A target oriented expeditious approach towards synthesis of certain bacterial rare sugar derivatives

Article abstract of DOI:10.1039/c6ob02670b

Bacterial rare amino deoxy sugars are found in the cell surface polysaccharides of multiple pathogenic bacterial strains, but are absent in the human metabolism. This helps in the differentiation between pathogens and host cells which can be exploited for target specific drug discovery and carbohydrate based vaccine development. The principal bacterial atypical sugar derivatives include 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT), 2,4-diacetamido-2,4,6-trideoxy-d-galactose (DATDG) and N-acetylfucosamine (FucNAc). Herein, a highly streamlined protocol leading to the aforesaid derivatives is presented. The highlights of the method lie in radical mediated 6-deoxygenation along with a one-pot like protection profile manipulation on suitably derivatised d-glucosamine or d-mannose motifs to obtain a vital quinovosaminoside or rhamnoside from which rare sugar derivatives were synthesized in a diversity oriented manner.

Full text of DOI:10.1039/c6ob02670b

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A target oriented expeditious approach towards synthesis of
certain bacterial rare sugar derivatives
Aritra Chaudhurya and Rina Ghosha*
Received 00th January 20xx,
Accepted 00th January 20xx
Bacterial rare amino deoxy sugars are found in the cell surface polysaccharides of multiple pathogenic bacterial strains, but
are absent in the human metabolism. This helps in the differentiation between pathogen and the host cell which can be
exploited for target specific drug discovery and carbohydrate based vaccine development. The principal bacterial atypical
sugar derivatives include 2-acetamido-4-amino-2,4,6-trideoxy-D-galactose (AAT), 2,4-diacetamido-2,4,6-trideoxy-D-
galactose (DATDG) and N-acetylfucosamine (FucNAc). Herein, a highly streamlined protocol leading to the aforesaid
derivatives is presented. The highlights of the method lie in radical mediated 6-deoxygenation along with a one-pot like
DOI: 10.1039/x0xx00000x
www.rsc.org/
protection profile manipulation on suitably derivatised D-glucosamine or D-mannose motifs to obtain
a vital
quinovosaminoside or rhamnoside from which rare sugar derivatives were synthesized in a diversity oriented manner.
displacements of various leaving groups at the C-6 position like
bromide, iodide, -OMs and -OTs. On the other hand, the
installation of nitrogenous functionalities at the C-4 position
Introduction
Bacterial rare sugars have been shown to be essential
components of the cell surface polysaccharide profiles of
various pathogenic bacterial strains like Shigella sonnei,
Streptococcus mitis, Streptococcus pneumonia, Neisseria
meningitides, Pseudomonas aeruginosa.1,2 These rare sugars
are mostly absent in the human metabolism. Hence, these can
be considered as highly attractive candidates towards vaccine
development against the aforesaid pathogenic bacteria.3
Therefore access to these rare sugars in sizeable quantity and
stereochemical purity is of great importance. However the
aforesaid requirements cannot be met using available
techniques of isolation from biological sources. It is hence
imperative that efficient synthetic methods be devised so as to
allow easy access to these compounds for further studies and
research directed towards understanding the roles played by
these sugars in the pathogenesis of virulent bacteria.
The derivatives in question include basic sugar units like
AAT (2-acetamido-4-amino-2,4,6- trideoxygalactose),4 DATDG
(2,4-diamino-2,4,6-trideoxygalactose)5 and FucNAc (N-
acetylfucosamine).6 Different synthetic strategies have been
employed by researchers over the past three decades in their
attempts to access the aforesaid synthetic targets.7 A principal
share of these strategies involves C-6 deoxygenation on D-
glucosamine7a and D-mannose7c derivatives followed by
inversion at C-4 position as well as de novo approaches.8 The
deoxygenation protocols employed include reductive
has been carried out via nucleophilic displacements on leaving
groups like –OTs, -OTf, or -OMs. Intramolecular displacement
strategy has also been employed for the introduction amine
8c
function at the C-4 position.7b, These methods have been
recently reviewed by Kulkarni et al.1
Despite the progress made, some of these strategies still
suffer from limitations which include long drawn synthetic
schemes requiring multiple steps, low overall yields or use of
expensive and hazardous reagents in large quantities in the
initial preparative stages. Considering the aforesaid limitations
and lack of flexibility experienced in synthesizing appropriate
amino sugar substrates there appears to be room left for
further research with particular emphasis on step minimization
through one-pot reactions. Herein, we wish to report an
efficient target oriented approach (Figure 1) by which multiple
rare sugar derivatives maybe accessed easily from the pivotal
intermediates 1a-c which are obtainable from the native
sugars via the corresponding 4,6-O-benzylidene O-/S-
glycosides.
PhthN
O
AAT
Y
RO
N3
AcO
RO
O
D-Glucosamine
or
D-Mannose
O
X
HO
RO
Y
Y
D-FucNAc
X
1a-c
N3
RO
a. Department of Chemistry, Jadavpur University, 188, Raja, S. C. Mullick Road,
Kolkata- 700 032. Email: ghoshrina@yahoo.com
O
Y
DATDG
b. Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
N3
Fig. 1 Retrosynthetic analysis
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Table 1 Optimisation of protocol for the protection of O-3
Results and discussion
Entry
1
Reactant
Reaction
Conditions
TBDMSOTf,
Lutidine,
DCM
Expected
Product
Yield
88%
Synthesis of D-quinovosamine derivatives 1a, 1b and 1c
In our previous studies related to the synthesis of D-
rhamnosides radical based redox rearrangement 4,6-O-
benzylidene derivatives9 of D-manno-thioglycosides led to
their corresponding 6-O-deoxy congeners in high yield and
selectivity on treatment with DTBP (Di-tert-butyl peroxide)/
TIPST (Tri-isopropylsilane thiol) with minimal interference
from the anomeric thioglycoside.10 Using this deoxygenation
protocol (Figure 2) on the D-glucosamine derived compounds
2a-c we got the corresponding D-quinovosaminoside
derivatives 3a-c in 89 to 94% yields. Encouraged by this result
we figured that access to the aforesaid bacterial rare sugars
2
TBDMSOTf,
Lutidine,
DCM
63%
3
4
5
BnOTCA,
DCM,
-
-
-
N.R.a
N.R.b
N.R.a
TMSOTf
TriBOT-PM,
TfOH cat.,
DCM
may be achieved via
1 (Fig. 1) if we could selectively deprotect
the 4-O-benzoyl and then follow it up with an inversion at that
position mediated via carbohydrate based triflates.11a-e
TriBOT-PM,
CSA cat.,
DCM
However, the 3-OH of 3b/3c (Figure 2) has to be suitably
protected prior to the selective deprotection at 4-OH. So, a
protecting group which would be compatible with subsequent
methoxide mediated debenzoylation at O-4 had to be
selected. This turned out to be rather difficult as the radical
mediated deoxygenation protocol responds best when the
other positions bear an acyl protection profile. But we cannot
use acyl protection at O-3 because that would rule out
selective debenzoylation at O-4 in the next step. The O-benzyl
and related protecting groups which are typically used as
orthogonal protection with respect to the acyl profile is also
ruled out because of their incompatibility with the radical
deoxygenation protocol.12 The next option was silylation which
was successfully carried out on 2b (Figure 2). However,
subsequent deoxygenation of the silylated derivative 2d11e
6
7
TriBOT-PM,
CSA cat.,
DCM
-
N.R.a
95%
TsNCO,
DCM
8
9
DHP, pTSA,
75%c
77%c
DCM
DHP, pTSA,
DCM
failed to give 3d in satisfactory yield and purity
.
