Serendipitous one-pot synthesis of chiral dienes from pyranosidic 2,4-bistriflates

Article abstract of DOI:10.1016/j.carres.2021.108351

Attempted nucleophilic displacements of L-rhamnosyl 2,4-bistriflates led to serendipitous formation of a chiral diene via competing cascade eliminations. The reaction also followed the same pathway with D-rhamnosyl and D-mannosyl 2,4-bistriflates substrat

Full text of DOI:10.1016/j.carres.2021.108351

Carbohydrate Research 505 (2021) 108351
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Note
Serendipitous one-pot synthesis of chiral dienes from pyranosidic
2,4-bistriflates
Diksha Rai, Someswara Rao Sanapala, Suvarn S. Kulkarni*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, 400076, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Attempted nucleophilic displacements of L-rhamnosyl 2,4-bistriflates led to serendipitous formation of a chiral
diene via competing cascade eliminations. The reaction also followed the same pathway with D-rhamnosyl and D-
mannosyl 2,4-bistriflates substrates providing access to dienes with opposite stereochemistry. The reaction
presumably proceeds through E2 elimination of C2 triflate followed by allylic rearrangement. The easily
accessible chiral dienes would be useful in the synthesis of natural products.
L-rhamnose
D-mannose
2,4-bistriflates
SN2 versus E2
Chiral diene
1. Introduction
serendipitously stumbled upon an interesting cascade elimination re-
action that led to the formation of chiral dienes which are difficult to
A variety of rare deoxy amino sugars are exclusively present on
bacterial cell surfaces [1]. The unusual sugars being absent on the host
surfaces are looked upon as important targets for development of spe-
cific diagnostics, inhibitors and vaccines [2,3]. Our laboratory has
developed a novel and efficient protocol for synthesis of a variety of rare
deoxy amino D-sugars [4]. In this synthetic strategy, changing the
sequence of addition of nucleophiles in a series of one-pot double
displacement reactions using azide, phthalimide and nitrite ions as nu-
cleophiles and mannose derived 2,4-bistrifluoromethanesulfonates (tri-
flates) as electrophiles enabled rapid access to various orthogonally
protected rare deoxy amino sugar building blocks. We also extended the
SN2 double displacement protocol to access deoxy amino L-sugars
starting from L-rhamnose and L-fucose [5,6]. The success of the SN2
displacements depends on the fine tuning of a variety of factors
including solvent, temperature, reagent, and stoichiometry. Above all,
the relative orientation of substituents on the sugar ring plays a crucial
role in controlling the steric and stereo electronic factors [7]. All these
factors should be carefully considered while designing a successful SN2
reaction. In substrates having multiple reaction centres, oftentimes it is
possible to position a bulky substituent to block the path of a particular
reaction and guide the nucleophile to the desired reaction centre to
obtain selectivity. However, it is commonly observed that sterically
blocking the SN2 reaction path of a nucleophile forces it to act as a base
and thereby facilitates the competing E2 elimination reaction. In the
course of our studies on SN2 displacements of pyranosidic triflates, we
synthesize otherwise. In this note, we give an account of this novel re-
action and our mechanistic explorations to understand how the cascade
elimination proceeds.
2. Results and discussion
As shown in Scheme 1, treatment of known diol 1 [5] with Tf2O and
pyridine afforded 2,4-bistriflate 2. Attempted SN2 displacement of crude
bistriflates with nucleophiles such as sodium azide or nitrite (TBANO2,
NaNO2) led to elimination product 3 exclusively in very good yields
(70–81%, over two steps). The structure of the unexpected diene was
confirmed from analysis of 1H NMR, 13C NMR and 2D spectra (See the
supporting information). Specifically, lack of peaks for PMP group, a
highly downfield shift of H-1 (7.43 ppm), the appearance of only 4 sugar
ring protons (H1, H2, H4, H5) with disappearance of H3 as indicated by
COSY spectrum and the presence of 4 carbons in olefinic region
(100–160 ppm) helped us to arrive at the unexpected structure.
Although the outcome of this reaction was far from our set goal of
nucleophilic displacements leading to rare sugars, we took a moment to
rationalize the course of the reaction. A closer inspection of transition
state model (Fig. 1) revealed that, for an SN2 reaction, the approach of a
nucleophile from the top face of the pyranose ring at C2 centre is ste-
rically hindered by the axially oriented O-para-methoxyphenyl group
(OPMP) [5]. Likewise, the nucleophile is not able to achieve SN2 tran-
sition state with the C4-triflate due to the unfavourable 1,3-diaxial
* Corresponding author.
