72.5, 73.3, 75.1, 75.7 (4 × CH2Ph), 87.0 (C-1), 127.0–138.6 (30C,
m), 4.54–4.64 (3 H, m), 4.72–4.85 (4 H, m), 4.94 (1 H, d, J 10.8),
arom.).
5.77 (1 H, d, J1,2 3.2, 1-H), 5.84 (1 H, d, J1′,2′ 4.7, 1′-H),
7.11–7.38 (20 H, m, arom.); 13C NMR (90 MHz, CDCl3):
δ (ppm) 25.3, 26.0, 26.5, 26.9 (4 × CH3), 50.0 (C-3), 67.7 (C-6),
2-Methylpropane-2-yl 2,3,4,6-tetra-O-benzyl-1-thio-
68.3 (C-6′), 71.0, 74.4, 77.1, 79.1, 80.4, 82.0, 84.4 (C-2, C-4, C-5,
α-D-glucopyranoside (5e)
C-2′, C-3′, C-4′, C-5′), 71.5, 73.3, 74.9, 75.5 (4 × CH2Ph), 86.4
Compound 4 (261 mg, 0.500 mmol) and thiol (2e, 3 × 281 μL,
(C-1′), 104.7 (C-1), 109.2, 111.7 (2 × Cq), 127.4–138.4 (24 C,
7.50 mmol) were reacted in toluene (5 mL) according to
arom.).
general method A. The crude product was purified using silica
gel chromatography in 88 : 12 n-hexane–EtOAc to give 5e
3,4,6-Tri-O-acetyl-1,5-anhydro-2-S-ethyl-D-mannitol (7), 3,4,6-
(122 mg, 40%) as white needles. Mp 91–92 °C (from EtOH)
tri-O-acetyl-1,5-anhydro-2-S-ethyl-D-glucitol (8) and ethyl 3,4,6-
(lit.45 mp 97–98 °C); [α]D22 +72.9 (c 0.40 in CHCl3), (lit.45
tri-O-acetyl-2-deoxy-1-thio-α-D-arabino-hexopyranoside (9)
[α]D +120); Rf 0.55 (85 : 15 n-hexane–EtOAc). Elemental
analysis: found: C, 74.4; H, 7.1; S, 5.2. Calc. for C38H44O5S: C, Compound 6 (544 mg, 2.00 mmol) and ethanethiol (2a,
74.5; H, 7.2; S, 5.2%; 1H NMR (360 MHz, CDCl3, Me4Si): 3 × 740 μL, 30.00 mmol) were reacted according to general
δ (ppm) 1.38 (9 H, s, 3 × CH3), 3.57 (1 H, dd, J 1.9, J 10.6), method A to give a mixture of 7, 8 and 9 which were separated
3.64–3.69 (1 H, br t, J 8.6, J 9.7), 3.74–3.83 (3 H, m), 4.25–4.28 using silica gel chromatography in 1 : 1 n-hexane–Et2O. (After
(1 H, m), 4.41, 4.45, 4.62 (3 × 1 H, 3 × d, J 12.2, J 11.0, J 12.1, column chromatography, compound 9 was contaminated by
CH2Ph), 4.70 (2 H, s, CH2Ph), 4.75, 4.83, 4.96 (3 × 1 H, 3 × d, the unreacted starting material, from which it could only be
3 × J 10.8, CH2Ph), 5.54 (1 H, d, J1,2 4.8, 1-H), 7.12–7.39 (20 H, separated after catalytic hydrogenation and a subsequent puri-
m, arom.); 13C NMR (90 MHz, CDCl3): δ (ppm) 31.5 (3 × CH3), fication using silica gel chromatography in 1 : 1 n-hexane–
43.7 (Cq), 68.4 (C-6), 70.4, 77.5, 79.4, 81.7, 82.9 (C-1, C-2, EtOAc.)
C-3, C-4, C-5), 72.4, 73.4, 74.9, 75.7 (4 × CH2Ph), 127.5–138.7
(24 C, arom.).
