Use of XtalFluor-E as an Alternative to POCl3 in the Vilsmeier-Haack Formylation of C-2-Glycals

Article abstract of DOI:10.1021/acs.joc.8b01006

We report the use of XtalFluor-E ([Et₂NSF₂]BF₄) as an alternative to POCl₃ in the Vilsmeier-Haack formylation reaction of C-2-glycals. Employing a XtalFluor-E/DMF combination allowed the desired C-2-formyl glyca

Full text of DOI:10.1021/acs.joc.8b01006

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Use of XtalFluor‑E as an Alternative to POCl3 in the Vilsmeier−Haack
Formylation of C‑2-Glycals
†
‡
‡
́
́
́
Majdouline Roudias, Frederic Vallee, Julien Martel, and Jean-Franco
̧
is Paquin*,†
†
́
́
́
́
CCVC, PROTEO, Departement de chimie, Universite Laval, 1045 avenue de la Medecine, Quebec, QC, Canada G1V 0A6
‡
́
OmegaChem Inc., 480 rue Perreault, Levis, QC, Canada G6W 7V6
S
* Supporting Information
ABSTRACT: We report the use of XtalFluor-E ([Et2NSF2]BF4) as an
alternative to POCl3 in the Vilsmeier−Haack formylation reaction of C-
2-glycals. Employing a XtalFluor-E/DMF combination allowed the
desired C-2-formyl glycals to be isolated in 11−90% yield. This method
was extended to the synthesis of a C-2-formylated disaccharide glycal.
Vilsmeier−Haack reaction6 remains the most employed
INTRODUCTION
■
technique as it offers a direct access to introduce the formyl
group at the C-2-position from readily accessible precursors
(eq 4).7 However, this reaction employs POCl3, a highly toxic
and corrosive reagent that reacts violently with water. Herein,
we report alternative conditions for the Vilsmeier−Haack
formylation where POCl3 is replaced by XtalFluor-E
([Et2NSF2]BF4),8−11 a less toxic and more hydrolytically
stable reagent, for the synthesis of C-2-formyl glycals
possessing diverse functional groups (eq 5).
C-2-Formyl-glycals, a class of carbohydrates incorporating an
α,β-unsaturated aldehyde, have been the subject of increased
attention as they afford valuable chiral building blocks. The
presence of a conjugated enal group, their built-in chirality, and
their synthetic versatility make them attractive intermediates in
synthetic organic chemistry.1 Apart from their synthetic
interest, C-2-formyl glycals have found applications in
medicinal, biological, supramolecular, and material chemistry.2
A number of methods have been reported for the preparation
of C-2-formylated glycals (Scheme 1, eqs 1−3),3−5 but the
Initial Vilsmeier−Haack formylation reaction on tri-OBn
glycal 1a was realized using 3 equiv of XtalFluor-E in DMF (1
M) during 18 h at 21 °C and showed promise with the
isolation of the corresponding formylated glucal 2a in 59%
yield (Table 1, entry 1). However, the reaction did not go to
completion and starting material was recovered. Leaving the
reaction longer (2 days) did not improve the conversion, and
2a was obtained in slightly lower yield (entry 2). Conducting
the reaction at higher temperatures resulted in lower yields and
led to the degradation of the starting material 1a (entry 3).12
Diluting the reaction did not furnish better results, and
concentrating the reaction led to solubility issues (entries 4
and 5). Various additives (pivalic acid, citric acid, DBU, and
DIPEA), in both catalytic and stoichiometric amounts, were
also tested, but no improvements were noticed (data not
shown). We next investigated the use of various cosolvents in a
1:1 mixture with DMF, and selected results are shown (entries
6−12).13 Gratifyingly, the formylated glucal was isolated in
80% yield when Et2O was used (entry 12). Increasing the
amount of Et2O in the mixture resulted in lower yield due the
insolubility of XtalFluor-E. Reducing the amount of XtalFluor-
E resulted in a much slower reaction (entries 12−14), probably
because it lowered the concentration of the formylating agent
(vide infra). Overall, the conditions shown in Table 1, entry
12, proved to be optimal.14
Scheme 1. Previous Methods and Current Approach
Received: April 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01006
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
labile groups) are compatible. Hence, 2i, 2j, 2k, and 2l were
isolated in 19%, 36%, 46%, and 27% yield, respectively. In
those cases, conversion was not complete under those
conditions. In general, the yields were found to be lower for
the formylation in the glucal series than in the galactal series.
This can be explained by electronic and steric effects of the 4-
protected group in the pseudoequatorial position that is closer
to the incoming Vilsmeier−Haack reagent and that decreases
the electron density of the double bond.15
Lellouche and co-workers reported the particular sensitivity
of silyl ether glucals toward Vilsmeier−Haack conditions.19
When these glucals were treated with the Vilsmeier−Haack
reagent, selective silyl deprotection of the C-6 primary alcohol
occurred followed by its O-formylation to afford the
corresponding O-6-formate. However, in the presence of an
excess of reagent neither subsequent O-formylation to di- or
triformates nor C-2 formylation was observed. In that context,
we were curious to try our conditions on 3,4-di-OBn-6-OTBS
glucal 1n. Interestingly, we did not isolate the expected
product from the C-6 formylation, but we isolated formyl
formate glucal 4 (obtained from the bis formylation at the O-6-
and C-2- positions) along with the formate glucal 3 (product of
the O-6-formylation) (Scheme 2, eq 1). In a similar way, when
subjected to our Vilsmeier−Haack conditions, 3,4-di-OPMB-6-
OTr glucal 1o provided 12% of the desired formyl glucal 2o
along with 10% of the formate glucal 5 and 22% yield of the
formyl formate glucal 6 (eq 2).
Table 1. Key Optimization Results for Formylation of 1a
Using XtalFluor-E
XtalFluor-E
(equiv)
cosolvent
(ratio)
conc
(M)
temp
(°C)
time
(h)
yield
a
entry
(%)
1
2
3
4
5
6
3
3
3
3
3
3
1
1
1
0.1
2
21
21
50
21
21
21
18
42
18
18
18
18
59
45
30
12
20
73
CH3CN
(1:1)
1
7
8
9
3
3
3
EtOAc
(1:1)
CHCl3
(1:1)
toluene
(1:1)
1
1
1
21
21
21
18
18
18
72
73
73
10
11
12
13
14
3
3
3
2
1
THF (1:1)
DCE (1:1)
Et2O (1:1)
Et2O (1:1)
Et2O (1:1)
1
1
1
1
1
21
21
21
21
21
18
18
18
18
18
65
67
80
18
8
a
Isolated yield of 2a after purification on silica gel.
Finally, our methodology was extended to disaccharide
glycal, in the form of hexa-OBn lactal 7. The corresponding
formyl lactal 8 was obtained in 56% yield, whereas a 37% yield
was obtained using classical Vilsmeier−Haack conditions
(Scheme 3).20
With respect to the reaction mechanism, we propose one
similar to the classical POCl3-promoted Vilsmeier−Haack
formylation but with a structurally different formylating agent
(Scheme 4).15,19a In the present case, nucleophilic attack of the
amide carbonyl group of DMF at the electrophilic sulfur of
[Et2NSF2]BF4 would generate intermediate 9.8a As the
We next evaluated the reactivity of different glycals
possessing diverse functional groups under the optimized
conditions. The results are summarized in Table 2 with the
corresponding yields of the formyl glycals reported so far in the
literature. Under our conditions, we obtained moderate to
excellent yields of the formylated ether protected products 2a−
f,m. These yields are comparable to the ones reported in the
literature or even better for some examples. The yields for
MOM protected products 2g and 2h are particularly low due
to their instability on silica gel. Acetyl and benzylidene (acid-
a b
,
Table 2. Scope of the Formylation of C-2-Glycals Using XtalFluor-E
a
b
Isolated yield of 2 after column chromatography. Literature isolated yield using a POCl3-mediated Vilsmeier−Haack protocol is provided in
parentheses, when available, with the appropriate reference.16−18 NR = not reported. N/A = not available. The reaction was performed in 1 M
DMF. The reaction was carried out with 0.1 equiv of DIPEA. The reaction was conducted at 0.5 M.
c
d
e
B
DOI: 10.1021/acs.joc.8b01006
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2. Unexpected Formylation Outcomes
potential of using a XtalFluor-E/DMF combination for the
formylation of other nucleophilic organic molecules.
