Reaction of selected carbohydrate aldehydes with benzylmagnesium halides: Benzyl versus o-tolyl rearrangement

Article abstract of DOI:10.3762/bjoc.10.202

The Grignard reaction of 2,3-O-isopropylidene-a-D-lyxo-pentodialdo-1,4- furanoside and benzylmagnesium chloride (or bromide) afforded a non-separable mixture of diastereomeric benzyl carbinols and diastereomeric o-tolyl carbinols. The latter resulted from an unexpected benzyl to o-tolyl rearrangement. The proportion of benzyl versus o-tolyl derivatives depended on the reaction conditions. Benzylmagnesium chloride afforded predominantly o-tolyl carbinols while the application of benzylmagnesium bromide led preferably to the o-tolyl carbinols only when used in excess or at higher temperatures. The structures of the benzyl and o-tolyl derivatives were confirmed unambiguously by NMR spectral data and X-ray crystallographic analysis of their 5-ketone analogues obtained by oxidation of the corresponding mixture of diastereomeric carbinols. A possible mechanism for the Grignard reaction leading to the benzyl→ o-tolyl rearrangement is also proposed.

Full text of DOI:10.3762/bjoc.10.202

Reaction of selected carbohydrate aldehydes with benzyl-
magnesium halides: benzyl versus o-tolyl rearrangement
Maroš Bella1, Bohumil Steiner1, Vratislav Langer2 and Miroslav Koóš*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1942–1950.
1Institute of Chemistry, Center for Glycomics, Slovak Academy of
Sciences, Dúbravská cesta 9, 845 38 Bratislava, Slovakia and
2Environmental Inorganic Chemistry, Department of Chemical and
Biological Engineering, Chalmers University of Technology, 412 96
Göteborg, Sweden
doi:10.3762/bjoc.10.202
Received: 25 May 2014
Accepted: 31 July 2014
Published: 20 August 2014
Email:
Associate Editor: S. Flitsch
Miroslav Koóš* - chemmiro@savba.sk
© 2014 Bella et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aldehyde; benzyl versus o-tolyl; carbohydrate; Grignard reaction;
rearrangement; X-ray crystallography
Abstract
The Grignard reaction of 2,3-O-isopropylidene-α-D-lyxo-pentodialdo-1,4-furanoside and benzylmagnesium chloride (or bromide)
afforded a non-separable mixture of diastereomeric benzyl carbinols and diastereomeric o-tolyl carbinols. The latter resulted from
an unexpected benzyl to o-tolyl rearrangement. The proportion of benzyl versus o-tolyl derivatives depended on the reaction condi-
tions. Benzylmagnesium chloride afforded predominantly o-tolyl carbinols while the application of benzylmagnesium bromide led
preferably to the o-tolyl carbinols only when used in excess or at higher temperatures. The structures of the benzyl and o-tolyl
derivatives were confirmed unambiguously by NMR spectral data and X-ray crystallographic analysis of their 5-ketone analogues
obtained by oxidation of the corresponding mixture of diastereomeric carbinols. A possible mechanism for the Grignard reaction
leading to the benzyl→o-tolyl rearrangement is also proposed.
Introduction
One of the most popular synthetic routes leading to the forma- some new unexpected impediments limiting its application in
tion of simple alkyl or aryl branched-chain sugars involves the the synthesis of branched carbohydrates.
addition of Grignard reagents. In this regard, a wide variety of
Grignard reagents have been added to the free or masked (as In the context of our studies on the synthesis of sugar amino
hemiacetal) carbonyl functionalities present in the molecule of a acids structurally related to iminosugar mannojirimycin (a
suitable fully O-protected saccharide, thereby making possible strong inhibitor of α-mannosidase), we have recently prepared,
the preparation of a series of useful carbohydrate derivatives by applying the Grignard reaction, several branched sugar
[1-8]. Despite the demonstrable advantages of the Grignard carbinols as intermediates for subsequent oxidation to ketones
reaction, there remain, in addition to the recognised drawbacks, affording the corresponding hydantoins (precursors of amino
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Beilstein J. Org. Chem. 2014, 10, 1942–1950.