E-mail address: suvarn@chem.iitb.ac.in (S.S. Kulkarni).
https://doi.org/10.1016/j.carres.2021.108351
Received 27 April 2021; Received in revised form 12 May 2021; Accepted 14 May 2021
Available online 18 May 2021
0008-6215/© 2021 Elsevier Ltd. All rights reserved.

D. Rai et al.
Carbohydrate Research 505 (2021) 108351
repulsion from the axially oriented C-2 triflate. This together with
equally unfavourable dipole-dipole repulsions practically thwart any
chances of nucleophilic displacements. Because the nucleophile is not
able to act as a nucleophile, it behaves as a base and finds a favourable
antiperiplanar arrangement of C3–H and C2-OTf groups leading to a
facile E2 elimination generating allylic triflate 4, which being unstable
probably undergoes a swift allylic rearrangement to afford the chiral 5
(S) diene 3.
which matched with para methoxy phenol standard. We isolated it and
also confirmed by 1H NMR. This observation placed the final piece of the
puzzle in place, as it was confirmed that para-methoxy phenoxide is the
side product of this reaction. Based on these experiments, a plausible
mechanism is suggested in Scheme 5. Accordingly, 2,4-bistriflate 2 first
undergoes an E2 elimination to generate allylic triflate 4, which being
highly reactive undergoes nitrite mediated allylic rearrangement to
generate intermediate 15. One more molecule of nitrite ion now attacks
the nitrogen centre in 15 to trigger a cascade reaction via elimination of
para-methoxy phenoxide ion to transiently fashion a bicyclic interme-
diate, which concomitantly gets dismantled with release of NO2 gas
resulting in the formation of the stable diene 3. Azide nulecophiles will
traverse a similar path.
We anticipated that a similar reaction should take place in D-rhamno
and D-manno series. This would allow us to obtain the chiral diene with
opposite stereochemistry. For this purpose, we quickly synthesized the
requisite D-series substrates as shown in Scheme 2.
Accordingly, D-mannose upon per-O-acetylation [8] followed by acid
catalysed nucleophilic displacement of anomeric acetate with PMPOH
afforded
α
-PMP glycoside 5 exclusively in 78% yield over two steps. The
3. Conclusions
´
acetate groups were removed under Zemplen conditions using NaOMe
in MeOH to obtain tetraol 6 which served as a common intermediate to
synthesize substrates 8 and 10. Regioselective O6 silylation of 6 afforded
7 (98%), which upon regioselective benzoylation in the presence of a
highly catalytic amount of Me2SnCl2 [9,10] furnished the desired diol 8
in 96% yield. Likewise, regioselective tosylation of 6 followed by LAH
reduction gave D-rhamno triol 9, which upon tin catalysed benzoylation
delivered diol 10 in 89% yield.
E2 elimination is a common competing side reaction alongside an
SN2 reaction. However cascade eliminations are uncommon. In this
note, we report a novel transformation of bistriflate 2 to diene 3, which
is not reported so far. The dienes 3 and 14 being a pair of enantiomeric
dienes will be very useful in the synthesis of natural products. Diene 12
is C6-OTBDPS analogue of diene 14 and is also a useful synthon as it
provides a handle for further functionalization at C6 position of the
diene.
As expected, diols 8 and 10 upon triflation and attempted SN2 dis-
placements with azide and nitrite nucleophiles afforded similar dienes
12 and 14 (Scheme 3).
4. Experimental
To probe the mechanism of this unusual elimination reaction we
conducted a few experiments using TBANO2 mainly due to its better
solubility in acetonitrile as compared to the other nucleophiles NaNO2
and NaN3. We observed that although the pH of the TBANO2 reaction is
slightly acidic, conducting the same reaction in basic medium by adding
1.2 equiv of Hünig base had no effect on the course of the reaction. So,
protonation may not be a necessary step in the mechanism. To see if
radicals are involved, we conducted reaction in the presence of 2.0 equiv
of TEMPO radical. This also did not have any effect on the reaction,
ruling out the intervention of any radical pathway. In order to isolate or
trap any reaction intermediates we conducted the reaction with lesser
amount of TBANO2 (Scheme 4). When we used 1.2 equiv of TBANO2 we
isolated upon column chromatography an inseparable 1:1 mixture of
alkene 4 and diene 3, along with unreacted bistriflate 2 and triflate
hydrolysis product. Use of 2.5 equiv of TBANO2 furnished a similar 1:1
mixture of 3 and 4; albeit more conversion was seen and the extent of
triflate hydrolysis and the unreacted starting material 2 was decreased.