Scheme 3. Formylation of a Disaccharide Glycal
EXPERIMENTAL SECTION
■
General Information. All commercial compounds were used as
received. Solvents were used as purchased unless stated as dry. Et2O,
THF, CH3CN, DCM, and toluene were purified using a Vacuum
Atmospheres Inc. solvent purification system. All air and water
sensitive reactions were carried out under an argon atmosphere.
Reactions were monitored by TLC on precoated plates (Silicycle
silica gel 60 Å F254), and products were visualized under 254 nm UV
light followed by staining with KMnO4 or DNPH when appropriate.
Purification was carried out using a Biotage Isolera one flash
chromatography system using Biotage KPSIL SNAP or Silicycle
SiliaSep silica gel cartridges. NMR spectra were recorded on an
Agilent DD2 500 spectrometer in the indicated solvent at 298 K.
Chemical shifts for 1H and 13C spectra are reported on the delta scale
in ppm and were referenced to residual solvent references or internal
TMS reference. Resonances are reported as follows: chemical shift (δ,
ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, sxt = sextet, m = multiplet, or a combination of the
above), coupling constant (Hz), integration, and attribution. H and C
signals were assigned using 2D correlations (HSQC and COSY) and
DEPT experiments, and hydrogen/carbon assignations refer to the
standard sugar nomenclature.22 High-resolution mass (HRMS)
spectra were recorded on a LC/MS-TOF Agilent 6210 using
electrospray ionization in positive mode (ESI+) at 100 °C. Infrared
spectra (IR) were recorded on an ABB MB 3000 FT-IR spectrometer
and on a Thermo Scientific Nicolet 380 FT-IR spectrometer.
Absorptions are described as s (strong), m (medium), w (weak),
and br (broad) and reported in cm−1. Melting points were measured
on a Stanford Research System OptiMelt MPA100 automated melting
formylation reaction proceeds and fluoride ions are released
into the reaction mixture (vide infra), 9 could potentially be
converted to 10,21 the fluoride equivalent of the Vilsmeier
reagent (Scheme 4a). We hypothesize that intermediate 9 or
10 could react similarly to the classical Vilsmeier reagent (11)
in promoting the formylation reaction of C-2-glycals (Scheme
4b). Here, the formylating agent (9 or 10) would react with a
C-2-glycal (1) to generate intermediate 12. Nitrogen-assisted
expulsion of the X group would produce the iminium 13 that
would, upon an aqueous workup, release the C-2-formyl glycal
(2). In the case of 9, the (diethylamino)difluoro-λ4-sulfanolate
expelled would decompose to diethylsulfuramidous fluoride
and fluoride, the latter being required for the potential
conversion of 9 to 10 (Scheme 4a).
In conclusion, we have reported the use of a XtalFluor-E/
DMF combination for the Vilsmeier−Haack formylation
reaction of C-2-glycals. The C-2-formyl-glycals were obtained
in yields similar to or even better than those reported in the
literature using the classical POCl3/DMF mixture. Addition-
ally, we showed that the formylation of a disaccharide glycal
was possible. Notably, this transformation showcases the
a
Scheme 4. Potential Nature of the Formylating Reagent
a
−
The BF4 counterion of XtalFluor-E has been omitted for clarity.
C
DOI: 10.1021/acs.joc.8b01006
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
point apparatus and are uncorrected. Optical rotations were recorded
on a Jasco DIP-360 digital polarimeter at 589 nm. Tri-OAc glucal 1i
and tri-OAc galactal 1j,23 tri-OBn glucal 1a and tri-OBn galactal
1b,23,24 tri-OPMB glucal 1c and tri-OPMB galactal 1d,23,25 tri-Oallyl
glucal 1e and tri-Oallyl galactal 1f,23,18 tri-OMOM glucal 1g and tri-
OMOM galactal 1h,23,26 3-OBn-4,6-benzylidene glucal 1k,27 6-F-3,4-
di-OAc galactal 1l and 6-F-3,4-di-OBn galactal 1m,28 3,4-di-OBn-6-
OTBS glucal 1n,23,19b 3,4-di-OPMB-6-OTr glucal 1o,23,29 and hexa-
OBn lactal 730 were prepared according to the methods in the
literature.
General Procedure for the Formylation of C-2 Glycals. To a
solution of glycal (50 mg) in dry DMF/Et2O (1:1, 1 M) was added
XtalFluor-E (3 equiv). After 18 h at rt, saturated brine (10 mL) and
EtOAc (10 mL) were added and the aqueous phase was separated and
extracted with EtOAc (2 × 10 mL). The organic phases were
combined, dried over MgSO4, filtered, concentrated in vacuo, and
purified on silica gel using an automated flash purification system
(AFP).
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihy-
dro-2H-pyran-5-carbaldehyde (2a). According to the general
procedure on a 0.12 mmol scale, formyl glucal 2a was isolated as a
yellow oil (42.5 mg, 80%) after purification by AFP (5−40% EtOAc/
hexanes, 3-15-3 CV). Data are in accordance with the one described
in the literature.24
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihy-
dro-2H-pyran-5-carbaldehyde (2b). According to the general
procedure on a 0.12 mmol scale, formyl galactal 2b was isolated as
a yellow oil (36.2 mg, 68%) after purification by AFP (5−40%
EtOAc/hexanes, 3-15-3 CV). Data are in accordance with the one
described in the literature.31
((2R,3S,4R)-3,4-Bis((4-methoxybenzyl)oxy)-2-(((4-
methoxybenzyl)oxy)methyl)-3,4-dihydro-2H-pyran-5-carbaldehyde
(2c). According to the general procedure on a 0.10 mmol scale, formyl
glucal 2c was isolated as a yellow oil (21.3 mg, 40%) after purification
by AFP (15−60% EtOAc/hexanes, 3-15-3 CV). FT-IR (ν/cm−1):
3001 (w), 2953 (w), 2932 (w), 2910 (w), 2862 (w), 2835 (w), 1672
(m), 1612 (m), 1512 (s), 1464 (m), 1302 (m), 1244 (s), 1173 (m),
1074 (s), 1032 (s). 1H NMR (500 MHz, CDCl3) (δH/ppm): 9.39 (s,
1H, CHO), 7.37 (s, 1H, H1), 7.22−7.12 (m, 6H, 6 × ArH), 6.90−
6.80 (m, 6H, 6 × ArH), 4.70−4.62 (m, 1H, H5), 4.58 (d, J = 11.1 Hz,
1H, CHHOPh), 4.50 (d, J = 11.2 Hz, 1H, CHHOPh), 4.47 (d, J =
11.7 Hz, 1H, CHHOPh), 4.45 (d, J = 11.5 Hz, 1H, CHHOPh), 4.39
(d, J = 11.8 Hz, 1H, CHHOPh), 4.38 (d, J = 11.1 Hz, 1H,
CHHOPh), 4.39−4.34 (m, 1H, H3), 3.81 (s, 3H, OCH3), 3.801 (s,
3H, OCH3), 3.800 (s, 3H, OCH3), 3.79−3.70 (m, 2H, CHH6 + H4),
3.56 (dd, J = 10.9, 4.5 Hz, 1H, CHH6). 13C NMR (125 MHz, CDCl3)
(δC/ppm): 190.4 (CHO, C7), 164.3 (CH, C1), 159.5 (C, CAr), 159.32
(C, CAr), 159.25 (C, CAr), 130.3 (C, CAr), 129.7 (C, CAr), 129.5 (CH,
CHAr), 129.42 (CH, CHAr), 129.41 (CH, CHAr), 129.3 (C, CHAr),
117.8 (C, C2), 113.9 (CH, CHAr), 113.8 (CH, CHAr), 113.7 (CH,
CHAr), 79.5 (CH, C5), 73.0 (CH2, CH2OPh), 72.1 (CH2, CH2OPh),
71.2 (CH2, CH2OPh), 70.9 (CH, C4), 68.2 (CH2, C6), 65.1 (CH,
C3), 55.28 (2 × CH3, 2 × OCH3), 55.27 (CH3, OCH3). HRMS (ESI-
TOF), m/z: [M + H]+ calcd for C31H35O8, 535.2326; found,
535.2315. [α]D22.8 −2.99 (c = 0.94, MeOH).
