Protective group-free synthesis of 3,4-dihydroxytetrahydrofurans from carbohydrates: Formal total synthesis of sphydrofuran

Article abstract of DOI:10.1016/j.carres.2012.09.004

Carbohydrates are taking a more prominent role in chemistry as an environmentally benign chemical feedstock. However, major efforts are still required to convert unprotected carbohydrates into high-value building blocks. We have investigated the protectiv

Full text of DOI:10.1016/j.carres.2012.09.004

Carbohydrate Research 362 (2012) 30–37
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Protective group-free synthesis of 3,4-dihydroxytetrahydrofurans
from carbohydrates: formal total synthesis of sphydrofuran
⇑
Henri A. van Kalkeren, Stefan van Rootselaar, Frank S. Haasjes, Floris P. J. T. Rutjes, Floris L. van Delft
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2012
Received in revised form 23 August 2012
Accepted 2 September 2012
Available online 11 September 2012
Carbohydrates are taking a more prominent role in chemistry as an environmentally benign chemical
feedstock. However, major efforts are still required to convert unprotected carbohydrates into high-value
building blocks. We have investigated the protective group-free Wittig reaction and subsequential acid
catalyzed intramolecular cyclization of unprotected carbohydrates to obtain 3,4-dihydroxytetrafurans.
In this process, we have found that, when using Lewis acids and poly-alcohol substrates, additional atten-
tion should always be given to the catalytic nature of the acid as it might involve its ligands instead of the
metal. Furthermore, we illustrate the viability of the concept by a straightforward formal total synthesis
Keywords:
Protective group-free
Wittig reaction
Allylic substitution
Dihydroxytetrahydrofurans
Total synthesis
of the natural product sphydrofuran from D-xylose.
Ó 2012 Elsevier Ltd. All rights reserved.
Sphydrofuran
1. Introduction
concept by a straightforward formal total synthesis of the natural
product sphydrofuran from D-xylose.
Besides the traditional role of biomass as a source of ‘green’ fuel,
interest is recently also growing in the use of biomass as a chemical
feedstock. Biomass is composed of a large variety of enantiopure
and valuable organic materials, with a prominent role for carbohy-
drates.1 Especially in the last decade, attention has shifted toward
the conversion of carbohydrates into valuable building blocks2
with the potential for further derivatization.3 One drawback of
the currently applied strategies is that carbohydrate stereochemis-
try is often (partly) lost in the initial reaction steps.4 From a fine-
chemical point of view, it is therefore important to investigate
additional methods in order to retain the chiral properties that ren-
der carbohydrates such versatile starting materials for production
of high-value building blocks.
We also recognized the potential of carbohydrates in this re-
spect, and have initiated a program aiming at the development of
methodologies for selective conversion of only one of the multiple
hydroxyl groups in a typical carbohydrate. To achieve such selec-
tivity, we envisioned an olefination of the aldehyde to install
a—more reactive—allylic alcohol A (Scheme 1). A subsequent
intramolecular allylic substitution was expected to yield the 2-sty-
ryltetrahydrofurans C in two straightforward steps. In this paper,
we report our investigations in this field, in particular focusing
on the influence of carbohydrate stereochemistry and double bond
electron density on both reactions. We illustrate the viability of the
2. Olefination
The Wittig olefination of unprotected carbohydrates to obtain
allylic alcohols has already been explored with both stabilized
and semi-stabilized ylides.5 The former gave rise to
a,b-unsatu-
rated esters that are typically isolated in low yield due to a facile
subsequent intramolecular oxa-Michael addition.5a,b,6 Further-
more, since electron-withdrawing esters would also destabilize
the envisioned carbocation intermediate in our subsequent substi-
tution reaction, we focused on the use of semi-stabilized ylides
based on benzylic organophosphorous compounds. Henk, Giannis
and Sandhoff have already shown that such olefinations of sugars
with unsubstituted phenyl rings proceed well,5e in contrast to
non-stabilized ylides which are too basic to react with unprotected
carbohydrates. Furthermore, the phenyl moiety of the resulting
styryl alcohol was expected to induce a stabilizing effect on the
intermediate (allylic) cation for our purpose. Hence, we initiated
our studies by the olefination of unprotected sugars with electronic
variations at the phenyl ring in the requisite Wittig reagents, in
particular an electron-donating methoxy and an electron-with-
drawing nitro substituent (Table 1). As expected, Wittig olefination
in all cases afforded mixtures of (E)- and (Z)-double bond geomet-
rical isomers.7 Interestingly, both the electron-donating and the
electron-withdrawing substituents had a negative effect on the
isolated yield. The olefins formed from
L-arabinose, D-xylose and
⇑
Corresponding author. Tel.: +31 24 365 2373; fax: +31 24 365 3393.
E-mail address: f.vandelft@science.ru.nl (F.L. van Delft).
D-glucose (6a,b, 8a,b, and 9a) were solids which could be readily
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.09.004

H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
31
3. Cyclization
With the olefinated carbohydrates at hand, we set out to ex-
plore the selective intramolecular hydroxyl substitutions to obtain
the desired 3,4-dihydroxytetrahydrofurans. The direct substitution
of allylic alcohols has been investigated extensively and two main
strategies have emerged, that is
p
–allyl complex formation9 and
Lewis acid-catalyzed activation.10 We decided to initially focus
on Lewis acids that had already been reported in the literature: Au-
Cl3,10a InCl3,10b FeCl3,10c and Bi(OTf)3.10d We realized that the chal-
lenge in applying Lewis acids lies in the inherent ability to form
chelates with carbohydrates instead of activation of the allylic
alcohol. Furthermore, the poor solubility of the—highly polar—car-
bohydrate derivatives 6–9 involved in our studies considerably
limited the choice of solvents.
Scheme 1. Two-stage strategy for the synthesis of 2-styryltetrahydrofuran 3,4-
diols C from unprotected carbohydrates.
We therefore initiated our research on Lewis acid activation
with the Bi(OTf)3 system developed by the group of Shibasaki, as
it allows usage of the solvent 1,4-dioxane.10d Under the reported
reaction conditions, the desired 3,4-dihydroxytetrahydrofurans
10a, 11a, and 13a were indeed formed (Table 2, entry 1),11 although
reaction times were much longer and isolated yields were lower
than reported for the monohydroxylated compounds.10d One po-
tential explanation involves the earlier mentioned catalyst inhibi-
tion by coordination to (multiple) hydroxyl functions, followed by
slow liberation of triflic acid that in turn could act as a Brønsted acid
catalyst for the hydroxyl substitution. Indeed, when we added triflic
acid instead of a Lewis acid, we observed a much higher reaction
rate and increased yield of products (entries 2, 8, and 12). A similar
phenomenon was observed for FeCl3 (entries 3 and 4), which in
these cases may lead to the formation of HCl as the active species.