7: (230 mg, 34%) colourless syrup; [α]2D2 −34.4 (c 0.61,
CHCl3); Rf 0.18 (1 : 1 n-hexane–Et2O). Elemental analysis:
found: C, 50.15; H, 6.5; S, 9.45. Calcd for C14H22O7S: C, 50.3;
H, 6.6; S, 9.6; H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 1.24
(3 H, t, J 7.4, CH3CH2), 2.06, 2.09, 2.10 (9 H, 3 s, 3 × CH3),
2.58–2.64 (2 H, q, CH2), 3.37–3.39 (1 H, m, 2-H), 3.58–3.62
1
[(2R,S)-2,3-Dihydroxy]propyl 2,3,4,6-tetra-O-benzyl-1-thio-
α-D-glucopyranoside (5i)
Compound 4 (261 mg, 0.500 mmol) and thiol (2i, 87 μL, (1 H, m, 5-H), 3.83 (1 H, dd, J1β,2 2.1, J1α,1β 12.2, 1β-H), 4.09
1.00 mmol) were reacted in toluene (5 mL) according to (1 H, dd, J1α,2 2.6, J1α,1β 12.2, 1-αH), 4.13 (1 H, dd, J5,6A 2.7, J6A,B
general method B. The crude product was purified using silica 12.2, 6-HA), 4.19 (1 H, dd, J5,6B 5.5, J6A,B 12.2, 6-HB), 5.10 (1 H,
gel chromatography in 1 : 1 CH2Cl2–EtOAc to give 5i (144 mg, dd, J2,3 4.4, J3,4 9.3, 3-H), 5.28 (1 H, t, J4,5 9.2, 4-H); 13C NMR
46%) as white crystals. Mp 60–61 °C (from EtOH); [α]D22 +71.2 (90 MHz, CDCl3): δ (ppm) 14.5 (CH3CH2), 20.5, 20.5, 20.6 (3 ×
(c 0.58 in CHCl3); Rf 0.51 (1 : 1 CH2Cl2–EtOAc). Elemental ana- CH3), 26.4 (CH2), 45.3 (C-2), 62.3 (C-6), 66.5 (C-4), 69.1 (C-1),
lysis: found: C, 70.2; H, 6.6; S, 4.9. Calc. for C37H42O7S: C, 73.7 (C-3), 76.6 (C-5), 169.2, 170.0, 170.4 (3 × CO).
70.45; H, 6.7; S, 5.1%; 1H NMR (360 MHz, CDCl3, Me4Si):
8: (163 mg, 24%) colourless syrup; [α]2D2 +71.1 (c 0.35,
δ (ppm) 2.50–2.79 (3 H, m), 3.38–3.85 (9 H, m), 4.20–4.27 (1 H, CHCl3); Rf 0.30 (1 : 1 n-hexane–Et2O). Elemental analysis:
m), 4.42–4.57 (3 H, m, CH2Ph), 4.64–4.77 (3 H, m, CH2Ph), found: C, 50.05; H, 6.7; S, 9.4. Calcd. for C14H22O7S: C, 50.3; H,
4.82, 4.94 (2 × 1 H, 2 × d, J 10.9, J 10.8, CH2Ph), 5.33 (1 H, d, 6.6; S, 9.6; 1H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 1.24
J1,2 4.2, 1-H), 7.13–7.37 (20 H, m, arom.); 13C NMR (90 MHz, (3 H, t, J 7.4, CH3CH2), 2.03, 2.08, 2.09 (9 H, 3 s, 3 × CH3),
CDCl3): δ (ppm) 34.3 (SCH2), 65.2 (OCH2), 68.6, 68.7 (C-6), 2.52–2.62 (2 H, m, CH2), 2.84–2.91 (1 H, m, 2-H), 3.40 (1 H, t,
70.7, 70.8, 71.2, 77.4, 79.3, 79.4, 82.2, 84.3, 84.9 (C-1, C-2, C-3, J1β,2 11.9, 1β-H), 3.58–3.63 (1 H, m, 5-H), 4.09 (1 H, dd, J5,6A
C-4, C-5, C-2′), 72.5, 72.5, 73.3, 73.3, 74.9, 75.6 (4 × CH2Ph), 2.1, J6A,B12.3, 6-HA), 4.14 (1 H, dd, J1α,2 5.1, J1α,1β 11.9, 1α-H),
127.5–138.4 (24 C, arom.).