(125 MHz, CDCl3) (δC/ppm): 189.5 (CHO, C7), 164.4 (CH, C1),
159.5 (C, CAr), 159.3 (C, CAr), 159.2 (C, CAr), 131.1 (C, CAr), 130.1
(C, CAr), 129.7 (CH, CHAr), 129.6 (C, CAr), 129.5 (CH, CHAr),
129.4 (CH, CHAr), 119.5 (C, C2), 114.0 (CH, CHAr), 113.9 (CH,
CHAr), 113.7 (CH, CHAr), 79.0 (CH, C5), 73.5 (CH2, CH2OPh),
73.2 (CH2, CH2OPh), 72.8 (CH, C4), 71.3 (CH2, CH2OPh), 68.2
(CH2, C6), 64.7 (CH, C3), 55.40 (CH3, OCH3), 55.37 (CH3, 2 ×
OCH3). HRMS (ESI-TOF), m/z: [M + H]+ calcd for C31H35O8,
535.2326; found, 535.2315. [α]2D2.8 −0.79 (c = 1.64, MeOH).
(2R,3S,4R)-3,4-Bis(allyloxy)-2-((allyloxy)methyl)-3,4-dihydro-2H-
pyran-5-carbaldehyde (2e). According to the general procedure on a
0.19 mmol scale using DMF (1 M) as the solvent instead, formyl
glucal 2e was isolated as a yellow oil (10.9 mg, 45%) after purification
by AFP (5−40% EtOAc/hexanes, 3-15-3 CV). FT-IR (ν/cm−1): 2920
(w), 2858 (w), 1672 (s), 1622 (s), 1456 (w), 1421 (m), 1294 (m),
1
1265 (w), 1198 (s), 1070 (s). H NMR (500 MHz, CDCl3) (δH/
ppm): 9.38 (s, 1H, CHO), 7.38 (s, 1H, H1), 5.96−5.81 (m, 3H, 3 ×
CHCH2), 5.32−5.13 (m, 6H, 3 × OCH2CH), 4.70 (app ddt, J =
7.9, 4.5, 2.0 Hz, 1H, H5), 4.29 (dd, J = 2.7, 2.0 Hz, 1H, H3), 4.20−
3.95 (m, 6H, 3 × CHHCH + 3 × CHHCH), 3.84 (app t, J = 2.3
Hz, 1H, H4), 3.76 (dd, J = 10.9, 7.9 Hz, 1H, CHH6), 3.62 (dd, J =
10.9, 4.5 Hz, 1H, CHH6). 13C NMR (125 MHz, CDCl3) (δC/ppm):
190.3 (CHO, C7), 164.3 (CH, C1), 134.7 (CH, CHCH2), 134.2
(CH, CHCH2), 134.0 (CH, CHCH2), 118.0 (CH2, OCH2CH),
117.59 (C, C2), 117.56 (CH2, OCH2CH), 116.8 (CH2, OCH2CH),
79.5 (CH, C5), 72.3 (CH2, CH2CH), 71.2 (CH, C4), 71.0 (CH2,
CH2CH), 70.8 (CH2, CH2CH), 68.4 (CH2, C6), 64.8 (CH, C3).
HRMS (ESI-TOF), m/z: [M + H]+ calcd for C16H23O5, 295.1540;
found, 295.1512. [α]2D2.8 +35.6 (c = 1.22, MeOH).
(2R,3R,4R)-3,4-Bis(allyloxy)-2-((allyloxy)methyl)-3,4-dihydro-2H-
pyran-5-carbaldehyde (2f). According to the general procedure on a
0.19 mmol scale, formyl galactal 2f was isolated as a yellow oil (50.5
mg, 90%) after purification by AFP (5−40% EtOAc/hexanes, 3-15-3
CV). FT-IR (ν/cm−1): 2955 (w), 2924 (m), 2854 (m), 1676 (m),
1620 (s), 1460 (w), 1408 (w), 1333 (w), 1263 (m), 1198 (s), 1090
1
(s). H NMR (500 MHz, CDCl3) (δH/ppm): 9.34 (s, 1H, CHO),
7.26 (s, 1H, H1), 5.96−5.86 (m, 3H, 3 × CHCH2), 5.33−5.10 (m,
6H, 3 × OCH2CH), 4.64 (dddd, J = 8.8, 5.4, 2.1, 1.4 Hz, 1H, H5),
4.47 (dd, J = 3.6, 1.4 Hz, 1H, H3), 4.22−4.16 (m, 3H, 3 × CHH
CH), 4.12−4.01 (m, 3H, 3 × CHHCH), 3.91 (dd, J = 11.8, 8.8 Hz,
1H, CHH6), 3.85 (dd, J = 11.9, 2.1 Hz, 1H, CHH6), 3.76 (dd, J = 5.4,
3.6 Hz, 1H, H4). 13C NMR (125 MHz, CDCl3) (δC/ppm): 189.3
(CHO, C7), 164.3 (CH, C1), 135.1 (CH, CHCH2), 134.4 (CH,
CHCH2), 134.0 (CH, CHCH2), 119.2 (C, C2), 117.8 (CH2,
OCH2CH), 117.5 (CH2, OCH2CH), 116.3 (CH2, OCH2CH), 78.7
(CH, C5), 73.1 (CH, C4), 72.4 (CH2, CH2CH), 72.3 (CH2,
CH2CH), 70.8 (CH2, CH2CH), 68.3 (CH2, C6), 64.2 (CH, C3).
HRMS (ESI-TOF), m/z: [M + H]+ calcd for C16H23O5, 295.1540;
found, 295.1519. [α]2D2.8 +24.2 (c = 0.74, MeOH).
(2R,3S,4R)-3,4-Bis(methoxymethoxy)-2-((methoxymethoxy)-
methyl)-3,4-dihydro-2H-pyran-5-carbaldehyde (2g). According to
the general procedure on a 0.18 mmol scale, formyl glucal 2g was
isolated as a yellow oil (6.1 mg, 11%) after purification by AFP (20−
70% EtOAc/hexanes, 3-15-3 CV). Caution! This compound is
particularly unstable and prone to decomposition during purification
by flash column chromatography. FT-IR (ν/cm−1): 2935 (w), 2893
(w), 2845 (w), 2826 (w), 1726 (w), 1672 (m), 1626 (s), 1443 (w),
1416 (w), 1292 (m), 1198 (s), 1149 (s), 1097 (s), 1024 (s). 1H NMR
(500 MHz, CDCl3) (δH/ppm): 9.38 (s, 1H, CHO), 7.41 (s, 1H, H1),
4.88 (d, J = 6.7 Hz, 1H, CHHOCH3), 4.77−4.75 (m, 1H, H5), 4.74
(d, J = 7.0 Hz, 1H, CHHOCH3), 4.69 (d, J = 7.1 Hz, 1H,
CHHOCH3), 4.67 (d, J = 6.7 Hz, 1H, CHHOCH3), 4.66 (d, J = 6.7
Hz, 1H, CHHOCH3), 4.66 (d, J = 6.7 Hz, 1H, CHHOCH3), 4.45
(app t, J = 2.2 Hz, 1H, H4), 4.10 (app t, J = 1.9 Hz, 1H, H3), 3.89 (dd,
J = 11.4, 8.7 Hz, 1H, CHH6), 3.73 (dd, J = 11.4, 4.2 Hz, 1H, CHH6),
3.41 (s, 3H, OCH3), 3.39 (s, 3H, OCH3), 3.38 (s, 3H, OCH3). 13C
NMR (125 MHz, CDCl3) (δC/ppm): 190.2 (CHO, C7), 163.7 (CH,
C1), 117.8 (C, C2), 96.9 (CH2, CH2OCH3), 96.8 (CH2, CH2OCH3),
95.7 (CH2, CH2OCH3), 79.8 (CH, C5), 70.1 (CH, C4), 66.1 (CH2,
C6), 63.7 (CH, C3), 56.2 (CH3, OCH3), 56.0 (CH3, OCH3), 55.6
((2R,3R,4R)-3,4-Bis((4-methoxybenzyl)oxy)-2-(((4-
methoxybenzyl)oxy)methyl)-3,4-dihydro-2H-pyran-5-carbaldehyde
(2d). According to the general procedure on a 0.10 mmol scale,
formyl galatal 2d was isolated as a yellow oil (35.5 mg, 67%) after
purification by AFP (15−60% EtOAc/hexanes, 3-15-3 CV). FT-IR
(ν/cm−1): 2955 (w), 2935 (w), 2910 (w), 2864 (w), 2837 (w), 2253
(w), 1672 (m), 1612 (s), 1512 (s), 1464 (m), 1302 (m), 1246 (s),
1
1198 (m), 1173 (s), 1086 (s). H NMR (500 MHz, CDCl3) (δH/
ppm): 9.35 (s, 1H, CHO), 7.27−7.20 (m, 7H, 6 × ArH + H1), 6.90−
6.84 (m, 6H, 6 × ArH), 4.70 (d, J = 10.9 Hz, 1H, CHHOPh), 4.66 (d,
J = 11.0 Hz, 1H, CHHOPh), 4.65−4.60 (m, 2H, H5 + CHHOPh),
4.57 (dd, J = 3.5, 1.4 Hz, 1H, H3), 4.50 (d, J = 11.6 Hz, 1H,
CHHOPh), 4.47 (d, J = 12.3 Hz, 1H, CHHOPh), 4.41 (d, J = 11.5
Hz, 1H, CHHOPh), 3.96−3.88 (m, 2H, 2 × H6), 3.820 (s, 3H,
OCH3), 3.816 (s, 6H, 2 × OCH3), 3.81−3.77 (m, 1H, H4). 13C NMR
D
DOI: 10.1021/acs.joc.8b01006
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(CH3, OCH3). HRMS (ESI-TOF), m/z: [M + H]+ calcd for
C13H23O8, 307.1387; found, 307.1399. [α]2D2.8 +8.56 (c = 0.90,
MeOH).