At this point we decided to change the order of the reactions.
Since the deoxygenation protocol is not affected by the
presence of free –OH at O-3, as long as the solubility of the
benzylidene substrate in octane is sufficient enough to permit
complete dissolution under reflux, we deoxygenated 2b/2c to
get 3b/3c. This opened up the option for acid mediated
benzylation at O-3. But unfortunately this could not yield an
efficient solution either as attempts made towards benzylation
a
b
Starting material was recovered; Starting material was decomposed; c Isolated
yield of products obtained as anomeric mixture of THP ether.
1,3,5-triazine (TRIBOT-PM)13 failed (Table 1, entries 3-6).
Silylation of 3b could be carried out but with a modest yield of
3d in 63% only (Table 1, entry 2). Subsequent debenzoylation
of 3d led to a complex mixture from which the expected
product could not be obtained in satisfactory yield (Table 2,
entry 5). As a result this route had to be abandoned.
using
benzyltrichloroacetimidate
(BnOTCA)
or
4-
methoxybenzylation using 2,4,6-Tris-(p-methoxybenzyloxy)-
Protection with the recently reported N-Tosylcarbamoyl13c
group led to 3e in high yield of 95% (Table 1, entry 7) and then
debenzoylated to 1c in 87% yield (Table 2, entry 6). Protection
of O-3 was also successfully achieved by converting 3b/3c to
their corresponding tetrahydropyranyl ether (THP) derivatives
by treatment with 3,4-di-hydro-2H-pyran (DHP) and p-
toluenesulfonic acid (p-TSA)14a to give 4a/4b (Table 1, entries 8
and 9).14b The next requirement was the selective
debenzoylation at O-4 (Table 2). After trying some variation of
temperature, reagent concentration and reaction time, a
suitable condition was found where the undesired
deprotection of N-phthaloyl group could be minimised.
O
O
X
Ph
HO
RO
O
BzO
RO
O
O
Y
RO
Y
Y
X
1
3
2
X
X
Y
R
X
Y
R
X
Y
R
2a NPhth SPh Ac
1a NPhth SPh THP
1b N3 OMP THP
1c NPhth SPh CONHTs
3a NPhth SPh Ac
3b NPhth SPh
2b NPhth SPh
2c N3 OMP
2d NPhth SPh TBS
H
H

H
H
3c N3 OMP
3d NPhth SPh TBS

3e NPhth SPh CONHTs
4a NPhth SPh THP
4b N3 OMP THP
Fig. 2 Synthesis of D-quinovosaminosides
2 | J. Name., 2012, 00, 1-3
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Table 2 Optimisation of conditions for deprotection at O-4
Entry
1
Reactant
Conc.a
0.05
Time
(h)
18
Expected
Product
Yieldc
N.R.d
N.R.e
N.R.e
84%
2
3
4
0.05
0.2
4h
1
0.08f
4
N.R.e
87%
5
6
0.2g
0.1
1h
-
Scheme 1 One pot synthesis of compounds 1a, 1b, and 1c. Reaction conditions: (a)
DTBP, TIPST, octane, reflux; (b) pTSA, DHP, DCM, rt; (c) NaOMe 0.08 M, DCM-MeOH, rt;
(d) TsNCO, DCM, rt.
12
This issue was, however, not observed with the N-
Tosylcarbamoyl group (Table 2, entry 6) where the yield of 1c
was not compromised upon scale up.
7
0.1
4
82%
The phthalimide protecting group at the C-2 position is a
participating group which leads to 1,2-trans glycosides. Since
many bacterial rare sugar derivatives found in Nature bear 1,2-
cis glycosidic linkages, a non-participating group has to be
introduced at C-2 position. Accordingly, the amino group at C-2
position of D-glucosamine was converted to its corresponding
azide,16a and then the resulting product was transformed to its
a
b
Molar concentration of NaOMe/MeOH solution. All reaction were done at rt
c
d
e
unless stated otherwise. Isolated yield. Starting material unconverted.
f
g
Starting material decomposed . DCM was added as co-solvent. Reaction was
not initiated at lower concentration and rt. h Reaction was done at 40 °C
corresponding 4,6-O-benzylidene derivative 2c 16b
On this
.
Development of one pot protocol for synthesis of 1a, 1b and 1c
occasion the one-pot three-step protocol (Scheme 1) led to the
intermediate 1b in fairly high yield of 72% even when the
reaction was scaled up (~3 fold).
After standardising the stepwise protocol for syntheses of 1a-
1c from 2b/2c, a 3-step sequential one-pot procedure for
synthesis of the same was envisioned. This involves
deoxygenation at the C-6 position, followed by acid catalyzed
tetrahydropyranylation at O-3, and finally debenzoylation
under Zémplen condition15a at O-4. Accordingly, compound
2b15b was converted to 1a/1c in 78% and 75% yields in one-
pot, respectively (Scheme 1).
However, the yield was considerably lowered (<30%) when the
protocol was scaled up (~3 fold) in case of 1a. TLC analysis
indicated that the first two steps responded well even on up
scaling the protocol, but the overall yield was getting lowered
possibly at the third step due to concomitant partial
deprotection of the phthalimido group during the
debenzoylation step. To address this problem, the conditions
of the debenzoylation had to be optimised. Despite our efforts
to address this problem with variation in reagent
concentration, reaction temperature and time, the yield could
not be improved upon scale up. The next option was to change
the protection profile of the pendant amine at C-2 position.
Synthesis of Rare sugar derivatives via triflate displacement
We next attempted the synthesis of the various rare sugar
derivatives via triflate mediated inversion at C-4 to reach AAT,
D-FucNAc and DATDG equivalents. Accordingly, compound 1a
was converted to its corresponding triflate derivative by
treatment with triflic anhydride and pyridine. The triflate so
obtained was then displaced by different nucleophiles like
acetate, azide and phthalimidate. However, similar attempts
with 1c (Table 2, entry 6) led to complex mixtures from which
desired products could not be obtained. The triflate mediated
displacements were excellent in terms of yield for compounds
5
(90%) and 10 (92%) where tetrabutylammonium acetate
(TBAOAc) was the nucleophile. Fairly high yields were obtained
for compounds (73%), 7 (73%), (78%), and (80%) using
6
8
9
azide and phthalimide as nucleophiles. (Scheme 3) The
reactions could all be carried out under ambient conditions.
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In a different approach, a DATDG-thioglycoside derivative
Journal Name
was synthesized starting from D-mannose and subsequently
glycosylated with the methyl ester L-serine. We began with the
known D-mannose based 4,6-O-benzylidene derivative 1117
which was further elaborated to the 2,3,4-triol derivative 127c
in one-pot over 3 steps. The steps include benzoyl protection
at O-2 and O-3,18 followed by deoxygenation, and
debenzoylation. Finally, selective introduction of the
naphthylmethyl group at the O-3 with Bu2SnO in toluene
generated 13 with an overall 68% yield over 4 steps. The diol
intermediate 13 was then converted to the DATDG-
thioglycoside derivative 14 via triflate mediated double parallel
inversion7c using sodium azide as the nucleophile in 89% yield.
