Vinyl sulfone modified hex-3-enopyranosides: novel routes to C3-C4 and C4-C5 cyclopropanated pyranosides

Article abstract of DOI:10.1002/ejoc.200900553

In a departure from metal-based cyclopropanation reactions, 4-sulfon.ylhex-3-ernopyranosides carrying a leaving group at either of the two γ-positions are used as efficient intermediates for the synthesis of C3-C4 and C4-C5 cyclopropanated pyranosides.

Full text of DOI:10.1002/ejoc.200900553

FULL PAPER
DOI: 10.1002/ejoc.200900553
Vinyl Sulfone Modified Hex-3-enopyranosides: Novel Routes to C3–C4 and
C4–C5 Cyclopropanated Pyranosides
Rahul Bhattacharya,[a] Debanjana Dey,[a] and Tanmaya Pathak*[a]
Keywords: Small-ring systems / Cyclization / Carbohydrates / Michael addition / Vinyl sulfone
In a departure from metal-based cyclopropanation reactions,
4-sulfonylhex-3-enopyranosides carrying a leaving group at
either of the two γ-positions are used as efficient intermedi-
ates for the synthesis of C3–C4 and C4–C5 cyclopropanated
pyranosides.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
branched chain sugar, easily synthesized from 4-sulfo-
nylhex-3-enopyranoside, would be a useful intermediate for
the preparation of otherwise inaccessible C3–C4 cyclopro-
panated pyranoside (Scheme 1). Moreover, the cyclopro-
pane ring attached to an electron-withdrawing group like
sulfone would be cleaved by electrophiles to afford new
ionic intermediates[1b] useful for further synthetic manipu-
lations. We therefore decided to synthesize and study the
reaction patterns of 4-sulfonylhex-3-enopyranoside ana-
logues 1 and 2 (Figure 1). It should be noted that barring
the sole report on the cycloaddition reactions of a 4-sul-
fonylhex-3-enopyranoside, the strategy for the functionali-
zation of the C3 carbon atom of a pyranoside ring of 4-
sulfonylhex-3,4-enopyranosides for the generation of
branched-chain sugars has not been explored at all.[8]
Introduction
Construction of cyclopropanes on carbohydrates has
been identified as an important area of research in synthetic
chemistry.[1] This particular combination offers a class of
strained and reactive cyclopropanes embedded in chiral ap-
pendages. Development of strategies for the synthesis of
this class of compounds is important, because in general,
chemists have long been fascinated by the presence of cyclo-
propane subunits in a wide range of natural products and
the usefulness of this strained cycloalkane in synthetic
chemistry.[2] Moreover, barring a few reports, the large
number of metal-mediated synthetic routes to cyclopro-
pane-fused furanosyl[1–3] and pyranosyl[2,4] carbohydrates
are based on the ritualistic use of glycals as starting materi-
als. Although glycals are suitable intermediates for the syn-
thesis of C1–C2 and C4–C5 cyclopropanated pyranosides,
there is virtually no method available till today for the syn-
thesis of C3–C4 cyclopropanated pyranosides.[1]
The attack of a nucleophile on the electron-deficient
double bond of “3-halo-1-alkenylsulfone” was used about
three decades back as an efficient strategy for the formation
of cyclopropanes.[5] However, the strategy remained grossly
underutilized mainly because of the unavailability of suit-
able vinyl sulfone based starting materials.[6] We realized the
vast potential of suitably designed vinyl sulfone modified
carbohydrates in the generation of a wide range of cyclo-
propanated carbohydrates.[7] We therefore opined that a 4-
sulfonylhex-3-enopyranoside carrying a leaving group at the
γ-position would be an effective intermediate for the syn-
thesis of a new class of C4–C5 cyclopropanated pyranos-
ides. We also envisaged that a suitably modified C3-
[a] Department of Chemistry, Indian Institute of Technology,
Kharagpur 721302, India
Fax: +91-3222-282252
E-mail: tpathak@chem.iitkgp.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900553.
Scheme 1. Strategy for the synthesis of cyclopropanated pyranos-
ides.
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R. Bhattacharya, D. Dey, T. Pathak
FULL PAPER
Figure 1. 4-Sulfonylhex-3-enopyranosides: the target molecules.