CHAr), 120.9 (C, C2), 101.5 (CH, OCHO), 80.0 (CH, C5), 75.1
(CH2, CH2OPh), 72.4 (CH, C4), 70.5 (CH, C3), 67.8 (CH2, C6).
HRMS (ESI-TOF), m/z: [M + Na]+ calcd for C21H20NaO5,
375.1203; found, 375.1212. [α]2D2.5 +0.68 (c = 0.44, CHCl3).
(2R,3R,4R)-3,4-Bis(methoxymethoxy)-2-((methoxymethoxy)-
methyl)-3,4-dihydro-2H-pyran-5-carbaldehyde (2h). According to
the general procedure on a 0.18 mmol scale, formyl galactal 2h was
isolated as a yellow oil (10.9 mg, 20%) after purification by AFP (20−
70% EtOAc/hexanes, 3-15-3 CV). Caution! This compound is
particularly unstable and prone to decomposition during purification
by flash column chromatography. FT-IR (ν/cm−1): 2924 (w), 2849
(w), 2826 (w), 2361 (w), 2341 (w), 1728 (w), 1676 (m), 1622 (s),
1443 (w), 1379 (w), 1273 (w), 1198 (m), 1149 (s), 1111 (s), 1020
(2S,3R)-2-(Fluoromethyl)-5-formyl-3,4-dihydro-2H-pyran-3,4-
diyl Diacetate (2l). According to the general procedure on a 0.22
mmol scale using DMF (1 M) as the solvent instead, formyl galactal
2l was isolated as a white solid (15.4 mg, 27%) after purification by
AFP (40−100% Et2O/hexanes, 3-15-3 CV). Mp: 119.5−122.7 °C.
FT-IR (ν/cm−1): 2958 (w), 1751 (s), 1683 (m), 1629 (m), 1506
1
(m), 1375 (w), 1238 (s), 1206 (s), 1043 (m), 1023 (m). H NMR
(500 MHz, CDCl3) (δH/ppm): 9.35 (s, 1H, CHO), 7.44 (s, 1H, H1),
6.02 (app d, J = 4.2 Hz, 1H, H3), 5.44 (app td, J = 4.1, 1.3 Hz, 1H,
H4), 4.77 (ddd, J = 49.3, 11.3, 8.8 Hz, 1H, CHH6), 4.69−4.61 (m,
1H, H5), 4.57 (ddd, J = 45.1, 10.5, 2.7 Hz, 1H, CHH6), 2.10 (s, 3H,
OCOCH3), 2.05 (s, 3H, OCOCH3). 19F NMR (470 MHz, CDCl3)
(δF/ppm): −227.1 (app br, s, 1F, CH2F). 13C NMR (125 MHz,
CDCl3) (δC/ppm): 187.3 (CHO, C7) 169.6 (C, CO), 169.3 (C,
CO), 163.6 (CH, C1), 116.6 (C, C2), 80.5 (d, J = 171.8 Hz, CH2,
C6), 76.1 (d, J = 21.7 Hz, CH, C5), 64.1 (d, J = 7.1 Hz, CH2, C4), 59.5
(CH, C3), 20.5 (CH3, 2 × COCH3). HRMS (ESI-TOF), m/z: [M +
H]+ calcd for C11H14FO6, 261.0769; found, 261.0777. [α]2D5.1 +51.9 (c
= 0.48, MeOH).
1
(s). H NMR (500 MHz, CDCl3) (δH/ppm): 9.35 (s, 1H, CHO),
7.28 (s, 1H, H1), 4.90 (d, J = 6.6 Hz, 1H, CHHOCH3), 4.86 (d, J =
6.9 Hz, 1H, CHHOCH3), 4.73 (d, J = 6.6 Hz, 1H, CHHOCH3), 4.71
(d, J = 6.9 Hz, 1H, CHHOCH3), 4.70 (d, J = 6.5 Hz, 1H,
CHHOCH3), 4.69 (d, J = 6.7 Hz, 1H, CHHOCH3), 4.69−4.67 (m,
1H, H3), 4.68−4.60 (m, 1H, H5), 4.06 (dd, J = 5.3, 3.7 Hz, 1H, H4),
4.03 (dd, J = 12.2, 8.9 Hz, 1H, CHH6), 3.97 (dd, J = 12.1, 2.2 Hz, 1H,
CHH6), 3.44 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 3.40 (s, 3H,
OCH3). 13C NMR (125 MHz, CDCl3) (δC/ppm): 189.0 (CHO, C7),
163.8 (CH, C1), 119.3 (C, C2), 97.2 (CH2, CH2OCH3), 96.7 (CH2,
CH2OCH3), 95.8 (CH2, CH2OCH3), 78.9 (CH, C5), 70.8 (CH, C4),
65.9 (CH2, C6), 63.4 (CH, C3), 56.01 (CH3, OCH3), 56.96 (CH3,
OCH3), 55.4 (CH3, OCH3). HRMS (ESI-TOF), m/z: [M + H]+
calcd for C13H23O8, 307.1387; found, 307.1406. [α]2D2.8 +4.73 (c =
0.55, MeOH).
(2R,3S,4R)-2-(Acetoxymethyl)-5-formyl-3,4-dihydro-2H-pyran-
3,4-diyl Diacetate (2i). According to the general procedure on a 0.36
mmol scale using DIPEA (0.1 equiv) as an additive, formyl glucal 2i
was isolated as a yellow oil (20.4 mg, 19%) after purification by
biotage (50−100% Et2O/hexanes, 3-10-3 CV). Data are in
accordance with the one described in the literature.5b
(2R,3R,4R)-2-(Acetoxymethyl)-5-formyl-3,4-dihydro-2H-pyran-
3,4-diyl Diacetate (2j). According to the general procedure on a 0.36
mmol scale using DIPEA (0.1 equiv) as an additive, formyl galactal 2j
was isolated as a yellow oil (38.6 mg, 36%) after purification by AFP
(50−100% Et2O/hexanes, 3-10-3 CV). FT-IR (ν/cm−1): 2962 (w),
2930 (w), 2851 (w), 2745 (w), 1740 (s), 1660 (m), 1626 (s), 1433
(w), 1371 (m), 1271 (s), 1194 (s), 1121 (w), 1043 (m), 1020 (m).
