Chemoselective Cleavage of p-Methoxybenzyl and 2-Naphthylmethyl Ethers Using a Catalytic Amount of HCl in Hexafluoro-2-propanol

Article abstract of DOI:10.1021/acs.joc.5b01030

A new, fast, mild and chemoselective deprotection method to cleave p-methoxybenzyl and 2-naphthylmethyl ethers using catalytic amounts of hydrochloric acid in a 1:1 mixture of hexafluoro-2-propanol (HFIP) and methylene chloride (DCM) is described. The scope of the methodology becomes apparent from 14 examples of orthogonally protected monosaccharides that are subjected to HCl/HFIP treatment. The applicability of the HCl/HFIP method is illustrated by the synthesis of a sulfated β-mannuronic acid disaccharide.

Full text of DOI:10.1021/acs.joc.5b01030

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Note
Chemoselective cleavage of para-methoxy benzyl and 2-naphthylmethyl
ethers using a catalytic amount of HCl in hexafluoro-iso-propanol
Anne Geert Volbeda, Hans Antonius Valentijn Kistemaker, Herman S.
Overkleeft, Gijsbert A. van der Marel, Dmitri V. Filippov, and Jeroen D. C. Codée
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01030 • Publication Date (Web): 31 Jul 2015
Downloaded from http://pubs.acs.org on August 9, 2015
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Chemoselective cleavage of para-methoxy benzyl and 2-naphthylmethyl ethers
using a catalytic amount of HCl in hexafluoro-iso-propanol
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Anne Geert Volbeda, Hans A.V. Kistemaker, Herman S. Overkleeft, Gijsbert A. van
der Marel, Dmitri V. Filippov and Jeroen D.C. Codée*
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Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
jcodee@chem.leidenuniv.nl
Abstract
A new, fast, mild and chemoselective deprotection method to cleave p-
methoxybenzyl and 2-naphthylmethyl ethers using catalytic amounts of hydrochloric
acid in a 1:1 mixture of hexafluoro-iso-propanol (HFIP) and methylene chloride
(DCM) is described. The scope of the methodology becomes apparent from fourteen
examples of orthogonally protected monosaccharides that are subjected to HCl/HFIP
treatment. The applicability of the HCl/HFIP method is illustrated by the synthesis of
a sulfated β-mannuronic acid disaccharide.
Protecting groups play a pivotal role in synthetic organic chemistry.1 In
oligosaccharide synthesis protecting groups are used to (temporarily) mask hydroxyl
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and amino groups to allow for selective modification of other functionalities on the
carbohydrate ring. Besides blocking specific functionalities that otherwise would
partake in a glycosylation event, the protective group pattern of carbohydrate
building blocks also has a profound effect on the outcome of a glycosylation reaction
in terms of yield and stereoselectivity. Various types of protecting groups are
available to mask carbohydrate hydroxyls, and amongst the most commonly used
groups are the benzyl-type ethers. Besides being robust to a wide variety of reaction
conditions, the sterically minimally intrusive benzyl-type ethers stand out because of
their non-participating nature. Therefore benzyl-type ethers are often the group of
choice to protect the C-2-OH when 1,2-cis linkages are to be installed. Substituted
benzyl ethers, such as the p-methoxybenzyl (PMB) and 2-naphthylmethyl (Nap)
ether are attractive, electron rich benzyl ethers, as they can be removed en route to
the oligosaccharide because using oxidative or acidic cleavage conditions.2 For their
removal, generally strong oxidizing agents, such as ceric ammonium nitrate or 1,2-
dichloro-3,4-dicyano-quinone (DDQ), in combination with biphasic reaction media,
are used. These conditions can be disadvantageous when dealing with sensitive
compounds or solid phase reactions.2 Alternatively, the PMB and Nap groups can be
split off under acidic conditions, using a large molar excess of rather strong Brønsted
or Lewis acids such as TFA3 or HF.pyridine4, the use of which can jeopardize the
integrity of acid labile functionalities in the molecule (acetals, silyl ethers etc.).
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Recently introduced methods to cleave PMB ethers include the use of FeCl3 and
AgSbF6/trimethoxybenzene.6 These methods require relatively long reaction times
and have not been employed to remove the more stable Nap ethers. The invention
of mild, homogeneous and fast reaction conditions to selectively remove PMB or
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Nap ethers will make these groups even more useful in (carbohydrate) synthesis and
open up routine application in both solution and solid phase settings.
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In search of such a reagent we were drawn to the work of Palladino and Stetsenko,
who recently described the use of hydrochloric acid in a fluorinated alcohol, such as
hexafluoro-iso-propanol (HFIP),7 to unmask tert-butyl protected hydroxyl and
carboxylic acid functions in solid phase peptide synthesis.8,9 The reactivity of this
deprotection system arises from the effective hydrogen bonding of the fluorinated
alcohol to the chloride leading to the generation of “naked” protons. In the synthesis
of poly adenoside diphosphate ribosylated (poly-ADPR) peptides we required mild
conditions to transform ribosyl glutamine 1 into building block 2, suitable for solid
phase synthesis (See Scheme 1).