Results and Discussion
A retrosynthetic analysis of the route to 1 and 2 necessi-
tated the introduction of the tolylthio group at the C4 posi-
tion of a hexopyranosyl sugar. One of the easiest ways of
forming a C–S bond would be the regioselective displace-
ment of suitably oriented and protected sulfonates or re-
gioselective ring opening of epoxides derived from carbo-
hydrates. However, it is reported that ring-opening reactions
at C3–C4 of epoxy sugars is not strictly regioselective.[9]
Moreover, the retrosynthetic analysis also revealed that 4-
thiopyranosides would be more easily accessible from 4-O-
mesylates. Therefore, 4-O-mesylate 5 (Scheme 2) was used
as a common starting material for the synthesis of both 1
and 2. Thus, known diol 3[10] was tritylated at room tem-
perature by using trityl chloride and pyridine to afford 4
within 48 h (Scheme 2). Mesylation of 4 afforded required
mesylate derivative 5 in 81% overall yield. Fully protected
α-glucomesylate 5 was treated with p-thiocresol in DMF in
the presence of 1,1,3,3-tetramethylguanidine (TMG) at
150–160 °C to afford galacto-derivative 6, as expected[11] in
89% yield within 5 h. Treatment of compound 6 with meth-
anolic NaOMe at reflux temperature for 7 h afforded com-
pound 7 in 97% yield. The corresponding sulfone derivative
8 was generated in quantitative yield within 6 h at room
temperature by oxidizing 7 with magnesium monop-
eroxyphthalate hexahydrate (MMPP) in MeOH. Com-
pound 8 was subjected to an elimination reaction by using
MsCl in pyridine at 0 to +4 °C to afford 1 in 88% yield
(Scheme 2).
Scheme 2. Synthesis of 6-O-tritylated vinyl sulfone modified hex-4-
enopyranoside 1.
Scheme 3. Synthesis of 6-O-mesylated vinyl sulfone-modifies hex-
4-enopyranoside 2.
For the synthesis of vinyl sulfone 2, compound 7 was
detritylated within 4 h using AcCl in MeOH at room tem-
perature to afford the diol 9 in high yield. Oxidation of the
sulfide 9 produced the corresponding sulfone 10, which was
subjected to mesylation to get the desired vinyl sulfone 2 in
76% overall yield (Scheme 3). Identities of vinyl sulfones 1
and 2 were established on the basis of spectroscopic and
analytical data. In both the cases the vinyl protons ap-
peared at δ = 6.86–6.96.
the bulky substituent at C3 preferred to orient itself at the
equatorial position and thus among all other possibilities,
the most stable products were formed. It should be noted
that compounds 11 and 12 represent a special class of
branched-chain sugars reported for the first time.[12]
Compound 1, upon reaction with nitromethane in the
presence of tBuOK in THF at reflux temperature, generated
a single compound 11 in 71% yield within 10 h. Dimethyl
malonate, in contrast, under similar reaction conditions af-
forded compound 12 in 77% yield in 16 h (Scheme 4). Com-
pounds 11 and 12 were identified as diequatorial products
(see later), which are expected to form because these are
thermodynamically more stable. Although it is difficult to
pinpoint the exact reasons for the diastereoselectivity of the
addition of nucleophiles to 1, it may be argued that the
Scheme 4. C3 Branched-chain sugars from 1.
In order to synthesize C3–C4 cyclopropanated pyranos-
incoming nucleophile added to C3 from a direction oppo- ides from branched-chain sugar 11, it was subjected to a
site to the disposition of the C2 OBn group; additionally, modified Nef carbonyl synthesis[13] to generate correspond-
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Novel Routes to C3–C4 and C4–C5 Cyclopropanated Pyranosides
ing aldehyde 13 (Scheme 5). The aldehyde was then reduced Hg in dry MeOH at room temperature, underwent desulfo-
with NaBH4 to the corresponding alcohol, and the alcohol nylation to afford compound 20 in 67% yield (Scheme 6).[14]
was mesylated under standard conditions. Crude mesylate The structure of compound 17 was unambiguously con-
14 was subjected to ring closure involving an intramolecular firmed by X-ray diffraction of the single crystals (Figure 2).
alkylation reaction in the presence of tBuOK dispersed in Because 17 was formed via 16 we assigned the gluco config-
THF to afford compound 15 in 63% overall yield uration to the latter. Cyclopropane 19 and corresponding
(Scheme 5). Attempted desulfonylation of 15 by using Mg/ branched-chain sugar 18 were expected to follow the same
MeOH or Na/Hg generated inseparable mixtures. Com- reaction pattern (Scheme 6). Compounds 11 and 12 were
pound 2, upon reaction with nitromethane in the presence identified unambiguously by converting them into 16 and
1
of tBuOK in THF at reflux temperature, generated a sepa- 18, respectively (Scheme 6; mixed H NMR spectroscopy).
rable mixture of compounds 16 and 17 (Scheme 6). The It may be argued that cyclopropane ring formation for com-
mixture was separated over silica gel and compound 16 was pounds 15, 17 and 19 was possible only if the attack of the
treated with a suspension of tBuOK in THF for 2 h at room C4 carbanion took place from the β-face of the sugar ring.
temperature to afford compound 17 in 83% combined
yield. Similarly, dimethyl malonate in the presence of
tBuOK in THF afforded compound 18 and 19. Separation
of the mixture over silica gel and treatment of compound
18 with tBuOK in THF afforded compound 19 in 81%
combined yield. Compound 19, upon treatment with Na/
Figure 2. Crystal structure (ORTEP) of 17.
