A surprising C-4 epimerization of 5-deoxy-5-sulfonylated pentofuranosides under Ramberg-Baecklund reaction conditions

Article abstract of DOI:10.1016/j.carres.2008.08.010

Treatment of methyl 5-deoxy-2,3-O-isopropylidene-5-(benzylsulfonyl)-β-d-ribofuranoside with CBr₂F₂-KOH/Al₂O₃ afforded the corresponding olefinic sugar. The methyl- and the isopropyl-analogues in contrast underwent epimerization at C-4 to generate the α-l-lyxo derivatives.

Full text of DOI:10.1016/j.carres.2008.08.010

Carbohydrate Research 343 (2008) 2826–2829
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
A surprising C-4 epimerization of 5-deoxy-5-sulfonylated pentofuranosides
under Ramberg–Bäcklund reaction conditions
*
Tarun Kumar Pal, Tanmaya Pathak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2008
Received in revised form 24 July 2008
Accepted 7 August 2008
Available online 12 August 2008
Treatment of methyl 5-deoxy-2,3-O-isopropylidene-5-(benzylsulfonyl)-b-D-ribofuranoside with CBr2F2–
KOH/Al2O3 afforded the corresponding olefinic sugar. The methyl- and the isopropyl-analogues in con-
trast underwent epimerization at C-4 to generate the -lyxo derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
a
-L
Keywords:
Sulfonylated carbohydrates
Ramberg–Bäcklund reaction
SO2-extrusion
Olefinic sugar
Epimerization
Ph
The SO2-extrusion reaction has been shown to be an efficient tool
for the creation of double bonds in various organic molecules1a
and at the anomeric position of various carbohydrates.1b Our inter-
est in the area of sulfonylated carbohydrates obtained after
Michael addition of nucleophiles to vinyl sulfone-modified carbo-
hydrates (Scheme 1)2 prompted us to study the utility of SO2-
extrusion reaction as a method for removing the sulfone group
from the Michael adducts. Since the SO2-extrusion reaction is
widely used for the creation of double bonds, we decided to study
this reaction for the synthesis of a series of exocyclic olefins at non-
anomeric carbons of carbohydrates.
OMe
OMe
R
(c)
O
O
O
O
O
O
CMe2
CMe2
4
1 R = TsO
2 R = BnS
3 R = BnO2S
(a)
(b)
Scheme 2. Reagents and conditions: (a) benzylmercaptan, NaOMe, DMF, 5 h, 90 °C,
81%; (b) MMPP, MeOH, 6 h, rt, 97%; (c) CBr2F2, DCM, tBuOH, KOH/Al2O3, 0 °C–rt, 1 h,
For this study, we selected the furanosyl sulfone 3 as the model
for studying the SO2-extrusion reaction (Scheme 2). Thus, the 5-O-
73%.
tosylated ribofuranoside 1,3 on treatment with benzylmercaptan
produced the 5-deoxy-5-thio analogue 2.4 Compound 2 was oxi-
dized with magnesium monoperoxyphthalate hexahydrate
(MMPP) in high yields to the corresponding sulfone 3. When com-
pound 3 was treated under modified Ramberg–Bäcklund condi-
tions (CBr2F2, KOH/Al2O3, DCM/tBuOH = 1:1, 0 °C–rt)5 for 1 h,
compound 4 was formed in good yield (73%) of the trans-isomer
in high selectivity, which was confirmed from the coupling con-
stant (16 Hz) values of the olefinic protons. It should be noted that
this is the first report on the synthesis of compound 4 although the
accidental synthesis of the corresponding C-4 epimer is reported in
the literature.6
RO
RO
O
O
NuH
R'O
OMe
R'O
OMe
ArO2S
Nu
ArO2S
pyranosides or furanosides
R, R' = Protecting groups; NuH = O, S, N or C nucleophile
Scheme 1. Addition of nucleophiles to vinyl sulfone-modified carbohydrates.