The thioglycoside 14 was further hydrolyzed to its
corresponding hemiacetal19 15 in 90% yield. Compound 15 was
then
directly
converted
to
its
corresponding
trichloroacetimidate which was subsequently glycosylated
with the serine derivative 16 in the presence of TMSOTf in THF
after which deprotection of the naphthylmethyl group yielded
the amino ester glycoside derivative 17 in 70% yield over three
steps (Scheme 2). It is to be noted that 17 can be utilised in the
total synthesis of the trisaccharide unit associated with the
pilin of N. meningitidis.19
Scheme 2 Synthesis of Serine linked DATDG derivative. Reaction Conditions: (a)BzCl,
Pyridine; (b) DTBP, TIPST, octane, reflux, 2h; (c) NaOMe 0.1 M, MeOH, rt, 12h; (d)
Bu2SnO, Toluene, reflux, 4h, 2-Bromomethylnaphthalene, CsF, DMF, rt, 12h; (e)
Pyridine., Tf2O, DCM, RT, 4h; (f) NaN3, DMF, rt, 12h; (g) NBS, THF-H2O, rt, 1h; (h) CCl3CN,
DBU, DCM, rt; (i) 16, TMSOTf, THF, -78 °C, 2h; (j) DDQ, DCM-H2O (19:1), rt, 2h.
Scheme 3 Diversity oriented synthesis of rare sugar derivatives. Reaction conditions: (a) Pyridine, DCM, Tf2O, rt; (b) TBAOAc, DMF, rt; (c) NaN3, DMF, rt; (d) PhthNK, DMF, rt.
4 | J. Name., 2012, 00, 1-3
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Phenyl 3-O-acetyl-4-O-benzoyl-2,6-di-deoxy-2-phthalimido-1-thio-
Conclusions
β-D-glucopyranoside (3a). White foamy solid (66.4 mg, 94%).
In short an efficient protocol has been described whereby
certain routinely prepared D-glucosamine or D-mannose
derived compounds can be converted into various bacterial
rare sugar derivatives in a target oriented manner; these
derivatives are pertinent to the total synthesis of cell surface
polysaccharides present in a variety of pathogenic bacterial
strains. The synthesis of bacterial cell surface polysaccharides
1
[α]28.3 = +25.48 (c 7.02, CHCl3). H NMR (500 MHz, CDCl3): δ
D
(ppm) 1.36 (3H, d, J = 6.0 Hz, H-6), 1.73 (3H, s, -OAc), 3.92 (1H,
m), 4.41 (1H, app. t, J = 10.5 Hz), 5.17 (1H, app. t, J = 9.5 Hz),
5.79 (1H, d, J = 10.5 Hz), 5.95 (1H, t, J = 10.0 Hz), 7.27-7.29 (3H,
m), 7.41-7.44 (4H, m), 7.56 (1H, t, J = 7.5 Hz), 7.74-7.75 (2H,
m), 7.86 (2H, s), 7.99 (2H, d, J = 8.0 Hz). 13C NMR (125 MHz
CDCl3): δ (ppm) 18.0, 20.5, 54.2, 71.6, 74.3, 74.8, 83.0, 123.8,
128.4, 128.7, 129.1, 129.2, 129.9, 131.4, 131.8, 133.2, 133.6,
134.4, 134.5, 165.5, 167.1, 168.1, 170.2. HRMS (ESI-TOF, m/z)
[M + Na]+ calculated for C29H25NO7SNa 554.1249 found
554.1234.
bearing such rare sugar residues has attracted a lot of
attention in recent times
16a,20
because these polysaccharides
are implicated in various stages of bacterial pathogenesis. The
one-pot protocol used to arrive at the vital intermediates
1a/1b is operationally simple and only requires solvent
removal in the intermediate steps. This method is likely to lend
flexibility in obtaining rare sugar derivatives and in turn aids
the cause of oligosaccharide synthesis involving such sugar
residues.
Phenyl 4-O-benzoyl-2,6-di-deoxy-2-phthalimido-1-thio-β-D-
glucopyranoside (3b): White foam (110 mg, 92%). [α]28
=
D
+39.44 (c 1.10, CHCl3). 1H NMR (300 MHz, CDCl3) δ (ppm) 1.35,
(3H, d, J = 6.1 Hz, H-6), 2.92 (1H. br s, -OH), 3.85 (1H, m), 4.37
(1H, m), 4.59 (1H, m), 4.98 (1H, m), 5.67 (1H, d, J = 10.4 Hz),
7.23-7.26 (3H, m), 7.38-7.42 (4H, m), 7.53 (1H, m), 7.65-7.69
(2H, m), 7.77-7.83 (2H, m), 7.99-8.02 (2H, m). 13C NMR (75
MHz CDCl3) δ (ppm) 18.0, 56.5, 71.2, 74.6, 77.6, 83.4, 123.3,
123.9, 127.9, 128.5, 128.9, 129.3, 129.8, 129.9, 131.5, 132.0,
132.1, 132.4, 133.5, 134.3, 166.6, 167.8, 168.5. HRMS (ESI-TOF,
m/z) [M + Na]+ calculated for C27H23NO6SNa 512.1144 found
512.1146.
Experimental
General
For reactions under anhydrous condition, all glassware was
stored in the oven and was flame-dried prior to use. All
reagents and solvents were commercially available. Reagents
were used without further purification, and solvents were
distilled prior to use. Dry dichloromethane (DCM) was
obtained by distillation over P2O5. Dimethylformamide (DMF)
was distilled over calcium hydride and methanol (MeOH) was
dried over magnesium turnings. Thin layer chromatography
(TLC) was done on glass plates coated with silica gel or on
Merck silica gel plates (60-F254) to monitor the reactions.
Elution was carried out with ethyl acetate/pet.ether (EA/PE)
unless specified otherwise. Visualization of spots was
accomplished by spraying the chromatograms with 5%
ethanolic solution of sulfuric acid followed by charring on a
Phenyl
2-azido-4-O-benzoyl-2,6-di-deoxy-1-thio-β-D-
glucopyranoside (3c). (Colorless syrup 89%). [α]29 = +144.42
D
(c 2.15, CHCl3) 1H NMR (300 MHz, CDCl3): δ (ppm) 1.25 (3H, d, J
= 6.2 Hz, H-6), 2.83 (1H, br s), 3.45 (1H, m), 3.79 (s, 3H), 4.20
(1H, m), 4.43 (1H, m), 4.97 (1H, m), 5.43 (d, J = 3.4 Hz, 1H),
6.85-6.88 (2H, m), 7.05-7.09 (2H, m), 7.45-7.50 (2H, m), 7.59-
7.64 (1H, m), 8.06-8.09 (2H, m). 13C NMR (75 MHz CDCl3) δ
(ppm) 17.5, 55.7, 63.5, 66.4, 70.1, 97.6, 114.8, 118.1, 128.6,
129.2, 129.9, 133.6, 150.6, 155.4, 166.7. HRMS (ESI-TOF, m/z)
[M + Na]+ calculated for C20H21N3O6Na 422.1328 found
422.1327.
hot-plate.