4.25 (1 H, dd, J5,6B 4.8, J6A,B 12.3, 6-HB), 4.98–5.00 (2 H, m, 3-H,
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4-H); 13C NMR (90 MHz, CDCl3): δ (ppm) 15.1 (CH3CH2), 20.5, 1-S-Phenyl-2,6-anhydro-1-deoxy-3,4,5,7-tetra-O-benzoyl-
20.6, 20.6 (3 × CH3), 25.3 (CH2), 45.1 (C-2), 62.3 (C-6), 69.5 D-glycero-D-gulo-heptitol (15) and 1-(phenylsulfinyl)-2,6-
(C-4), 70.2 (C-1), 73.9 (C-3), 76.4 (C-5), 169.6, 170.1, 170.5 (3 × anhydro-1-deoxy-3,4,5,7-tetra-O-benzoyl-D-glycero-D-gulo-
CO).
9: (46 mg, 7%) white crystals, mp 50–52 °C (EtOH), (lit.46
heptitol (15b)
Compound 14 (225 mg, 0.380 mmol) and thiol (2b, 78 μL,
0.760 mmol) were reacted in toluene (4 mL) according to
general method B. The crude product was purified using silica
gel chromatography in 98 : 2 CH2Cl2–acetone to give 15
(197 mg, 74%) as a colourless syrup. [α]2D2 +4.0 (c 0.50 in
CHCl3); Rf 0.45 (75 : 25 n-hexane–EtOAc). Elemental analysis:
found: C, 69.9; H, 4.7; S, 4.4. Calc. for C41H34O9S: C, 70.1; H,
mp 51–52 °C); [α]2D2 +207.7 (c 0.25, CHCl3) (lit.46 [α]D +183);
Rf 0.36 (1 : 1 n-hexane–Et2O). Analysis: found: C, 50.4; H, 6.75;
S, 9.6. Calcd for C14H22O7S: C, 50.3; H, 6.6; S, 9.6; 1H NMR
(360 MHz, CDCl3, Me4Si): δ (ppm) 1.29 (3 H, t, J 7.4, CH3CH2),
2.01, 2.05, 2.09 (9 H, 3 s, 3 × CH3), 2.13–2.30 (2 H, m),
2.50–2.68 (2 H, m), 4.04 (1 H, dd, J 1.8, J 11.9), 4.33–4.42 (2 H,
m), 4.98 (1 H, t, J 9.5), 5.21–5.28 (1 H, m), 5.45 (1 H, d, J 5.5);
13C NMR (90 MHz, CDCl3): δ (ppm) 14.7 (CH3CH2), 20.7, 20.7,
20.9 (3 × CH3), 24.9 (CH2), 35.2 (C-2), 62.3 (C-6), 68.0, 69.4,
69.6 (C-3, C-4, C-5), 79.6 (C-1), 169.9, 170.0, 170.6 (3 × CO).
1
4.9; S, 4.6%; H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 3.16
(1 H, dd, J1A,2 8.0, J1A,B 14.3, 1-HA), 3.27 (1 H, dd, J1B,2 2.7, J1A,B
14.3, 1-HB), 3.97–4.03 (1 H, m, 2-H), 4.09–4.14 (1 H, m, 6-H),
4.43 (1 H, dd, J6,7A 5.3, J7A,B 12.2, 7-HA), 4.59 (1 H, dd, J6,7B 2.8,
J7A,B 12.2, 7-HB), 5.59 (1 H, t, J 9.6), 5.70 (1 H, t, J 9.7), 5.91
(1 H, t, J 9.5), 7.08–7.54 (17 H, m, arom.), 7.80–8.06 (8 H, m,
arom.); 13C NMR (90 MHz, CDCl3): δ (ppm) 35.8 (C-1), 63.1
(C-7), 69.6, 72.0, 74.1, 76.0, 77.8 (C-2, C-3, C-4, C-5, C-6),
126.2–135.9 (30C, arom.), 165.1, 165.3, 165.8, 166.0 (4 × CO).
When the crude 15 was purified using silica gel chromato-
graphy using 75 : 25 n-hexane–EtOAc as the eluent, the sulf-
oxide derivative 15b was isolated in 8% yield and pure 15 was
isolated in 61% yield.