With respect to stereoselectivity, an epimeric mixture at C-2
was obtained for every tetrahydrofuran formed. The relative con-
purified by crystallization from ethanol, while the olefins from D-ri-
bose (7a,b and 9b) were oils that had to be purified by silica gel
column chromatography. In the latter cases, significant amounts
of unreacted phosphonium salts were isolated together with the
products. The problematic separation of the product and phospho-
rus waste nicely underlines the need for catalytic variants of the
stoichiometric Wittig reactions, a field which is currently rapidly
developing, but is unfortunately not mature enough for applica-
tions with unprotected carbohydrates.8
Table 1
Wittig olefination of unprotected carbohydrates
figuration of the L-arabinose and D-ribose derivatives 10a and
11a, respectively, could be unambiguously proven by isopropyli-
dene protection, which enabled separation of diastereoisomers
by column chromatography and structure elucidation by 2D-
NMR techniques and subsequent deprotection. This also led to
the identification of the diastereoisomers of 10b, while 12a and
12b were identified by the literature comparison.12 Based on the
stereochemical analyses, we concluded that the stereochemistry
of the starting material is highly decisive for the C-2:C-3 cis:trans
ratio after cyclization: for all substrates except 8b (entry 13), the
major product of cyclization is formed through inversion of
stereochemistry at the allylic position. As expected, methoxy-
substituents have a positive effect on the cyclization rate, by virtue
of stabilization of the intermediate benzylic cation. Apart from
that, a remarkable positive effect of methoxy substitution was
found on both the (E):(Z) ratio of olefination (exclusively the (E)-
isomer was formed), and the cis:trans ratio at C-2 and C-3 upon
Carbohydrate
Olefin
Yield (%)
(E):(Z) ratio
L
-Arabinose (2)
6a: R = Ph
6b: R = 4-PMP
6c: R = 4-PNP
71
22
7
70:30
55:45
53:47
D-Ribose (3)
cyclization (high preference of trans) for
-ribose-derived olefins (entries 7 and 8).
L-arabinose and
7a: R = Ph
7b: R = 4-PMP
60
11
50:50
80:20
D
4. Formal total synthesis
8a: R = Ph
83
39
72:28
62:38
The 3,4-dihydroxytetrahydrofuran motif is an integral part of
several biologically active compounds, for example secosyrins,
syributins, varitriol, and sphydrofuran.13 We set out to explore
the synthesis of sphydrofuran (18, Fig. 1), a widespread metabolite
from streptomycetes.14 Sphydrofuran has been synthesized previ-
ously by the groups of Russo, Schmid, Wong, and Rizzacasa by a
variety of strategies.15 We envisioned that our newly developed
method would lead directly to compound 17, also an intermediate
in the total synthesis described by Di Florio and Rizzacasa.15e An
important benefit to follow such a strategy is the fact that all four
stereoisomers obtained after our Wittig olefination–cyclization
D
-Xylose (4)
8b: R = 4-PMP
9a: R = Ph
9b: R = 4-PMP
68
12
60:40
51:49
D-Glucose (5)
For phosphoniumcounterion X, see Section 6. 4-PMP = 4-para-methoxyphenyl,
4-PNP = 4-para-nitrophenyl.

32
H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
Table 2
Lewis and Brønsted acid-catalyzed allylic activation and subsequent cyclization to 3,4-dihydroxytetrahydrofurans
Entry
Derivative 6
Product
Acid catalysta (mol %)
Time (h)
Yieldb,c (%)
C-2:C-3 cis:trans ratio
(E):(Z) ratio
1
2
3
4
6
6a
6a
6a
6a
6a
10a
10a
10a
10a
10a
Bi(OTf)3 (5)
TfOH (10)
FeCl3 (5)
HCl (5)
—
18
3.5
72
72
96
38
49
44d
37d
0
41 (cis)
59 (trans)
25 (cis)
75 (trans)
45 (cis)
55(trans)
32 (cis)
68 (trans)
—
1:0
5:1
1:0
7:1
1:0
4:1
7:1
5:1
—
7
8
6b
6b
10b
10b
Bi(OTf)3(5)
TfOH (10)
3
67
51
12 (cis)
88 (trans)
11 (cis)
1:0
87:1
1:0
1:0
0.3
89 (trans)
9
7a
11a
TfOH (10)
18
58
69 (cis)
31 (trans)
2:1
9:1
11
12
8a
8a
12a
12a
Bi(OTf)3 (5)
TfOH (5)
18
52
65
40 (cis)
60 (trans)
40 (cis)
1:0
5:1
1:0
5:1
3.5
60 (trans)
13
8b
12b
TfOH (5)
0.5
45
50 (cis)
50 (trans)
1:0
1:0
a
b
c
For Bi(OTf)3-catalyzed reactions, KPF6 (5 mol %) and CaSO4 (1.1 equiv) were added as well. With TfOH, CaSO4 (1.1 equiv) was added.
Isolated yield.
Remaining starting material was recovered for some reactions, see Section 6 for more details.
Reaction performed at 40 °C.
d
O
OH
OH
1. olefination
HO
2. acid catalysis
HO
R
HO
HO
OH
OH
Ar
formal total
synthesis
O
O
Scheme 2. Retrosynthetic analysis of sphydrofuran.
O
Me
OH
After benzylation17 and ozonolysis, the resulting aldehyde 13
was further oxidized to carboxylic acid 15 by either Pinnick18 or
silver oxide oxidation (Scheme 3). Subsequent esterification with
allyl alcohol led to the requisite intermediate 16 as a C-2 epimeric
mixture. As anticipated, Ireland–Claisen rearrangement of the epi-
meric mixture of 16 converged to intermediate 17 in the same dia-
stereomeric ratio as from the diastereomerically trans-16 as
reported by Rizzacasa, who already demonstrated the successful
further conversion of 17 into the desired sphydrofuran.15e
OH
sphydrofuran
HO
OH
Figure 1.
sequence would convert to a single diastereoisomeric intermediate
17 via the Ireland–Claisen rearrangement.16 The latter rearrange-
ment would involve an allylic ester that would be accessible from
12a via subsequent oxidative double bond cleavage, then oxidation
to the carboxylic acid, and finally esterification (Scheme 2).