acids) via the Bucherer–Bergs reaction in the next step, which product entailed the participation of both of the equatorially
were finally transformed into sugar amino acids (precursors of disposed 2- and 6-acetoxy groups present in the substrate. The
biologicaly active iminosugars). Thus, using methylmagnesium non-acetylated substrates (like O-benzyl) afforded solely non-
iodide, some alanine-branched sugars were obtained [9,10]. rearranged benzyl derivatives. Our results represent the situa-
Analogously, leucine derivatives were synthesised starting from tion where the benzyl→o-tolyl rearrangement occurs during the
isobutylmagnesium bromide [11]. Unexpected difficulties were Grignard reaction between 1 or 2 and the non-anomeric free
encountered in an attempt to prepare the benzyl-branched sugar aldehyde function (C-5 position of the furanose) of an O-alkyl
carbinol, as a precursor of the final phenylalanine-branched (methyl and isopropylidene)-protected carbohydrate.
sugar, using benzylmagnesium chloride (1) or benzylmagne-
sium bromide (2) in the Grignard reaction with 2,3-O-iso- First, the addition reaction of aldehyde 3 with 1 under the stan-
propylidene-α-D-lyxo-pentodialdo-1,4-furanoside (3). In this dard Grignard reaction conditions (method A, see Experimental
case, the corresponding o-tolyl derivative was obtained as the part) was examined. Based on the NMR spectral data of the
major product instead of the expected benzyl compound isolated product, a mixture of 5-(R) and 5-(S) o-tolyl deriva-
(Scheme 1). Therefore, this reaction was subjected to more tives 4 and 5 together with a mixture of 5-(R) and 5-(S) benzyl
detailed inspection.
derivatives 6 and 7 (Scheme 1) in the ratio of approximately 3:1
was confirmed, indicating the substantial predominance of the
benzyl→o-tolyl rearrangement. In the subsequent experiments
Results and Discussion
Although 1 and 2 have frequently been used for the introduc- (methods B–E), the influence of the reaction conditions
tion of the benzyl group into a carbohydrate molecule [12-18], (temperature, reactants ratio, solvent, sequence of reactants ad-
the benzyl→o-tolyl rearrangement has, to the best of our knowl- dition) was examined, with the aim of suppressing the forma-
edge, only been reported once. In this regard, Panigot and tion of the rearranged products 4 and 5. As the preliminary
Curley [19] showed that the reaction of 1 with 2,3,4,6-tetra-O- experiments revealed that the addition of a solution of Grignard
acetyl-α-D-glucopyranosyl bromide (or chloride) produced a reagent 2 into a solution of the carbohydrate aldehyde 3 (i.e.,
3:1 mixture of 2-(β-D-glucopyranosyl)toluene and (β-D- reverse addition of reactants) in the mole ratio of 1.3:1 had
glucopyranosyl)phenylmethane isolated as the corresponding some positive effect in respect of the yield (but not of the
2,3,4,6-tetra-O-acetates. However, this is not a case of the proportion of isomers) of the Grignard reaction products, we
typical Grignard reaction where the Grignard reagent is coupled applied these parameters in subsequent experiments. It was
with a carbonyl compound. Moreover, the anomeric position found that the application of 2 instead of 1 also afforded a mix-
was involved in the reaction and there was an important limita- ture of o-tolyl and benzyl carbinols but their proportion was
tion: the formation of the unexpected o-tolyl rearrangement dependent on the reaction conditions (see Table 1 and Table 2).
Scheme 1: Grignard reaction of aldehyde 3 and oxidation of the resulting mixture of alcohols 4–7. Reagents and conditions: a) PhCH2MgCl (1) or
PhCH2MgBr (2) (1.2 equivalents), Et2O; see methods A–E in Experimental; b) PDC, DCM, Ac2O, reflux, 3 h.
1943

Beilstein J. Org. Chem. 2014, 10, 1942–1950.
The mixture of diastereomeric carbinols 6 and 7 resulted as a separated and purified using column chromatography and
main product of the “normal” Grignard reaction only at lower recrystallisation. Their structures were established on the basis
temperature without excess of 2. Only a minor positive effect of 1H and 13C NMR spectral data. The EI mass spectra and the
on the formation of “normal” addition products 6 and 7 was data of elemental analysis were also confirmative. The singlet
observed using 2-methyltetrahydrofuran as a solvent as well as signal observed for the H1 atom strongly supports the α-con-
the addition of an equivalent of CeCl3·2LiCl in THF to the reac- figuration at the anomeric atom C1 with the equatorially posi-
tion mixture, although it is known that the application of these tioned H1 and H2. A singlet (three protons) at δ = 3.91 and a
reagents favours the addition of Grignard reagents to carbonyl singlet (two protons) at δ = 2.48 clearly indicate the methyl (in
compounds to afford higher yields [20-22].
o-tolyl) and methylene (in benzyl) groups, respectively. Finally,
the o-tolyl structure and benzyl structure of the moieties at C-5
atom of ketone 8 (Figure 1) and ketone 9 (Figure 2), respective-
ly, (the numbering of the atoms is in accordance with the
numbering recommended by the IUPAC Nomenclature of
Carbohydrates [23]) was unambiguously confirmed by single-
crystal X-ray analysis.