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TIPSO
TIPSO
O
OBn
O
OBn
O
O
O
HCl/HFIP
90%
O
NHFmoc
NHFmoc
N
N
H
OPMB
H
PMBO
HO
OH
1
2
Scheme 1: HCl/HFIP in poly-ADPR synthesis
To this end both PMB ethers at the C2 and C3 positions, installed to allow for the
stereoselective construction of the 1,2-cis ribosyl linkage, had to be removed. We
found that the use of TFA in DCM rapidly cleaved both ethers but also led to
substantial epimerization at the anomeric center. The use of oxidative conditions
(DDQ in DCM/H2O) led to the formation of several side products. In contrast, the use
of a catalytic amount of HCl in HFIP prevented these side reactions and resulted in
the clean removal of the PMB ethers. Encouraged by this profitable outcome we set
out to explore the scope and limitations of the latter cleavage method, the result of
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which we present here. We have found that a catalytic amount of HCl can be
sufficient to cleave both PMB and Nap ethers, while chemoselectivity between these
two ethers can also be attained. We demonstrate the applicability of the use of Nap-
ethers and their HCl/HFIP mediated removal in the synthesis of a sulfated
mannuronic acid disaccharide. The non-participating nature of the Nap-ethers in the
building blocks used in this synthesis is crucial for the stereoselective formation of
the β-mannuronic acid linkage.10
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The first substrate we subjected to a catalytic amount of HCl (0.1 equiv) in DCM/HFIP
was O-glycoside 3, carrying a PMB group at C-4 (Table 1, entry 1). Upon addition of a
preformed HCl/HFIP mixture to a solution of 3 in DCM/HFIP, the reaction mixture
turned dark purple within seconds, indicative for the formation of para-
methoxybenzyl cationic species. Within minutes all substrate had been consumed
and transformed into a single product (4). Besides the formation of the desired
alcohol, TLC analysis showed the formation of a lipophilic side product. LC-MS
analysis of this side product indicated this to be a PMB derived polymer, indicating
that the PMB cations, released during the reaction are not scavenged by HFIP, but in
stead react with another PMB ether in a Friedel-Crafts manner, resulting in the
formation of the polymer.5,11
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entry
substrate
product
yield
BnO
PMBO
BnO
BnO
HO
BnO
O
O
1a
96%
BnO
4BnO
OMe
OMe
7
3
8
9
Cbz
Cbz
O
5N
Bn
O
5N
Bn
O
O
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BnO
BnO
2a
82%
BnO
BnO
OPMB
OH
5
6
AcO
AcO
O
O
AcO
AcO
SPh
SPh
3a
4a
5a
90%
81%
80%
BnO
BnO
OPMB
OH
7
9
8
AcO
AcO
O
O
AcO
AcO
SPh
SPh
PMBO
HO
OBn
OBn
10
12
OPMB
O
OH
O
AcO
AcO
AcO
HO
AcO
PMBO
SPh
SPh
SPh
11
R
R = SPh,
85%
O
O
BnO
6b*
BnO
HO
PMBO
OPiv
R = OH
(n.d.)
OPiv
13
14
SPh
R
R = SPh,
75%
O
O
BnO
BnO
7b*
PMBO
HO
OBn
OBn
R = H, 14%
15
16, 17
OBn
O
OBn
O
AcO
AcO
8b
86%
AcO
AcO
HO
NapO
18
20
21
23
19
12
22
24
STol
STol
OH
O
ONap
O
AcO
AcO
AcO
NapO
9c
67%
80%
48%
AcO
HO
SPh
SPh
OH
O
OPMB
O
AcO
AcO
AcO
NapO
AcO
10a
11d
NapO
SPh
SPh
TBSO
AcO
BnO
TBSO
AcO
BnO
O
O
SPh
SPh
OH
OPMB
OH
O
OPMB
O
R = OTBS,
63%
R
AcO
NapO
TBSO
AcO
NapO
12d
R = OH,
24%
SPh
SPh
25
26
TBDPSO
AcO
TBDPSO
AcO
O
O
SPh
SPh
13d
89%
BnO
BnO
OH
OPMB
27
29
28
30
OH
O
OPMB
O
TBDPSO
AcO
NapO
TBDPSO
AcO
NapO
14d,e
88%
SPh
SPh
Table 1: Deprotection of PMB and Nap ethers with HCl/HFIP. a)
0.1 eq. HCl/HFIP; b) 1.0 eq. HCl/HFIP, 3.0 eq. TES, *=0ºC; c)
2.0 eq. HCl/HFIP, 5.0 eq. TES; d) 0.1 eq. HCl/HFIP, 1.0 eq. TES;
e) 95:5 DCM/TFA 0ºC
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The same conditions (0.1 equiv. HCl DCM/HFIP 1 : 1) also cleanly cleaved the PMB
group from the C2-OH in rhamnoside 5 (entry 2), carrying an aminopentanol spacer.
The anomeric acetal was completely stable under the conditions used. We next
explored various thioglycosides. Glucoside 7, carrying a single PMB group at C2-OH,
was subjected to the deprotection mixture to uneventfully afford alcohol 8. Likewise,
the C3-O-PMB ether was cleanly removed from glucoside 9 to give glucoside 10.
Mannoside 11, carrying two PMB ethers, was deprotected equally efficient leading
to diol 12 in 80% yield (entry 5). When rhamnoside 13 was subjected to the
deprotection conditions (0.1 equiv. HCl DCM/HFIP 1 : 1), a complex mixture resulted.
Notably, the characteristic purple color was absent and the reaction required hours
to reach completion. Besides the desired product 14, anomeric lactol 14b was
formed in this reaction, indicating that alkylation of the anomeric thiofunction by the
PMB cation occurred as a side reaction. Expulsion of the activated aglycon then leads
to hydrolysis of the thioglycoside.12 To circumvent this side reaction, we added
triethylsilane (TES) to the reaction mixture to scavenge the released PMB cations.