These side products viz. alkene 4 and starting material 2 or its hydro-
lysed product were not encountered when we conducted the reaction
using 4 equivalents of TBANO2. These experiments proved that the
allylic triflate 4 is the reaction intermediate which being highly reactive
gets rearranged to diene 3. Moreover, both the sequential eliminations 2
→ 4 → 3 are mediated by nitrite anions: 4 equivalents are necessary to
complete the cascade elimination. So, it remains to see how the nitrite
ions or azide ions are converting alkene 4 into diene 3 and how the
anomeric functionality is displaced? To answer these questions, we
carefully carried out the TLC analyses of reaction mixture. We did not
observe any spot related to quinone side product. However, treating the
crude mixture with Amberlite acidic resin resulted in a new spot on TLC
4.1. General methods
All reactions were conducted under the dry nitrogen atmosphere.
Solvents (CH2Cl2 >99%, THF 99.5%, CH3CN 99.8%, HMPA 99.5%, DMF
99.5%) were purchased in capped bottles and dried under sodium or
CaH2. All other solvents and reagents were used without further puri-
fication. All glassware used was oven dried before use. TLC was per-
formed on pre-coated Aluminium plates of Silica Gel 60 F254 (0.25 mm,
E. Merck). Developed TLC plates were visualized under a short-wave UV
lamp and by heating plates that were dipped in ammonium molybdate/
cerium (IV) sulfate solution. Silica gel column chromatography was
performed using Silica Gel (100–200 mesh) and employed a solvent
polarity correlated with TLC mobility. NMR experiments were con-
ducted on 500 and 400 MHz instrument using CDCl3 (D, 99.8%) as a
solvent. Chemical shifts are relative to the deuterated solvent peaks and
are in parts per million (ppm). 1H–1H COSY was used to confirm proton
assignments. Mass spectra were acquired in the ESI mode. Specific
rotation experiments were measured at 589 nm (Na) and 25 ◦C. IR
spectra were recorded on an FT-IR spectrometer.
4.2. Experimental procedures
4.2.1. 4-Methoxyphenyl 3-O-benzoyl-
α-L-rhamnopyranoside (1)
Me2SnCl2 (22 mg, 0.102 mmol) and DIPEA (0.71 mL, 4.08 mmol)
were added to a stirred solution of 4-methoxyphenyl α-L-rhamnopyr-
anoside (0.550 g, 2.04 mmol) in THF (5 mL). To this, BzCl (0.4 mL, 3.06
mmol) was added, after 4 h, the reaction mixture was quenched with 1 N
HCl (5 mL) and extracted with EtOAc (10 mL x 2). The combined organic
Scheme 1. Serendipitous formation of diene via cascade elimination.
2

D. Rai et al.
Carbohydrate Research 505 (2021) 108351
layers were dried over Na2SO4, concentrated in vacuo, and purified by
L-rhamnose) at 0 ◦C under nitrogen. The ice bath was removed, and the
mixture was kept for stirring at room temperature for 15 min. When
acetylation was completed (confirmed by TLC), PerAc compound was
diluted with CHCl3 and washed with NaHCO3, dried over Na2SO4,
filtered, and concentrated. The vacuum dried per-Ac compound was
dissolved in dry CH2Cl2, and p-methoxy phenol (1.1 mL, 10.96 mmol)
and BF3⋅Et2O (1.3 mL, 10.96 mmol) were sequentially added and the
mixture was allowed to stir for 12 h. The reaction was quenched by
addition of saturated NaHCO3 and the mixture was extracted with CHCl3
(100 mL x 2). The combined organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (20% ethyl acetate:
silica gel (100–200 mesh) column chromatography (30% ethyl acetate:
25
petroleum ether) to afford 1 as a off-white solid (0.695 g, 92%). [
α]
D
ꢀ 7.46 (c 0.06, CHCl3); IR (CHCl3)
ν 3448, 3020, 2929, 2399, 1714,
1656, 1216, 929, 768, 669 cmꢀ 1; 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J
= 8.1 Hz, 2H, ArH), 7.62–7.59 (m, 1H, ArH), 7.48–7.46 (m, 2H, ArH),
7.04 (d, J = 9.1 Hz, 2H, ArH), 6.85 (d, J = 8.9 Hz, 2H, ArH), 5.51 (dd, J
= 9.9, 3.1 Hz, 1H, H-3), 5.43(bs, 1H, H-1), 4.37 (bs, 1H, H-2), 3.98–3.88
(m, 2H, H-5, H-4), 3.80 (s, 3H, OMe), 1.37 (d, J = 5.9 Hz, 3H, H-6); 13
C
NMR (125 MHz, CDCl3) δ 166.9, 155.0, 150.2, 133.6, 129.9, 129.5,
128.6, 117.6, 114.7, 98.4, 75.3, 71.4, 69.7, 69.4, 55.7, 17.6; HRMS calcd
for C20H22NaO7 [M+Na]+ 397.1262, found 397.1258.