Column chromatography and flash column
chromatography were performed using 60-120 and 230-400
mesh silica, respectively. Petroleum ether (PE, 60-80°C) was
used for chromatographic purpose. Melting points recorded
are uncorrected. NMR spectra were recorded on NMR
spectrometers operating at 300 MHz, 500 MHz and 600 MHz
for 1H-NMR and at 75 MHz, 125 MHz and 150 MHz for 13C-
NMR in CDCl3 / DMSO-d6. Peak assignments were obtained
Phenyl 4-O-benzoyl-3-O-tert-butyldimethylsilyl--2,6-di-deoxy-
2-phthalimido-1-thio-β-D-glucopyranoside (3d). Compound
3b (180 mg, 0.37 mmol) was dissolved in DCM (10 ml) and
stirred with 4Å MS at room temperature for 10 mins. The
temeperature was lowered to 0 °C and then 2,6-lutidine (0.1
ml, 0.44 mmol) and TBDMSOTf (0.1 ml, 0.74 mmol) were
added successively. The reaction mixture was allowed to stir at
the same temperature for 4 h and then slowly brought up to
room temperature and stirred for another 4 h. TLC at this point
showed optimum conversion of starting material to product.
The reaction mixture was diluted with DCM (20 ml) and the
organic layer was washed with saturated NH4Cl solution (100
ml). The aqueous layer was extracted with DCM (20 ml x 4)
and the combined organic layer was dried over anhydrous
Na2SO4. The DCM was removed under reduced pressure and
the crude residue was purified by column chromatography to
1
1
using H -1H COSY, and H -13C HSQC experiments for 1a and
1b. Mass spectral data were recorded by HRMS (ESI-TOF).
Specific rotations were measured on a JASCO (P-1020) digital
polarimeter using a cell of 50 mm-path length.
Representative procedure for the synthesis of 3a from 2a.
Compound 2a (70 mg, 0.13 mmol) was suspended in octane (5
ml) and di-tert-butylperoxide (DTBP) (0.02 ml, 0.13 mmol) and
tri-isopropylsilanethiol (TIPST) (3 µl, 0.013 mmol) were added,
and the reaction mixture was refluxed under argon
atmosphere for 2 h. TLC at this point showed the reaction to
be complete. The octane was removed under reduced
pressure, and the residue was purified by column
give the product 3d. White foam (140 mg, 63%). [α]25
=
D
+24.04 (c 2.01, CHCl3). 1H NMR (300 MHz, CDCl3) δ (ppm) -0.46
chromatography (10% EA/PE) to yield the product 3a
.
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(32% EA/PE) to give the product 1a. The product was further
crystallized from DCM/PE.
(3H, s), -0.29 (3H, s), 0.56 (9H, s), 1.29 (3H, d, J = 5.9 Hz, H-6),
3.82 (1H, m), 4.39 (1H, m), 4.74 (1H, m), 5.14 (1H, m), 5.61 (1H,
d, J = 10.7 Hz), 7.25 (1H, m), 7.37-7.48 (5H, m), 7.57 (1H, m),
7.76-7.88 (5H, m), 8.04 (2H, d, J = 7.1 Hz). 13C NMR (75 MHz
CDCl3) δ (ppm) -4.4, -4.1, 17.5, 18.0, 25.4, 56.8, 71.3, 74.8,
77.3, 83.5, 123.2, 123.7, 126.4, 127.8, 127.9, 128.2, 128.5,
128.8, 128.9, 129.8, 129.9, 131.7, 131.9, 132.3, 133.3, 134.3,
134.4, 165.5, 167.2, 168.7. HRMS (ESI-TOF, m/z) [M + Na]+
calculated for C33H37NO6SSiNa 626.2009 found 626.2016.
Phenyl 2, 6-di-deoxy-2-phthalimido-3-O-tetrahydropyranyl-1-thio-
β-D-glucopyranoside (1a). White needle shaped crystals (265
1
mg, 78%). Mp 138 °C. [α]29D = +73.46 (c 0.84, CH3CN) H NMR
(300 MHz, DMSO-d6) δ (ppm) 0.86 (1H, m, H-THP), 1.10-1.23
(3H, m, H-THP), 1.27 (3H, d, J = 5.9 Hz, H-6), 1.49-1.61 (2H, m,
H-THP), 2.83 (2H, m, -OCH2-THP), 3.12 (1H, m, H-4), 3.50 (1H,
m, H-5), 3.99 (1H, m, H-2), 4.17 (1H, m, H-3), 4.47 (1H, m, OH-
4), 5.49 (1H, m, H-1-THP), 5.59 (1H, d, J = 10.2 Hz, H-1), 7.28-
7.32 (5H, m, arom.-H), 7.86-7.92 (4H, m, arom.-H). 13C NMR
(75 MHz DMSO-d6) δ (ppm) 18.4 (C-6), 20.6 (THP), 25.0 (THP),
31.0 (THP), 55.2 (C-2), 63.6 (5-OCH2-THP), 75.9 (C-4), 76.8 (C-
5), 79.9 (C-3), 82.9 (C-1), 102.1(C-1 THP), 123.2 (arom.-C),
123.7, 127.8, 129.6, 130.9, 131.7, 131.9, 133.2, 135.0, 167.8 (-
CO- NPhth), 168.5 (-CO- NPhth). HRMS (ESI-TOF, m/z) [M +
Na]+ calculated for C25H27NO6SNa 492.1457 found 492.1456.
Phenyl 4-O-benzoyl-3-O-(N-Tosyl)carbamoyl-2,6-di-deoxy-2-
phthalimido-1-thio-β-D-glucopyranoside (3e). Compound 3b
(240 mg, 0.49 mmol) was dissolved in DCM (5 ml) and TsNCO
(0.24 ml, 1.48 mmol) was added at room temperature. The
reaction mixture was allowed stir at room temperature for 4 h.
TLC (1:2 EA/PE) at this point indicated completion of the
reaction. The reaction mixture was diluted with DCM (20 ml)
and the organic layer was washed with water (100 ml). The
aqueous layer was extracted thrice with DCM (20 ml). The
combined organic layer was dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography (33% EA/PE) to give the
4’-Methoxyphenyl 2-azido -2, 6-di-deoxy -3-O-tetrahydropyranyl-
α-D-glucopyranoside (1b). White crystals (683 mg, 72%). Mp 124
desired product 3e. White foam (320 mg, 95%). [α]27.4
=
D
29
1
°C. [
α
]
= +111.58 (c 1.03, CH3CN). H NMR (600 MHz, DMSO-
D
1
+14.60 (c 1.42, CHCl3). H NMR (300 MHz, CDCl3) δ (ppm) 1.30
(3H, d, J = 6.1 Hz, H-6), 2.28 (3H, s, -Me), 3.87 (1H, m), 4.35
(1H, m), 5.05 (1H, m), 5.71 (1H, d, J = 10.5 Hz), 5.79 (1H, m),
6.88 (2H, d, J = 7.9 Hz), 7.25-7.31 (3H, m), 7.37-7.42 (4H, m),
7.51-7.58 (3H, m), 7.73-7.88 (6H, m), 8.27 (1H, m). 13C NMR (75
MHz CDCl3) δ (ppm) 17.8, 21.7, 53.9, 73.8, 73.9, 74.6, 83.1,
123.7, 123.9, 126.5, 127.7, 128.3, 128.5, 128.8, 128.9, 129.2,
129.7, 129.8, 131.1, 131.3, 133.0, 133.4, 134.2, 134.3, 135.1,
143.4, 144.3, 149.6, 165.5, 167.1, 167.9. HRMS (ESI-TOF, m/z)
[M + Na]+ calculated for C35H20N2O9S2Na 686.1393 found
686.1389.