We started our synthetic efforts toward sphydrofuran from
2-styryltetrahydrofuran 3,4-diol 12a, as obtained by the Wittig
olefination and triflic acid-catalyzed intramolecular hydroxyl
5. Conclusion
A new protective group-free method has been developed to
access 2-styryltetrahydrofuran diols in two steps from cheap
substitution of D-xylose in a 54% yield over two steps (Scheme 3).

H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
33
bombarded with Xenon atoms with an energy of 3 keV. During
the high resolution FAB-MS measurements a resolving power of
10.000 (10% valley definition) was used.
6.1. General procedure Wittig reactions Table 1
An adapted method published by Giannis et al.5e was used: KOt-
Bu (2 equiv) was added to a solution of the phosphonium com-
pound (2 equiv) in dry 1,4-dioxane (carbohydrate concentration
0.2 M) and stirred at room temperature for 30 min. and then at
80 °C for 30 min. Next, the carbohydrate (1 equiv) was added and
the mixture was heated to reflux until full or no further conversion
of the reaction was confirmed by TLC. The specific isolation of the
products is described for the individual carbohydrates.
6.2. (2S,3R,4S)-6-Phenylhex-5-ene-1,2,3,4-tetraoli (6a)
L
-Arabinose (10.00 g, 66.7 mmol) was reacted with benzyltri-
Scheme 3. (a) KOt-Bu (2 equiv), BnPPh3Cl (2 equiv), 1,4-dioxane, reflux, 4.5 h, 83%;
(b) TfOH (5 mol %), 1,4-dioxane, rt, 3.5 h, 65%; (c) NaH (2.1 equiv), BnBr (2.2 equiv),
À20 °C ? rt, 2.5 h, 80%; d) O3, PPh3, DCM, À78 °C ? rt, 97%; (e) NaClO2 (1.2 equiv),
NaH2PO4 (7 equiv), 2-methyl-2-butene (20 equiv), t-BuOH/H2O, 0 °C ? rt, 16 h,
94%; (f) AgNO3 (2 equiv), KOH (6 equiv), EtOH/H2O, 0 °C ? rt, 1.5 h, 90%; (g) DCC
(1.2 equiv), DMAP (0.2 equiv), allyl alcohol (1.3 equiv), DCM, 0 °C, 3.5 h, 69%; (h)
LDA (2 equiv), HMPA (6.4 equiv), TMSCl/Et3N (3.5 equiv), THF, À98 °C ? rt, then
TMSCHN2 (6 equiv), MeOH/PhMe, 62%.
phenylphosphonium chloride (51.80 g, 133 mmol) and KOt-Bu
(14.95 g, 133 mmol) for 2 h. The mixture was then concentrated
in vacuo and the residue was stirred vigorously in DCM (2 L) and
then extracted with water (2 Â 1 L). The water was evaporated
and the resulting solid (32 g) was recrystallized from ethanol to
give the product as a white powder (10.55 g, 71%, (E)/(Z) = 70:30).
IR (neat)
m
3232 (br), 2904, 1437, 1201, 1076, 1021 cmÀ1
.
1H
NMR (400 MHz, DMSO-d6)
d
7.43–7.19 (m, 5H), 6.56 (d,
carbohydrates. Olefination of the masked aldehyde functionality
proceeded successfully with semi-stabilized benzylic Wittig re-
agents, and was followed by an acid-catalyzed cyclization to afford
the desired tetrahydrofurans. It was found that the use of Lewis
acids for the latter purpose can be misleading as the in situ liber-
ated protic acids themselves act as the catalytic species. Further-
more, we successfully demonstrated that the resulting 3,4-
dihydroxytetrahydrofurans present versatile chiral building blocks
for total synthesis of chiral and enantiopure natural products, as
exemplified by a straightforward formal synthesis of sphydrofuran
from intermediate compound 12a.
J = 16.1 Hz, 0.7H), 6.46 (d, J = 11.9 Hz, 0.3H), 6.39 (dd, J = 16.0,
5.7 Hz, 0.7H), 5.88 (dd, J = 11.9, 9.5 Hz, 0.3H), 4.71–4.30 (m, 4H),
3.64–3.36 (m, 5H). 13C NMR (75 MHz, DMSO-d6) d 133.8, 132.4,
128.9, 128.8, 128.7, 128.6, 128.2, 127.1, 126.9, 126.1, 74.2, 74.1,
71.6, 71.2, 71.0, 65.5, 63.6, 63.5; HRMS (EI+) calc for C12H14O3
[MÀH2O]+ 206.0943, found 206.0951.
6.3. (2S,3R,4S)-6-(4-Methoxyphenyl)hex-5-ene-1,2,3,4-tetraoli
(6b)
L-Arabinose (1.00 g, 6.7 mmol) was reacted with (4-methoxy-
benzyl)(triphenyl)phosphonium chloride (5.58 g, 13.3 mmol) and
KOt-Bu (1.50 g, 13.3 mmol) for 4 h. Next, water (3 mL) was added
and the solvents were evaporated. Column chromatography
(DCM/MeOH 1:0 ? 9:1) gave the desired product as a white crys-
talline powder (374 mg, 22%, (E)/(Z) = 54:46).
6. Experimental section
Solvents were dried by purging over activated alumina columns
in an MBraun MB SPS800 and stored under nitrogen. Chemical re-
agents were purchased from commercial sources and were used
without further purification, or in-house prepared as indicated be-
low. Reactions were carried out under an inert atmosphere of dry
nitrogen or argon. Standard syringe techniques were applied for
the transfer of dry solvents and air- or moisture-sensitive reagents.