Because we initially reasoned that the addition of a scavenger would necessitate the
use of at least an equimolar amount of HCl, we used 1 equivalent of HCl and 3
equivalents of scavenger. These conditions resulted in clean removal of the PMB
group from rhamnoside 13 and the isolation of alcohol 14 in 85% yield (entry 6).
When the same conditions were used to cleave the PMB group from rhamnoside 15
the desired alcohol 16 was obtained in 75% alongside desulfurized compound 17
(entry 7). Here, activation of the thiofunction in 15 or 16 could not be completely
suppressed because of the high reactivity of the rhamnoside, being a 6-deoxy
glycoside featuring solely “arming” benzyl ether protecting groups. Of note, the
anomeric linkage in O-rhamnoside 5/6 (entry 2) is completely stable under the acidic
conditions.
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Since Nap ethers can be removed under acidic conditions, we investigated whether
Nap ethers can also be cleaved using the HCl/HFIP cocktail. We subjected mannoside
18 to the catalytic cleavage conditions described above (0.1 equiv. HCl DCM/HFIP 1 :
1). These conditions proved not forceful enough to cleave the Nap ether and the
reaction progressed very slow and led to a low yield of the desired alcohol. We
therefore raised the amount of acid to an equimolar amount. The addition of triethyl
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silane as a scavenger led to the clean and controllable formation of alcohol 19 (entry
8). Similarly, deprotection of bis-Nap ether 20 proceeded uneventfully to give diol 12
(entry 9). Based on these results we reasoned that the difference in reactivity of the
PMB and Nap ethers towards the HCl/HFIP combination should allow for the
selective removal of a PMB ether in the presence of a Nap ether. The addition of a
catalytic amount of HCl to mannoside 21 proved this hypothesis and the PMB ether
in 21 was selectively cleaved to give alcohol 22 in good yield (entry 10). We next
explored the orthogonality of the PMB ether with respect to commonly used silyl
ethers.1,13 Removal of the PMB ether in 23 and 25 was accompanied by partial
cleavage of tert-butyldimethylsilyl (TBS) groups at the primary hydroxyl function
(entries 11 and 12). Although we were not able to identify conditions that left the
TBS ethers untouched it was found during the optimization of these reactions that a
catalytic amount of HCl could be used in combination with a stoichiometric amount
of scavenger (TES). Besides, the more acid stable tert-butyldiphenylsilyl (TBDPS) was
stable to this catalytic cleavage cocktail and selective deprotection of the PMB ether
in 27 in the presence of a TBDPS ether gave glucosyl alcohol 28 in 89% yield (entry
13). Similarly, the PMB ether in mannoside 29 was selectively deblocked, leaving
both the primary TBDPS ether and the secondary napthyl ether unaffected (entry
14). When mannoside 29 was subjected to 5% trifluoroacetic acid in DCM,1
compound 30 was obtained in 77% yield, where oxidative removal of the C-2-O-PMB
using DDQ,1 resulted in a complex mixture.
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Having established a robust protocol for the removal of PMB and/or Nap ethers, we
moved to explore the reagent system in the context of the assembly of sulfated
oligo-β-mannuronic acids (SOMAs)14. These molecules have been reported to display
a variety of appealing biological activities, including anti-cancer15, anti-HIV,16 anti-
influenza activity.17 To firmly establish the activity of SOMAs and decipher structure-
activity relationships for this class of molecules well-defined fragments with a well-
defined sulfate substitution pattern would be very valuable agents. To site-
specifically introduce sulfate groups temporary protecting groups are required to
mask the hydroxyl precursors. Substituted benzyl ethers, such as the PMB and Nap
ether, represent excellent temporary protecting groups in this regard, because of the
advantages mentioned above: they are sterically minimally intrusive and they do not
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provide neighboring group participation (from either the C-2 or C-3 position) and
building blocks featuring Nap or PMB ethers should perform equally well in
glycosylation reactions as building blocks carrying benzyl ethers. Indeed, when
mannuronic acid building blocks 31 and 32, featuring a single Nap ether at C-2 or two
Nap ethers at C2 and C-3, respectively, were condensed disaccharide 33 was formed
in 72% yield with excellent stereoselectivity. Deprotection of the multiple Nap-ethers
using a 10:1 TFA/toluene mixture,3 resulted in a complex mixture of products due to
incomplete Nap removal.
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ONap
O
ONap
O
MeO2C
LevO
BnO
MeO2C
LevO
BnO
ONap
O
MeO2C
25, TfOH,
-40°C, DCM,
72%
NPh
CF3
O
NapO
O
OMe
33
31
ONap
O
MeO2C
HO
NapO
HCl/HFIP, TIS
DCM/HFIP, 86%
32
OMe
Et3N.SO3,
DMF, 55°C,
100%
OSO3
O
OH
O
MeO2C
MeO2C
OSO3
O
OH
O
MeO2C
MeO2C
LevO
BnO
LevO
BnO
O
O3SO
O
HO
OMe
OMe
35
34
LiOH, H2O2,
THF/H2O, 66%
Pd/C, H2,
H2O, 42%
OSO3
O
OSO3
O
OOC
OOC
OSO3
O
OSO3
O
OOC
OOC
HO
BnO
HO
HO
O
O
O3SO
O3SO
OMe
OMe
36
37
Scheme 2: SOMA synthesis
When this disaccharide was treated with three equivalents of HCl (one for each Nap
group) in DCM/HFIP in the presence of five equivalents of TES, fast and clean
removal of the Nap ethers was observed. However, we also observed that the keto-
function of the levulinoyl ester was partially reduced, leading to a 4-pentenol ester
at the C-4’ and concomitant removal of this group. To circumvent this side reaction
we switched to the use of tri-iso-propyl silane (TIS) as a scavenger, and the use of
this reagent in conjunction with the HCl/HFIP combination led to the uneventful
transformation of disaccharide into triol 34. Under these conditions both, the α- and
β-mannuronic acid linkages, were completely stable. As described above, PMB
ethers can be removed using a catalytic amount of HCl in the presence of an excess
scavenger. We therefore explored the use of 0.5 equivalents of HCl (0.17 equivalents
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per Nap ether) in conjunction with 3.3 equivalents TIS (1.1 equivalent per Nap
ether). Under these conditions, the three Nap ethers were rapidly cleaved to give
dimer 34 in 82% yield. Of note, when we tried to unmask the Nap ethers in 33 using
oxidative conditions (DDQ in DCM/H2O) a complex mixture resulted, in which a 2,3-
naphthylidene side product was formed besides the desired triol. From this reaction
disaccharide 34 was isolated in 47% yield.18 Having triol 34 in hand, we installed the
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o
three sulfate groups using SO3⋅Et3N at elevated temperature (55 C). Ensuing
saponification (LiOH/H2O2) of both the methyl and levulinoyl esters and final
debenzylation then gave the target disaccharide 37.