Conclusions
We have established a new strategy for the synthesis of a
hitherto unknown C3–C4 cyclopropanated pyranoside
from new branched chain sugars. On the other hand, a C3-
Scheme 5. Synthesis of C3–C4 cyclopropanated pyranoside 15.
branched chain sugar was used to synthesize C4–C5 cyclo-
propanated pyranosides in one step. These diverse classes
of cyclopropanated pyranosides were obtained from closely
related vinyl sulfone modified carbohydrates. Additionally,
this novel route also provides access to “acceptor” cyclo-
propanes ready to undergo further transformations.
Experimental Section
General Methods: All reactions were conducted under a N2 atmo-
sphere. Melting points were determined in open-end capillary tubes
and are uncorrected. Carbohydrates and other fine chemicals were
obtained from commercial suppliers and were used without purifi-
cation. Solvents were dried and distilled following 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 plate dipped in 5% H2SO4/MeOH solution. Column
chromatography was performed on silica gel (230–400 mesh). 1H
and 13C NMR for most of the compounds were recorded at 200/
400 and 50/100 MHz, respectively at 25 °C. DEPT experiments
were carried out to identify the methylene carbon atoms. Optical
rotations were recorded at 589 nm.
Methyl 2-O-Benzyl-3-O-benzoyl-4-deoxy-4-(4-methylphenyl)sulfan-
yl-6-O-triphenylmethyl-α- -galactopyranoside 6: To a solution of
Scheme 6. Synthesis of C4–C5 cyclopropanated pyranosides 17, 19
and 20.
D
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R. Bhattacharya, D. Dey, T. Pathak
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known compound 3 (4.2 g, 10.45 mmol) in dry pyridine (35 mL)
was added trityl chloride (4.37 g, 15.7 mmol), and the reaction mix-
ture was stirred at room temperature for 48 h under an atmosphere
of N2. The resulting solution was then cooled to 0 °C. To this co-
oled solution was added dropwise methanesulfonyl chloride
(3.2 mL, 42 mmol) in dry pyridine (15 mL) at 0 °C. The mixture
was left overnight at 4 °C. The reaction mixture was poured into
saturated aqueous NaHCO3 (70 mL), and the aqueous phase was
extracted with dichloromethane (3ϫ30 mL). The organic extracts
were collected together, dried with anhydrous Na2SO4 and filtered,
and the filtrate was evaporated under reduced pressure. The re-
sulting residue was purified over silica gel to yield white solid 5
(5.9 g, 72% over two steps). To a well-stirred solution of p-thio-
cresol (4.3 g, 34.63 mmol) and TMG (4.56 g, 36.36 mmol) in dry
DMF (20 mL) was added a solution of compound 5 (5.0 g,
6.92 mmol) in dry DMF (10 mL), and the resulting solution was
heated at 150–160 °C under an atmosphere of N2 for a period of
6 h, cooled to room temperature and poured into saturated aque-
ous NaCl solution (80 mL). The mixture was extracted with EtOAc
(3ϫ30 mL). The EtOAc layer was dried with anhydrous Na2SO4
and evaporated under reduced pressure. The resulting syrup was
purified over silica gel (EtOAc/petroleum ether, 1:3) to yield 6
(4.53 g, 89%). Colourless jelly. [α]3D0 = +46.2 (c = 0.625, CHCl3).
1H NMR (200 MHz, CDCl3): δ = 2.06 (s, 3 H), 3.34–3.39 (m, 1
H), 3.43 (s, 3 H), 3.56–3.59 (m, 1 H), 3.90–3.93 (m, 1 H), 4.08–4.15
(m, 2 H), 4.64–4.75 (m, 3 H), 5.47–5.52 (m, 1 H), 6.64 (d, J =
7.98 Hz, 2 H), 7.01 (d, J = 8.10 Hz, 2 H), 7.12–7.41 (m, 16 H),
7.43–7.52 (m, 8 H), 7.79–7.83 (m, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 20.7, 54.3, 55.0, 64.6 (CH2), 68.5, 72.8, 73.2 (CH2),
74.7, 86.9, 98.4, 126.9, 127.6, 127.8, 128.2, 128.5, 129.2, 129.5,
129.6, 131.5, 132.0, 132.6, 136.4, 137.9, 143.8, 165.5 ppm. HRMS
(ESI+): calcd. for C47H45O6S [M + H] 737.2937; found 737.2933.