d6) δ (ppm) 1.14 (3H, d, J = 6.3 Hz, H-6), 1.49-1.57 (4H, m, H-
THP), 1.70-1.75 (2H, m, H-THP), 3.14 (1H, m, H-4), 3.34 (1H, m,
H-2), 3.51 (1H, m, -OCH2-THP ), 3.71 (4H, s, -OMe, H-5), 3.97
(1H, m, -OCH2-THP ), 4.02 (1H, m, H-3), 5.14 (1H, s, H-1-THP),
5.47 (2H, s, OH-4, H-1), 6.89 (2H, d, J = 8.4 Hz, arom. H-OMP),
7.00 (2H, d, J = 7.8 Hz, arom. H-OMP). 13C NMR (150 MHz
DMSO-d6) δ (ppm) 17.9 (C-6), 19.6 (C-THP), 25.5 (C-THP), 30.8
(C-THP), 55.8 (-OMe), 61.8 (C-2), 61.9 (OCH2-THP), 68.9 (C-5),
75.4 (C-3), 76.8 (C-4), 97.9 (C-1), 99.5 (C-1 THP), 115.2 (arom.
C-OMP), 118.5 (arom. C-OMP), 150.5 (arom. C-OMP), 155.2
(arom. C-OMP). HRMS (ESI-TOF, m/z) [M + Na]+ calculated for
C18H25N3O6Na 402.1641 found 402.1638.
Representative one-pot protocol for the synthesis of 1a from 2b.
Compound 2b (355 mg, 0.7 mmol) was suspended in octane
(15 ml), and DTBP (0.14 ml, 0.7 mmol) and TIPST (0.02 ml, 0.08
mmol) were added. The reaction mixture was refluxed for 2 h
under argon atmosphere. TLC at this point showed the
reaction to be complete. The solvent was removed under
reduced pressure. The crude residue was dissolved in DCM (6
ml), and DHP (0.08ml, 0.09 mmol) was added. The
temperature was lowered to 0 °C, and pTSA (14 mg, 7 µmol)
was added. The temperature was then raised to room
temperature, and the reaction mixture was stirred for 2 h. TLC
at this point showed completion of the second step. The
solvent was removed under reduced pressure. The crude
residue was dissolved in methanol (5 ml), and NaOMe/MeOH
solution (1 ml, 1M) was added followed by DCM (2 ml). The
reaction was carried on for 4 h at which point the optimum
conversion of starting materials to product was observed. The
reaction mixture was quenched with DOWEX 50W resin and
subsequently filtered under suction. The filtrate was
evaporated to dryness under reduced pressure and the crude
residue was co-evaporated with toluene to ensure dryness.
The dry mass was purified by flash column chromatography
Phenyl 3-O-(N-Tosyl)carbamoyl-2,6-di-deoxy-2-phthalimido-1-thio-
β-D-glucopyranoside (1c). Compound 3e (300 mg, 0.44 mmol)
was dissolved in NaOMe/MeOH (0.1M, 6ml) solution at room
temperature. The reaction mixture was allowed to stir
overnight at room temperature. TLC (1:2 EA/PE) at this point
indicated completion of the reaction. The reaction mixture was
neutralised with DOWEX 50W resin and then filtered under
suction. The filtrate was concentrated under reduced pressure
and the crude residue was purified by column chromatography
(EA) to give the desired product 1c. White foam (220 mg, 87%).
[α]28D = 39.29 (c 1.54, CHCl3). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.36 (3H, d, J = 6.0 Hz, H-6), 2.35 (3H, s, Me), 3.32 (1H,
m), 3.60 (1H, m), 4.20 (1H, m), 5.46 (1H, m), 5.63 (1H, d, J =
10.5 Hz), 7.06-7.36 (7H, m), 7.65-7.75 (6H, m). 13C NMR (75
MHz CDCl3) δ (ppm) 17.9, 21.7, 53.8, 74.3, 76.2, 82.9, 123.7,
127.9, 128.0, 128.9, 129.4, 131.1, 131.4, 131.9, 132.4, 134.0,
134.2, 135.3, 144.5, 151.1, 167.3, 167.9. HRMS (ESI-TOF, m/z)
[M + Na]+ calculated for C28H26NO8S2Na 582.1131 found
582.1129.
6 | J. Name., 2012, 00, 1-3
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One-pot protocol for the synthesis of 1c from 2b. Compound 2b 25.4, 30.1, 55.8, 58.8, 61.6, 65.6, 69.4, 69.8, 94.7, 97.9, 115.2,
(1.0 g, 2.06 mmol) was suspended in n-Octane (50 ml) along 118.8, 150.5, 155.3, 170.7. HRMS (ESI-TOF, m/z) [M + Na]+
with DTBP (0.38 ml, 2.06 mmol) and TIPST (0.05 ml, 0.2 mmol). calculated for C20H27N3O7Na 444.1747 found 444.1749.
The reaction mixture was refluxed for 2 h. The solvent was
4’-Methoxyphenyl 2, 4- di- azido- 3- O- tetrahydropyranyl- 2, 4, 6-
removed under the reduced pressure and the residue was co-
evaporated twice with Toluene (10 ml). The dried residue was
dissolved in DCM (15 ml) and TsNCO (0.9 ml, 6.1 mmol) was
tri-deoxy- α- D- galactopyranoside (6). Colorless oil (77.3 mg,
73%). [α]27.7 = +85.03 (c 3.48, CH3CN). 1H NMR (300 MHz,
D
DMSO-d6) δ (ppm) 1.11 (3H, d, J = 6.1 Hz, H-6), 1.52 (4H, m),
1.69-1.77 (2H, m), 3.57 (1H, m), 3.68-3.75 (4H, m), 3.92 (1H,
m), 4.10 (1H, m), 4.41-4.44 (2H, m), 5.06 (1H, s), 5.48 (1H, d, J
= 3.2 Hz), 6.85 (2H, d, J = 8.9 Hz), 6.96 (2H, d, J = 8.8 Hz). 13C
NMR (75 MHz DMSO-d6) δ (ppm) 17.6, 18.9, 25.3, 29.7, 55.8,
58.7, 61.6, 62.3, 65.5, 71.8, 94.5, 97.8, 115.1, 118.8, 150.4,
added. The reaction mixture was allowed to stir at room
temperature for 4 h. The DCM was removed under reduced
pressure and the residue was again co-evaporated twice with
Toluene (10 ml). The dried residue was next dissolved in
NaOMe/ MeOH (0.1M, 20 ml). The reaction mixture was
allowed to stir overnight at room temperature. The reaction
mixture was neutralised with DOWEX 50W resin and then
filtered under suction. The filtrate was concentrated under
reduced pressure and the crude residue was purified by
155.3. HRMS (ESI-TOF, m/z) [M
C18H24N6O5Na 427.1706 found 427.1705.
+
Na]+ calculated for
4’-Methoxyphenyl
2- azido- 4- phthalimido- 3-O-
column chromatography (EA) to give the desired product 1c
.
tetrahydropyranyl- 2, 4, 6- tri-deoxy- α- D- galactopyranoside (7).