petroleum ether) to afford the desired product 5 as a viscous liquid
25
4.2.2. 4-Methoxyphenyl 3-O-benzoyl-2,4-bis-triflouromethanesulfonyl-1-
(74%, 9.30 g). [
α]
D +56.52 (c 0.207, CHCl3); IR (CHCl3)
ν
3019, 2400,
α
-L-rhamnopyranoside (2)
1735, 1503, 1422, 1217, 1042, 928, 771, 669, 625 cmꢀ 1; 1H NMR (500
MHz, CDCl3) δ 6.96–6.95 (m, 2H, ArH), 6.77–6.75 (m, 2H, ArH), 5.48
(dd, J = 9.9, 3.1 Hz, 1H, H-3), 5.38–5.35 (m, 2H, H-1, H-2), 5.29 (t, J =
9.3 Hz, 1H, H-4), 4.23–4.20 (m, 1H, H-6), 4.09–4.01 (m, 2H, H-5, H-6’),
3.69 (s, 3H, OCH3), 2.12 (s, 3H, COCH3), 1.99 (s, 3H, COCH3), 1.97 (s,
3H, COCH3), 1.96 (s, 3H, COCH3); 13C NMR (125 MHz, CDCl3): δ 170.4,
169.9, 169.8, 169.7, 155.4, 149.6, 117.8, 114.6, 96.6, 69.4, 68.9, 68.8,
65.9, 62.1, 55.5, 20.8, 20.6; HRMS calcd for C21H26NaO11 [M+Na] +
477.1365, found 477.1367.
Triflouromethanesulfonic anhydride (0.23 mL, 1.39 mmol) was
added to a solution of compound 1 (0.130 g, 0.35 mmol) in pyridine
(0.17 mL, 2.08 mmol) and CH2Cl2 (2.0 mL) at 0 ◦C. After 15 min stirring
at the same temperature, the reaction was quenched by addition of ice
water and the mixture was extracted with CH2Cl2 (15 mL x 2). The
combined organic layer was washed with 2 N HCl and aq. NaHCO3,
dried over anhydrous Na2SO4, filtered, and concentrated to give foam
product 2, which was used for the next step without any purification. For
the confirmation, NMR characterization has been done for 2,4-bistriflate
compound 2. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 7.3 Hz, 2H, ArH),
7.66–7.65 (m, 1H, ArH), 7.54–7.51 (m, 2H, ArH), 7.08–7.66 (m, 2H,
ArH), 6.91–6.90 (m, 2H, ArH), 6.01 (dd, J = 9.9, 3.1 Hz, 1H, H-3), 5.57
(d, J = 1.3 Hz, 1H, H-1), 5.45–5.44 (m, 1H, H-2), 5.57 (t, J = 9.9 Hz, 1H,
H-4), 4.38–4.33 (m, 1H, H-5), 3.82 (s, 3H, OMe), 1.50 (d, J = 6.3 Hz, 3H,
H-6); 13C NMR (125 MHz, CDCl3) δ 166.9, 155.0, 150.2, 133.6, 129.9,
129.5, 128.6, 117.6, 114.7, 98.4, 75.3, 71.4, 69.7, 69.4, 55.7, 17.6.
4.2.5. 4-Methoxyphenyl 6-O-TBDPS-1-α-D-mannopyranoside (7)
To a solution of compound 5 (3.6 g, 9.22 mmol) in anhydrous MeOH
(40 mL), NaOMe (0.81 g, 0.5 M) was added at room temperature. After
complete consumption of the starting material, Amberlyte IR120H+ (4
g, strong resin) was added to quench the excess sodium methoxide. After
stirring for 10 min, the reaction mixture was filtered through funnel and
washed with MeOH (100 mL). The solution was concentrated under
reduced pressure and the crude product 6 (2.27 g, quant.) was as such
used for the next step.