Conclusion
In summary, a new, fast and homogeneous deprotection method for electron-rich
benzyl type ethers is described employing HCl in HFIP. PMB and Nap ethers can be
removed with a catalytic amount of acid in a selective manner without affecting
other groups. PMB ethers can also be selectively cleaved with respect to Nap ethers
by limiting the amount of HCl. The ease of cleavage of these groups under the
established conditions is a valuable asset for the utility of the PMB and Nap ethers in
synthetic (carbohydrate) chemistry. The mild, fast and homogeneous reactions
conditions should allow for their use in a solid phase reaction setting. Also in
stereoselective glycosylation reactions that are mediated through external
nucleophiles (“moderators”) the use of a protecting group scheme that builds on all-
benzyl ether type protecting groups that can be selectively removed, will be very
valuable.19
Experimental section
General experimental procedures. All chemicals were used as received unless stated
otherwise. 1H and 13C NMR spectra were recorded on a 400/100 MHz, 500/125 MHz,
600/150 MHz or a 850/214 MHz spectrometer. Chemical shifts (δ) are given in ppm
relative to tetramethylsilane as internal standard. Coupling constants are given in Hz.
All individual signals were assigned using 2D-NMR spectroscopy, HH-COSY, HSQC and
HMBC. IR spectra are reported in cm−1. Flash chromatography was performed on
silica gel 60 (0.04 – 0.063 mm). TLC-analysis was followed by detection by UV-
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absorption (254 nm) where applicable and by spraying with 20% sulfuric acid in
ethanol followed by charring at ~150 °C or by spraying with a solution of
(NH4)6Mo7O24·H2O (25 g/l) and (NH4)4Ce(SO4)4·2H2O (10 g/l) in 10% sulfuric acid in
water followed by charring at 50 °C. LC-MS standard eluents used were A: 100% H2O,
B: 100% acetonitrile, C: 1% TFA in H2O. The column used was a C18 column (4.6
mmD × 50 mmL, 3μ particle size). All analyses were 13 min, with a flow-rate of 1
ml/min. High-resolution mass spectra were recorded on a LTQ-Orbitrap equipped
with an electrospray ion source in positive mode (source voltage 3.5 kV, sheath gas
flow 10, capillary temperature 275ºC) with resolution R=60.000 at m/z=400 (mass
range = 150-4000) and dioctylphtalate (m/z=391.28428) as "lock mass". HCl/HFIP
solution were freshly prepared prior to use.
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Methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (4) Compound 321 (0.117 g, 0.200
mmol) was dissolved in 1:1 DCM/HFIP (2 mL) and 0.1 mL 0.2M HCl/HFIP was added.
After 150 seconds the reaction was quenched by addition of sat. aq. NaHCO3. The
mixture was diluted DCM and the organic layer is washed with sat. aq. NaCl, dried
over MgSO4 and concentrated. Purification by column chromatography (Tol/EtOAc)
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gave 4 in 96% yield (0.0891 g, 0.19 mmol). TLC Rf 0.35 (Tol/EtOAc, 9/1, v/v); H-
NMR(CDCl3, 500 MHz): δ 7.39 – 7.20 (m, 15H, CHarom), 4.99 (d, 1H, J=11.5 Hz, CHH
OBn), 4.78 – 4.70 (m, 2H, CHH OBn, CHH OBn), 4.68 – 4.61 (m, 2H, CHH OBn, H-1),
4.55 (q, 2H, J=12.1, 12.1, 12.1 Hz, CH2 OBn), 3.78 (t, 1H, J=9.2, 9.2 Hz, H-3), 3.74 –
3.64 (m, 3H, H-5, H-6), 3.59 (t, 1H, J=9.2, 9.2 Hz, H-4), 3.52 (dd, 1H, J=9.6, 3.5 Hz, H-
2), 3.37 (s, 3H, OMe), 2.37 (s, 1H, 4-OH); 13C-NMR(CDCl3, 126 MHz): δ 138.9, 138.2,
138.1 (Cq), 128.6, 128.5, 128.4, 128.2, 128.0, 128.0, 127.9, 127.7, 127.7 (CHarom), 98.3
(C-1), 81.6 (C-3), 79.7 (C-2), 75.5 (CH2Bn), 73.7 (CH2Bn), 73.2 (CH2Bn), 70.9 (C-4), 70.0
(C-50, 69.6 (C-6), 55.3 (CH3 OMe);
N-benzyl-N-benzyloxycarbonyl-5-aminopentanyl-3,4-di-O-benzyl-2-O-p-
methoxybenzyl-α-L-rhamno-pyranoside
(5)
N-benzyl-N-benzyloxycarbonyl-5-
aminopentanyl-3,4-di-O-benzyl-α-L-rhamno-pyranoside (0.908 g, 1.39 mmol) was
coevaporated twice with anhydrous toluene before being dissolved in DMF (4 mL).