White foam (893 mg, 75%). NMR and other characterisation
data were found to be in agreement with that obtained for the
same compound synthesized via step wise protocol.
Yellowish oil. (89 mg, 73%). [α]25 = +113.67 (c 1.17, CH3CN).
D
1H NMR (300 MHz, DMSO-d6) δ (ppm) 0.91 (3H, d, J= 6.2 Hz, H-
6), 1.07-1.24 (2H, m), 1.35-1.41 (4H, m), 3.54 (1H, m), 3.70 (3H,
s), 3.86 (1H, m), 4.25 (1H, m), 4.44 (1H, m), 4.63 (1H, m), 4.70
(1H, m), 4.99 (1H, m), 5.72 (1H, d, J= 3.5 Hz), 6.89 (2H, d, J= 8.9
Hz), 7.04 (2H, d, J= 8.9 Hz), 7.92 (m, 4H). 13C NMR (75 MHz
DMSO-d6) δ (ppm) 16.8, 18.9, 25.2, 30.4, 51.5, 55.8, 59.5, 61.7,
64.5, 69.4, 95.1, 98.3, 115.2, 118.7, 123.9, 131.4, 135.6, 150.6,
155.3, 168.4, 169.7. HRMS (ESI-TOF, m/z) [M + Na]+ calculated
for C26H28N4O7Na 531.1856 found 531.1847.
Representative procedure for triflate mediated displacement for
the synthesis of compound 5 from 1b. Compound 1b (40 mg, 0.1
mmol) was dissolved in DCM (5 ml) and pyridine (0.02 ml, 0.2
mmol). The temperature was lowered to 0 °C, triflic anhydride
(0.05 ml, 0.3 mmol) was added, and the reaction mixture was
allowed to attain room temperature. The reaction mixture was
stirred at room temperature for 2 h. After completion of the
reaction (monitored by TLC), the mixture was diluted with
DCM (10 ml), and the solution was washed with water (50 ml).
The organic layer was dried over Na2SO4, and then the solvent
was evaporated under reduced pressure. The crude residue
was co-evaporated with dry toluene (5 ml), and the dried
residue was dissolved in DMF (5 ml). Tetrabutylammonium
Acetate (TBAOAc) (49 mg, 0.16 mmol) was added, and the
reaction mixture was stirred rigorously for 12 h at room
temperature. After the completion of the reaction (monitored
by TLC) the solvent was removed under reduced pressure, and
the crude residue was dissolved in DCM (15 ml). The organic
layer was washed with water (50 ml) and collected. The
aqueous layer was extracted thrice with DCM (10 ml) and the
combined organic layer was dried over Na2SO4. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography (5% EA/PE) to give the
Phenyl 2,4- di- phthalimido-3-O-tetrahydropyranyl-2, 4, 6- tri-
deoxy- 1-thio-β-D-galactopyranoside (8). Colorless viscous gel (48
1
mg, 78%). [α]25D = +44.67 (c 1.04, CH3CN). H NMR (300 MHz,
DMSO-d6) δ (ppm) 0.94 (1H, m), 1.13-1.23 (4H, m), 1.29-1.34
(4H, m), 3.01 (1H, m), 3.77-3.82 (2H, m), 4.36-4.46 (2H, m),
4.62 (1H, s), 4.94 (1H, d, J = 3.2 Hz), 5.61 (1H, d, J = 10.2 Hz),
7.19-7.33 (7H, m), 7.81-7.92 (6H, m). 13C NMR (75 MHz DMSO-
d6) δ (ppm) 17.5, 19.5, 25.2, 30.7, 51.0, 61.9, 67.5, 74.4, 75.1,
83.2, 96.0, 123.4, 123.8, 127.5, 129.5, 130.5, 131.4, 131.7,
133.8, 135.2, 135.2, 167.9, 168.5. HRMS (ESI-TOF, m/z) [M +
Na]+ calculated for C33H30N2O7SNa 621.1671 found 621.1678.
Phenyl 4- azido- 2- phthalimido- 3- O- tetrahydropyranyl- 2,4,6- tri-
deoxy- 1- thio- β- D-galactopyranoside (9). Colorless syrup (110
1
mg, 80%). [α]29.3 = +64.46 (c 0.71, CH3CN). H NMR (300 MHz,
D
DMSO-d6) δ (ppm) 0.93 (1H, m), 1.15-1.32 (6H, m), 1.44-1.56
(2H, m), 2.87-3.02 (2H, m), 3.94 (1H, m), 4.28-4.35 (2H, m),
4.69-4.73 (2H, m), 5.58 (1H, d, J= 10.5 Hz), 7.18-7.32 (5H, m),
7.84-7.94 (4H, m). 13C NMR (75 MHz DMSO-d6) δ (ppm) 17.6,
18.9, 24.4, 29.9, 50.9, 61.9, 63.2, 72.6, 74.7, 82.5, 97.3, 122.9,
123.3, 127.2, 129.0, 130.4, 130.8, 131.1, 132.5, 134.7, 134.7,
167.2, 167.8. HRMS (ESI-TOF, m/z) [M + Na]+ calculated for
C25H26N4O5SNa 517.1522 found 517.1525.
desired product 5.
4’-Methoxyphenyl 4-O-acetyl 2- azido- 2, 6- di-deoxy- 3- O-
tetrahydropyranyl - α- D- galactopyranoside (5). White foam (40
mg, 90%). [α]29.2 = +122.75 (c 1.23, CH3CN). 1H NMR (300
D
MHz, DMSO-d6) δ (ppm) 0.99 (3H , d, J = 6.2 Hz, H-6), 1.21-1.70
(6H, m), 2.09 (3H, s), 3.55 (1H, br s), 3.64-3.70 (4H, m), 3.87
(1H, m), 4.20 (1H, m), 4.36 (1H, m), 4.83 (1H, s), 5.35 (1H, s),
5.55 (1H, d, J = 3.2 Hz), 6.88 (2H, d, J = 8.9 Hz), 6.98 (2H, d, J =
8.9 Hz). 13C NMR (75 MHz DMSO-d6) δ (ppm) 16.3, 19.0, 20.9,
Phenyl 4- O- acetyl- 2- phthalimido-3- O- tetrahydropyranyl-2, 4, 6-
tri-deoxy- 1-thio-β-D-galactopyranoside (10). Colorless oil (93.7
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J. Name., 2013, 00, 1-3 | 7
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1
mg, 92%). [α]29 = +47.29 (c 3.07, CH3CN). H NMR (300 MHz, under reduced pressure and the residue was purified by
D
DMSO-d6) δ (ppm) 0.89 (1H, m), 1.11-1.13 (4H, m), 1.19-1.39 column chromatography (30% EA/PE) to give the product 13
1
(4H, m), 2.11 (3H, s), 2.93-2.97 (2H, m), 4.03 (1H, m), 4.29 (1H, (0.55 g, 68%) over 4 steps. [α]27.8D = +89.22 (c 4.46, CHCl3). H
m), 4.57-4.64 (2H, m), 5.33 (1H, m), 5.65 (1H, d, J = 10.6 Hz), NMR (300 MHz, CDCl3) δ (ppm) 1.31 (3H, d, J = 6.2 Hz, H-6),
7.22-7.35 (5H, m), 7.84-7.92 (4H, m). 13C NMR (75 MHz DMSO- 3.67-3.70 (2H, m), 4.16 (1H, m), 4.30 (1H, s), 4.77 (1H, d, J =
d6) δ (ppm) 16.9, 19.4, 21.0, 25.0, 30.4, 51.5, 62.2, 70.0, 72.4, 11.5 Hz), 4.89 (1H, d, J = 11.5 Hz), 5.54 (1H, s), 7.28 (2H, m),
73.2, 83.0, 96.9, 123.5, 123.9, 127.8, 129.5, 130.9, 131.2, 7.44 (2H, d, J = 6.7 Hz), 7.48-7.53 (4H, m), 7.83-7.89 (4H, m).