Reactions were followed by thin layer chromatography (TLC) on
silica gel-coated plates (Merck 60 F254). Detection was performed
with UV-light, and/or by charring at ꢀ150 °C after dipping into a
solution of aqueous basic KMnO4 or in a solution of ninhydrin. Col-
umn or flash chromatography was carried out using Silicycle Silica-
IR (neat)
m ;
3285 (br), 2930, 1605, 1510, 1439, 1245, 1076, cmÀ1
1H NMR (400 MHz, DMSO-d6) d 7.34 (m, 2H), 6.89 (m, 2H), 6.46 (d,
J = 15.8 Hz, 0.5H), 6.37 (d, J = 11.9 Hz, 0.5H), 6.20 (dd, J = 16.0,
6.0 Hz, 0.5H), 5.47 (dd, J = 11.8, 9.7 Hz, 0.5H), 4.30–4.66 (m, 4H),
3.74 (d, J = 3.8 Hz, 3H), 3.23–3.62 (m, 5H). 13C NMR (75 MHz,
DMSO-d6) d 158.5, 158.3, 131.9, 130.2, 129.8, 129.73, 129.3,
128.6, 128.4, 127.3, 114.0, 113.6, 74.3, 74.2, 71.6, 71.3, 71.1, 65.5,
63.6, 63.5, 55.1. HRMS (EI+) calcd for C13H18O5 [M]+ 254.1154,
found 254.1149.
flash P60Ò (40–63
lm). Melting points were analyzed with a Büchi
6.4. (2S,3R,4S)-6-(4-Nitrophenyl)hex-5-ene-1,2,3,4-tetraoli (6c)
melting point B-545. IR spectra were recorded on an ATI Mattson
Genesis Series FTIR spectrometer. NMR spectra were recorded on
a Bruker DMX 300 (300 MHz), a Varian 400 (400 MHz) and a Bru-
ker Avance III (500 MHz) spectrometer. 1H NMR chemical shifts are
given in ppm with respect to tetramethylsilane (TMS, d 0.00 ppm)
as internal standard, 13C NMR shifts are given in ppm with respect
to CDCl3 (d 77.00 ppm), DMSO-d6 (39.52), or MeOH-d4 (49.00).
High resolution mass spectra were recorded on a JEOL AccuTOF
(ESI), or a MAT900 (EI, CI, and ESI). Fast Atomic Bombardment
(FAB) mass spectrometry was carried out using a JEOL JMS SX/SX
102A four-sector mass spectrometer, coupled to a JEOL MS-
MP9021D/UPD system program. Samples were loaded in a matrix
solution (3-nitrobenzyl alcohol) on to a stainless steel probe and
L-Arabinose (300 mg, 2.00 mmol) was reacted with (4-nitroben-
zyl)triphenylphosphonium bromide (1.91 g, 4.00 mmol) and KOt-
Bu (448 mg, 4.00 mmol). Next, water (2 mL) was added and the
solvents were evaporated. After column chromatography (MeCN/
H2O 1:0 ? 9:1) and recrystallization the product was isolated as
a pale yellow solid (40 mg, 7%, (E)/(Z) = 53:47).
1H NMR (400 MHz, DMSO-d6) d 8.22–8.16 (m, 2H), 7.71–7.64
(m, 2H), 6.70 (ABq, J = 16 Hz, 1H), 6.61 (d, J = 12.1 Hz, 0.5H), 6.10
(dd, J = 11.9, 9.5 Hz, 0.5H), 4.82 (d, J = 6.3 Hz, 0.5H), 4.78 (d,
J = 6.7 Hz, 0.5H), 4.67–4.41 (m, 3H), 4.35 (q, J = 5.3 Hz, 1H), 3.65–
3.26 (m, 4H). 13C NMR (75 MHz, DMSO-d6) d 146.0, 144.0, 143.7,

34
H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
138.4, 137.7, 129.9, 127.3, 127.0, 126.8, 123.9, 123.4, 73.9, 71.5,
71.2, 70.9, 65.5, 63.5, 63.4.
(3 Â 200 mL). The combined water layers were concentrated in
vacuo and the crude product was purified by flash chromatography
(DCM/MeOH 1:0 ? 9:1) to give product 8b as a white powder
(3.32 g, 39%, (E)/(Z) = 62:38).
6.5. (2R,3S,4S)-6-Phenylhex-5-ene-1,2,3,4-tetraoli (7a)
IR (neat)
m .
3336 (br), 2907, 1607, 1511, 1246, 1091 cmÀ1 1H
D
-Ribose (1.50 g, 10.0 mmol) was reacted with benzyltriphenyl-
NMR (400 MHz, DMSO-d6) d 7.44–7.31 (m, 2H), 6.92–6.85 (m,
2H), 6.49 (d, J = 15.9 Hz, 0.6H), 6.44 (d, J = 11.8 Hz, 0.4H), 6.15
(dd, J = 16.0, 6.5 Hz, 0.6H), 5.57 (dd, J = 11.8, 9.6 Hz, 0.4H), 4.81–
4.06 (m, 4H), 3.75 (s, 1.8H), 3.74 (s, 1.2H), 3.54–3.37 (m, 5H). 13C
NMR (75 MHz, DMSO-d6) d 158.6, 158.3, 130.9, 130.2, 130.0,
129.6, 129.2, 129.0, 128.8, 127.4, 114.0, 113.6, 73.7, 73.4, 72.8,
71.6, 71.5, 67.3, 62.9, 62.8, 55.1. HRMS (FAB+) calcd for C13H19O5
[M+H]+ 255.1232 found 255.1230.
phosphonium chloride (7.77 g, 20.0 mmol) and KOt-Bu (2.24 g,
20.0 mmol) for 2 h. Next, water (3 mL) was added and the solvents
were evaporated. Column chromatography (DCM/MeOH 1:0 ?
9:1) gave the product as a brown oil (1.94 g, 60%, (E)/(Z) = 51:49)
contaminated with an additional amount of benzyltriphenylphos-
phonium chloride (31 w/w%).
IR (neat)
m
3235 (br), 2885, 1489, 1429, 1286, 1061 cmÀ1. 1H 1H
NMR (400 MHz, DMSO-d6) d 7.49–7.20 (m, 5H), 6.56–6.52 (m, 1H),
6.38 (dd, J = 16.1, 6.3 Hz, 0.5H), 5.78 (dd, J = 11.9, 9.5 Hz, 0.5H),
5.16–4.28 (m, 4H), 3.62–3.27 (m, 5H). 13C NMR (75 MHz, DMSO-
d6) d 137.1, 136.8, 132.4, 130.9, 130.6, 129.5, 128.8, 128.5, 128.0,
127.1, 126.9, 126.1, 74.9, 74.7, 72.61, 72.59, 72.5, 67.5, 63.34,
63.26. HRMS (EI+) calcd for C12H14O3 [M-H2O]+ 206.0943 found
206.0931.
6.9. (2R,3R,4R,5S)-7-(4-Methoxyphenyl)hept-6-ene-1,2,3,4,5-
pentaoli (9b)
D-Glucose (300 mg, 2.78 mmol) was reacted with (4-methoxy-
benzyl)triphenylphosphonium chloride (3.33 g, 5.55 mmol) and
KOt-Bu (623 mg, 5.55 mmol) for 3 h. Next, water (5 mL) was added
and the solvents were evaporated. Column chromatography (DCM/
MeOH 1:0 ? 5:1) gave product 9b as a yellow oil with low yield
(99 mg, 12%, d.r. (E)/(Z) = 51:49) with an additional inseparable
amount of unreacted (4-methoxybenzyl)triphenylphosphonium
chloride (31 w/w%).