The mixture was cooled to 0°C, after which sodium hydride (60% dispersion in
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mineral oil, 0.08 g, 2.08 mmol) was added. The mixture was stirred for 10 minutes
followed by addition of para-methoxybenzylchloride (0.28 mL, 2.08 mmol). After 115
minutes, the reaction was quenched with sat. aq. NaHCO3, diluted with Et2O and
washed with water. The organic layer was dried over MgSO4 and concentrated.
Purification by column chromatography (Tol/EtOAc) gave 5 in 75% yield (0.802 g,
1.03 mmol). 1H-NMR (CDCl3, 400 MHz): δ 7.30 (m, 22H, CHarom), 7.17 (s, 1H, CHarom),
6.83 (d, 2H, J=8.6 Hz, CHarom), 5.17 (d, 2H, J=9.4 Hz, CH2 Cbz), 4.93 (d, 1H, J=10.8 Hz,
CHH OBn), 4.72 – 4.54 (m, 6H, CHH OBn, CH2 OBn, CH2 OPMB, H-1), 4.48 (s, 2H, CH2
Bn), 3.82 – 3.73 (m, 5H, CH3 OMe, H-2, H-3), 3.66 – 3.50 (m, 3H, H-5, CH2), 3.33 –
3.10 (m, 1H, H-4, CH2), 1.66 – 1.37 (m, 5H, CH2), 1.34 – 1.07 (m, 6H, CH3 H-6, CH2);
13C-NMR (CDCl3, 101 MHz): δ 159.3, 138.8, 138.0, 130.6 (Cq), 129.6, 128.7, 128.6,
128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4, 113.9 (CHarom), 98.1 (C-
1), 80.7 (C-3), 80.4 (C-4), 75.6 (CH2Bn), 74.6 (C-2), 72.5, 72.2 (CH2 PMB/Bn), 68.1 (C-
5), 67.3 (CH2Bn), 55.4 (CH3 OMe), 50.7, 50.3 (CH2), 29.3 (CH2), 23.5 (CH2), 18.2 (CH3 C-
6); HRMS: [M+NH4]+ calculated for C48H59N2O8 791.42659, found 791.42758.
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N-benzyl-N-benzyloxycarbonyl-5-aminopentanyl-3,4-di-O-benzyl-α-L-rhamno-
pyranoside (6) Compound 5 (0.157 g, 0.200 mmol) was dissolved in 1:1 DCM/HFIP (2
mL) and 0.1 mL 0.2M HCl/HFIP was added. After 150 seconds the reaction was
quenched by addition of sat. aq. NaHCO3. The mixture was diluted DCM and the
organic layer is washed with sat. aq. NaCl, dried over MgSO4 and concentrated.
Purification by column chromatography (Tol/EtOAc) gave 6 in 82% yield (0.108 g,
0.165 mmol). TLC Rf 0.15 (Tol/EtOAc, 9/1, v/v); IR (neat, cm-1): 694, 731, 910, 984,
1028, 1051, 1069, 1096, 1227, 1304, 1362, 1421, 1452, 1472, 1497, 1695, 1728,
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2930; H NMR(CDCl3, 500 MHz): δ 7.37 – 7.17 (m, 20H, CHarom), 5.17 (d, 2H, J=11.1
Hz, CH2 Cbz), 4.87 (d, 1H, J=10.9 Hz, CHH OBn), 4.75 (s, 1H, H-1), 4.69 – 4.60 (m, 3H,
CH2 OBn), 4,49 (s, 2H, CH2 OBn), 3.99 (s, 1H, H-2), 3.81 (d, 1H, J=7.0 Hz, H-3), 3.68 (m,
1H, H-5), 3.58 (m, 1H, CH2) 3.44 (t, 1H, J=9.3, 9.3 Hz, H-4), 3.26 – 3.19 (m, 3H, CH2),
2.41 (bs, 1H, 2-OH), 1.53 – 1.47 (m, 4H, 2 x CH2), 1.30 – 1.26 (m, 5H, CH3-6, CH2); 13C-
NMR (CDCl3, 126 MHz): δ 138.5, 138.1, (Cq), 128.6, 128.6, 128.5, 128.5, 128.1,
128.0, 127.9, 127.9, 127.8, 127.4 (CHarom), 99.0 (C-1), 80.3 (C-3), 80.1 (C-4), 75.5
(CH2Bn), 72.1 (CH2), 68.7 (C-2), 67.4 (CH2), 67.4 (C-5), 67.3 (CH2 Cbz), 50.6, 50.3
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(CH2Bn), 47.2, 46.2 (CH2), 29.2 (CH2), 23.5 (CH2), 18.0 (CH3-6). Analytical data are
identical to literature precendence.
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Phenyl
4,6-di-O-acetyl-3-O-benzyl-2-O-p-methoxybenzyl-1-thio-β-D-
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glucopyranoside (7) Phenyl 4,6-O-benzylidene-3-O-benzyl-2-O-p-methoxybenzyl-1-
thio-β-D-glucopyranoside (1.76 g, 3.00 mmol) was dissolved in DCM/MeOH (15 mL/
15 mL) and p-toluenesulfonic acid monohydrate (0.06 g, 0.30 mmol) was added.