131.6, 133.1, 135.3, 135.4, 167.7, 168.3, 170.6. HRMS (ESI-TOF, 13C NMR (75 MHz, CDCl3) δ (ppm) 17.6, 69.2, 69.5, 71.9, 72.0,
m/z) [M + Na]+ calculated for C27H29NO7SNa 534.1562 found 79.9, 87.4, 125.7, 126.3, 126.5, 127.1, 127.4, 127.8, 127.9,
534.1565.
128.7, 129.1, 131.4, 133.2, 133.3, 134.0, 134.7. HRMS (ESI-TOF,
m/z) [M + Na]+ calculated for C23H24O4SNa 419.1293 found
419.1294.
One-pot protocol on the D-Mannose based scaffold 11.
Phenyl 3- O- (2’-methyl)naphthyl- 1- thio- β- D-rhamnopyranoside
(13). Compound 11 (960 mg, 2.67 mmol) was dissolved in DCM Phenyl 2,4- di- azido- 3- O- (2’-methyl)naphthyl- 2,4,6- tri- deoxy-
(20 ml) and pyridine (4 ml). The reaction mixture was cooled to 1- thio- β- D-galactopyranoside (14). Diol 13 ( 0.55 g, 1.38 mmol)
0 °C, and benzoyl chloride (0.68 ml, 5.86 mmol) was added was dissolved in DCM (25 ml) and pyridine (2 ml). The
dropwise. The reaction vessel was brought to room temperature was lowered to 0 °C and triflic anhydride (1.38
temperature and stirred for 12 h. After completion of the ml, 8.2 mmol) was added, and the reaction mixture was
reaction (monitored by TLC), the solvent was removed under allowed to attain room temperature. The reaction mixture was
reduced pressure, and the residue was co-evaporated thrice stirred at room temperature for 4 h. After completion of the
with toluene (10 ml) to ensure removal of pyridine. The crude reaction (monitored by TLC), the reaction mixture was diluted
residue was next suspended in dry octane (40 ml). DTBP (0.50 with DCM (30 ml), and the solution was washed with water
ml, 2.7 mmol) and TIPST (0.06 ml, 0.27 mmol) were added and (250 ml). The organic layer was dried over Na2SO4, and then
then the reaction mixture was refluxed for 1.5 h. After the solvent was evaporated under reduced presure. The crude
completion of the reaction (monitored by TLC), the solvent residue was co-evaporated with dry toluene (20 ml), and the
was removed under reduced pressure, and the residue was co- dried residue was dissolved in DMF (15 ml). NaN3 (0.45 g, 6.9
evaporated with toluene (10 ml). The residue was next mmol) was added, and the reaction mixture was stirred
dissolved in methanol (18 ml) and NaOMe/MeOH 1M (2 ml) rigorously for 12 h at room temperature. After the completion
was added dropwise at 0°C. The reaction vessel was brought to of the reaction (monitored by TLC) the solvent was removed
room temperature and stirred for 14 h. After completion of under reduced pressure, and the crude residue was dissolved
the reaction (monitored by TLC), the reaction mixture was in DCM (30 ml). The organic layer was washed with water (250
neutralized with Dowex 50W resin. The resin was filtered out, ml) and collected. The aqueous layer was extracted thrice with
and the filtrate was collected. The solvent was evaporated DCM (30 ml), and the combined organic layer was dried over
7c
under reduced pressure to give the product 12
.
A part of the Na2SO4. The solvent was removed under reduced pressure,
crude residue was purified by column chromatography (EA) for and the residue was purified by column chromatography (10%
characterization by NMR. The remaining bulk of the material EA/PE) to give the product 14. (0.54 g, 90%). [α]27.7 = +85.73
D
1
was carried forward to the next step without further (c 3.48, CH3CN). H NMR (300 MHz, CDCl3) δ (ppm) 1.32 (3H, d,
purification. H NMR (300 MHz, DMSO-d6) δ (ppm) 1.17 (3H, d, J = 6.2 Hz, H-6), 3.47-3.69 (4H, m), 4.29 (1H, d, J = 9.8 Hz), 4.89
1
J = 5.4 Hz, H-6), 3.17-3.22 (2H, m), 3.83 (1H, m), 4.77-4.85 (2H, (2H, s), 7.31-7.33 (3H, m), 7.49-7.60 (5H, m), 7.83-7.89 (4H, m).
m), 4.98-5.01 (2H, m), 7.19 (1H, m), 7.27-7.37 (4H, m). 13C NMR 13C NMR (75 MHz, CDCl3) δ (ppm) 17.9, 61.2, 62.6, 72.8, 73.4,
(75 MHz DMSO-d6) δ (ppm) 18.1, 71.6, 72.4, 73.9, 75.9, 86.0, 81.3, 86.4, 125.8, 126.3, 126.4, 127.1, 127.8, 127.9, 128.3,
125.9, 128.3, 128.9, 136.5. Compound 12 (0.67 g, 2.6 mmol) 128.6, 128.9, 131.4, 133.2, 133.2, 133.3, 134.4. HRMS (ESI-TOF,
was suspended in toluene (35 ml) and dibutyl tin oxide (0.67 g, m/z) [M + Na]+ calculated for C23H22N6O2SNa 469.1423 found
2.7 mmol) was added. The reaction mixture was refluxed for 4 469.1428.
h and then cooled to room temperature. The solvent was next
N-(benzyloxycarbonyl)- 2,4- di- azido- 2,4,6- tri- deoxy-α- D-
galactopyranosyl- L- serine methyl ester (17). Compound 14
(0.54 g,1.36 mmol) was dissolved in THF/H2O (4:1) (20 ml). The
temperature was lowered to 0 °C, N-bromosuccinimide (0.65
g, 3.65 mmol) was added, and the reaction mixture was stirred
at room temperature for 1 h. After completion of the reaction
(monitored by TLC), the solvent was evaporated under
reduced pressure. The residue was dissolved in DCM (30 ml),
and the solution was washed successively with Na2S2O3
solution (200 ml) and NaHCO3 solution (200 ml) after which
removed under reduced pressure, and DMF (30 ml) was
added. CsF (0.8 g, 5.3 mmol) and 2-bromomethyl naphthalene
(0.68 g, 2.9 mmol) were added. The reaction mixture was
stirred at room temperature for 12 h. After completion of the
reaction (monitored by TLC), the solvent was removed under
reduced pressure. The crude residue was dissolved in DCM (30
ml) and washed with brine solution (250 ml). The aqueous
layer was extracted thrice with DCM (40 ml) and the combined
organic layer was dried over Na2SO4. The solvent was removed
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the organic layer was collected. The aqueous layers were acknowledges the CSIR, India for providing senior research
extracted thrice with DCM (30 ml), and the combined organic fellowship.
layer was dried over Na2SO4. The solvent was removed under
reduced pressure, and the residue was purified by column
Notes and references
chromatography (15% EA/PE) to give the product 15 as an
anomeric mixture (α:β 1: 1.46). The ratio of the isomers was
determined by the ratio of the integration of 1H NMR (300
MHz, CDCl3) signals at δ 5.26 (d, J= 3.3 Hz) and δ4.39 (d, J= 8.0
Hz) corresponding to the α and β isomer respectively. (0.39 g,
1
2
M. Emmadi, S. Kulkarni, Nat. Prod. Rep. 2014, 31, 870-879.
D. H. Dube, K. Champasa, B. Wang, Chem. Commun., 2011,
47, 87-101.