1H NMR (500 MHz, CDCl3) (δH/ppm): 9.32 (s, 1H, CHO), 7.38 (s,
1H, H1), 6.00 (app d, J = 4.4 Hz, 1H, H3), 5.42 (app t, J = 3.8 Hz, 1H,
H4), 4.57−4.50 (m, 1H, H5), 4.43 (dd, J = 12.2, 8.3 Hz, 1H, CHH6),
4.28 (dd, J = 12.2, 4.0 Hz, 1H, CHH6), 2.10 (s, 3H, OCOCH3), 2.09
(s, 3H, OCOCH3), 2.04 (s, 3H, OCOCH3). 13C NMR (125 MHz,
CDCl3) (δC/ppm): 187.4 (CHO, C7), 170.5 (C, CO), 169.8 (C,
CO), 169.5 (C, CO), 163.6 (CH, C1), 116.6 (C, C2), 75.3 (CH,
C5), 64.0 (CH, C4), 61.3 (CH2, C6), 59.9 (CH, C3), 20.7 (CH3,
COCH3), 20.5 (CH3, 2 × COCH3). HRMS (ESI-TOF), m/z: [M +
H]+ calcd for C13H17O8, 301.0918; found, 301.0934. [α]2D2.0 +104.3 (c
= 1.61, MeOH).
(2S,3R)-3,4-Bis(benzyloxy)-2-(fluoromethyl)-3,4-dihydro-2H-
pyran-5-carbaldehyde (2m). According to the general procedure on
a 0.15 mmol scale, formyl galactal 2m was isolated as a yellow oil
(45.0 mg, 84%) after purification by AFP (10−40% EtOAc/hexanes,
3-15-3 CV). FT-IR (ν/cm−1): 2875 (w), 1676 (m), 1624 (s), 1455
1
(w), 1267 (m), 1200 (s), 1062 (s), 1045 (w). H NMR (500 MHz,
CDCl3) (δH/ppm): 9.40 (s, 1H, CHO), 7.41−7.26 (m, 11H, 10 ×
ArH + H1), 4.90 (ddd, J = 50.5, 11.4, 8.2 Hz, 1H, CHH6), 4.82 (ddd,
J = 46.8, 11.5, 2.0 Hz, 1H, CHH6), 4.81−4.75 (m, 1H, H5), 4.73 (s,
2H, CH2OPh), 4.71 (d, J = 11.9 Hz, 1H, CHHOPh), 4.64 (td, J = 3.1,
1.3 Hz, 1H, H3), 4.55 (d, J = 11.9 Hz, 1H, CHHOPh), 3.87 (ddd, J =
5.7, 3.4, 2.2 Hz, 1H, H4). 19F NMR (470 MHz, CDCl3) (δF/ppm):
−221.2 (app dt, J = 49.6, 48.9 Hz, 1F, CH2F). 13C NMR (125 MHz,
CDCl3) (δC/ppm): 189.2 (CHO, C7), 164.0 (CH, C1), 138.4 (C,
CAr), 137.0 (C, CAr), 128.7 (CH, CHAr), 128.3 (CH, CHAr), 128.2
(CH, CHAr), 127.72 (CH, CHAr), 127.66 (CH, CHAr), 127.59 (CH,
CHAr), 119.4 (C, C2), 82.0 (d, J = 166.6 Hz, CH2, C6), 78.1 (d, J =
20.0 Hz, CH, C5), 73.6 (CH2, CH2OPh), 72.9 (d, J = 8.1 Hz, CH,
C4), 71.4 (CH2, CH2OPh), 63.7 (CH, C3). HRMS (ESI-TOF), m/z:
[M + H]+ calcd for C21H22FO4, 357.1497; found,: 357.1519. [α]2D5.1
−90.8 (c = 0.46, MeOH).
((2R,3S,4R)-3,4-Bis(benzyloxy)-3,4-dihydro-2H-pyran-2-yl)methyl
Formate (3) and ((2R,3S,4R)-3,4-bis(benzyloxy)-5-formyl-3,4-dihy-
dro-2H-pyran-2-yl)methyl Formate (4). According to the general
procedure on a 0.11 mmol scale, formate glucal 3 was first isolated as
a yellow oil (7.3 mg, 19%) followed by formyl formate glucal 4 as a
yellow oil (9.1 mg, 22%) after purification by AFP (5−60% EtOAc/
hexanes, 3-15-3 CV). Data for 3 are in accordance with the one
described in the literature.19b Data for 4 follow. FT-IR (ν/cm−1):
2953 (m), 2924 (s), 2854 (m), 1724 (s), 1672 (m), 1626 (m), 1456
(m), 1379 (w), 1163 (s), 1090 (m), 1074 (m). 1H NMR (500 MHz,
CDCl3) (δH/ppm): 9.45 (s, 1H, CHO), 8.07 (q, J = 0.7 Hz, 1H,
COCHO), 7.39 (s, 1H, H1), 7.37−7.29 (m, 9H, 9 × ArH), 7.25−7.22
(m, 1H, 1 × ArH), 4.75−4.68 (m, 1H, H5), 4.70 (d, J = 11.6 Hz, 1H,
CHHOPh), 4.60 (ddd, J = 12.5, 9.0, 0.7 Hz, 1H, CHH6), 4.60 (d, J =
11.6 Hz, 1H, CHHOPh), 4.55 (d, J = 12.0 Hz, 1H, CHHOPh), 4.46
(d, J = 11.6 Hz, 1H, CHHOPh), 4.45 (dd, J = 4.8, 2.1 Hz, 1H, H3),
4.26 (ddd, J = 12.4, 3.2, 0.7 Hz 1H, CHH6), 3.77 (app t, J = 2.2 Hz,
1H, H4). 13C NMR (125 MHz, CDCl3) (δC/ppm): 190.3 (CHO,
C7), 163.6 (CH, C1), 160.3 (CH, C8), 137.9 (C, CAr), 136.9 (C, CAr),
128.6 (CH, CHAr), 128.5 (CH, CHAr), 128.2 (CH, CHAr), 128.0
(CH, CHAr), 127.9 (CH, CHAr), 127.8 (CH, CHAr), 118.0 (C, C2),
77.8 (CH, C5), 72.6 (CH2, CH2OPh), 71.8 (CH2, CH2OPh), 71.3
(CH, C4), 64.5 (CH, C3), 62.0 (CH2, C6). HRMS (ESI-TOF), m/z:
[M + H]+ calcd for C22H23O6, 383.1489; found, 383.1490. [α]D22.8
+2.00 (c = 0.35, MeOH).