6.6. (2R,3S,4S)-6-(4-Methoxyphenyl)hex-5-ene-1,2,3,4-tetraoli
(7b)
D-Ribose (100 mg, 0.67 mmol) was reacted with (4-methoxy-
benzyl)triphenylphosphonium chloride (558 mg, 1.33 mmol) and
KOt-Bu (149 mg, 1.33 mmol) for 2.5 h. Next, water (1 mL) was
added and the solvents were evaporated. Column chromatography
(DCM/MeOH 1:0 ? 5:1 and then MeCN/H2O 1:0 ? 9:1) gave the
product as a yellow oil (18 mg, 11%, (E)/(Z) = 79:21) with an insep-
arable and large amount of unreacted (4-methoxybenzyl)triphen-
ylphosphonium chloride (73 w/w%).
IR (neat) m .
3278 (br), 2907, 1610, 1506, 1247, 1027 cmÀ1 1H
NMR (400 MHz, DMSO-d6) d 7.45–7.32 (m, 2H), 6.91–6.87 (m,
2H), 6.52–6.43 (m, 1H), 6.13 (dd, J = 16.0, 6.7 Hz, 0.5H), 5.52 (dd,
J = 11.8, 9.6 Hz, 0.5H), 4.84–4.14 (m, 5H), 3.75 (s, 1H), 3.74 (s,
1H), 3.65–3.38 (m, 6H). LRMS (FAB+) calc for C14H20NaO6
[M+Na]+ 307.12 found 307.14.
1H NMR (400 MHz, CD3OD) d 7.42–7.34 (m, 2H), 6.89–6.86 (m,
2H), 6.63 (d, J = 11.3 Hz, 0.2H), 6.60 (d, J = 16.0 Hz, 0.8H), 6.24 (dd,
J = 16.0, 7.4 Hz, 0.8H), 5.72 (dd, J = 11.7, 9.7 Hz, 0.2H), 4.72 (dd,
J = 9.6, 4.5 Hz, 0.2H), 4.41–4.38 (m, 0.8H), 3.79 (s, 0.6H), 3.78 (s,
2.4H), 3.69–3.58 (m, 4H). HRMS (EI+) calcd for C13H18O5 [M]+
236.1047, found 236.1047.
6.10. General procedures for cyclization reactions in Table 2
6.10.1. Method A
The olefinated carbohydrate was added to 1,4-dioxane (0.2 m)
and CaSO4 (1.1 equiv) was added. The mixture was stirred for
10 min at rt before Bi(OTf)3 and KPF6 (0.05 equiv) were added.
The mixture was stirred for the indicated time and MeOH and silica
(20 Â mass of olefinated carbohydrate) were added. The mixture
was filtrated and concentrated and the product was purified by
column chromatography (heptane:EtOAc 1:1).
6.7. (2R,3R,4S)-6-Phenylhex-5-ene-1,2,3,4-tetraoli (8a)
D-Xylose (5.00 g, 33.3 mmol) was reacted with benzyltriphenyl-
phosphonium chloride (25.90 g, 66.7 mmol) and KOt-Bu (7.47 g,
66.7 mmol) for 3 h. Next, water (5 mL) was added and the solvents
were evaporated. After column chromatography (DCM/MeOH 1:0
? 10:1), the product was isolated as a white crystalline powder
(4.40 g, 59%, (E)/(Z) = 72:28).
6.10.2. Method B
The olefinated carbohydrate was added to 1,4-dioxane (0.2 M)
and CaSO4 (1.1 equiv) was added. The mixture was stirred for
10 min. at rt and triflic acid was added. The mixture was stirred
for the indicated time and MeOH and silica (20 Â mass of olefinat-
ed carbohydrate) were added. The mixture was filtrated and
concentrated and the product was purified by column chromatog-
raphy (heptane:EtOAc 1:1).
IR (neat)
m
3338 (br), 2907, 1606, 1511, 1443, 1096 cmÀ1
.
1H
NMR (400 MHz, DMSO-d6)
d
7.50–7.19 (m, 5H), 6.57 (d,
J = 15.5 Hz, 0.7H), 6.52 (d, J = 11.9 Hz, 0.3H), 6.33 (dd, J = 16.0,
6.2 Hz, 0.7H), 5.70 (dd, J = 11.9, 9.6 Hz, 0.3H), 4.85 (d, J = 4.6 Hz,
0.7H), 4.74 (d, J = 5.1 Hz, 0.3H), 4.51–4.41 (m, 1H), 4.39–4.28 (m,
1H), 4.25–4.19 (m, 0.7H), 4.09 (q, J = 5.3 Hz, 0.3H), 3.55–3.34 (m,
5H). 13C NMR (75 MHz, DMSO-d6) d 136.62, 134.05, 133.92,
132.76, 130.28, 130.18, 130.01, 128.86, 128.12, 126.99, 126.14,
73.29, 71.61, 67.23, 62.72. HRMS (EI+) calcd for C12H16O4 [M-
H2O]+ 206.0943, found 206.0936.
6.10.3. Method C
The olefinated carbohydrate was added to 1,4-dioxane (0.2 m)
and FeCl3 or HCl was added. The mixture was heated to 40 °C
and stirred for the indicated time. Then, MeOH and silica
(20 Â mass of olefinated carbohydrate) were added. The mixture
was filtrated and concentrated. The product was purified by col-
umn chromatography (heptane:EtOAc 1:1).
6.8. (2R,3R,4S)-6-(4-Methoxyphenyl)hex-5-ene-1,2,3,4-tetraoli
(8b)i
6.11. (3S,4S)-2-Styryltetrahydrofuran-3,4-dioli (10a)
D-Xylose (5.00 g, 33.3 mmol) was reacted with (4-methoxyben-
zyl)triphenylphosphonium chloride (27.90 g, 66.7 mmol) and
KOt-Bu (7.47 g, 66.7 mmol) for 3 h. Next, water (5 mL) was added
and the solvents were evaporated. The residue was dissolved in
DCM (200 mL) and the mixture was extracted with water
Method A: 38% 10a, 25% recovered starting material.
Method B: 49% 10a, no starting material remaining.
Method C (FeCl3): 44% 10a, some starting material remaining,
but not isolated.