Table 1: Reaction conditions for the Grignard reaction.
Method Entrya
Conditionsb
Conditionsc
A
B
C
D
E
1/3 = 3:1
0.5 h, rt
3 h, reflux
1.5 h, rt
1.5 h, rt
2 h, rt
2/3 = 1.3:1
2/3 = 2.5:1
2/3 = 1.3:1
1/3 = 1.3:1
0.5 h, −25 °C
0.5 h, −25 °C
0.5 h, rt
The formation of o-tolyl isomers 4 and 5 can be explained by
the possible reaction sequence (path 1) depicted in Scheme 2.
The first step involves an addition of the Grignard reagent to the
saccharide aldehyde, producing a trienic magnesium alkoxide
intermediate A (magnesium salt of 2-R-hydroxymethyl-1-meth-
ylene-1,2-dihydrobenzene, where R is the saccharide moiety)
which, upon quenching with aqueous NH4Cl, affords (via an
intermediate B) the corresponding o-tolyl isomer (a mixture of
0.5 h, −25 °C
1.5 h, rt
aMole ratio of reagent 1 or 2 and aldehyde 3 taken into the Grignard
reaction; btime and temperature for addition of reactant 1 or 2 to 3 (in
case of method A, reverse addition of reactants was applied, i.e., alde-
hyde 3 was added to Grignard reagent 1; creaction time and tempera-
ture after addition of reactants.
Since all attempts to separate and purify carbinols 4–7 using diastereomeric alcohols 4 and 5). A similar mechanism was
column chromatography were unsuccessful even after acetyla- proposed [24,25] for the reaction of 1-naphthylmethyl-
tion, their physical and spectral data are not given here in detail. magnesium chloride (10) with some aldehydes and ketones
In this regard, the ratio of the R and S isomers thus formed has (Scheme 3). However, in this case, a trienic magnesium alk-
not been studied. However, based on the NMR data (signals for oxide intermediate E (magnesium salt of 2-hydroxymethyl-1-
methyl and methylene group of o-tolyl and benzyl group, res- methylene-1,2-dihydronaphthalene, an analogue of intermedi-
pectively) of the isolated crude mixture of products 4–7, it was ate A in Scheme 2, path 1), produced by an addition of the
possible to determine the relative ratio of o-tolyl and benzyl Grignard reagent 10 to the monomeric formaldehyde (11, R1 =
isomers. Finally, for the separation of o-tolyl isomer from R2 = H), was unstable and decomposed by a reversible process
benzyl isomer, a mixture of all four chromatographically non- into the Grignard reagent and aldehyde. The latter underwent a
separable isomeric alcohols 4–7 was oxidised using PDC, Prins-type reaction with the magnesium alkoxide intermediate
thereby destroying the chiral center at C-5 position of the E in the presence of MgCl2, to give magnesium salt G which,
saccharide moiety, to afford a mixture of the two corres- upon quenching with aqueous NH4Cl, affords 1-(2-hydroxy-
ponding crystalline ketones 8 and 9. These were successfully ethyl)-2-hydroxymethylnaphthalene H (an analogue of diol D in
Table 2: Overall yields of 8 and 9 from oxidation of mixture of carbinols 4–7.
Entrya
Overall yield
Ketone 8
Method
8/9 ratio
4–7
8 and 9
Ketone 9
A
B
C
D
E
0.62 g
1.37 g
1.17 g
0.82 g
0.96 g
0.59 g, 20%
1.29 g, 44%
1.11 g, 38%
0.77 g, 26%
0.89 g, 30%
0.44 g, 15%
0.30 g, 10%
0.58 g, 20%
0.56 g, 19%
0.62 g, 21%
0.15 g, 5%
0.99 g, 34%
0.53 g, 18%
0.21 g, 7%
0.27 g, 9%
3:1
1:3
1.1:1
2.7:1
2.3:1
aAmount of mixture of carbinols 4–7 taken into oxidation obtained from 10 mmol of aldehyde 3 applying methods A–E.