4.2.3. (S)-2-Methyl-2H-pyran-4-yl-benzoate (3)
To a solution of the 2,4-bistriflate in acetonitrile (2 mL) was added
tetrabutylammonium nitrite (163 mg, 0.56 mmol) at rt. The reaction
was kept at stirring for 12 h and then the solvent was evaporated on
rotary evaporator. The residue was purified by silica gel (100–200 mesh)
column chromatography using 15% EtOAc: pet ether as eluents to give 3
as a yellow viscous compound (41 mg, 81% over 2 steps). Similar results
TBDPSCl (0.5 mL) was added to a solution of compound 6 (0.250 g,
0.87 mmol) in Py (2 mL) at 0 ◦C under nitrogen. The ice bath was
removed, and the mixture was kept for stirring at room temperature for
12 h. When reaction was completed (confirmed by TLC), the reaction
was diluted with ethyl acetate and quenched by addition of 2 N HCl, and
the mixture was extracted with ethyl acetate (30 mL x 2). The combined
organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by column chro-
have been observed for the product 3 with the sodium azide in HMPA
25
and NaNO2 in HMPA. [
α]
D ꢀ 4.48 (c 0.067, CHCl3); IR (CHCl3)
ν
3020,
2926, 2400, 1733, 1216, 769, 669, 628 cmꢀ 1
;
1H NMR (500 MHz,
matography on silica gel (50% ethyl acetate: petroleum ether) to afford
25
CDCl3) δ 8.09 (d, J = 7.3 Hz, 2H, ArH), 7.61 (t, J = 7.4 Hz, 1H, ArH),
7.50–7.47 (m, 1H, 1H ArH), 7.43 (d, J = 6.1 Hz, 1H, H-1), 5.68 (d, J =
3.8 Hz, 1H, H-4), 5.56 (d, J = 5.9 Hz, 1H, H-2), 4.86–4.81 (m, 1H, H-5),
1.50 (d, J = 6.7 Hz, 3H, H-6); 13C NMR (125 MHz, CDCl3) δ 165.2, 162.5,
133.6, 130.0, 128.9, 128.7, 128.5, 105.4, 77.1, 71.3, 14.2; HRMS calcd.
for C13H13O3 [M+H]+ 217.0864, found 217.0859.
the desired product 7 as a viscous liquid (98%, 0.450 g). [
α]
D +50.00
(c 0.14, CHCl3); IR (CHCl3)
ν 3418, 3071, 2931, 2857, 1589, 1507,
1217, 1106, 1037, 970, 825, 749, 703, 614 cmꢀ 1
;
1H NMR (500 MHz,
CDCl3) δ 7.68–7.66 (m, 4H, ArH), 7.45–7.35 (m, 4H, ArH), 6.97–6.95
(m, 2H, ArH), 6.79–6.77 (m, 2H, ArH), 5.41 (s, 1H, H-1) 4.15–4.13 (m,
1H, H-2) 4.07 (dd, J = 9.2, 2.6 Hz, 1H, H-3), 3.97–3.89 (m, 3H, H-4, H-5,
H-6’), 3.83–3.79 (m, 1H, H-6), 3.77 (s, 3H, OCH3), 1.06 (s, 9H, CH3); 13
C
4.2.4. 4-Methoxyphenyl 2,3,4,6-tetra-O-acetyl-1-
α
-D-mannopyranoside
NMR (125 MHz, CDCl3): δ 154.9, 150.2, 135.6, 135.6, 132.8, 129.9,
127.84, 127.8, 117.9, 114.6, 98.6, 71.5, 71.3, 71.2, 70.4, 70.2, 70.1,
65.0, 55.6, 26.8, 19.2; HRMS calcd for C29H36NaO7Si [M+Na] +
547.2122, found 547.2123.
(5)
To a mixture of D-mannose (5.0 g, 27.75 mmol) and acetic anhydride
(15.7 mL, 166.5 mmol) was added freshly dried Cu(OTf)2 (0.03 mol% of
Fig. 1. Transition states for SN2 Vs E2 reaction in 2.
3

D. Rai et al.
Carbohydrate Research 505 (2021) 108351
Scheme 2. Synthesis of D-manno and D-rhamno substrates.
Scheme 3. Cascade eliminations in D-manno and D-rhamno series.
Scheme 4. Effect of reagent stoichiometry on elimination.