6-Deoxy-1,2 : 3,4-di-O-isopropylidene-7-S-phenyl-α-D-galacto-
heptopyranose (11)
Compound 10 (256 mg, 1.00 mmol) and thiol (2b, 205 μL,
2.00 mmol) were reacted in toluene (7 mL) according to
general method B. The crude product was purified using silica
gel chromatography in 98 : 2 CH2Cl2–EtOAc to give 11 (168 mg,
46%) as a colourless syrup. [α]2D2 −15.3 (c 0.30 in CHCl3);
Rf 0.49 (99 : 1 CH2Cl2–acetone). Elemental analysis: found: C,
62.4; H, 7.2; S, 8.65. Calc. for C19H26O5S: C, 62.3; H, 7.15; S,
Compound 15b: colourless syrup. [α]2D2 +23.5 (c 0.47 in
CHCl3); Rf 0.56 (1 : 1 n-hexane–EtOAc). Elemental analysis:
found: 68.2; H, 4.6; S, 4.65%. Calc. for C41H34O10S: C, 68.5; H,
4.8; S, 4.5%; 1H NMR (360 MHz, CDCl3, Me4Si): δ (ppm)
2.91–3.04 (2 H, m), 3.13 (1 H, dd, J 4.5, J 13.6), 3.34 (1 H, dd,
J 7.5, J 13.6), 3.90–3.95 (1 H, m), 4.00–4.06 (1 H, m), 4.25–4.39
(3 H, m), 4.43–4.56 (2 H, m), 4.68 (1 H, dd, J 2.8, J 12.3),
5.43–5.54 (2 H, m), 5.62 (1 H, t, J 9.8), 5.73 (1 H, t, J 9.8), 5.83
(1 H, t, J 9.6), 5.96 (1 H, t, J 9.6), 7.23–8.11 (50 H, m, arom.);
13C NMR (90 MHz, CDCl3): δ (ppm) 58.4, 60.8 (C-1), 63.1 (C-7),
69.3, 69.4, 71.7, 72.0, 72.1, 72.5, 73.8, 74.1, 76.1, 76.4 (C-2, C-3,
C-4, C-5, C-6), 123.8–143.8 (60C, arom.), 165.1, 165.2, 165.5,
165.7, 165.7, 166.2 (8 × CO).
1
8.75%; H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 1.32, 1.33,
1.44, 1.59 (12 H, 4 × s, 4 × CH3), 1.73–1.82 (1 H, m, 6-HA),
2.01–2.11 (1 H, m, 6-HB), 2.95–3.03 (1 H, m, 7-HA), 3.11–3.18
(1 H, m, 7-HB), 3.99–4.04 (1 H, m, 5-H), 4.09 (1 H, dd, J4,5 1.6,
J3,4 7.9, 4-H), 4.30 (1 H, dd, J2,3 2.3, J1,2 5.0, 2-H), 4.59 (1 H, dd,
J2,3 2.3, J3,4 7.9, 3-H), 5.52 (1 H, d, J1,2 5.0, 1-H), 7.12–7.33 (5 H,
m, arom.); 13C NMR (90 MHz, CDCl3): δ (ppm) 24.3, 24.9, 25.9,
26.0 (4 × CH3), 29.3, 29.6 (C-6, C-7), 65.6, 70.4, 70.8, 72.8 (C-2,
C-3, C-4, C-5), 96.4 (C-1), 108.5, 109.0 (2 × Cq), 125.7, 128.7,
129.0 (5 C, arom.), 136.2 (Cq, arom.).
3-Deoxy-3-C-(phenylthiomethyl)-1,2 : 5,6-di-O-isopropylidene-
α-D-allofuranose (13)
Compound 12 (256 mg, 1.00 mmol) and thiol (2b, 205 μL,
2.00 mmol) were reacted in toluene (5 mL) according to
general method B. The crude product was purified using silica
1-S-Ethyl-2,6-anhydro-1-deoxy-3,4,5,7-tetra-O-benzoyl-D-glycero-
D-gulo-heptitol (16)
gel chromatography in 98 : 1 : 1 CH2Cl2–EtOAc–TEA to give 13 Compound 14 (140 mg, 0.236 mmol) and thiol 2a (87 μL,
(117 mg, 32%) as white crystals. Mp 41–42 °C; [α]2D2 +99.0 1.18 mmol) were reacted in toluene (3 mL) according to
(c 0.42 in CHCl3); Rf 0.42 (98 : 2 CH2Cl2–EtOAc). Elemental ana- general method A. The crude product was purified using silica