chloride (1.0 mL, 13.6 mmol) in dry pyridine (5 mL) at 0 °C. The
mixture was left overnight at 4 °C. The reaction mixture was
poured into saturated aqueous NaHCO3 (70 mL), and the aqueous
phase was extracted with dichloromethane (3ϫ30 mL). The or-
ganic extracts were collected together, dried with anhydrous
Na2SO4 and filtered. Et3N (5 mL) was added to the filtrate, and
after 15 min the solvent was evaporated under reduced pressure.
The resulting residue was purified over silica gel (EtOAc/petroleum
ether, 1:3) to yield 1 (2.56 g, 88%). White solid. M.p. 132–134 °C.
1
[α]3D0 = –18.7 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ =
2.40 (s, 3 H), 3.19–3.23 (m, 1 H), 3.33 (s, 1 H), 3.50–3.54 (m, 1 H),
4.23–4.25 (m, 1 H), 4.30–4.31 (m, 1 H), 4.63 (d, J = 12.4 Hz, 1 H),
4.75 (d, J = 12.4 Hz, 1 H), 4.84 (d, J = 3.2 Hz, 1 H), 7.11 (d, J =
0.4 Hz, 1 H), 7.16–7.32 (m, 22 H), 7.33 (d, J = 7.2 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 21.6, 55.5, 64.3 (CH2), 68.9,
71.9, 72.0 (CH2), 86.7, 96.3, 126.9, 127.7, 127.9, 128.1, 128.2, 128.6
128.7, 129.6, 136.4, 137.0, 138.2, 138.9, 143.7, 144.2 ppm. HRMS
(ESI+): calcd. for C40H39O6S [M + H]+ 647.2467; found 647.2463.
Methyl
mesyl-α-
2-O-Benzyl-3,4-dideoxy-4-(4-methylphenyl)sulfonyl-6-O-
D-erythro-hex-3-enopyranoside (2): To a solution of com-
pound 7 (3.8 g, 6.0 mmol) in MeOH (40 mL) at 0 °C was added
acetyl chloride (0.1 mL, 1.40 mmol). The reaction mixture was
stirred for 4 h (TLC) at ambient temperature. The volatile matters
were evaporated under reduced pressure, and the residual reaction
mixture was worked up in the usual way (see above) to yield 9. To a
solution of crude 9 in MeOH (40 mL) was added MMPP (10.75 g,
21.74 mmol). The reaction mixture was stirred for 6 h at ambient
temperature and filtered, and the filtrate was evaporated under re-
duced pressure. The resulting residue was neutralized with satu-
rated aqueous NaHCO3 (70 mL). The mixture was worked up in
the usual way to yield 10. Compound 10 was converted into 2
(2.21 g, 76%) by following the procedure described for the synthesis
Methyl
phenylmethyl-α-
2-O-Benzyl-4-deoxy-4-(4-methylphenyl)sulfanyl-6-O-tri-
-galactopyranoside (7): To a solution of 6 (4.0 g,
of 1. Colourless jelly (eluent: EtOAc/petroleum ether, 1:3). [α]3D0
=
1
D
–24.3 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 2.37 (s,
3 H), 2.90 (s, 3 H), 3.21 (s, 3 H), 4.15–4.18 (m, 1 H), 4.21–4.22 (m,
1 H), 4.40–4.44 (m, 1 H), 4.51–4.57 (m, 2 H), 4.67 (d, J = 12.4 Hz,
1 H), 4.76 (d, J = 3.6 Hz, 1 H), 6.97 (s, 1 H), 7.05–7.38 (m, 7 H),
7.67 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.6, 37.5, 55.9, 66.8, 69.5 (CH2), 71.6, 72.2 (CH2), 96.5, 127.8,
128.1, 128.3, 128.6, 130.0, 135.6, 136.1, 136.8, 140.0, 145.1 ppm.
HRMS (ESI+): calcd. for C22H27O8S2 [M + H]+ 483.1147; found
483.1143.