When TLC analysis showed complete consumption of the starting material, the
reaction was neutralized with Et3N. The crude was dissolved in pyridine (12 mL),
cooled to 0°C, followed by addition of 1.3 mL Ac2O. The reaction was stirred
overnight after which it was quenched with EtOH and concentrated. The crude
mixture was diluted with EtOAc, washed with 1M HCl, sat. aq. NaCl, dried over
MgSO4 and concentrated. Column purification (hexanes/EtOAc) gave compound 7 in
84% yield (1.428 g, 2.52 mmol). 1H-NMR(CDCl3, 500 MHz): δ 7.57 (dd, 2H, J=7.6, 1.9
Hz, CHarom), 7.36 – 7.19 (m, 10H, CHarom), 6.86 (d, 2H, J=8.6 Hz, CHarom), 5.03 (t, 1H,
J=9.7, 9.7 Hz, H-4), 4.82 (m, 2H, 2x CHH OBn/OPMB), 4.67 – 4.57 (m, 3H, H-1, 2x CHH
OBn/OPMB), 4.20 (dd, 1H, J=12.2, 5.7 Hz, H-6), 4.10 (dd, 1H, J=12.2, 2.2 Hz, H-6),
3.77 (s, 3H, OMe), 3.64 (t, 1H, J=9.1, 9.1 Hz, H-3), 3.60 – 3.49 (m, 2H, H-2, H-5), 2.06
(s, 3H, CH3 Ac), 1.90 (s, 3H, CH3 Ac); 13C NMR(CDCl3, 126 MHz): δ 170.6, 169.6 (C=O
Ac), 159.4, 138.0, 133.2 (Cq), 132.1, 130.0 (CHarom), 129.8 (Cq), 128.9, 128.4, 127.8,
127.7, 113.8 (CHarom), 87.5 (C-1), 83.7 (C-3), 80.2 (C-2), 75.8 (C-5), 75.4, 75.2
(CH2Bn/PMB), 69.6 (C-4), 62.6 (C-6), 55.2 (CH3 OMe), 20.7, 20.7 (CH3 Ac); HRMS:
[M+NH4]+ calculated for C31H38NO8S 584.23126, found 584.23162.
Phenyl 4,6-di-O-acetyl-3-O-benzyl-1-thio-β-D-glucopyranoside (8) Compound 7
(0.134 g, 0.236 mmol) was dissolved in 1:1 DCM/HFIP (2 mL) and 0.12 mL 0.2M
HCl/HFIP was added. After 15 min the reaction was quenched by addition of sat. aq.
NaHCO3. The mixture was diluted DCM and the organic layer is washed with sat. aq.
NaCl, dried over MgSO4 and concentrated. Purification by column chromatography
(Tol/EtOAc) gave 8 in 88% yield (0.093 g, 0.207 mmol). TLC Rf 0.50 (PE/EtOAc, 2/1,
v/v); [α]D20 -6.8 (c 1, DCM); IR (neat, cm-1): 692, 740, 1026, 1220, 1365, 1739, 2885,
2953, 3375; 1H-NMR (CDCl3, 500 MHz): δ 7.58 – 7.52 (m, 3H, CHarom), 7.36 – 7.24 (m,
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13H, CHarom), 4.98 (t, 1H, J=9.8 Hz, H-4), 4.83 (d, 1H, J=11.8 Hz, CHH Bn), 4.69 (d, 1H,
J=11.8 Hz, CHH Bn), 4.51 (d, 1H, J=9.3 Hz, H-1), 4.21 – 4.10 (m, 2H, H-6), 3.62 – 3.51
(m, 3H, H-2, H-3, H-5), 2.65 (s, 1H, 2-OH), 2.07 (s, 3H, CH3 Ac); 13C-NMR (CDCl3, 126
MHz): δ 170.8, 169.7 (C=O Ac), 138.2 (Cq), 133.3 (CHarom), 131.3 (Cq), 129.1, 128.5,
128.5, 127.9, 127.9 (CHarom), 88.1 (C-1), 82.9 (C-3), 76.2 (C-5), 74.8 (CH2Bn), 72.5 (C-
2), 69.5 (C-4), 62.7 (C-6), 29.8, 20.9 (CH3 Ac); HRMS: [M+Na]+ calculated for
C23H26O7SNa 469.12915, found 469.12830.
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Phenyl
4,6-di-O-acetyl-2-O-benzyl-3-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (9) Phenyl 4,6-O-benzylidene-3-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (0.443 g, 0.92 mmol) was coevaporated twice with anhydrous
toluene before being dissolved in DMF (5 mL). The mixture was cooled to 0°C, after
which sodium hydride (60% dispersion in mineral oil, 0.07 g, 1.84 mmol) was added.