lysis: found: C, 62.05; H, 7.3; S, 8.9. Calc. for C19H26O5S: C, gel chromatography in 98 : 2 CH2Cl2–acetone to give 16
62.30; H, 7.15; S, 8.75%; 1H NMR (360 MHz, CDCl3, Me4Si): (143 mg, 93%) as a colourless syrup; [α]2D2 +23.5 (c 0.47 in
δ (ppm) 1.32, 1.37, 1.42, 1.53 (12 H, 4 × s, 4 × CH3), 2.13–2.21 CHCl3); Rf 0.45 (75 : 25 n-hexane–EtOAc). Elemental analysis:
(1 H, m, 3-H), 3.09 (1 H, dd, J3,SCH2A 11.5, JSCH2AB 13.5, SCH2A), found: C, 67.65; H, 5.05; S, 5.0. Calc. for C37H34O9S: C, 67.9; H,
1
3.52 (1 H, dd, J3,SCH2B 3.2, JSCH2A,B 13.5, SCH2B), 3.77 (1 H, dd, 5.2; S, 4.9%; H NMR (360 MHz, CDCl3, Me4Si): δ (ppm) 1.14
J3,4 9.7, J4,5 7.5, 4-H), 3.89 (1 H, dd, J5,6A 5.6, J6A,B 8.2, 6-HA), (3 H, t, J 7.4, CH3) 2.57–2.71 (2 H, m, CH2S), 2.74–2.83 (2 H, m,
3.94–3.99 (1 H, m, 5-H), 4.09 (1 H, dd, J5,6B 5.9, J6A,B 8.2, 6-HB), 1-HA,B), 4.00–4.06 (1 H, m, 2-H), 4.14–4.19 (1 H, m, 6-H), 4.46
4.76 (1 H, t, J 3.6, 2-H), 5.71 (1 H, d, J1,2 3.6, 1-H), 7.14–7.40 (1 H, dd, J6,7A 5.4, J7A,B 12.2, 7-HA), 4.66 (1 H, dd, J6,7B 2.7, J7A,B
(5 H, m, arom.); 13C NMR (90 MHz, CDCl3): δ (ppm) 25.3, 26.3, 12.2, 7-HB), 5.59 (1 H, t, J 9.6), 5.68 (1 H, t, J 9.7), 5.93 (1 H, t,
26.6, 26.8 (4 × CH3), 27.9 (SCH2), 48.8 (C-3), 67.9 (C-6), 76.7 J 9.6), 7.22–7.56 (12 H, m, arom.), 7.80–8.07 (8 H, m, arom.);
(C-5), 80.7 (C-4), 81.0 (C-2), 104.8 (C-1), 109.6, 112.0 (2 × Cq), 13C NMR (90 MHz, CDCl3): δ (ppm) 14.4 (CH3), 27.3 (CH2S),
125.5, 128.2, 128.8 (5 C, arom.), 136.3 (Cq, arom.).
32.8 (C-1), 63.2 (C-7), 69.6, 71.8, 74.2, 76.0, 80.0 (C-2, C-3, C-4,
5348 | Org. Biomol. Chem., 2013, 11, 5339–5350
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C-5, C-6), 128.1–133.3 (24 C, arom.), 165.1, 165.2, 165.8, 166.0
(4 × CO).
4 K. L. Killops, L. M. Campos and C. J. Hawker, J. Am. Chem.
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5 P. Jonkheijm, D. Weinrich, M. Köhn, H. Engelkamp,
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H. Schroeder, R. Wacker, R. Breinbauer, C. M. Niemeyer
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Biomol. Chem., 2009, 7, 3910.
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(b) M. Fiore, M. Lo Conte, S. Pacifico, A. Marra and
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203.
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12 D. A. Fulton and J. F. Stoddart, J. Org. Chem., 2001, 66,
8309.
13 R. A. Ortiz, A. E. G. Valdez, M. G. M. Aguilar and
M. L. B. Duarte, Carbohydr. Polym., 2009, 78, 282.
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4422.
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A. Borbás, Org. Lett., 2012, 14, 4650.