5.43 mmol) in MeOH (30 mL) was added NaOMe (0.3 g,
5.55 mmol), and the resulting solution was heated at reflux under
an atmosphere of N2 for 7 h, cooled to room temperature and the
solvent was evaporated. The residue thus obtained was dissolved
in EtOAc (30 mL). The organic layer was washed with saturated
aqueous NH4Cl solution (2ϫ20 mL) and separated. The organic
layer was then dried with anhydrous Na2SO4 and concentrated un-
der reduced pressure to get crude 7 (1.63 g, 97%). Colourless jelly
(eluent: EtOAc/petroleum ether, 1:3). [α]3D0 = +41.9 (c = 0.31,
Methyl 2-O-Benzyl-3,4-dideoxy-3-C-nitromethyl-4-(4-methylphen-
yl)sulfonyl-6-O-triphenylmethyl-α-D-glucopyranoside (11): To a sus-
1
CHCl3). H NMR (200 MHz, CDCl3): δ = 2.31 (s, 3 H), 3.33 (s, 3
H), 3.38–3.52 (m, 2 H), 3.56–3.60 (m, 2 H), 3.90–3.92 (m, 1 H),
4.14–4.23 (m, 1 H), 4.60–4.76 (m, 3 H), 5.47–5.52 (m, 1 H), 6.99 (d,
J = 7.97 Hz, 2 H), 7.21–7.47 (m, 22 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.0, 55.1, 59.4, 64.4 (CH2), 68.8, 69.1, 73.1 (CH2),
78.5, 87.0, 98.1, 127.0, 127.1, 127.8, 127.9, 128.1, 128.4, 128.6,
129.7, 132.5, 137.1, 138.0, 143.8 ppm. HRMS (ESI+): calcd. for
C40H41O5S [M + H] 633.2675; found 633.2673.
pension of 90% tBuOK (0.33 g, 2.94 mmol) in dry THF (5 mL) at
0 °C was added CH3NO2 (0.15 mL, ≈2.5 mmol), and the resulting
solution was stirred for 15 min at that temperature under an atmo-
sphere of N2. A solution of 1 (0.33 g, 0.5 mmol) in dry THF
(10 mL) was added dropwise to the reaction mixture. The resulting
solution was then heated at reflux with continuous stirring under
an atmosphere of N2 for 10–16 h. The reaction mixture was cooled
to room temperature, and the volatile matters were evaporated un-
der reduced pressure. The residue obtained was triturated with
EtOAc (30 mL). The organic layer was washed with a saturated
aqueous solution of NH4Cl (3ϫ30 mL) and separated. The or-
ganic layer was dried with anhydrous Na2SO4 and filtered, and the
filtrate was evaporated under reduced pressure to get a residue. The
crude residue was then purified by column chromatography over
silica gel (EtOAc/petroleum ether, 1:4) to obtain 11 (0.26 g, 71%).
White solid. M.p. 131–133 °C. [α]2D8 = +24.7 (c = 0.625, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.97–3.03 (m, 1
H), 3.17–3.21 (m, 1 H), 3.28 (s, 3 H), 3.50–3.53 (m, 1 H), 3.58–3.62
(m, 1 H), 3.96–4.02 (m, 1 H), 4.05–4.09 (m, 1 H), 4.56–4.66 (m, 3
Methyl 2-O-Benzyl-3,4-dideoxy-4-(4-methylphenyl)sulfonyl-6-O-tri-
phenylmethyl-α-D-erythro-hex-3-enopyranoside (1): To a solution of
compound 7 (3.8 g, 6.0 mmol) in MeOH (40 mL) was added
MMPP (10.75 g, 21.74 mmol), and the reaction mixture was stirred
for 6 h at room temperature. The reaction mixture was filtered, and
the filtrate was evaporated under reduced pressure. The resulting
residue was neutralized with saturated aqueous NaHCO3 (70 mL).
The mixture was extracted with EtOAc (3ϫ30 mL). The organic
layer was separated and dried with anhydrous Na2SO4 and filtered,
and the filtrate was concentrated to dryness under reduced pressure
to yield 8 quantitatively (3.9 g). To a solution of 8 (3.0 g,
4.52 mmol) in dry pyridine (15 mL) was added methanesulfonyl
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Novel Routes to C3–C4 and C4–C5 Cyclopropanated Pyranosides
H), 5.02–5.15 (m, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.23–7.38 (m, 20 derivatives (slower moving compound by TLC) was then treated
H), 7.45 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): with a suspension of 90% tBuOK (0.17 g, 1.6 mmol) in dry THF
δ = 21.6, 34.7, 55.1, 59.7, 64.5 (CH2), 66.5, 72.7 (CH2), 73.8 (CH2),
75.2, 86.6, 95.0, 127.0, 127.7, 128.2, 128.3, 128.4, 128.6, 128.7,
129.9, 135.2, 137.1, 143.7, 145.0 ppm. HRMS (ESI+): calcd. for
C41H42NO8S [M + H]+ 708.2631; found 708.2630.
(5 mL) at room temperature for 2 h under an atmosphere of N2.