3
4
A, Adibekian, P. Stallforth, M.-L. Hecht, D. B. Werz, P.
Gagneux, P. H. Seeberger, Chem. Sci., 2011, 2, 337-344.
90%). HRMS (ESI-TOF, m/z) [M
+
Na]+ calculated for
(a) L. Kenne, B. Lindberg, K. Petersson, E. Katzenellenbogen,
E. Romanowska, Carbohydr. Res., 1980, 78, 119-126; (b) B.
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Karlsson, P.-E. Jansson, U. B. S. Sørensen, Eur. J. Biochem.,
1999, 265, 1091-1097.
C17H18N6O3Na 377.1338 found 377.1334. This inseparable
anomeric mixture was used for the next step. Compound 15
(0.39 g, 1.10 mmol) was dissolved in DCM (10 ml).The
temperature was brought down to -5 °C. CCl3CN (0.25 ml, 2.5
mmol) and DBU (0.04 ml, 0.25 mmol) were added and the
reaction mixture was stirred at -5 °C for 2 h. After completion
of the reaction (monitored by TLC), the solvent was
evaporated under reduced pressure. The residue was
chromatographed through a short silica bed to give the
corresponding trichloroacetimidate (0.43 g, 79%). The
trichloroacetimidate was carried forward to the next step. The
trichloroacetimidate (0.33g, 0.67 mmol) was dissolved in THF
(6 ml) along with the amino acid acceptor 16 (0.25 g, 1.00
mmol) and 3Å MS. The temperature was lowered to -78 °C.
TMSOTf (0.06 ml, 0.33 mmol) was added and the reaction
mixture was stirred for 2 h. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched with
Et3N (0.1 ml, 0.72 mmol) at -78 °C. The solvent was evaporated
under reduced pressure. The residue was dissolved in
DCM/H2O (19:1) (20 ml) and DDQ (0.18 g, 0.79 mmol) was
added and the reaction mixture was stirred at room
5
6
E. Stimson, M. Vriji, K. Makepeace, A. Dell, H. R. Morris, G.
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Spruit, H. S. Overkleeft, G. A. van der Marel, J. D. C. Codée,
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temperature for
2 h. After completion of the reaction
Provoost, J. Mazurek, H. S. Overkleeft, G. A. van der Marel,
Tetrahedron Lett., 2007, 48, 2697-2700.
(monitored by TLC), the reaction mixture was diluted with
DCM (30 ml), washed successively with sodium bicarbonate
(aq. sat.) (150 ml) and water (100 ml), and the organic layer
was collected. The aqueous layers were extracted thrice with
DCM (20 ml). The combined organic layer was dried over
Na2SO4. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography (30%
EA/PE) to give the product 17. White foam (0.20 g, 70%).
(a) L. M. Jeppesen, I. Lundt, C. Pedersen, Acta Chem. Scand.,
1973, 27, 3579-3585; (b) H. -S. Dang, B. P. Roberts, J. Sekhon,
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10 A. Chaudhury, S. K. Maity, R. Ghosh, Beilstein J. Org. Chem.,
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G. –J. Boons, Tetrahedron Lett., 2002, 43, 7805-7807.
12 D. Crich, Q. J. Yao, J. Am. Chem. Soc., 2004, 126, 8232-8236.
13 (a) T. Iversen, D. R. Bundle, J. Chem. Soc., Chem. Commun.,
1981, 1240-1241; (b) K. Yamada, H. Fujita, M. Kitamura, M.
Kunishima, Synthesis, 2013, 45, 2989-2997; (c) S. Manabe,
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14 (a) T. W. Green,P. G. M. Wuts in Protecting Groups in Organic
Synthesis, 3rd Ed, Wiley-Interscience, New,York 1999, pp. 49-
54 and pp. 708-711; (b) NMR characterisation of compounds
4a/4b was complicated as these were both obtained as
inseparable anomeric mixtures of the THP ether. Hence,
characterization was done at the next step where both the
products 1a and 1b could be crystallized.
[α]28.3 = +94.51 (c 1.83, CHCl3). 1H NMR (500 MHz, CDCl3) δ
D
(ppm) 1.24 (3H, d, J = 6.5 Hz, H-6), 3.39 (1H, dd, J = 10.5, 3.5
Hz), 3.70 (1H, d, J = 3.5 Hz), 3.78 (4H, br s), 3.95-4.01 (3H, m),
4.13 (1H, dd, J = 10.5, 3.5 Hz), 4.83 (1H, d, J = 3.5 Hz), 5.10-5.15
(2H, m), 5.73 (1H, d, J = 7.5 Hz), 7.31-7.37 (5H, m). 13C NMR
(125 MHz, CDCl3) δ (ppm) 17.2, 53.0, 54.5, 60.4, 66.1, 66.5,
67.4, 68.5, 69.1, 98.9, 128.3, 128.5, 128.7, 136.3, 156.0, 170.3.
HRMS (ESI-TOF, m/z) [M + Na]+ calculated for C18H23N7O7Na
472.1557 found 472.1545. The data was found to be in
agreement with that reported in literature.19
Acknowledgements
RG acknowledges the CSIR (02(0186)/14/EMR-II) and DST
(SR/S1/OC-61/2012), India for the financial supports. AC
15 (a) G. Zemplén, Ber. Dtsch. Chem. Ges,. 1926, 59, 1254-1266;
(b) N. Basu, S. K. Maity, S. Roy, S. Singha, R. Ghosh,
Carbohydr. Res., 2011, 346, 534-539.
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16 (a) E. D. Goddard-Borger, R. V. Stick, Org. Lett., 2007,
Journal Name
9
,
3797-3800; (b) C. M. Pedersen, I. Figueroa-Perez, B.
Lindner,A. J. Ulmer, U. Zähringer, R. Schmidt, Angew. Chem.,
Int. Ed., 2010, 49, 2585-2590.
17 A. Ali, R. J. B. H. N. van der Berg, H. S. Overkleeft, G. A. van
der Marel, J. D. C. Codée, Tetrahedron, 2010, 66, 6121-6132.
18 Benzoylation of diol 22 is necessary to improve substrate
solubility in octane in the next deoxygenation step. Complete
solubility of the starting material in the solvent under reflux
was found to be imperative for proper conversion of
reactant to product.
19 M. Emmadi, S. Kulkarni, Org. Biomol. Chem., 2013, 11, 3098-
3102.
20 M. Emmadi, S. Kulkarni, Carbohydr. Res., 2014, 399, 57-63.
10 | J. Name., 2012, 00, 1-3
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