After having this encouraging result, we decided to generalize
the reaction by treating several carbohydrate-derived sulfones
* Corresponding author.
E-mail address: tpathak@chem.iitkgp.ernet.in (T. Pathak).
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.08.010

T. K. Pal, T. Pathak / Carbohydrate Research 343 (2008) 2826–2829
2827
OMe
RS
OMe
O
RO2S
(a)
(b)
O
1
O
O
O
O
CMe2
CMe2
5 R = Me
6 R = CH(CH3)2 (88%)
7 R = Me (91%)
8 R = CH(CH3)2 (92%)
(c)
X
Y
(c) or (d)
OMe
O
OMe
O
O
O
RO2S
CMe2
O
O
9 X = Y = H
10 X = Y = Me
CMe2
11 R = Me
12 R = CH(CH3)2
Scheme 3. Reagents and conditions: (a) alkylmercaptan, NaOMe, DMF, 5 h, 90 °C;
(b) MMPP, MeOH, 6 h, rt; (c) CBr2F2, DCM, tBuOH, KOH/Al2O3, 0 °C–rt, 3 h (for 11:
yield 42%, for 12: yield 30%); (d) DCM, tBuOH, KOH/Al2O3, 0 °C–rt, 3 h (for 11: yield
76%, for 12: yield 65%).
Figure 1. ORTEP diagram of compound 12.
under modified Ramberg–Bäcklund conditions. Thus, the tosylate 1
was converted to the sulfides 54 and 6 using methyl- and isopro-
pylmercaptan respectively (Scheme 3). The sulfides were oxidized
to the corresponding sulfones 7 and 8 using MMPP. When com-
pounds 7 and 8 were subjected to modified Ramberg–Bäcklund
conditions, we were surprised to note that the expected olefinic
compounds 9 and 10 were not formed. Analysis of the NMR data
revealed that the major products were structurally close to the
starting materials 7 and 8 indicating the possibility of isomeriza-
tion. The identities of products 11 and 12 were established as fol-
lows. The sharp singlets at ꢀ5.0 ppm in starting materials 7/8 and
the products 11/12 confirmed the trans-relationship of H-1 and H-
2 in these compounds.6 The only noticeable change was observed
for H-4 protons,6 which shifted approximately from d 4.71–4.75
(for 7 and 8) to d 4.43–4.47 (for 11 and 12). This change indicated
that inversion at C-4 had occurred. However, we looked for an
alternative method for the confirmation of the structures of 11
and 12. The single crystal X-ray diffraction studies of compounds
12 (Fig. 1) confirmed that Ramberg–Bäcklund reaction conditions
OMe
BnX
O
(a)
no reaction
O
O
CMe2
2 X = S
13 X = O
Scheme 4. Reagents and conditions: (a) DCM, tBuOH, KOH/Al2O3, 0 °C–rt, 3 h.
ization at C-4. Interestingly, when 11 and 12 were treated with
KOH/Al2O3 in BuOH, unreacted starting materials were isolated,
proving thereby that the conversion of 7/8 to 11/12 was irrevers-
ible. The strain energies of the b-D-ribo-derivative 8 and the a-L-
lyxo analogue 12 were compared using MM2 calculations. Com-
pound 12 was found to be more stable than 8 by 1.75 kcal/mol.
The single point energy calculations using DMOL3 also revealed that
12 was more stable than 8.
t
did convert the b-D-ribo-derivative 8 to the a-L-lyxo analogue 12
(Scheme 3). By analogy, we concluded that compound 7 also
underwent similar isomerization to afford 11 (Scheme 3).