The volatile matters were then evaporated under reduced pressure.
The residue obtained in each case was triturated with EtOAc
(30 mL). The organic layer was washed with a saturated aqueous
solution of NH4Cl (3ϫ30 mL) and separated. The organic layer
was dried with anhydrous Na2SO4 and filtered, and the filtrate was
evaporated under reduced pressure to get a residue. The crude resi-
due obtained in each case was then purified over silica gel (EtOAc/
petroleum ether, 1:4) and the pure product was combined with the
previously obtained desired cyclopropane derivative to afford 17
Methyl 2-O-Benzyl-3,4-dideoxy-3-C-bis(methoxycarbonyl)methyl-4-
(4-methylphenyl)sulfonyl-6-O-triphenylmethyl-α-D-glucopyranoside
(12): Following the procedure described for the preparation of 11,
H2C(CO2Me)2 (0.15 mL, ≈2.5 mmol) was treated with 1 (0.33 g,
0.5 mmol) to get compound 12 within 16 h (0.31 g, 77%). White
solid (eluent: EtOAc/petroleum ether, 1:4). M.p. 112–114 °C. [α]2D8
= +31.2 (c = 0.625, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.41
(s, 3 H), 3.15 (s, 3 H), 3.18–3.25 (m, 1 H), 3.42–3.46 (m, 1 H), 3.50
(s, 3 H), 3.58–3.60 (m, 1 H), 3.67 (s, 3 H), 3.75–3.84 (m, 1 H), 3.98–
4.02 (m, 1 H), 4.39–4.43 (m, 1 H), 4.46–4.48 (m, 2 H), 4.54–4.60
(m, 2 H), 7.21–7.37 (m, 17 H), 7.40–7.48 (m, 5 H), 7.56 (d, J =
8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 36.1,
49.5, 52.1, 52.3, 54.9, 61.6, 64.9 (CH2), 66.9, 72.8 (CH2), 74.7, 95.6,
126.9, 127.7, 127.8, 127.9, 128.2, 128.5, 129.0, 129.6, 134.9, 137.8,
143.9, 144.7, 168.8, 169.2 ppm. HRMS (ESI+): calcd. for
C45H47O10S [M + H]+ 779.9137; found 779.9136.
(0.185 g, 83%). White crystalline solid. M.p. 141–143 °C [α]2D8
=
+35.1 (c = 0.625, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.07–
1.10 (m, 1 H), 1.96–1.99 (m, 1 H), 2.48 (s, 3 H), 2.93 (s, 3 H), 3.20–
3.26 (m, 2 H), 3.74–3.76 (m, 1 H), 4.24 (s, 1 H), 4.44–4.50 (m, 2
H), 4.54–4.59 (m, 1 H), 5.14–5.17 (m, 1 H), 7.21–7.34 (m, 5 H),
7.42 (d, J = 8.0 Hz, 2 H), 7.83 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 15.5 (CH2), 21.7, 32.3, 42.2, 51.5, 55.3,
72.9 (CH2), 76.1 (CH2), 77.2, 95.1, 128.1, 128.3, 128.4, 128.5, 129.8,
133.6, 136.7, 145.2 ppm. HRMS (ESI+): calcd. for C22H26NO7S
[M + H]+ 448.1430; found 448.1428.
Methyl 2-O-Benzyl-4,6-cyclo-3-C-bis(methoxycarbonyl)methyl-4-(4-
methylphenyl)sulfonyl-3,4,6-trideoxy-α-D-glucopyranoside (19): Fol-
Methyl 2-O-Benzyl-3,4-dideoxy-3,4-cyclo-C-methylene-4-(4-meth-
ylphenyl)sulfonyl-6-O-triphenylmethyl-α-
D-glucopyranoside
(15):
lowing the procedure described for the preparation of 17,
H2C(CO2Me)2 (0.15 mL, ≈2.5 mmol) was treated with 2 (0.24 g,
0.5 mmol) to get compound 19 within 8 h. Yield: 0.21 g, 81%.
Colourless jelly (eluent: EtOAc/petroleum ether, 1:4). [α]2D8 = +37.1
(c = 0.625, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.32–1.35
(m, 1 H), 1.86–1.89 (m, 1 H), 2.46 (s, 3 H), 3.02 (s, 3 H), 3.07 (s, 3
H), 3.46 (s, 3 H), 3.48–3.51 (m, 1 H), 3.77 (s, 3 H), 4.02–4.05 (m,
1 H), 4.22–4.33 (m, 3 H), 4.43–4.46 (m, 1 H), 4.58–4.62 (m, 2 H),
4.74–4.77 (m, 1 H), 7.19–7.29 (br. s, 5 H), 7.40 (d, J = 8.0 Hz, 2
H), 7.80 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 21.7, 36.0, 37.6, 49.4, 52.4, 55.3, 61.4, 64.8, 71.1 (CH2), 72.9
(CH2), 74.4, 95.7, 128.0, 128.3, 128.5, 129.5, 130.0, 133.0, 137.4,
145.8, 168.8, 168.9 ppm. HRMS (ESI+): calcd. for C26H31O9S [M
+ H]+ 519.1689; found 519.1682.