(2R,4aR,8R,8aS)-8-(Benzyloxy)-2-phenyl-4,4a,8,8a-
tetrahydropyrano[3,2-d][1,3]dioxine-7-carbaldehyde (2k). Accord-
ing to the general procedure on a 0.15 mmol scale using DMF/Et2O
(1:1, 0.5 M) as the solvent instead, formyl glucal 2k was isolated as a
yellow solid (24.3 mg, 46%) after purification by AFP (5−40%
EtOAc/hexanes, 3-15-3 CV). Data are in accordance with the one
partially described in the literature.32 Mp: 105.8−110.0 °C. FT-IR (ν/
cm−1): 3067 (w), 3032 (w), 2959 (w), 2924 (m), 2854 (m), 1726
(w), 1684 (s), 1622 (s), 1497 (w), 1452 (m), 1367 (m), 1273 (s),
1
1225 (m), 1186 (s), 1155 (m), 1094 (s), 1068 (s), 1005 (s). H
NMR (500 MHz, CDCl3) (δH/ppm): 9.42 (s, 1H, CHO), 7.52−7.28
(m, 11H, 10 × ArH + H1), 5.65 (s, 1H, OCHO), 5.01 (d, J = 10.7 Hz,
1H, CHHOPh), 4.89 (d, J = 10.8 Hz, 1H, CHHOPh), 4.65 (dd, J =
7.3, 0.9 Hz, 1H, H3), 4.49 (dd, J = 10.4, 5.0 Hz, 1H, CHH6), 4.11
(dd, J = 10.3, 7.4 Hz, 1H, H5), 4.01 (app tdd, J = 10.4, 4.9, 0.6 Hz,
1H, H4), 3.93 (app t, J = 10.3 Hz, 1H, CHH6). 13C NMR (125 MHz,
CDCl3) (δC/ppm): 188.6 (CHO, C7), 162.5 (CH, C1), 138.2 (C,
CAr), 136.7 (C, CAr), 129.2 (CH, CHAr), 128.34 (CH, CHAr), 128.32
(CH, CHAr), 128.29 (CH, CHAr), 127.7 (CH, CHAr), 126.0 (CH,
E
DOI: 10.1021/acs.joc.8b01006
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
((2R,3S)-3,4-Bis((4-methoxybenzyl)oxy)-3,4-dihydro-2H-pyran-2-
yl)methyl Formate (5), (2R,3S,4R)-3,4-bis((4-methoxybenzyl)oxy)-2-
((trityloxy)methyl)-3,4-dihydro-2H-pyran-5-carbaldehyde (2o), and
(2R,3S,4R)-2-(hydroxymethyl)-3,4-bis((4-methoxybenzyl)oxy)-3,4-
dihydro-2H-pyran-5-carbaldehyde (6). According to the general
procedure on a 0.16 mmol scale using DMF (1 M) as solvent instead,
formate glucal 5 was first isolated as a yellow oil (6.5 mg, 10%)
followed by formyl glucal 2o (13.1 mg, 12%) as a yellow oil and
formyl formate glycal 6 as a yellow oil (15.6 mg, 22%) after
purification by AFP (50−100% Et2O/hexanes, 3-10-3 CV). Data for 5
follow. FT-IR (ν/cm−1): 2934 (w), 2837 (w), 1724 (s), 1647 (w),
1612 (m), 1512 (s), 1464 (w), 1302 (w), 1248 (s), 1175 (m), 1094
(dd, J = 10.8, 8.0 Hz, 1H, CHH6), 3.75 (dd, J = 9.8, 7.6 Hz, 1H, HII),
3.61 (dd, J = 10.9, 4.5 Hz, 1H, CHH6), 3.57−3.52 (m, 2H, CHHVI
+
CHHVI), 3.52−3.44 (m, 2H, HIII + HV). 13C NMR (125 MHz,
CDCl3) (δC/ppm): 190.1 (CHO, C7), 163.8 (CH, C1), 138.46 (C,
CAr), 138.45 (C, CAr), 138.37 (C, CAr), 138.36 (C, CAr), 137.78 (C,
CAr), 137.62 (C, CAr), 128.5 (CH, CHAr), 128.43 (CH, CHAr), 128.38
(2 × CH, 2 × CHAr), 128.35 (CH, CHAr), 128.3 (CH, CHAr), 128.24
(CH, CHAr), 128.18 (CH, CHAr), 127.9 (CH, CHAr), 127.83 (2 ×
CH, 2 × CHAr), 128.81 (CH, CHAr), 127.80 (CH, CHAr), 127.7 (CH,
CHAr), 127.64 (CH, CHAr), 127.61 (CH, CHAr), 127.57 (CH, CHAr),
127.5 (CH, CHAr), 117.8 (C, C2), 103.0 (CH, CI), 82.0 (CH, CIII),
79.0 (CH, CII), 78.8 (CH, C5), 75.3 (CH2, CH2OPh), 74.6 (CH2,
CH2OPh), 73.62 (CH, CV), 73.58 (CH2, CH2OPh), 73.3 (CH2 +
CH, CH2OPh + CIV), 73.1 (CH2, CH2OPh), 72.5 (CH2, CH2OPh),
71.8 (CH, C4), 68.7 (CH2, CVI), 68.2 (CH2, C6), 66.6 (CH, C3).
HRMS (ESI-TOF), m/z: [M + H]+ calcd for C55H57O10, 877.3946;
found, 877.3953. [α]2D2.8 −1.98 (c = 1.22, MeOH).
1
(m), 1034 (m). H NMR (500 MHz, CDCl3) (δH/ppm): 8.05 (app
q, J = 0.8 Hz, 1H, COCHO), 7.30−7.27 (m, 2H, 2 × ArH), 7.25−
7.21 (m, 2H, 2 × ArH), 6.94−6.84 (m, 4H, 4 × ArH), 6.38 (dd, J =
6.2, 1.4 Hz, 1H, H1), 4.91 (dd, J = 6.2, 2.7 Hz, 1H, H2), 4.78 (d, J =
11.0 Hz, 1H, CHHOPh), 4.61 (d, J = 11.4 Hz, 1H, CHHOPh), 4.60
(d, J = 11.0 Hz, 1H, CHHOPh), 4.50 (d, J = 11.3 Hz, 1H,
CHHOPh), 4.46 (ddd, J = 12.1, 2.9, 0.7 Hz, 1H, CHH6), 4.42 (ddd, J
= 11.9, 5.3, 0.7 Hz, 1H, CHH6), 4.19 (dddd, J = 6.1, 2.7, 1.4, 0.5 Hz,
1H, H3), 4.09 (ddd, J = 8.4, 5.2, 3.1 Hz, 1H, H5), 3.82 (s, 3H,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01006.
■
S
OCH3), 3.81 (s, 3H, OCH3), 3.74 (dd, J = 8.6, 6.1 Hz, 1H, H4). 13
C
NMR (125 MHz, CDCl3) (δC/ppm): 160.6 (CH, C7), 159.4 (C,
CAr), 159.3 (C, CAr), 144.1 (CH, C1), 130.2 (C, CAr), 129.83 (C,
CAr), 129.80 (CH, CHAr), 129.43 (CH, CHAr), 113.90 (CH, CHAr),
113.89 (CH, CHAr), 100.4 (C, C2), 75.1 (CH, C3), 74.8 (CH, C5),
73.29 (CH, C4), 73.28 (CH2, CH2OPh), 70.2 (CH2, CH2OPh), 62.2
(CH2, C6), 55.31 (CH3, OCH3), 55.30 (CH3, OCH3). HRMS (ESI-
TOF), m/z: [M + NH4]+ calcd for C23H30NO7, 432.2017; found,
432.2028. [α]2D2.2 +0.04 (c = 0.22, CHCl3). Data for 2o are in
accordance with the one described in the literature.29 Data for 6
follow. FT-IR (ν/cm−1): 2959 (m), 2924 (s), 2854 (m), 1724 (m),
1672 (m), 1626 (m), 1512 (s), 1464 (m), 1379 (w), 1302 (m), 1248
NMR spectra for the known (1H) and new compounds
(1H, 13C, 19F) prepared (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jean-francois.paquin@chm.ulaval.ca.
■
ORCID
Jean-Franco̧ is Paquin: 0000-0003-2412-3083
Notes
The authors declare no competing financial interest.
1
(s), 1171 (s). H NMR (500 MHz, CDCl3) (δH/ppm): 9.44 (s, 1H,
CHO), 8.07 (app d, J = 0.6 Hz, 1H, COCHO), 7.37 (s, 1H, H1),
7.26−7.23 (m, 2H, 2 × ArH), 7.17−7.12 (m, 2H, 2 × ArH), 6.90−
6.85 (m, 4H, 4 × ArH), 4.66 (app ddt, J = 9.1, 3.4, 1.9 Hz, 1H, H5),
4.62 (d, J = 11.3 Hz, 1H, CHHOPh), 4.58 (ddd, J = 12.5, 9.0, 0.7 Hz,
1H, CHH6), 4.53 (d, J = 11.3 Hz, 1H, CHHOPh), 4.48 (d, J = 11.7
Hz, 1H, CHHOPh), 4.41 (dd, J = 2.7, 1.8 Hz, 1H, H3), 4.38 (d, J =
11.7 Hz, 1H, CHHOPh), 4.23 (ddd, J = 12.5, 3.1, 0.9 Hz 1H, CHH6),
3.82 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.72−3.70 (m, 1H, H4).