We further treated compounds 7 and 8 with KOH/Al2O3 in
tBuOH excluding CBr2F2 and isolated compounds 11 and 12. It
should be noted that compounds 11 and 12 were obtained in
42% and 30% yields, respectively, under Ramberg–Bäcklund reac-
tion conditions, but formed in higher yields (76% and 65%, respec-
tively) when CBr2F2 was not used as one of the reagents (Scheme
3). The epimerization reaction was therefore one of the several
other transformations occurring under Ramberg–Bäcklund reac-
tions. The isomerization in the absence of CBr2F2 confirmed the
role of a strong base like KOH in the isomerization process. Impor-
tantly, a strong organic base like 1,1,3,3-tetramethylguanidine
(TMG) failed to isomerize 7 or 8. In order to gather additional infor-
mation, the benzyl sulfide derivative 2 and the benzyl-protected ri-
bose analogue 137 were also treated with KOH/Al2O3 in tBuOH
(Scheme 4). Both the compounds remained unchanged under these
reaction conditions, which was confirmed by NMR data. This
experiment established the necessity of having a strong electron-
withdrawing group like sulfone at the C-5 position for the epimer-
It has been reported that the treatment of methyl 2,3-O-isopro-
pylidene-b-D-ribofuranosiduronic acid methyl ester with slight ex-
cess of NaOMe in MeOH caused an epimerization at C-4.8 In this
case, the acidic proton at C-4 of the uronic acid ester was ab-
stracted by base to give an intermediate carbanion, which was rep-
rotonated to form the a-L-lyxo derivative. However, in our case the
possibility of abstraction of the H-4 proton was ruled out because it
was attached to C-4 and was far removed (b) from the sulfone
group at C-5. A comparable scenario was reported when the ylide
generated from methyl 5-deoxy-2,3-O-isopropylidene-5-(triphen-
ylphosphonio)-b-
D-ribofuranoside iodide underwent isomerization
to an
a
-L
-lyxo derivative through an open chain structure.6 We
believe that the easy halogenation1a of the benzyl CH2 carbon of
3 resulted in the SO2-extrusion product 4 (Scheme 2). However,
under similar reaction conditions, halogenation of carbons on both
sides of the SO2 group in 7 and 8 did not occur efficiently. The
acidic C-5 proton was removed by the strong base KOH to generate
14, which underwent intramolecular ring-opening6 to generate the

2828
T. K. Pal, T. Pathak / Carbohydrate Research 343 (2008) 2826–2829
NaHCO3 soln (30 mL). The soln was washed with EtOAc
-
(3 ꢁ 10 mL). The combined organic layers were dried over anhyd
Na2SO4, filtered and the filtrate was concentrated under dimin-
ished pressure to get a residue which was purified over silica gel
(1:4 EtOAc–petroleum ether) to the sulfone 3 (0.482 g, 97%). White
OMe
OMe
RO2S
RO2S CH
O
O
(a)
solid. Mp: 86 °C. ½a D29:2
ꢂ
ꢃ31.6 (c 0.16, CHCl3). 1H NMR (CDCl3): d
O
O
O
O
1.30 (s, 3H), 1.48 (s, 3H), 3.07–3.14 (m, 1H), 3.20–3.29 (m, 1H),
3.32 (s, 3H), 4.25–4.36 (m, 2H), 4.58 (d, J = 6.0 Hz, 1H), 4.70 (t,
J = 6.8 Hz, 1H), 4.75 (d, J = 5.6 Hz, 1H), 5.02 (s, 1H), 7.42 (br s,
5H). 13C NMR (CDCl3): d 24.9, 26.3, 55.3 (CH2), 55.5, 60.5 (CH2),
80.4, 83.8, 84.7, 110.1, 112.9, 127.3, 128.9, 129.1, 130.8. Anal. Calcd
for C16H22O6S: C, 56.12; H, 6.48. Found: C, 56.45; H, 6.50.