1944

Beilstein J. Org. Chem. 2014, 10, 1942–1950.
Figure 1: Molecular structure (DIAMOND drawing with adjacent ChemDraw image) of o-tolyl derivative 8. Atomic displacement ellipsoids are drawn at
30% probability level and H atoms are shown as small spheres of arbitrary radii.
Figure 2: Molecular structure (DIAMOND drawing with adjacent ChemDraw image) of benzyl derivative 9. Atomic displacement ellipsoids are drawn
at 50% probability level and H atoms are shown as small spheres of arbitrary radii.
Scheme 2, path 2) and 1-methylnaphthalene (12). On the other starting ketone 11 without the formation (via an intermediate F)
hand, the reaction of 10 with ketones produced either normal of 1-methyl-2-substituted-naphthalenes I, analogues of o-tolyl
benzylic alcohols, rearranged alcohols or a mixture of both, derivatives 4 and 5 (Scheme 2, final step of path 1), which were
depending on the steric hindrance. However, the rearranged in present study, by contrast, isolated as stable products. More-
alcohols representing 1-methylene-2-substituted-1,2-dihydron- over, path 2 in Scheme 2 can be excluded, since no diols of type
aphthalenes F (analogues of intermediate B in Scheme 2) were C (analogues of diols H in Scheme 3) were detected in the reac-
unstable and decomposed to 1-methylnaphthalene (12) and the tion mixture.
1945

Beilstein J. Org. Chem. 2014, 10, 1942–1950.
Scheme 2: Proposed mechanism for Grignard reaction leading to benzyl→o-tolyl rearrangement (path 1). R = saccharide moiety; a = NH4Cl, H2O.
Scheme 3: Proposed mechanism [24,25] for Grignard reaction leading to 1-naphthylmagnesiumchloride→1-methylnaphthalene rearrangement. R1,
R2 = H, alkyl, cycloalkyl, phenyl, benzyl; a = NH4Cl, H2O.
To extend and confirm these observations, the analogous addi- accordingly, no further detailed inspections of the reaction
tion of 1 as well as 2 to another two representative carbohy- mixtures were performed.
drate aldehydes – 3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-
pentodialdo-1,4-furanose and 1,2:3,4-di-O-isopropylidene-α-D- X-ray analysis
galacto-hexodialdo-1,5-pyranose were investigated next. Unfor- Single crystals (stable at ambient temperature) suitable for
tunately, only very complex reaction mixtures (including X-ray diffraction were obtained by the slow crystallisation of 8
diatereomeric carbinols, biphenyl, polymeric impurities, etc.) and 9 from MeOH by cooling in a refrigerator. The preliminary
resulted under the above reaction conditions. However, analysis orientation matrices and final cell parameters were obtained
of the NMR spectral data of these mixtures showed the absence using Siemens SMART and Siemens SAINT software [26]. The
of CH3 protons of the o-tolyl moiety, indicating that the data were empirically corrected for absorption and other effects
benzyl→o-tolyl rearrangement did not occur in these cases; using the SADABS program [27] based on the method of
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Beilstein J. Org. Chem. 2014, 10, 1942–1950.
Blessing [28]. The crystal and experimental data for 8 and 9 are
summarised in Table 3 and Table 4. The structure was solved
by direct methods and refined by full-matrix least-squares on
all F2 data using Bruker SHELXTL [29]. The non-H atoms
were refined anisotropically. All the hydrogen atoms were
constrained to the geometrically idealised positions using an
appropriate riding model. Molecular graphics were obtained
using the program DIAMOND [30].
Table 4: Crystallographic and experimental dataa for compound 9.
Crystal data
Empirical formula
Formula weight
Crystal size
C16H20O5
292.32
0.98 x 0.21 x 0.12 mm
Needle
Crystal description
Crystal colour
Colourless
Monoclinic
P21
Crystal system
Space group
Table 3: Crystallographic and experimental dataa for compound 8.