Compound 11 (0.71 g, 1 mmol) was dissolved in tBuOH (30 mL)
at 60 °C. To the warm solution was added tBuOK (0.28 g,
2.5 mmol). The mixture was stirred under an atmosphere of N2 for
20 min while cooling to room temperature and then ethyl acetate
(75 mL) was added. This was immediately followed by an ice-cold
solution of KMnO4 (0.156 g, 1 mmol) in water (30 mL). The mix-
ture was stirred vigorously for 20 min, and then the mixture was
extracted with EtOAc (3ϫ10 mL). The combined organic layers
were dried with anhydrous Na2SO4 and filtered, and the filtrate
was concentrated under reduced pressure to get residue 13. The
crude residue was dissolved in ethanol (10 mL), cooled in an ice
bath and sodium borohydride (2.5 equiv/mmol) was added; the
solution was stirred for 16 h. Then the reaction mixture was poured
into ice-cold water, and the mixture was extracted with EtOAc
(3ϫ10 mL). The combined organic layers were dried with anhy-
drous Na2SO4 and filtered, and the filtrate was concentrated under
reduced pressure to get a residue. The residue was then mesylated
by using standard conditions, and the mesylate derivative was
treated with tBuOK (0.34 g, 3.0 mmol) and THF (3 mL) for 3 h at
room temperature to get a residue. The resulting residue was puri-
fied over silica gel (EtOAc/petroleum ether, 1:4) to afford 15
(0.43 g, 65%). Colourless jelly. [α]2D8 = +17.1 (c = 0.625, CHCl3).
1H NMR (400 MHz, [D6]DMSO): δ = 0.89–0.93 (m, 1 H), 1.53–
1.57 (m, 1 H), 1.71–1.76 (m, 1 H), 2.42 (s, 3 H), 2.84–2.88 (m, 1
H), 3.00 (s, 3 H), 3.35–3.39 (m, 2 H), 4.20 (d, J = 7.2 Hz, 1 H),
4.49–4.59 (m, 3 H), 7.24–7.38 (m, 22 H), 7.52 (d, J = 8.0 Hz, 2
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 11.8 (CH2), 18.8,
20.9, 21.5, 54.9, 64.5, 65.1 (CH2), 70.6 (CH2), 72.2, 86.4, 94.4,
127.5, 128.0, 128.2, 128.3, 128.6, 128.7, 128.9, 129.9, 135.3, 138.5,
144.1, 144.9 ppm. HRMS (ESI+): calcd. for C41H41O6S [M + H]+
661.2624; found 661.2621.
Methyl
3,4,6-trideoxy-α-
2-O-Benzyl-4,6-cyclo-3-C-bis(methoxycarbonyl)methyl-
-glucopyranoside (20): Compound 19 (0.2 g,
D
0.4 mmol) was desulfonylated at room temperature by using Na/
Hg (6%)[7b] in MeOH in 4 h to afford 20 (0.095 g, 67%). Colourless
jelly (eluent: EtOAc/petroleum ether, 1:4). [α]2D8 = +34.8 (c = 0.625,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.30–0.33 (m, 1 H),
0.55–0.58 (m, 1 H), 1.46–1.50 (m, 1 H), 3.13–3.15 (m, 1 H), 3.32–
3.39 (m, 2 H), 3.41 (s, 3 H), 3.58 (s, 3 H), 3.64 (d, J = 6.4 Hz, 1
H), 3.69 (s, 3 H), 4.39 (s, 1 H), 4.50 (s, 2 H), 7.28–7.36 (m, 5
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 9.81 (CH2), 14.8, 33.1,
47.3, 52.2, 53.6, 55.5, 72.5 (CH2), 76.4, 95.8, 127.8, 128.1, 128.3,
137.8, 168.8, 169.1 ppm. HRMS (ESI+): calcd. for C19H25O7 [M +
H]+ 365.1600; found 365.1601.