CMe2
CMe2
7/8
14
-
OMe
OMe
O
O
-
RO2S
C
H
RO2S CH
O
O
O
O
2.3. Methyl (E)-5,6-dideoxy-2,3-O-isopropylidene-6-phenyl-b-D-
ribo-hex-5-enofuranoside 4
CMe2
CMe2
15
16
CBr2F2 (1 ml) was dropwise added to a vigorously stirred mix-
ture of the sulfone 3 (0.2 g, 0.58 mmol), alumina-supported KOH
(2 g),5 tBuOH (20 ml) and DCM (10 ml) kept at 5–10 °C. The reac-
tion mixture was stirred at room temperature for an additional
5 h, after which the solid catalyst was removed by suction filtration
through Celite bed. The filtrate was evaporated to dryness. The fil-
ter cake was washed thoroughly with DCM and the washes were
combined with the residue from the first filtrate. The resultant or-
ganic soln was washed with brine and water, dried and evaporated.
The residue was purified on silica gel (1:4 EtOAc–petroleum ether)
OMe
O
RO2S
O
O
CMe2
11/12
Scheme 5. Reagents and conditions: (a) DCM, tBuOH, KOH/Al2O3, 0 °C–rt, 3 h.
resulting in 4 (0.118 g, 73%). Hydroscopic solid. ½a D29:2
ꢃ40.3 (c 0.13,
ꢂ
CHCl3). 1H NMR (CDCl3): d 1.32 (s, 3H), 1.51 (s, 3H), 3.38 (s, 3H),
4.53–4.63 (m, 2H), 4.70–4.75 (m, 1H), 4.95 (s, 1H), 6.35 (dd, J = 8,
16 Hz, 1H), 6.72 (d, J = 16 Hz, 1H), 7.24–7.36 (m, 3H), 7.42–7.46
(m, 2H). 13C NMR (CDCl3): d 24.9, 26.1, 54.7, 80.9, 81.6, 85.3,
107.2, 112.6 (C), 123.2, 126.7, 127.9, 128.4, 134.3, 136.4. Anal.
Calcd for C16H20O4: C, 69.55; H, 7.30. Found: C, 70.04; H, 7.46.
Michael acceptor 15 (Scheme 5). Intramolecular cyclization of 15
generated the carbanion 16, which was protonated to afford
lyxo derivatives 11 and 12 (Scheme 5). Formation of the final prod-
uct is expected to be controlled by the stereochemical and elec-
tronic environment.8
a-L-
In conclusion, we have identified a b-D-ribo to a-L-lyxo isomer-
ization for the first time under Ramberg–Bäcklund reaction condi-
tions. Although the desired olefin was formed in the case of benzyl
sulfone derivative, the methyl- and isopropyl sulfones underwent
epimerization at C-4. We may conclude that the Ramberg–
Bäcklund SO2-extrusion reaction using CBr2F2–KOH/Al2O3 is not
an efficient reagent system for the creation of double bond at the
2.4. Methyl 5-deoxy-2,3-O-isopropylidene-5-isopropylthio-b-D-
ribofuranoside 6
A mixture of isopropylmercaptan (0.26 mL, 2.79 mmol) and
NaOMe (0.226 mg, 4.19 mmol) in DMF (10 mL) was stirred for
30 min. Compound 1 (0.5 g, 0.39 mmol) was added and the mix-
ture was heated at 90 °C with stirring under N2. After 4–5 h, the
reaction mixture was poured into satd soln of NaHCO3 (60 mL)
and the product was extracted with EtOAc (3 ꢁ 20 mL). The com-
bined organic layers were dried over anhyd Na2SO4, filtered and
the filtrate was concentrated under diminished pressure. The resi-
due was purified over silica gel (1:4 EtOAc–petroleum ether to ob-
C-5 site of 5-deoxy-2,3-O-isopropylidene-5-(alkylsulfonyl)-b-D-
ribofuranosides.