H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
35
Method C (HCl): 37% 10a, some starting material remaining, but
not isolatedIR (neat)
3350 (br), 2921, 1491, 1124, 1042 cmÀ1 1H
NMR (400 MHz, DMSO-d6) 7.48–7.21 (m, 5H), 6.67 (d,
158.75, 131.1, 129.7, 129.4, 129.1, 127.54, 127.51, 127.2,
124.5, 114.02, 113.98, 86.2, 82.2, 81.7, 78.3, 77.4, 77.0, 73.04,
72.95, 55.1. HRMS (EI+) calc for C13H16O4 [M]+ 236.1049, found
236.1053.
m
.
d
J = 11.8 Hz, 0.1H), 6.58 (d, J = 16.4 Hz, 0.4H), 6.52 (d, J = 16.6 Hz,
0.5H), 6.36 (dd, J = 16.0, 7.4 Hz, 0.4H), 6.27 (dd, J = 15.9, 6.8 Hz,
0.5H), 5.61 (dd, J = 11.8, 9.3 Hz, 0.1H), 5.02–4.75 (m, 2H), 4.45–
3.54 (m, 5H). 13C NMR (75 MHz, DMSO-d6) d 136.7, 136.5, 132.7,
131.5, 131.2, 130.5, 129.4, 128.7, 128.6, 128.1, 127.8, 127.5, 127.4,
127.3, 126.29, 126.28, 81.9, 81.7, 76.73, 76.67, 76.2, 72.7, 72.5,
72.4, 71.6, 70.7, 70.4. HRMS (EI+) calcd for C12H14O3 [M+]
206.0943, found 206.0937.
6.16. (3R,4R)-3,4-Bis(benzyloxy)-2-styryltetrahydrofuran (13)
Sodium hydride (0.186 g, 4.66 mmol) was dissolved in dry DMF
(11 mL), and cooled to À20 °C under N2 and stirred for 10 min. Ole-
fin 12a (0.496 g, 2.24 mmol) was added dropwise over 30 min fol-
lowed by dropwise addition of benzyl bromide (0.585 ml,
4.92 mmol). The reaction mixture was allowed to warm to room
temperature and was left to stir for 2.5 h. Then the reaction mix-
ture was added to ice water (50 mL) and extracted with DCM
(3 Â 50 mL). The organic layer was washed with water and brine,
dried over Na2SO4, and concentrated in vacuo. Flash column chro-
matography (EtOAc:heptane 1:30 ? 1:4) yielded 13 (0.72 g, 80%,
d.r. (E)/(Z) 76:24).
6.12. (3S,4S)-2-(4-Methoxystyryl)tetrahydrofuran-3,4-dioli
(10b)
Method A: 67% 10b, no starting material remaining.
Method B: 51% 10b, no starting material remaining.
IR (neat)
m .
3342 (br), 2938, 1604, 1511, 1249, 1174, 1117 cmÀ1
1H NMR (400 MHz, DMSO-d6) d 7.41–7.34 (m, 2H), 6.92–6.86 (m,
2H), 6.51 (d, J = 16.0 Hz, 0.9H), 6.45 (d, J = 16.0 Hz, 0.1H), 6.20
(dd, J = 16.0, 7.7 Hz, 0.1H), 6.10 (dd, J = 15.9, 7.0 Hz, 0.9H), 4.95–
4.70 (m, 2H), 4.34–3.76 (m, 3H), 3.75 (s, 3H), 3.74–3.42 (m, 2H).
IR (neat)
m
3028, 2865, 1494, 1453, 1364, 1332, 1205, 1097,
1056, 1027, 968 cmÀ1
.
1H NMR (300 MHz, CDCl3) d 7.45–7.18
(m, 15H), 6.73–6.62 (m, 1H), 6.40 (dd, J = 16.0, 7.6 Hz, 0.26H),
6.30 (dd, J = 15.9, 7.5 Hz, 0.5H), 5.84 (dd, J = 11.6, 9.4 Hz, 0.24H),
4.74 (dd, J = 9.9, 4.0 Hz, 0.27H), 4.66–4.47 (m, 4.35H), 4.43 (dd,
J = 7.4, 4.4 Hz, 0.5H), 4.24 (dd, J = 9.7, 5.0 Hz, 0.3H), 4.20–4.05
(m, 2H), 4.05–3.94 (m, 2H), 3.93 (d, J = 4.6 Hz, 0.1H), 3.86 (dd,
J = 9.7, 2.3 Hz, 0.3H). 13C NMR (75 MHz, CDCl3) d 137.93, 137.81,
136.97, 136.73, 133.45, 132.95, 132.28, 130.33, 129.13, 128.62,
128.36, 127.88, 127.47, 126.77, 125.07, 88.87, 88.32, 84.84,
84.04, 83.72, 83.54, 83.09, 81.98, 79.88, 72.42, 72.28, 71.68,
71.48. HRMS (FAB+) calcd for C26H27O3 [M+H]+ 387.1960, found
387.1955.
13C NMR (75 MHz, DMSO-d6)
d 158.8, 131.0, 130.4, 129.1,
127.6, 126.9, 125.2, 114.0, 82.2, 82.0, 76.2, 72.7, 72.4, 71.6, 70.6,
70.4, 55.1. HRMS (EI+) calc for C13H16O4 [M+] 236.1049, found
236.1046.
6.13. (3R,4R)-2-Styryltetrahydrofuran-3,4-dioli (11a)
Method B: 58% 11a, 24% recovered starting material IR (neat)
m
3370 (br), 2922, 1493, 1448, 1116 cmÀ1 1H NMR (400 MHz,
.
DMSO-d6) d 7.46–7.20 (m, 5H), 6.68–6.59 (m, 0.4H), 6.54 (d,
J = 16.5 Hz, 0.5H), 6.36 (dd, J = 16.0, 7.4 Hz, 0.4H), 6.28 (dd,
J = 16.0, 6.8 Hz, 0.3H), 5.91 (dd, J = 11.7, 9.2 Hz, 0.3H), 5.61 (dd,
J = 9.4, 11.6 Hz, 0.03H), 5.00–4.70 (m, 2H), 4.52–3.54 (m, 5H). 13C
NMR (75 MHz, DMSO-d6) d 136.7, 136.5, 136.3, 131.8, 131.2,
130.5, 129.3, 129.2, 128.6, 128.2, 127.8, 127.5, 127.4, 127.2,
126.2, 81.9, 81.7, 76.3, 76.2, 72.7, 72.6, 72.5, 71.64, 71.58, 70.7,
70.4. HRMS (EI+) calculated for C12H14O3 [M+] 206.0943, found
206.0937.