4.2.6. 4-Methoxyphenyl 3-O-benzoyl-6-O-TBDPS-1-
α
-D-mannopyranoside
1507, 1273, 1220, 1111, 1035, 826, 761, 667, 615 cmꢀ 1; 1H NMR (500
MHz, CDCl3) δ 8.17–8.15 (m, 2H, ArH), 7.72–7.69 (m, 4H, ArH),
7.49–7.39 (m, 9H, ArH), 7.05–7.03 (m, 2H, ArH), 6.82–6.80 (m, 2H,
ArH), 5.60 (dd, J = 9.7, 3.1 Hz, 1H, H-3), 5.45 (d, J = 1.6 Hz, 1H, H-1),
4.37–4.36 (m, 1H, H-2), 4.31 (t, J = 9.3 Hz, 1H, H-4), 3.99–3.95 (m, 3H,
H-5, H-6, H-6’), 3.78 (s, 3H, OCH3), 1.09 (s, 9H, CH3); 13C NMR (125
MHz, CDCl3) δ 166.7, 155.1, 150.2, 135.7, 135.6, 133.5, 133.0, 132.9,
132.98, 132.6, 130.0, 129.9,129.7, 128.5, 128.2, 127.8, 127.7, 117.9,
114.6, 98.7, 74.9, 72.6, 69.3, 67.3, 64.5, 55.7, 26.9, 19.2; HRMS calcd.
for C36H40NaO8Si [M+Na]+ 651.2383, found 651.2385.
(8)
Me2SnCl2 (8.2 mg, 0.04 mmol) and DIPEA (0.30 mL, 1.49 mmol)
were added to a stirred solution of 7 (0.390 g, 0.744 mmol) in THF (4
mL). To this, BzCl (0.13 mL, 1.12 mmol) was added, after 4 h, the re-
action mixture was quenched with 1 N HCl (5 mL) and extracted with
EtOAc (30 mL x 2). The combined organic layers were dried over
Na2SO4, concentrated in vacuo, and purified by silica gel (100–200
mesh) column chromatography (30% ethyl acetate: petroleum ether) to
25
afford 8 as a off-white solid (0.450 g, 96%). [
α]
+42.99 (c 0.107,
D
CHCl3); IR (CHCl3)
ν 3479, 3071, 3014, 2932, 2857, 1716, 1601, 1563,
4

D. Rai et al.
Carbohydrate Research 505 (2021) 108351
Scheme 5. Proposed reaction mechanism.
4.2.7. 4-Methoxyphenyl 1-
α
-D-rhamnopyranoside (9)
3H, H-6); 13C NMR (125 MHz, CDCl3) δ 166.9, 155.0, 150.2, 133.6,
TsCl (1.99 g, 10.48 mmol) was added to a solution of compound 6
(2.0 g, 6.99 mmol) in Py (20 mL) at 0 ◦C under nitrogen. The mixture
was kept for stirring for 12 h. When reaction was completed (confirmed
by TLC), the reaction was diluted with ethyl acetate and quenched by
addition of 2 N HCl, the mixture was extracted using ethyl acetate (100
mL x 2). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The dried tosyl com-
pound (3.0 g, 6.81 mmol) was dissolved in dry THF (15 mL) and slowly
added through canula into a solution of LAH (0.776 g, 20.43 mmol) in
THF (15 mL) at 0 ◦C under nitrogen. After the addition, the reaction was
set for stirring at 85 ◦C for 6 h. After completion of reaction, LAH was
quenched using ethyl acetate and 2 N H2SO4. The combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated. The
residue was purified by column chromatography on silica gel (70% ethyl
129.9, 129.5, 128.6, 117.6, 114.7, 98.4, 75.2, 71.3, 69.7, 69.3, 55.7,
17.6; HRMS calcd. for
397.1258.
C
20H22NaO7 [M+Na]+ 397.1256, found
4.2.9. 4-Methoxyphenyl 3-O-benzoyl-6-O-TBDPS-2,4-bis-
triflouromethanesulfonyl-1- -D-mannopyranoside (11)
α
Triflouromethanesulfonic anhydride (0.15 mL, 0.89 mmol) was
added to a solution of compound 8 (0.140 g, 0.22 mmol) in pyridine
(0.11 mL, 1.34 mmol) and CH2Cl2 (2.0 mL) at 0 ◦C. After 15 min stirring
at the same temperature, the reaction was quenched by addition of ice
water and the mixture was extracted with DCM (15 mL x 2). The com-
bined organic layer was washed with 2 N HCl and aq. NaHCO3, dried
over anhydrous Na2SO4, filtered, and concentrated to give foam product
11, which was used for the next step without any purification. For
confirmation NMR characterization has been done for 2,4-bistriflate
compound. 1H NMR (500 MHz, CDCl3) δ 8.21–8.19 (m, 2H, ArH),
7.79–7.66 (m, 4H, ArH), 7.57–7.42 (m, 9H, ArH), 6.89–6.88 (m, 2H,
ArH), 6.82–6.79 (m, 2H, ArH), 6.01 (dd, J = 10.1, 3.1 Hz, 1H, H-3), 5.82
(t, J = 9.9 Hz, 1H, H-4), 5.50 (d, J = 1.5 Hz, 1H, H-1), 5.47–5.46 (m, 1H,
H-2), 4.15–3.86 (m, 3H, H-5, H-6, H-6’), 3.80 (s, 3H, OCH3), 1.15 (s, 9H,
CH3); 13C NMR (125 MHz, CDCl3) δ 165.2, 155.8, 149.1, 136.2, 135.6,
134.2, 133.1, 132.7, 130.6, 130.3, 129.9, 129.8, 128.9, 128.7, 127.8,
127.7, 127.6, 117.4, 114.8, 95.6, 81.5, 75.7, 70.6, 68.2, 60.8, 55.7, 26.6,
19.2.