1. Experimental
2.1. General methods
tain the sulfide 6 (0.32 g, 88%). Glassy liquid. ½a D29:2
ꢃ74.0 (c 0.45,
ꢂ
Melting points were determined in open-end capillary tubes,
and are uncorrected. Carbohydrates and other fine chemicals were
obtained from commercial suppliers and are used without purifica-
tion. Solvents were dried and distilled following the standard pro-
cedures. TLC was carried out on precoated plates (Merck Silica Gel
60, F254), and the spots were visualized with UV light or by charring
the plates dipped in 5% H2SO4/MeOH soln. Column chromatogra-
phy was performed on silica gel (60–120 or 230–400 mesh). 1H
and 13C NMR spectra for most of the compounds were recorded
at 200/400 and 50.3/100 MHz, respectively, in CDCl3 unless stated
otherwise. Optical rotations were recorded at 589 nm.
CHCl3). 1H NMR (CDCl3): d 1.27 (m, 6H), 1.32 (s, 3H), 1.48 (s, 3H),
2.51–2.62 (m, 1H), 2.76–2.80 (m, 1H), 2.94–3.02 (m, 1H), 3.34 (s,
3H), 4.21–4.25 (m, 1H), 4.59 (d, J = 6 Hz, 1H), 4.70 (d, J = 5.6 Hz,
1H), 4.96 (s, 1H). 13C NMR (CDCl3): d 23.3, 23.4, 24.8, 26.3, 34.0
(CH2), 34.7, 54.9, 83.3, 85.2, 86.1, 109.5, 112.3 (C). HRESIMS: calcd
for C12H22O4SNa [M+Na]+: 285.1137; found: 285.1142.
2.5. Methyl 5-deoxy-2,3-O-isopropylidene-5-methylsulfonyl-b-
D-ribofuranoside 7
Compound 5 (0.28 g, 1.19 mmol) was converted to 7 (0.29 g,
91%) following the general procedure described above for the syn-
2.2. Methyl 5-benzylsulfonyl-5-deoxy-2,3-O-isopropylidene-b-
thesis of compound 3. White solid. Mp: 62 °C. ½a D29:2
ꢃ21.1 (c 0.2,
ꢂ
D-ribofuranoside 3
CHCl3). 1H NMR (CDCl3): d 1.32 (s, 3H), 1.48 (s, 3H), 3.01 (s, 3H),
3.14–3.19 (m, 1H), 3.38–3.44 (m, 4H), 4.62 (d, J = 5.6 Hz, 1H),
4.71–4.75 (m, 2H), 5.01 (s, 1H). 13C NMR (CDCl3): d 24.9, 26.3,
41.9, 55.8, 58.9 (CH2), 81.2, 83.8, 84.6, 110.4, 113.0 (C). HRESIMS:
calcd for C10H18O6SNa [M+Na]+: 289.0722; found: 289.0729.
To a well-stirred soln of 2 (0.45 g, 1.45 mmol) in dry MeOH
(40 mL) was added MMPP (3.6 g, 7.25 mmol), and the mixture
was stirred under N2. After 6 h, MeOH was evaporated to dryness
under diminished pressure and the residue was dissolved in satd.

T. K. Pal, T. Pathak / Carbohydrate Research 343 (2008) 2826–2829
2829
2.6. Methyl 5-deoxy-2,3-O-isopropylidene-5-isopropylsulfonyl-
4.48 (m, 1H), 4.57 (d, J = 5.8 Hz, 1H), 4.70–4.73 (m, 1H), 4.90 (s,
1H). 13C NMR (CDCl3): d 13.9, 16.1, 24.7, 25.9, 49.4 (CH2), 53.7,
54.6, 73.8, 80.2, 84.5, 106.9, 112.7. HRMS [ES+, (M+Na)+] calcd for
C12H22O6SNa: 317.1035; obsd, 317.1030.