Unit cell dimensions
a = 10.5035(14) Å
b = 5.7075(8) Å,
β = 96.268(3)°
Crystal data
c = 12.3449(16) Å
735.64(17) Å3
2
Empirical formula
Formula weight
Crystal size
C16H20O5
Volume
292.32
Z
1.00 x 0.36 x 0.18 mm
Needle
Calculated density
Absorption coefficient
F(000)
1.320 Mg/m3
0.098 mm−1
312
Crystal description
Crystal colour
Colourless
Orthorhombic
P212121
Crystal system
Space group
Data collection
Unit cell dimensions
a = 8.0419(2) Å
b = 10.0156(2) Å
c = 19.2682(3) Å
1551.95(6) Å3
4
Measurement device type
Measurement method
Temperature
Siemens SMART CCD
ω-scans
153(2) K
Volume
Wavelength
0.71073 Å
Z
Monochromator
Graphite
Calculated density
Absorption coefficient
F(000)
1.251 Mg/m3
0.093 mm−1
624
Theta range for data
collection
2.42 to 29.20°
Index ranges
−14 ≤ h ≤ 14,
−7 ≤ k ≤ 7,
−16 ≤ l ≤ 16
Data collection
Reflections collected/unique 10030/2175 [R(int) = 0.0516]
Completeness to θ = 29.20° 99.4%
Measurement device type
Measurement method
Temperature
Siemens SMART CCD
ω-scans
Absorption correction
Multi-scan
173(2) K
Max. and min. transmission
0.9884 and 0.9104
Wavelength
0.71073 Å
Monochromator
Graphite
Refinement
θ range for data collection
Index ranges
2.11 to 28.33°
−10 ≤ h ≤10,
−13 ≤ k ≤13,
−25 ≤ l ≤25
Refinement method
Full-matrix least-squares on
F2
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R indices (all data)
2175/1/193
Reflections collected/unique 21019/2217 [R(int) = 0.0496]
Completeness to θ = 28.33° 99.7%
1.002
R1 = 0.0329, wR2 = 0.0802
R1 = 0.0411, wR2 = 0.0842
0.188 and −0.195 e·Å−3
Absorption correction
Multi-scan
Max. and min. transmission
0.9835 and 0.9132
Largest diff. peak and hole
aStandard deviations in parentheses.
Refinement
Refinement method
Full-matrix least-squares on
F2
Based on the calculated values of the ring-puckering para-
meters (Q, Φ, θ) [31] (Table 5) and relevant torsion angles
(Table 6), the conformations of the five-membered
O4–C1–C2–C3–C4 furanose ring and the five-membered 1,3-
dioxolane ring (O2–C2–C3–O3–C14) in compounds 8 and 9
were established. It was found that the furanose ring in 8
adopted the OE (O4E) conformation distorted significantly to the
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R indices (all data)
2217/0/214
1.025
R1 = 0.0322, wR2 = 0.0797
R1 = 0.0398, wR2 = 0.0850
0.198 and −0.149 e·Å−3
Largest diff. peak and hole
aStandard deviations in parentheses.
1947

Beilstein J. Org. Chem. 2014, 10, 1942–1950.
OT1 (O4TC1, twisted on O4–C1, O4-endo) direction. The con- dene-α-D-xylo-pentodialdo-1,4-furanose and 1,2:3,4-di-O-iso-
formation of the five-membered 1,3-dioxolane ring in 8 can be propylidene-α-D-galacto-hexodialdo-1,5-pyranose were used as
described as a 4E (C14E) shifted significantly to the 4TO starting sugar aldehydes. The structures of o-tolyl and benzyl
(C14TO2, twisted on C14–O2, C14-endo) direction. Regarding derivatives 8 and 9 were unambiguously confirmed by X-ray
compound 9, an inspection of the relevant data revealed an crystallographic analysis. Compounds 8 and 9 represent prof-
almost perfect OE (O4E) conformation of the furanose ring and itable synthetic blocks for the synthesis of structurally modified
the E4 (EC14) conformation distorted significantly to the OT4 iminosugars and sugar moiety-containing heterocycles, amino
(O2TC14, twisted on O2–C14, C14-exo) direction of the 1,3- acids, etc.
dioxolane ring.
Experimental
Reagents and apparatus: The starting methyl 2,3-O-isopropyl-
Table 5: Puckering parametersa for the five-membered furanose ring
and the five-membered 1,3-dioxolane ring in compounds 8 and 9.
idene-α-D-lyxo-pentodialdo-1,4-furanoside was prepared
according to a recognised method [32,33]. Benzylmagnesium
chloride (1) and benzylmagnesium bromide (2) solutions (1 M
in diethyl ether) and the other reagents and solvents were
commercially available products and were used as received.