acetate: petroleum ether) to afford the desired product 9 as a white solid
25
(71%, 1.33 g). [
α]
+100.65 (c 0.153, CHCl3); IR (CHCl3) ν 3778,
D
3682, 3369, 2931, 1618, 1508, 1448, 1219, 1108, 1040, 983, 827, 749
cmꢀ 1; 1H NMR (500 MHz, MeOD) δ 6.89–6.87 (m, 2H, ArH), 5.19 (d, J =
1.3 Hz, 1H, H-1) 3.90–3.88 (m, 1H, H-2), 3.73 (dd, J = 9.5, 3.4 Hz, 1H,
H-3), 3.63 (s, 3H, OCH3), 3.60–3.57 (m, 1H, H-5), 3.35 (t, J = 9.5 Hz,
1H, H-4), 2.1–2.0 (m, 1H, OH), 1.13 (d, J = 6.2 Hz, 3H, CH3); 13C NMR
(125 MHz, MeOD): δ 155.4, 150.8, 117.8, 114.5, 99.6, 72.8, 71.2, 71.1,
69.4, 55.0, 17.0; HRMS calcd for C13H18O6Na [M+Na]+ 293.1014,
found 293.0996.
4.2.8. 4-Methoxyphenyl 3-O-benzoyl-
α
-D-rhamnopyranoside (10)
4.2.10. (R)-2-(Tertbutyl diphenyl silyloxy methyl)-2H-pyran-4-yl-benzoate
(12)
Me2SnCl2 (29 mg, 0.13 mmol) and DIPEA (0.92 mL, 5.26 mmol)
were added to a stirred solution of triol 9 (0.710 g, 2.63 mmol) in THF
(8 mL). To this, BzCl (0.5 mL, 3.95 mmol) was added, after 4 h, the
reaction mixture was quenched with 1 N HCl (5 mL) and extracted with
EtOAc (30 mL x 2). The combined organic layers were dried over
Na2SO4, concentrated in vacuo, and purified by silica gel (100–200
To a solution of the 2,4-bistriflate (0.108 g, 0.121 mmol) in aceto-
nitrile (1.5 mL) was added tetrabutylammonium nitrite (83.5 mg, 0.56
mmol) at rt. The reaction kept at stirring for 12 h and then solvent was
evaporated on rotary evaporator. The residue was purified by silica gel
(100–200 mesh) column chromatography using 10% EtOAc: pet ether as
eluents to give 12 as a yellow viscous compound (41 mg, 81% over 2
mesh) column chromatography (30% ethyl acetate: petroleum ether) to
25
afford 10 as an off-white solid (0.860 g, 89%). [
α]
D +118.00 (c 0.20,
steps). Similar results have been observed for the product 12 with the
25
CHCl3); IR (CHCl3)
ν
3457, 2935, 1704, 1507, 1451, 1316, 1280, 1215,
sodium azide in HMPA and NaNO2 in HMPA. [
α]
+58.33 (c 0.20,
D
1113, 1028, 984, 829, 751, 713 cmꢀ 1
;
1H NMR (500 MHz, CDCl3) δ
CHCl3); IR (CHCl3) ν 3019, 2400, 1734, 1216, 1046, 924, 766, 669
8.11–8.10 (m, 2H, ArH), 7.61–7.58 (m, 1H, ArH), 7.47–7.44 (m, 2H,
ArH), 7.04–7.02 (m, 2H, ArH), 6.85–6.83 (m, 2H, ArH), 5.50 (dd, J =
9.5, 3.2 Hz, 1H, H-3), 5.42 (d, J = 1.7 Hz, 1H, H-1), 4.37–4.36 (m, 1H, H-
2), 3.96–3.89 (m, 2H, H-5, H-4), 3.80 (s, 3H, OMe), 1.36 (d, J = 5.9 Hz,
cmꢀ 1; 1H NMR (500 MHz, CDCl3) δ 7.68–7.60 (m, 5H, ArH), 7.47–7.44
(m, 3H, ArH), 7.40–7.36 (m, 4H, ArH), 7.35 (d, J = 6.1 Hz, 1H, H-1),
7.31–7.29 (m, 3H, ArH), 5.89 (d, J = 4.8 Hz, 1H, H-4), 5.49 (d, J = 6.1
Hz, 1H, H-2), 4.79–4.76 (m, 1H, H-5), 4.07–3.97 (m, 2H, H6 & H6’),
5