1,2 : 3,4-Di-O-isopropylidene-6-S-(5-acetamido-4,7,8,9,-tetra-
O-acetyl-2,6-anhydro-5-deoxy-3-yl-D-glycero-D-galacto-uronic
acid methyl ester)-6-thio-α-D-galactopyranose (19)
Compound 17 (473 mg, 1.00 mmol) and thiol 18 (553 mg,
2.0 mmol) were reacted according to general method B; the
addition of DPAP (5 × 25 mg, 5 × 0.100 mmol), deoxygenation
and 15 min irradiation were repeated 5 times. The crude
product was separated using column chromatography in 7 : 3
n-hexane–EtOAc into two fractions. The first fraction with
higher mobility (230 mg, Rf 0.78) proved to be a disulfide
derivative of 18.47 The second fraction (650 mg, Rf 0.05) was a
mixture of compounds with a very similar mobility, including
two main components. This mixture was purified again using
column chromatography in 1 : 9 n-hexane–EtOAc to give 19
(173 mg, 23%) as a colourless syrup and unreacted glycal 17
(163 mg, 35%; Rf 0.38). Compound 19: [α]2D4 −20.3 (c 0.25,
CHCl3); Rf 0.37 (1 : 9 n-hexane–EtOAc). Elemental analysis:
found: C, 51.4; H, 6.3; N, 1.9; S, 4.3. Calc. for C32H47NO17S: C,
51.3; H, 6.3; N, 1.9; S, 4.3%; 1H NMR (CDCl3, 400 MHz):
δ (ppm) 1.32, 1.40, 1.56 (12 H, 3 × s, 4 × CH3), 1.89, 2.02, 2.05,
2.10, 2.13, 2.16 (15 H, 5 × s, 5 × CH3), 2.69–2.74 (1 H, m, 6-HA),
2.84–2.90 (1 H, m, 6-HB) 3.63–3.65 (1 H, m, 3-H), 3.79 (3 H, s,
OCH3), 3.82–3.84 (2 H, m, 5′-H, 6-H), 4.16–4.22 (2 H, m, 5-H,
9-HA), 4.27–4.29 (2 H, m, 2′-H, 4′-H), 4.36 (1 H, d, J2,3 1.1, 2-H),
4.57–4.59 (1 H, m, 3′-H), 4.66–4.70 (1 H, m, 9-HB), 5.26–5.30
(2 H, m, 7-H, 8-H), 5.46 (1 H, d, J1′,2′ 4.7, 1′-H), 5.66 (1 H, d,
J 9.3, NH); 13C NMR (CDCl3, 100 MHz): δ (ppm) 20.7, 20.8, 20.9
(4 × CH3), 23.2 (CH3), 24.3, 24.8, 25.9 (4 × CH3), 32.4 (C-6′),
47.1 (C-5), 48.7 (C-3), 52.4 (C-1), 62.4 (C-9), 66.9 (C-5′), 68.3
(C-7), 70.4, 70.6, 70.7 (C-2′, C-3′, C-4′), 71.6 (C-8), 73.1 (C-4),
78.0 (C-2), 96.5 (C-1′), 109.1, 108.6 (2 × Cq), 167.4, 170.2, 170.3,
170.5, 170.6 (6 × CO).
18 R. Davuluri and L. M. Lerner, Carbohydr. Res., 1972, 22,
345.
19 TLC monitoring of test reactions of 1 with 2a showed very
similar conversions after a 15 min irradiation and a 1 h
irradiation; therefore, 15 min irradiation cycles were
applied in all cases. It was found that after a 15 min
irradiation the 0.1 equiv. of the initiator was completely
consumed and the next cycle of irradiation only slightly
promoted the reaction without adding another portion of
DPAP. Adding 3 × 0.1 equiv. of DPAP proved to be more
effective than adding 0.3–0.5 equiv. of DPAP in one portion
before starting the reaction. Our attempts to increase the
conversion of glycal 1 with thiols 2b or 2c by applying
excess of the thiols (6 equiv.) and irradiating for 6 × 15 min
of the reaction mixtures were unsuccessful.
Acknowledgements
The work was supported by the TÁMOP 4.2.1/B-09/
1/KONV-2010–0007 project. The project is co-financed by the
European Union and the European Social Fund. Financial
support from the Hungarian Research Fund (OTKA K 79126 to
HP) and the Bolyai János Research Fellowship (to MT) of the
Hungarian Academy of Sciences is also acknowledged.
20 K. Griesbaum, Angew. Chem., Int. Ed., 1970, 9, 273.
21 (a) The explanation is in accordance with the results of Ito
and Matsuda21b that the reactivities of substituted benze-
nethiyl radicals toward vinyl monomers are controlled by
the stabilities of the thiyl radicals and the addition rates
are inversely proportional to their thermodynamic stabi-
lities; (b) O. Ito and M. Matsuda, J. Am. Chem. Soc., 1979,
101, 5732.
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tion mixture.
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5350 | Org. Biomol. Chem., 2013, 11, 5339–5350
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