Melting points were determined using a Boetius PHMK 05
microscope. Specific rotations were determined on a Jasco
P-2000 digital polarimeter. Microanalyses were performed on a
Fisons EA 1108 analyser. The 1H and 13C NMR spectra (in
CDCl3, internal standard Me4Si) were recorded on a Varian
600 MHz VNMRS spectrometer equipped with HCN 13C
enhanced salt-tolerant cold probe operating at 599.84 and
150.84 MHz working frequencies, respectively. Advanced tech-
niques from the Varian pulse sequence library of 2D homo- and
hetero-correlated spectroscopy (gCOSY, gTOCSY, gHSQCAD,
gHMBCAD, and gH2BC) including 1D sequences with selec-
tive excitations (1DNOESY, 1DTOCSY, and 1DROESY) were
used for the signal assignments. The quaternary carbon atoms
were identified on the basis of a semi-selective INEPT experi-
ment and a 1D INADEQUATE pulse sequence technique.
When reporting assignments of NMR signals, the data for the
phenyl moiety are identified by a prime. The EI mass spectra
(70 eV) were obtained on a Q-Tof Premier instrument (Waters).
Column chromatography was performed as flash chromatog-
raphy on Silica Gel 60 (E. Merck, 0.063–0.200 mm). The IR
spectra (ATR) were measured using a Nicolet 6700 FTIR spec-
trometer. Thin-layer chromatography was performed on pre-
coated Silica Gel 60 F254 plates (E. Merck). Visualisation was
achieved by spraying the plates with 5% (v/v) solution of
H2SO4 in ethanol and heating at ca 200 °C.
Ring
Parameter Compound
8
9
Furanose
Q (Å)
Φ (°)
Q (Å)
Φ (°)
0.3467(16)
8.1(3)
0.3206(16)
353.8(9)
1,3-Dioxolane
0.3299(16)
155.1(3)
0.2146(16)
332.9(4)
aStandard deviations in parentheses.
Table 6: Relevant torsion angles (°)a for the five-membered furanose
ring and the five-membered 1,3-dioxolane ring in compounds 8 and 9.
Ring
Torsion angle
Compound
8
9
Furanose
O4–C1–C2–C3
C1–C2–C3–C4
C2–C3–C4–O4
C3–C4–O4–C1
C4–O4–C1–C2
26.34(16)
17.62(18)
−5.02(16) 3.34(18)
−17.45(15) −23.03(17)
35.47(15)
35.73(16)
−39.06(17) −33.52(17)
−6.58(16) 3.57(18)
1,3-Dioxolane O2–C2–C3–O3
C2–C3–O3–C14 −16.04(16) 11.31(17)
C3–O3–C14–O2 32.66(16) −21.76(17)
O3–C14–O2–C2 −37.19(16) 24.23(17)
C14–O2–C2–C3 26.66(16) −17.24(17)
aStandard deviations in parentheses.
Conclusion
In summary, various reaction conditions were employed for the
synthesis of carbinols 4–7 from Grignard reagent 1 (or 2) and Synthesis of methyl (5R)-2,3-O-isopropylidene-5-C-(2-
sugar aldehyde 3. Depending on the reaction conditions, the methylphenyl)-α-D-lyxofuranoside (4), methyl (5S)-2,3-O-
ratio of o-tolyl carbinols 4 and 5 (products of the benzyl→o- isopropylidene-5-C-(2-methylphenyl)-α-D-lyxofuranoside
tolyl rearrangement) versus non-rearranged benzyl carbinols 6 (5), methyl 6-deoxy-2,3-O-isopropylidene-6-phenyl-α-D-
and 7 varied from 3:1 to 1:3 (based on the isolated o-tolyl and mannofuranoside (6), and methyl 6-deoxy-2,3-O-isopropyli-
benzyl ketones 8 and 9, respectively). It seems that the dene-6-phenyl-β-L-gulofuranoside (7)
benzyl→o-tolyl rearrangement is specific for 2,3-O-isopropyli-
dene-α-D-lyxo-pentodialdo-1,4-furanoside because no re- Method A: Methyl 2,3-O-isopropylidene-α-D-lyxo-pentodi-
arrangement was observed when 3-O-benzyl-1,2-O-isopropyli- aldo-1,4-furanoside (3) (2.02 g, 10.0 mmol) in diethyl ether
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Beilstein J. Org. Chem. 2014, 10, 1942–1950.