D. Rai et al.
Carbohydrate Research 505 (2021) 108351
1.05 (s, 9H, CH3); 13C NMR (125 MHz, CDCl3) δ 187.5, 164.8, 162.0,
135.6, 135.5, 133.5, 132.6, 132.5, 130.3, 130.1, 129.9, 129.8, 128.9,
128.6, 128.5, 127.8, 127.7, 105.6, 80.6, 68.7, 61.2, 26.6, 19.1; HRMS
calcd. for C29H31O4Si [M+H]+ 471.1982, found 471.1986.
Acknowledgements
S.S.K. thanks the Science and Engineering Research Board, Depart-
ment of Science and Technology (grant No. CRG/2019/000025), and
Department of Biotechnology (BT/INF/22/SP23026/2017) for financial
support. D.R. thanks DST for Inspire research fellowship and S.R.S.
thanks UGC for research fellowship.
4.2.11. 4-Methoxyphenyl 3-O-benzoyl-2,4-bis-triflouromethanesulfonyl-1-
α
-D-rhamno pyranoside (13)
Triflouromethanesulfonic anhydride (0.23 mL, 1.39 mmol) was
added to a solution of compound 10 (0.130 g, 0.35 mmol) in pyridine
(0.17 mL, 2.08 mmol) and CH2Cl2 (2.0 mL) at 0 ◦C. After 15 min stirring
at the same temperature, the reaction was quenched by addition of ice
water and the mixture was extracted with CH2Cl2 (15 mL x 2). The
combined organic layer was washed with 2 N HCl and aq. NaHCO3,
dried over anhydrous Na2SO4, filtered, and concentrated to give foam
product 13, which was used for the next step without any purification.
For the confirmation NMR characterization has been done for 2,4-bistri-
flate compound 13. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 7.3 Hz, 2H,
ArH), 7.68–7.65 (m, 1H, ArH), 7.54–7.51 (m, 2H, ArH), 7.08–7.66 (m,
2H, ArH), 6.91–6.90 (m, 2H, ArH), 6.01 (dd, J = 10.3, 3.2 Hz, 1H, H-3),
5.57 (d, J = 1.3 Hz, 1H, H-1), 5.45 (bs, 1H, H-2), 5.11 (t, J = 9.9 Hz, 1H,
H-4), 4.38–4.33 (m, 1H, H-5), 3.82 (s, 3H, OMe), 1.50 (d, J = 6.2 Hz, 3H,
H-6); 13C NMR (125 MHz, CDCl3) δ 165.1, 155.9, 149.1, 134.2, 130.2,
128.6, 127.8, 119.6, 119.4, 117.7, 117.0, 116.9, 114.9, 95.7, 82.1, 81.9,
67.8, 66.5, 55.7, 17.3.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.carres.2021.108351.
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83% over 2 steps). Similar results have been observed for the product 14
25
with the sodium azide in HMPA and NaNO2 in HMPA. [
α
]
D +22.22 (c
0.027, CHCl3); IR (CHCl3)
ν 3696, 3019, 2929, 2398, 1732, 1216, 929,
768, 669, 628 cmꢀ 1; 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.3 Hz,
2H, ArH), 7.61 (t, J = 7.4 Hz, 1H, ArH), 7.49–7.47 (m, 1H, 1H ArH), 7.43
(d, J = 6.1 Hz, 1H, H-1), 5.67 (d, J = 3.9 Hz, 1H, H-4), 5.56 (d, J = 6.1
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Hz, 1H, H-2), 4.86–4.81 (m, 1H, H-5), 1.50 (d, J = 6.8 Hz, 3H, H-6); 13
C
NMR (125 MHz, CDCl3) δ 165.2, 162.5, 133.6, 130.0, 128.7, 128.5,
105.4, 77.1, 71.3, 14.2; HRMS calcd. for C13H13O3 [M+H]+ 217.0859,
found 217.0859.
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Declaration of competing interest
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The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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6