6.17. (3S,4R)-3,4-Bis(benzyloxy)tetrahydrofuran-2-
carbaldehyde (14)
Olefin 13 (2.40 g, 5.96 mmol) was dissolved in DCM/MeOH (1:1,
30 mL) and cooled to À78 °C. Ozone was bubbled through the solu-
tion until the solution was persistently blue. N2 was bubbled
through to clear the remaining ozone. Triphenylphosphine
(3.13 g, 11.92 mmol) was added and the reaction mixture was stir-
red for 18 h. The reaction mixture was concentrated in vacuo and
the crude product was purified by column chromatography
(EtOAc/heptane 1:30 ? 1:4) yielding aldehyde 14 as a yellowish
oil (1.87 g, 97%, d.r. 3:7).
6.14. (3S,4R)-2-Styryltetrahydrofuran-3,4-dioli (12a)
Method A: 58% 12a, 29% recovered starting material.
Method B: 65% 12a, 16% recovered starting material.
IR (neat)
m
3030, 2928, 2871, 1729, 1495, 1453, 1096 cmÀ1
.
1H
IR (neat)
m
3265 (br), 2946, 2894, 1493, 1055, 1041, 1024 cmÀ1
.
NMR (300 MHz, CDCl3) d
9.69 (d, J = 1.8 Hz, 0.3H), 9.62 (d,
1H NMR (400 MHz, DMSO-d6) d 7.45–7.21 (m, 5H), 6.61 (d,
J = 15.9 Hz, 0.4H), 6.55 (m, 0.6H), 6.37–6.28 (m, 0.9H), 5.78 (dd,
J = 11.8, 9.4 Hz, 0.1H), 5.36–4.98 (m, 2H), 4.49–3.47 (m, 5H). 13C
NMR (75 MHz, DMSO-d6) d 136.8, 136.5, 132.2, 131.4, 130.3,
130.0, 129.6, 128.8, 128.7, 128.6, 128.2, 127.53, 127.47, 127.2,
127.1, 126.31, 126.28, 86.0, 82.5, 82.2, 81.5, 81.2, 78.3, 77.5, 77.3,
77.0, 73.2, 73.1. HRMS (EI+) calc for C12H14O3 [M]+ 206.0943, found
206.0943.
J = 1.0 Hz, 0.7H), 7.40–7.18 (m, 10H), 4.57–4.34 (m, 5H), 4.29–
4.02 (m, 4H). 13C NMR (75 MHz, CDCl3) d 202.50, 128.07, 128.03,
127.58, 127.50, 127.28, 127.16, 86.52, 84.46, 84.17, 83.45, 80.90,
80.10, 72.26, 71.35, 70.48. HRMS (FAB+) calc for C19H21O4 [M+H]+
313.1440, found 313.1445.
6.18. (3S,4R)-3,4-Bis(benzyloxy)tetrahydrofuran-2-carboxylic
acid (15)
6.15. (3S,4R)-2-(4-Methoxystyryl)tetrahydrofuran-3,4-dioli
6.18.1. Silver oxide oxidation
(12b)
Aldehyde 21 (22.6 mg, 72 lmol) was dissolved in ethanol
(0.4 mL). Silver nitrate (24.6 mg, 0.145 mmol) in water (0.2 mL)
was added. At 0 °C KOH (26.4 mg, 0.470 mmol) in water (0.2 mL)
was added. The black suspension was stirred for 1.5 hours (silver
particles were observed). The reaction mixture was filtered over
Celite and washed with 6% aqueous KOH (3 Â 0.5 mL). The remain-
ing aqueous solution was acidified to pH 2 with HCl (0.1 m) and ex-
tracted with Et2O (3 Â 5 mL). The organic layer was washed with
brine, dried, and concentrated in vacuo. Acid 15 was obtained as
a colorless oil (21.5 mg, 90%).
Method B: 65% 12b, no starting material remaining.
IR (neat)
m
3366 (br), 2925, 1604, 1511, 1456, 1300, 1174, 1024,
.
969, 813 cmÀ1
1H NMR (400 MHz, DMSO-d6) d 7.39–7.31 (m, 2H),
6.92–6.86 (m,ffj 2H), 6.54 (d, J = 16.0 Hz, 0.5H), 6.48 (d, J = 15.9 Hz,
0.5H), 6.22–6.11 (m, 1H), 5.27 (d, J = 4.7 Hz, 0.5H), 5.11 (d,
J = 3.4 Hz, 0.5H), 5.04 (d, J = 3.8 Hz, 0.5H), 4.98 (d, J = 4.5 Hz,
0.5H), 4.08 (m, 4H), 3.75 (s, 3H), 3.66 (dd, J = 9.2, 2.6 Hz, 0.6H),
3.49 (d, J = 3.5 Hz, 0.5 H). 13C NMR (75 MHz, DMSO-d6) d 158.78,

36
H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
6.18.2. Pinnick oxidation
J = 17.1, 10.3, 7.4, 6.8 Hz, 1H), 5.11 (ddt, J = 10.8, 2.1, 1.2 Hz, 1H),
5.07 (dtd, J = 3.2, 2.1, 1.2 Hz, 1H), 4.56 (ABq, Vab = 12.1 Hz,
Aldehyde 21 (20 mg, 0.064 mmol) and 2-methyl-2-butene
(136 L, 281 mmol) were dissolved in t-BuOH (300 L) and then
D
l
l
J = 11.9 Hz, 2H), 4.44 (s, 2H), 4.28 (dd, J = 9.7, 4.6 Hz, 1H), 4.10–
4.06 (m, 1H), 4.04 (ddd, J = 9.7, 2.3, 0.8 Hz, 1H), 4.01–3.99 (m,
1H), 3.71 (s, 3H) 2.77 (ddt, J = 14.0, 7.4, 1.1 Hz, 1H), 2.68 (ddt,
J = 14.1, 6.8, 1.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 171.52,
137.60, 137.42, 132.65, 128.48, 128.39, 127.87, 127.71, 127.59,
118.51, 89.74, 87.52, 82.81, 72.89, 72.21, 71.54, 51.92, 40.44. HRMS
(FAB+) calcd for C23H26O5 [M+H]+ 383.1858, found 383.1852.
an aqueous solution of NaClO2 (6,95 mg, 0077 mmol) and NaH2PO3
(53,8 mg, 0448 mmol) at 0 °C was dropwise added. The reaction
mixture was stirred at 0 °C for 30 min and left to stir overnight
at room temperature. Then, the mixture was acidified to pH 1
and extracted with EtOAc (3 Â 5 mL). The combined organic layers
were washed with water (5 mL) and brine (5 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. Acid 15 was obtained as
a colorless oil (19.8 mg, 94%).