(30 mL) was added dropwise into benzylmagnesium chloride methyl 6-deoxy-2,3-O-isopropylidene-6-phenyl-α-D-lyxo-
(1, 1.0 M solution in diethyl ether, 13 mL, 13 mmol) at ambient hexofuranosid-5-ulose (9): A mixture of alcohols 4–7 (1.47 g,
temperature in the course of 30 min. Subsequently, the mixture 5.0 mmol) in CH2Cl2 (25 mL) was added dropwise to a magnet-
was stirred and heated under reflux for 3 h. After cooling, it was ically stirred solution of pyridinium dichromate (PDC, 2.45 g,
poured into a saturated NH4Cl solution pre-cooled to 5 °C. The 6.5 mmol) and acetic anhydride (1.3 mL) in CH2Cl2 (25 mL)
organic layer was separated and the aqueous layer was under cooling in an ice-water bath followed by heating under
extracted with diethyl ether (3 × 50 mL). The combined organic reflux for 3 h. The greater part of CH2Cl2 was evaporated and
layers were dried (Na2SO4), filtered and evaporated under the chromic salts were precipitated by the addition of a mixture
reduced pressure to give a crude oily product which was puri- of EtOAc/hexane 1:1. After filtration and evaporation of the
fied on a column of silica gel using EtOAc/hexane 1:4 as an solvents under reduced pressure, the product thus obtained was
eluent, affording a mixture of alcohols 4–7 (Rf = 0.44, 0.62 g, purified on a column of silica gel using EtOAc/hexane 1:4 as an
21%).
eluent, affording ketone 8 (Rf = 0.6) and ketone 9 (Rf = 0.7)
with a total yield of 94–96% (percentage of 8 and 9 together in
Method B: Benzylmagnesium bromide (2, 1.0 M solution in oxidation step). These were recrystallised from methanol. The
diethyl ether, 13 mL, 13 mmol) pre-cooled to −5 °C was added overall isolated yields of 8 and 9 (depending on the method
dropwise to a magnetically stirred solution of aldehyde 3 used for preparation of the starting mixture of alcohols 4–7)
(2.02 g, 10.0 mmol) in diethyl ether (30 mL) under cooling at from two reaction steps (Grignard reaction and PDC oxidation)
−25 °C in the course of 30 min. Subsequently, the mixture was starting from 10 mmol of aldehyde 3 are summarised in
stirred at ambient temperature for an additional 1.5 h and Table 2.
poured into a saturated NH4Cl solution pre-cooled to 5 °C. The
organic layer was separated and the aqueous layer was 8: colourless solid; mp 105–106 °C;
+12 (c 1, MeOH);
extracted with diethyl ether (3 × 50 mL). The combined organic 1H NMR (600 MHz, CDCl3) δ 7.60–7.22 (m, 5H, Ph), 5.26 (d,
layers were dried (Na2SO4), filtered and evaporated under J3,4 = 4.3 Hz, 1H, H-4), 5.12 (s, 1H, H-1), 4.99 (dd, J2,3 = 5.7
reduced pressure to give a crude oily product which was puri- Hz, J3,4 = 4.3 Hz, 1H, H-3), 4.58 (d, J2,3 = 5.7 Hz, 1H, H-2),
fied on a column of silica gel using EtOAc/hexane 1:4 as an 3.41 (s, 3H, OCH3), 2.48 (s, 3H, CH3), 1.41 and 1.21 (2s, each
eluent, affording a mixture of alcohols 4–7 (Rf = 0.44, 1.37 g, 3H, Me2C) ppm; 13C NMR (150 MHz, CDCl3) δ 196.7 (C-5),
46%).
138.6 (C-2′), 136.7 (C-1′), 131.8 (C-6′), 131.2 (C-4′), 127.4
(C-3′), 125.3 (C-5′), 113.3 (CMe2), 107.2 (C-1), 84.4 (C-2),
Method C: Benzylmagnesium bromide (2, 1.0 M solution in 83.8 (C-4), 81.0 (C-3), 55.1 (OCH3), 25.8 and 25.0 [(CH3)2C],
diethyl ether, 25 mL, 25 mmol) and aldehyde 3 (2.02 g, 20.3 (CH3) ppm; EIMS m/z (Ir/%): 292 (5), 277 (20), 261 (10),
10.0 mmol) in diethyl ether (30 mL) were allowed to react 203 (20), 192 (100), 173 (38), 161 (34), 145 (16), 119 (95), 115
under the same reaction conditions as in method B to give (after (11), 113 (6), 91 (18), 43 (50); IR (ATR) ν: 2987, 2928, 2834,
column chromatography) a mixture of alcohols 4–7 (Rf = 0.44, 1695 (C=O), 1602, 1569, 1487, 1453, 1379, 1278, 1205, 1163,
1.17 g, 39.5%).