CCDC-732518 (for 17) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
Methyl 2-O-Benzyl-4,6-cyclo-3-C-nitromethyl-4-(4-methylphenyl)-
sulfonyl-3,4,6-trideoxy-α-D-glucopyranoside (17): Following the pro-
1
cle): H and 13C NMR spectra for new compounds.
cedure described for the addition of C-nucleophiles to 1, CH3NO2
(0.15 mL, ≈ 2.5 mmol) was treated with 2 (0.24 g, 0.5 mmol) to af-
ford a mixture of two compounds within 8 h. The compound mix-
ture was separated by column chromatography over silica gel and
the desired cyclopropane derivative was preserved. The mesylate
Acknowledgments
T.P. thanks the Department of Science and Technology (DST),
New Delhi for financial support. R.B. and D.D. thank the Council
Eur. J. Org. Chem. 2009, 5255–5260
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5259

R. Bhattacharya, D. Dey, T. Pathak
FULL PAPER
[6] a) D. Gravel, C. Leboeuf, Can. J. Chem. 1982, 60, 574–587; b)
K. Ogura, T. Iihama, K. Takahashi, H. Iida, Bull. Chem. Soc.
Jpn. 1984, 57, 3347–3348; c) J. Zindel, A. de Meijere, Synthesis
1994, 2, 190–194; d) D. B. Reddy, M. R. Sarma, A. S. Reddy,
N. S. Reddy, Ind. J. Chem. B 2000, 39B, 901–903; e) V. Padmav-
athi, M. R. Sarma, K. V. Reddy, A. Padmaja, D. B. Reddy, Het.
Chem. 2003, 14, 155–159.
for Scientific and Industrial Research, New Delhi for a fellowship.
DST is also thanked for creation of the 400 MHz facility under
the IRPHA (Intensification of Research in High Priority Areas)
program and DST-FIST (Fund for Improvement of Science and
Technology Infrastructure) for the single-crystal X-ray facility.
[7] a) I. Das, T. K. Pal, T. Pathak, J. Org. Chem. 2007, 72, 9181–
9189; b) A. K. Atta, T. Pathak, J. Org. Chem. 2009, 74, 2710–
2717.
[1] a) G. S. Cousins, J. O. Hoberg, Chem. Soc. Rev. 2000, 29, 165–
174; b) M. Yu, B. L. Pagenkopf, Tetrahedron 2005, 61, 321–
347.
[2] a) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem.
Rev. 2003, 103, 977–1050; b) H.-U. Reissig, R. Zimmer, Chem.
Rev. 2003, 103, 1151–1196; c) O. G. Kulinkovich, Chem. Rev.
2003, 103, 2597–2632.
[3] a) J. S. Brimacombe, M. E. Evans, E. J. Forbes, A. B. Foster,
J. M. Webber, Carbohydr. Res. 1967, 4, 239–243; b) T. Sasaki,
K. Minamoto, H. Suzuki, J. Org. Chem. 1973, 38, 598–607; c)
M. Kawana, H. Kuzuhara, Synthesis 1995, 5, 544–552; d) J.
[8] C. W. Holzapfel, T. L. van der Merwe, Tetrahedron Lett. 1996,
37, 2303–2306.
[9] N. R. Williams, Adv. Carbohydr. Chem. Biochem. 1970, 25, 109–
179.
[10]
D. E. Ward, B. F. Kaller, J. Org. Chem. 1994, 59, 4230–4238.
[11] a) F. W. Lichtenthaler, P. Heidel, J. Org. Chem. 1974, 39, 1457–
1462; b) O. Varela, D. Cicero, R. M. de Lederkremer, J. Org.
Chem. 1989, 54, 1884–1890.
Gagneron, G. Gosselin, C. Mathe, J. Org. Chem. 2005, 70, [12] For selected references on branched-chain sugars, see: I. Das,
6891–6897; e) P. Besada, D. H. Shin, S. Costanzi, H. Ko, C.
Mathe, J. Gagneron, G. Gosselin, S. Maddileti, T. K. Harden,
K. A. Jacobson, J. Med. Chem. 2006, 49, 5532–5543; f) I.
Nowak, J. F. Cannon, M. J. Robins, J. Org. Chem. 2007, 72,
532–537.
T. K. Pal, C. G. Suresh, T. Pathak, J. Org. Chem. 2007, 72,
5523–5533 and references cited therein.
[13] N. Kornblum, A. S. Erickson, W. J. Kelly, B. Henggeler, J. Org.
Chem. 1982, 47, 4534–4538.
[14] It is expected that other nucleophiles would also trigger this
type of cyclopropanation reaction, see ref.[7a]
Received: May 19, 2009
[4] S. A. Testero, R. A. Spanevello, Carbohydr. Res. 2006, 341,
1057–1760.
[5] J. J. Eisch, J. E. Galle, J. Org. Chem. 1979, 44, 3277–3279.
Published Online: September 3, 2009
5260
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5255–5260