b-
D-ribofuranoside 8
Compound 6 (0.5 g, 1.9 mmol) was converted to 8 (0.51 g, 92%)
following the procedure described for the synthesis of 3. White so-
lid. Mp: 67 °C. ½a D29:2
ꢂ
ꢃ72.0 (c 0.12, CHCl3). 1H NMR (CDCl3): d 1.32
Acknowledgements
(s, 3H), 1.40 (s, 3H), 1.41 (s, 3H), 1.48 (s, 3H), 3.07–3.12 (m, 1H),
3.17–3.24 (m, 1H), 3.33–3.38 (m, 4 H), 4.62 (d, J = 6 Hz, 1H), 4.75
(t, J = 6.8 Hz, 1H), 4.83 (d, J = 5.6 Hz, 1H), 4.99 (s, 1H). 13C NMR
(CDCl3): d 14.4, 15.7, 24.9, 26.3, 53.1 (CH2), 53.7, 55.5, 80.6, 83.9,
84.7, 110.2, 112.9. HRESIMS: calcd for C12H22O6SNa [M+Na]+:
317.1035; found: 317.1047.
T.K.P thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India for a fellowship. Financial support by the
Department of Science and Technology (DST), New Delhi, India is
gratefully acknowledged. DST is also thanked for the creation of
400 MHz facility under IRPHA program and DST-FIST for single
crystal X-ray facility.
2.7. Methyl 5-deoxy-2,3-O-isopropylidene-5-methylsulfonyl-
a-
Supplementary data
L
-lyxofuranoside 11
Complete crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 688742. Copies of this information may be obtained free
of charge from the Director, Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge, CB21EZ, UK (fax: +44-1223-
336033, e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.a-
c.uk), and spectra of 3–4, 6–8, 11–12 all new compounds. Full 1H
NMR and 13C NMR are available online. Supplementary data asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.carres.2008.08.010.
The mixture of the sulfone 7 (0.1 g, 0.37 mmol), alumina-sup-
ported KOH (2 g),5 tBuOH (20 ml) and DCM (10 ml) was stirred vig-
orously at room temperature for 3 h. Then the solid catalyst was
removed by suction filtration through Celite bed. The filtrate was
evaporated to dryness. The filter cake was washed thoroughly with
DCM and the washes were combined with the residue from the
first filtrate. The resultant organic soln was washed with brine
and water, dried and evaporated. The residue was purified on silica
gel (1:4 EtOAc–petroleum ether) to 11 (0.076 g, 76%). Glassy liquid.
½
a 2D9:2
ꢂ
ꢃ72.9 (c 0.75, CHCl3). 1H NMR (CDCl3): d 1.30 (s, 3H), 1.45 (s,
3H), 3.04 (s, 3H), 3.23–3.27 (m, 1H), 3.33 (s, 3H), 3.40–3.47 (m, 1H),
4.43–4.47 (m, 1H), 4.58 (d, J = 6 Hz, 1H), 4.71–4.73 (m, 1H), 4.92 (s,
1H). 13C NMR (CDCl3): d 24.6, 25.9, 42.5, 54.7, 54.8 (CH2), 74.2, 80.2,
84.4, 107.0, 112.8. HRESIMS: calcd for C10H18O6SNa [M+Na]+:
289.0722; found: 289.0718.
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2.8. Methyl 5-deoxy-2,3-O-isopropylidene-5-isopropylsulfonyl-
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a
-
L-lyxofuranoside 12
4. (a) Ingles, D. L.; Whistler, R. L. J. Org. Chem. 1962, 27, 3896–3898; (b) Pakulski, Z.;
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Compound 8 (0.1 g, 0.34 mmol) was converted to 12 (0.065 g,
65%) following the procedure described for the synthesis of 11.
White solid. Mp: 72 °C. ½a D29:2
ꢂ
ꢃ36.5 (c 0.15, CHCl3). 1H NMR
(CDCl3): d 1.31 (s, 3H), 1.39 (s, 3H), 1.43 (s, 3H), 1.44 (s, 3H),
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3.14–3.24 (m, 1H), 3.26–3.37 (m, 4H), 3.42–3.54 (m, 1H), 4.43–