The mixture was stirred for 10 minutes followed by addition of benzylbromide (0.21
mL, 1.84 mmol). When TLC analysis showed complete consumption of the starting
material, the reaction was quenched with sat. aq. NaHCO3. The mixture was diluted
with Et2O, washed with sat. aq. NaCl, dried over MgSO4 and concentrated. The crude
was dissolved in DCM/MeOH (15 mL/ 15 mL), followed by addition of p-
toluenesulfonic acid monohydrate until the pH was acidic. The reaction was stirred
for 95 minutes after which it was neutralized with Et3N and concentrated. The diol
was dissolved in 5 mL pyridine, cooled to 0°C and 0.35 mL Ac2O was added. After
overnight stirring, the reaction was quenched with MeOH and concentrated. Column
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purification (Pent/EtOAc) gave compound 9 in 58% yield (0.301 g, 0.53 mmol). H-
NMR(CDCl3, 500 MHz): δ 7.59 – 7.53 (m, 2H, CHarom), 7.43 – 7.20 (m, 8H, CHarom), 7.15
(d, 2H, J=8.6 Hz, CHarom), 6.84 (d, 2H, J=8.6 Hz, CHarom), 5.02 (t, 1H, J=9.7, 9.7 Hz, H-4),
4.87 (d, 1H, J=10.2 Hz, CHH OBn), 4.72 (m, 2H, CH2 OBn/OPMB), 4.65 (d, 1H, J=9.8
Hz, H-1), 4.58 (d, 1H, J=11.0 Hz, CHH OBn/OPMB), 4.21 (dd, 1H, J=12.2, 5.7 Hz, H-6),
4.11 (dd, 1H, J=12.2, 2.1 Hz, H-6), 3.77 (s, 3H, CH3 OMe), 3.65 (t, 1H, J=9.1, 9.1 Hz, H-
3), 3.62 – 3.48 (m, 3H, H-2, H-5), 2.07 (s, 3H, CH3 Ac), 1.95 (s, 3H CH3 Ac); 13C
NMR(CDCl3, 126 MHz): δ 170.7, 169.6 (C=O Ac), 159.3, 137.8, 133.2 (Cq), 132.3
(CHarom), 130.1 (Cq), 129.5, 129.0, 128.5, 128.3, 128.0, 127.9, 113.9 (CHarom), 87.5 (C-
1), 83.4 (C-3), 80.6 (C-2), 76.9 (C-5), 75.6, 75.1 (CH2 OBn/OPMB), 69.8 (C-4), 62.7 (C-
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6), 55.3 (CH3 OMe), 20.9, 20.9 (CH3 Ac); HRMS: [M+NH4]+ calculated for C31H38NO8S
584.23126, found 584.23145.
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Phenyl 4,6-di-O-acetyl-2-O-benzyl-β-D-glucopyranoside (10) Compound 9 (0.107 g,
0.188 mmol) was dissolved in 1:1 DCM/HFIP (2 mL) and 0.1 mL 0.2M HCl/HFIP was
added. After 20 min the reaction was quenched by addition of pyridine and the
mixture was concentrated. Purification by column chromatography (Tol/EtOAc) gave
10 in 81% yield (0.068 g, 0.152 mmol). TLC: Rf 0.38 (PE/EtOAc, 2/1, v/v); [α]D20 -45.6
(c 1, DCM); IR (neat, cm-1): 700, 744, 1028, 1043, 1228, 1371, 1739, 2922, 3477; 1H-
NMR (CDCl3, 500 MHz): δ 7.58 – 7.54 (m, 2H, CHarom), 7.37 – 7.26 (m, 8H, CHarom),
4.95 (d, 1H, J=10.9 Hz, H-1), 4.90 (t, 1H, J=9.7, 9.7 Hz, H-4), 4.71 (d, 1H, J=10.9 Hz,
CHH Bn), 4.64 (d, 1H, J=9.8 Hz, CHH Bn), 4.22 (dd, 1H, J=12.2, 5.7 Hz, H-6), 4.14 (dd,
1H, J=12.2, 2.3 Hz, H-6), 3.73 (t, 1H, J=9.0, 9.0 Hz, H-3), 3.60 (ddd, 1H, J=10.0, 5.7, 2.3
Hz, H-5), 3.43 – 3.39 (t, 1H, J=10 Hz, 8.5 Hz, H-2), 2.68 (s, 1H, 3-OH), 2.08 (s, 3H), 2.07
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(s, 3H) ppm; C-NMR (CDCl3, 125 MHz): δ 170.8, 170.6 (C=O Ac), 137.9 (Cq), 133.3
(Cq), 132.2, 129.1, 128.7, 128.4, 128.3, 127.9 (CHarom), 87.3 (C-1), 80.7 (C-2), 76.5 (C-
3), 75.7 (C-5), 75.5 (CH2Bn), 70.4 (C-4), 62.8 (C-6), 20.9, 20.9 (CH3 Ac); HRMS:
[M+Na]+ calculated for C23H26O7SNa 469.12915, found 469.12861.