13C NMR (125 MHz, CDCl3) (δC/ppm): 190.3 (CHO, C7), 163.5
(CH, C1), 160.3 (CH, C8), 159.6 (C, CAr), 159.3 (C, CAr), 130.1 (C,
CAr), 129.6 (CH, CHAr), 129.5 (CH, CHAr), 128.9 (C, CAr), 118.1
(C, C2), 114.0 (CH, CHAr), 113.8 (CH, CHAr), 77.9 (CH, C5), 72.2
(CH2, CH2OPh), 71.3 (CH2, CH2OPh), 70.8 (CH, C4), 64.2 (CH,
C3), 62.0 (CH2, C6), 55.29 (CH3, OCH3), 55.27 (CH3, OCH3).
HRMS (ESI-TOF), m/z: [M + H]+ calcd for C24H27O8, 443.1700;
found, 443.1708. [α]2D2.8 −18.9 (c = 0.46, MeOH).
ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and
Engineering Research Council of Canada, OmegaChem, and
■
́
Universite Laval.
REFERENCES
■
(1) For review on C-2-formyl glycals as chiral building blocks, see:
Ramesh, N. G.; Balasubramanian, K. K. 2-C-Formyl Glycals:
Emerging Chiral Synthons in Organic Synthesis. Eur. J. Org. Chem.
2003, 2003, 4477−4487.
(2) For review on applications of C-2-formyl glycals, see: Ramesh, N.
G. Applications of 2-C-Formyl-Glycals in Organic Synthesis. Eur. J.
Org. Chem. 2014, 2014, 689−707.
(2R,3S,4R)-4-(Benzyloxy)-2-((benzyloxy)methyl)-3-
(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-
tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydro-2H-pyran-5-carbalde-
hyde (8). According to the general procedure on a 0.06 mmol scale
using DMF (1 M) instead as the solvent, formyl lactal 6 was isolated
as a yellow oil (28.9 mg, 56%) after purification by AFP (5−40%
EtOAc/hexanes, 3-15-3 CV). Data are in accordance with the one
partially described in the literature.20 FT-IR (ν/cm−1): 3030 (w),
2959 (w), 2924 (m), 2854 (m), 1676 (m), 1626 (s), 1497 (w), 1452
(3) (a) Lopez, J. C.; Lameignere, E.; Lukacs, G. Straightforward
route to 2- and 3-formyl hex-1- and −2-enopyranosides and their
highly stereoselective hetero Diels−Alder reaction with ethyl vinyl
ether. J. Chem. Soc., Chem. Commun. 1988, 514−515. (b) Cristobal
Lopez, J.; Lameignere, E.; Burnouf, C.; de los Angeles Laborde, M.;
Ghini, A. A.; Olesker, A.; Lukacs, G. Efficient routes to pyranosidic
homologated conjugated enals and dienes from monosaccharides.
Tetrahedron 1993, 49, 7701−7722.
1
(m), 1364 (w), 1292 (w), 1198 (m), 1070 (s). H NMR (500 MHz,
(4) Burnouf, C.; Lopez, J. C.; de los, A.; Laborde, M.; Olesker, A.;
Lukacs, G. An efficient route to homologated pyranosidic conjugated
enals. Tetrahedron Lett. 1988, 29, 5533−5534.
CDCl3) (δH/ppm): 9.39 (s, 1H, CHO), 7.40−7.22 (m, 31H, 30 ×
ArH + H1), 4.93 (d, J = 11.6 Hz, 1H, CHHOPh), 4.83−4.77 (m, 1H,
H5), 4.77 (d, J = 10.8 Hz, 1H, CHHOPh), 4.74 (d, J = 11.9 Hz, 1H,
CHHOPh), 4.70 (d, J = 12.0 Hz, 1H, CHHOPh), 4.69 (d, J = 11.6
Hz, 1H, CHHOPh), 4.69 (d, J = 10.7 Hz, 1H, CHHOPh), 4.63 (d, J
= 11.5 Hz, 1H, CHHOPh), 4.62 (d, J = 11.7 Hz, 1H, CHHOPh),
4.56 (app t, J = 2.3 Hz, 1H, H3), 4.52 (d, J = 12.0 Hz, 1H,
CHHOPh), 4.45 (d, J = 12.1 Hz, 2H, CHHOPh + CHHOPh), 4.40
(d, J = 11.8 Hz, 1H, CHHOPh), 4.38 (d, J = 7.7 Hz, 1H, HI), 4.18
(app t, J = 2.0 Hz, 1H, H4), 3.88 (dd, J = 3.1, 1.0 Hz, 1H, HIV), 3.81
(5) (a) Jung, M. E.; Choe, S. W. T. Stereospecific intramolecular
formyl transfer via radical cyclization-fragmentation: Preparation of
alkyl 2-deoxy-2α-formylglucopyranosides and similar compounds.
Tetrahedron Lett. 1993, 34, 6247−6250. (b) Choe, S. W. T.; Jung,
M. E. Preparation of various C-2 branched carbohydrates using
intramolecular radical reactions. Carbohydr. Res. 2000, 329, 731−744.
̈
(6) Vilsmeier, A.; Haack, A. Uber die Einwirkung von Halogen-
phosphor auf Alkyl-formanilide. Eine neue Methode zur Darstellung
F
DOI: 10.1021/acs.joc.8b01006
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Note
̈
̈
sekundarer und tertiarer p-Alkylamino-benzaldehyde. Ber. Dtsch.
Chem. Ges. B 1927, 60, 119−122.
(13) Other solvents, such as nitromethane, 2-methyltetrahydrofuran,
methyl tert-butyl ether, dichloromethane, and 1,4-dioxane, provided
lower yields of 2a (<58%).
(7) Ramesh, N. G.; Balasubramanian, K. K. Vilsmeier-haack reactoin
of glycals - a short route to C-2-formyl glycals. Tetrahedron Lett. 1991,
32, 3875−3878.
(14) XtalFluor-E proved optimal for this transformation. Indeed, no
1
product (2a) was detected by H NMR in the crude mixture when
(8) XtalFluor-E was initially designed as a deoxofluorinating agent.
For the initial reports, see: (a) Beaulieu, F.; Beauregard, L.-P.;
Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Heureux, A.
Aminodifluorosulfinium Tetrafluoroborate Salts as Stable and
Crystalline Deoxofluorinating Reagents. Org. Lett. 2009, 11, 5050−
5053. (b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. B.;
Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.;
Couturier, M. Aminodifluorosulfinium Salts: Selective Fluorination
Reagents with Enhanced Thermal Stability and Ease of Handling. J.
DAST or Deoxofluor were used instead of XtalFluor-E, while
employing XtalFluor-M provided 2a in 15% yield by NMR.
(15) Zhong, M.; Meng, X.-B.; Li, Z.-J. Synthesis of γ-aminobutyric
acid analogs based on carbohydrate scaffolds. Carbohydr. Res. 2010,
345, 1099−1106.
(16) Preindl, J.; Jouvin, K.; Laurich, D.; Seidel, G.; Furstner, A.
Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine
Derivatives: Mechanistic and Synthetic Aspects. Chem. - Eur. J.
2016, 22, 237−247.
(17) Sagar, R.; Park, J.; Koh, M.; Park, S. B. Diastereoselective
Synthesis of Polycyclic Acetal-Fused Pyrano[3,2-c]pyran-5(2H)-one
Derivatives. J. Org. Chem. 2009, 74, 2171−2174.
(18) Chatterjee, N.; Pandit, P.; Halder, S.; Patra, A.; Maiti, D. K.
Generation of Nitrile Oxides under Nanometer Micelles Built in
Neutral Aqueous Media: Synthesis of Novel Glycal-Based Chiral
Synthons and Optically Pure 2,8-Dioxabicyclo[4.4.0]decene Core. J.
Org. Chem. 2008, 73, 7775−7778.
(19) (a) Koeller, S.; Lellouche, J.-P. Preparation of formate esters
from O-TBDMS/O-TES protected alcohols. A one-step conversion
using the Vilsmeier-Haack complex POCl3·DMF”,. Tetrahedron Lett.
1999, 40, 7043−7046. (b) Lellouche, J.-P.; Koeller, S. The Particular
Sensitivity of Silyl Ethers of d-Glucal toward Two Vilsmeier−Haack
Reagents POCl3·DMF and (CF3SO2)2Ο·DMF. Their Unique and
Selective Conversion to the Corresponding C(6)-O-Formates. J. Org.