Acknowledgements
IR (neat)
m .
2916, 1729, 1494, 1453, 1345, 1259, 1093 cmÀ1 1H
NMR (500 MHz, CDCl3) d 7.48–7.24 (m, 10H), 4.80–4.02 (m, 9H).
13C NMR (125 MHz, CDCl3) d 172.11, 171.63, 137.28, 137.09,
137.04, 136.99, 84.77, 82.25, 81.47, 80.80, 80.57, 73.45, 72.08,
71.61, 71.38. HRMS (FAB+) calc for C19H21O5 [M+H]+ 329.1389,
found 329.1390.
This research has been performed within the framework of the
CatchBio program. The authors gratefully acknowledge the support
of the SmartMix Program of the Netherlands Ministry of Economic
Affairs and the Netherlands Ministry of Education, Culture, and
Science.
6.19. (3S,4R)-Allyl 3,4-bis(benzyloxy)tetrahydrofuran-2-
carboxylate (16)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2012.
09.004.
To a solution of acid 22 (95 mg, 0.305 mmol) in dry CH2Cl2
(0.5 mL) at 0 °C, allyl alcohol (25.0
lL, 0.368 mmol), DCC (70 mg,
0.34 mmol) and DMAP (8 mg, 0.07 mmol) were subsequently
added. The white suspension was stirred for 2.5 hours, and then di-
luted with ether (10 mL). The reaction mixture was filtered over
Celite, washed with HCl (0.1 M, 5 mL), saturated aqueous NaHCO3
(5 mL) and brine. The organic layer was dried over Na2SO4, filtered
and concentrated. Purification by column chromatography (EtOAc/
heptane 1:30 ? 1:10) yielded ester 16 as a colorless oil (74 mg,
69%, d.r. cis/trans 1:4).15e
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IR (neat)
m .
2929, 1756, 1727 cmÀ1 1H NMR (300 MHz, CDCl3) d
7.47–7.22 (m, 10H), 6.00–5.80 (m, 1H), 5.32 (ddq, J = 17.2, 7.3,
1.5 Hz, 1H), 5.22 (ddq, J = 10.4, 3.8, 1.2 Hz, 1H), 4.83–3.96 (m,
11H). 13C NMR (75 MHz, CDCl3) d 170.4, 169.3, 137.6, 137.4,
131.8, 128.6, 128.5, 128.1, 128.0, 127.9, 127.9, 127.8, 118.9, 85.8,
83.2, 81.9, 81.5, 80.3, 72.6, 71.9, 71.4, 66.0, 65.8. HRMS (FAB+) calcd
for C22H25O5 [M+H]+ 369.1702, found 369.1704.
6.20. (2R,3S,4R)-2-Allyl-3,4-bis(benzyloxy)tetrahydrofuran-2-
carboxylic acid (17)
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Diisopropylamine (42
(0.75 mL) at 0 °C under argon and n-butyllithium (1.6 M in hex-
anes, 183 L, 0.293 mmol) was added dropwise. The mixture was
lL, 0.293 mmol) was dissolved in THF
l
stirred for 30 min and then cooled to À78 °C to be added dropwise
via a cannula to a solution of allyl ester 16 (54 mg, 0.147 mmol)
and a freshly centrifuged mixture of TEA/TMSCl (1:1, 1.56 mL) in
THF (0.75 mL) and HMPA (0.163 mL, 0.938 mmol) at –98 °C. The
mixture was stirred for 1 h and saturated aqueous NH4Cl (2 mL)
and Et2O (2 mL) were added. The layers were separated and the
aqueous layer was extracted with DCM (3 Â 2 mL). The combined
organic layers were washed with brine and dried over MgSO4.
The crude carboxylic acid was concentrated to dryness (300 mg)
9. (a) Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169–208; (b)
Muzart, J. Tetrahedron 2005, 61, 4179–4212.
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Ramesh, N. G. Tetrahedron 2010, 66, 599–604; (c) Guérinot, A.; Serra-Muns, A.;
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Ed. 2007, 46, 409–413.
and redissolved in 0.75 mL toluene and 250 lL MeOH and TMS-
11. A complex mixture was found when the reaction was performed with
glucose derivative 9a.
D-
diazomethane (0.440 mL, 0.879 mmol, 2 M in Et2O) was added.
The mixture was stirred for 16 h and HCl (1 mL, 0.1 M) was added
to quench the excess TMS-diazomethane. After the mixture turned
colorless, it was extracted with DCM (3 Â 2 mL) and the combined
organic layers were washed with saturated aqueous NaHCO3
(2 mL) and dried over MgSO4. After concentration in vacuo and
purification by column chromatography (2R,3S,4R)-methyl 2-al-
12. See Supplementary data for details of the analysis of isomeric mixtures.
13. (a) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.; Mclaughlin, J. L. J.
Chem. Soc., Perkin Trans. 1 1990, 1655–1661; (b) Fang, X.-P.; Anderson, J. E.;
Chang, C.-J.; McLaughlin, J. L.; Fanwick, P. E. J. Nat. Prod. 1991, 54, 1034–1043;
(c) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Mclaughlin, J. L. Tetrahedron 1991,
47, 9751–9758; (d) Cao, S. G.; Wu, X. H.; Sim, K. Y.; Tan, B. K. H.; Pereira, J. T.;
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lyl-3,4-bis(benzyloxy)tetrahydrofuran-2-carboxylate
0.091 mmol, 62% yield, d.r 9:1) was isolated as a colorless oil.
IR (neat)
2947, 2863, 1735, 1454, 1214, 1093, 737, 698 cmÀ1
1H NMR (400 MHz, CDCl3) d 7.41–7.23 (m, 10zH), 5.82 (dddd,
(35 mg,
14. (a) Umezawa, S.; Usui, T.; Umezawa, H.; Tsuchiya, T.; Takeuchi, T.; Hamada, M.
J. Antibiot. 1971, 24, 85–92; (b) Bindseil, K. U.; Henkel, T.; Zeeck, A.; Bur, D.;
Niederer, D.; Séquin, U. Helv. Chim. Acta 1991, 74, 1281–1286.
m
.

H. A. van Kalkeren et al. / Carbohydrate Research 362 (2012) 30–37
37
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6359–6366; (e) Di Florio, R.; Rizzacasa, M. A. J. Org. Chem. 1998, 63, 8595–8598.
17. Benzylation was found to be essential for the stability of the aldehyde.
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S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.