1110, 1088, 1072, 1011, 964, 922, 886, 856, 825, 784, 761, 729,
659, 647, 619, 591 cm−1; anal. calcd (%) for C16H20O5
Method D: Benzylmagnesium bromide (2, 1.0 M solution in (292.33): C, 65.70; H, 6.90; found (%): C, 65.56; H, 6.81.
diethyl ether, 13 mL, 13 mmol) and aldehyde 3 (2.02 g,
10.0 mmol) in diethyl ether (30 mL) were allowed to react at 9: colourless solid; mp 72–73 °C;
+5 (c 1, MeOH); 1H
ambient temperature applying the reaction mixture work-up NMR (600 MHz, CDCl3) δ 7.33–7.21 (m, 5H, Ph), 5.07 (s, 1H,
procedure as in method B to give (after column chromatog- H-1), 4.99 (dd, J2,3 = 5.7 Hz, J3,4 = 4.2 Hz, 1H, H-3), 4.56 (d,
raphy) a mixture of alcohols 4–7 (Rf = 0.44, 0.82 g, 28%).
J2,3 = 5.7 Hz, 1H, H-2), 4.50 (d, J3,4 = 4.2 Hz, 1H, H-4), 3.91
(s, 2H, H-6), 3.32 (s, 3H, OCH3), 1.45 and 1.28 (2s, each 3H,
Method E: Benzylmagnesium chloride (1, 1.0 M solution in Me2C) ppm; 13C NMR (150 MHz, CDCl3) δ 203.7 (C-5), 133.5
diethyl ether, 13 mL, 13 mmol) and aldehyde 3 (2.02 g, (C-1′), 129.9 (C-3′, C-5′), 128.5 (C-2′, C-6′), 126.9 (C-4′), 113.1
10.0 mmol) in diethyl ether (30 mL) were allowed to react (CMe2), 107.6 (C-1), 84.4 (C-4), 84.2 (C-2), 81.0 (C-3), 55.0
under the same reaction conditions as in method B to give (after (OCH3), 47.1 (C-6), 25.8 and 24.5 [(CH3)2C] ppm; EIMS m/z
column chromatography) a mixture of alcohols 4–7 (Rf = 0.44, (Ir/%): 292 (5), 277 (5), 203 (36), 192 (21), 173 (13), 161 (15),
0.96 g, 33%).
115 (20), 113 (19), 99 (21), 91 (100), 87 (17), 85 (14), 83 (6),
65 (11), 59 (16), 55 (8), 45 (31), 43 (30), 41 (9); IR (ATR) ν:
Synthesis of methyl 2,3-O-isopropylidene-5-C-(2- 2992, 2937, 2868, 2838, 1722, 1600, 1493, 1456, 1433, 1377,
methylphenyl)-α-D-lyxo-pentodialdo-1,4-furanoside (8) and 1263, 1238, 1209, 1154, 1121, 1091, 1060, 1029, 996, 968, 874,
1949

Beilstein J. Org. Chem. 2014, 10, 1942–1950.
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doi:10.1002/anie.198405561
798, 753, 720, 699, 658, 611, 560, 513 cm−1; anal. calcd (%)
for C16H20O5 (292.33): C, 65.70; H, 6.90; found (%): C, 65.52;
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Crystallographic data for structures 8 and 9 have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication nos. CCDC 1001956 and 1001957. Copies
of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +
44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk or via:
http://www.ccdc.cam.ac.uk).
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Acknowledgements
The financial support from the Slovak Research and Develop-
ment Agency (Grant no. APVV-0484-12) and Scientific Grant
Agency (Grant nos. VEGA 2/0101/11 and 1/0962/12) is grate-
fully acknowledged. This contribution is the result of the project
implementation: Centre of Excellence for Glycomics, ITMS
26240120031, supported by the Research & Development
Operational Programme funded by the ERDF.
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1950