Chem. 2001, 66, 693−696.
̈
́
Org. Chem. 2010, 75, 3401−3411. (c) Mahe, O.; L’Heureux, A.;
Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.;
Paquin, J.-F. Deoxofluorination Reactions Using N,N-Disubstituted
Aminodifluorosulfinium Tetrafluoroborate Salts. J. Fluorine Chem.
2013, 153, 57−60.
(9) According to the US Hazardous Materials Identification System
(HMIS) and as found on the MSDS sheets provided by Sigma-
Aldrich (accessed online on May 30, 2018), POCl3 is classified as a
severe hazard for health and a serious hazard for reactivity. By
comparison, XtalFluor-E is classified as a serious hazard for health and
a minimal hazard for reactivity.
(10) XtalFluor-E can also be used as an activating agent. For relevant
contributions from our group, see: (a) Pouliot, M.-F.; Angers, L.;
Hamel, J.-D.; Paquin, J.-F. Synthesis of 1,3,4-oxadiazoles from 1,2-
diacylhydrazines using [Et2NSF2]BF4 as a practical cyclodehydration
agent. Org. Biomol. Chem. 2012, 10, 988−993. (b) Pouliot, M.-F.;
Angers, L.; Hamel, J.-D.; Paquin, J.-F. Synthesis of 2-oxazolines and
related N-containing heterocycles using [Et2NSF2]BF4 as a cyclo-
dehydration agent. Tetrahedron Lett. 2012, 53, 4121−4123.
(20) Feit, B. A.; Kelson, I. K.; Gerull, A.; Abramson, S.; Schmidt, R.
R. Glycosidation of 3,4,6-Tri-O-Benzyl-2-Ethenyl-d-Glucal − A Route
to 2-C-(β-Methyl)Methylene Glycosides. J. Carbohydr. Chem. 2000,
19, 661−675.
́
(c) Pouliot, M.- F.; Mahe, O.; Hamel, J.-D.; Desroches, J.; Paquin,
(21) The AsF6− and SbF6− salts of 8 have been prepared before, see:
Henle, H.; Geisel, M.; Mews, R. Synthesis and Reactions of
Fluorinated Iminum Salt. J. Fluorine Chem. 1984, 26, 133−148.
(22) Fraser-Reid, B.; Tatsuta, K.; Thiem, J. Glycoscience; Springer-
Verlag: Berlin, Heidelberg, 2008.
J.-F. Halogenation of Primary Alcohols Using a Tetraethylammonium
Halide/[Et2NSF2]BF4 Combination. Org. Lett. 2012, 14, 5428−5431.
́
(d) Mahe, O.; Desroches, J.; Paquin, J.-F. Amide Formation Using In
Situ Activation of Carboxylic Acids with [Et2NSF2]BF4. Eur. J. Org.
́
Chem. 2013, 2013, 4325−4331. (e) Keita, M.; Vandamme, M.; Mahe,
O.; Paquin, J.-F. Synthesis of isocyanides through dehydration of
formamides using XtalFluor-E. Tetrahedron Lett. 2015, 56, 461−464.
(f) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F. In
situ activation of benzyl alcohols with XtalFluor-E: formation of 1,1-
diarylmethanes and 1,1,1-triarylmethanes through Friedel−Crafts
benzylation. Org. Biomol. Chem. 2015, 13, 2243−2246. (g) Keita,
M.; Vandamme, M.; Paquin, J.-F. Synthesis of Nitriles from
Aldoximes and Primary Amides Using XtalFluor-E. Synthesis 2015,
47, 3758−3766. (h) Vandamme, M.; Bouchard, L.; Gilbert, A.; Keita,
M.; Paquin, J.-F. Direct Esterification of Carboxylic Acids with
Perfluorinated Alcohols Mediated by XtalFluor-E. Org. Lett. 2016, 18,
6468−6471. (i) Lebleu, T.; Paquin, J.-F. Direct allylation of benzyl
alcohols, diarylmethanols, and triarylmethanols mediated by Xtal-
Fluor-E. Tetrahedron Lett. 2017, 58, 442−444.
(23) Humenik, M.; Kutschy, P.; Kovacik, V.; Bekesova, S. 1,2-
Anhydrosaccharides and 1,2-Cyclic Sulfites as Saccharide Donors in
Convergent Synthesis of Glucopyranosyl-, Mannopyranosyl- and
Ribofuranosylbenzocamalexin. Collect. Czech. Chem. Commun. 2005,
70, 487−506.
(24) Moore, P. W.; Schuster, J. K.; Hewitt, R. J.; Stone, M. R. L.;
Teesdale-Spittle, P. H.; Harvey, J. E. Divergent synthesis of 2-C-
branched pyranosides and oxepines from 1,2-gem-dibromocyclopropyl
carbohydrates. Tetrahedron 2014, 70, 7032−7043.
(25) Furstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott,
R. Ring-Closing Alkyne Metathesis. Application to the Total Synthesis
of Sophorolipid Lactone. J. Org. Chem. 2000, 65, 8758−8762.
̈
̀
(26) Lafont, D.; Descotes, G. Synthese de phosphoramidates de 2-
́
desoxy-2-iodoglycosyles. Carbohydr. Res. 1987, 166, 195−210.
(11) For recent contributions from other groups, see: (a) Brand-
(27) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. A facile synthesis
of 4,6-O-benzylidene glucal. Tetrahedron: Asymmetry 2003, 14, 1767−
1769.
̈
statter, M.; Roth, F.; Luedtke, N. W. Synthesis of 2-Oxazolines by in
Situ Desilylation and Cyclodehydration of β-Hydroxyamides. J. Org.
Chem. 2015, 80, 40−51. (b) Nonn, M.; Kiss, L.; Haukka, M.; Fustero,
(28) Wagner, S.; Mersch, C.; Hoffmann-Roeder, A. Fluorinated
Glycosyl Amino Acids for Mucin-Like Glycopeptide Antigen
Analogues. Chem. - Eur. J. 2010, 16, 7319−7330.
S.; Fulop, F. A Novel and Selective Fluoride Opening of Aziridines by
̈
̈
XtalFluor-E. Synthesis of Fluorinated Diamino Acid Derivatives. Org.
Lett. 2015, 17, 1074−1077. (c) Yi, Y.; Gholami, H.; Morrow, M. G.;
Borhan, B. XtalFluor-E® mediated proto-functionalization of N-vinyl
amides: access to N-acetyl N,O-acetals. Org. Biomol. Chem. 2017, 15,
9570−9574.
(29) Lim, D.; Park, S. B. Synthesis of Molecular Frameworks
Containing Two Distinct Heterocycles Connected in a Single
Molecule with Enhanced Three-Dimensional Shape Diversity. Chem.
- Eur. J. 2013, 19, 7100−7108.
(12) The formyl glycals are prone to decomposition and need to be
stored at low temperature, see: Bari, A.; Feist, H.; Michalik, D.;
Michalik, M.; Peseke, K. Synthesis of Heterocyclic Compounds by
Ring Transformations of 2-Formyl Pentose Glycals. Synthesis 2004,
17, 2863−2868.
(30) Upreti, M.; Ruhela, D.; Vishwakarma, R. A. Synthesis of the
Tetrasaccharide Cap Domain of the Antigenic Lipophosphoglycan of
Leishmania donovani Parasite. Tetrahedron 2000, 56, 6577−6585.
(31) Preindl, J.; Schulthoff, S.; Wirtz, C.; Lingnau, J.; Fu
̈
rstner, A.
Polyunsaturated C-Glycosidic 4-Hydroxy-2-pyrone Derivatives: Total
G
DOI: 10.1021/acs.joc.8b01006
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The Journal of Organic Chemistry
Note
Synthesis Shows that Putative Orevactaene Is Likely Identical with
Epipyrone A. Angew. Chem., Int. Ed. 2017, 56, 7525−7530.
(32) Jung, M. E.; Choe, T. S. W. Total synthesis of cyclophellitol and
(1R,2S)-cyclophellitol from d-mannose. J. Org. Chem. 1995, 60,
3280−3281.
H
DOI: 10.1021/acs.joc.8b01006
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