Phenyl
4,6-di-O-acetyl-2,3-di-O-p-methoxybenzyl-1-thio-α-D-mannopyranoside
(11) Phenyl 4,6-O-benzylidene-1-thio-α-D-mannopyranoside (1.85 g, 5.13 mmol)
was coevaporated twice with anhydrous toluene before being dissolved in DMF (13
mL). The mixture was cooled to 0°C, after which sodium hydride (60% dispersion in
mineral oil, 0.62 g, 15 mmol) was added. The mixture was stirred for 10 minutes
followed by addition of para-methoxybenzylchloride (2.16 mL, 15 mmol). When TLC
analysis showed complete consumption of the starting material, the reaction was
quenched with sat. aq. NaHCO3. The mixture was diluted with EtOAc, washed with
sat. aq. NaCl, dried over MgSO4 and concentrated. The crude was dissolved in MeOH
(50 mL), followed by addition of p-toluenesulfonic acid monohydrate (0.09 g, 0.45
mmol). The reaction was stirred for 95 minutes after which it was neutralized with
Et3N and concentrated. The compound was purified by column chromatography
(Pent/EtOAc). The diol was dissolved in 20 mL pyridine, cooled to 0°C and 2.17 mL
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Ac2O was added. After overnight stirring, the reaction was quenched with EtOH and
concentrated. Column purification (Pent/EtOAc) gave compound 11 in 64% yield
(1.95 g, 3.26 mmol). 1H NMR(CDCl3, 399 MHz): δ 7.45 – 7.38 (m, 2H, CHarom), 7.33 –
7.17 (m, 7H, CHarom), 6.85 (m, 4H, CHarom), 5.52 (d, 1H, J=1.6 Hz, H-1), 5.39 (t, 1H,
J=9.7, 9.7 Hz, H-4), 4.66 – 4.54 (m, 2H, CH2PMB), 4.51 – 4.36 (m, 2H, CH2PMB), 4.31
(ddd, 1H, J=9.6, 6.1, 2.1 Hz, H-6), 4.23 (dd, 1H, J=12.0, 6.1 Hz, H-5), 4.11 (dd, 1H,
J=12.0, 2.2 Hz, H-6), 3.97 – 3.91 (m, 1H, H-2), 3.83 – 3.68 (m, 7H, 2x CH3 OMe, H-3),
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2.04 (s, 3H, CH3 Ac), 2.01 (s, 3H, CH3 Ac); C-NMR(CDCl3, 100 MHz): δ 170.7, 169.7
(C=O Ac), 159.4, 133.8 (Cq), 131.6 (CHarom), 129.9, 129.8 (Cq), 129.6, 129.3, 129.1,
127.7, 113.9, 113.8 (CHarom), 85.9 (C-1), 76.5 (C-3), 75.2 (C-2), 71.9, 71.5 (CH2PMB),
70.0 (C-5), 68.2 (C-4), 63.0 (C-6), 55.3 (CH3 OMe), 21.0, 20.8 (CH3 Ac); HRMS:
[M+NH4]+ calculated for C32H40NO9S 614.24183, found 614.24212.
Phenyl 4,6-di-O-acetyl-1-thio-α-D-mannopyranoside (12) Compound 11 (0.112 g,
0.188 mmol) was dissolved in 1:1 DCM/HFIP (2 mL) and 0.12 mL 0.2M HCl/HFIP was
added. After 3 min the reaction was quenched by addition of sat. aq. NaHCO3. The
mixture was diluted DCM and the organic layer is washed with sat. aq. NaCl, dried
over MgSO4 and concentrated. Purification by column chromatography (Pent/EtOAc)
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gave 12 in 79% yield (0.053 g, 0.148 mmol). TLC: Rf 0.21 (PE/EtOAc, 1/1, v/v); [α]D
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+169.0 (c 1, DCM); IR (neat, cm-1): 744, 1051, 1232, 1735, 2933, 3300; H-NMR
(CDCl3, 400 MHz): δ 7.57 – 7.39 (m, 2H, CHarom), 7.39 – 7.19 (m, 3H, CHarom), 5.60 (d,
1H, J=1.4 Hz, H-1), 5.11 (t, 1H, J=9.7 Hz, H-4), 4.46 (ddd, 1H, J=10.0, 5.8, 2.2 Hz, H-5),
4.34 (dd, 1H, J=12.1, 5.9 Hz, H-6), 4.23 (dd, 1H, J=3.5, 1.6 Hz, H-2), 4.08 (dd, 1H,
J=12.1, 2.2 Hz, H-6), 3.94 (dd, 1H, J=9.4, 3.4 Hz, H-3), 3.29 (s, 2H, 2-OH, 3-OH), 2.15
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(s, 3H, CH3 Ac), 2.03 (s, 3H, CH3 Ac); C NMR (CDCl3, 100 MHz) δ 171.9, 171.0 (C=O
Ac), 133.3 (Cq SPh), 131.7, 129.2, 127.9 (CHarom), 87.6 (C-1), 72.2 (C-2), 70.8 (C-3),
70.2 C-4), 69.1 (C-5), 62.7 (C-6), 21.1, 20.9 (CH3 Ac); HRMS: [M+Na]+ calculated for
C16H20O7SNa 379.08219, found 379.08213.
Phenyl 4-O-benzyl-2-O-Pivaloyl-1-thio-α-L-rhamnopyranoside (14) Compound 132c
(0.156 g, 0.276 mmol) was dissolved in a 1:1 DCM/HFIP mixture (2.8 mL) and TES
(0.13 mL, 0.84 mmol) was added. The mixture was cooled to 0°C and 1.4 mL of a
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0.2M HCl/HFIP solution was added. After TLC and TLC/MS analysis showed complete
conversion of the starting material in a lower running spot, the reaction was
quenched with sat. aq. NaHCO3 and diluted with DCM. The aqueous layer was
washed with DCM and the combined organic layers were washed with a sat. aq. NaCl
solution, dried over MgSO4 and concentrated. Silica gel column purification afforded
compound 14 in 85% yield (0.102 g, 0.23 mmol). TLC: Rf 0.55 (PE/EtOAc, 9/1, v/v);
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[α]D -123.0 (c 1, DCM); IR (neat, cm-1): 690, 738, 1097, 1151, 1280, 1479, 1730,
2972, 3469; 1H-NMR (CDCl3, 400 MHz): δ 7.50 – 7.42 (m, 2H, CHarom), 7.40 – 7.21 (m,
8H, CHarom), 5.36 (d, 1H, J=1.2 Hz, H-1), 5.33 (dd, 1H, J=3.3, 1.5 Hz, H-2), 4.81 (d, 1H,
J=11.2 Hz, CHH Bn), 4.74 (d, 1H, J=11.2 Hz, CHH Bn), 4.24 (dq, 1H, J=9.5, 6.2, 6.2, 6.2
Hz, H-5), 4.09 (d, 1H, J=10.4 Hz, H-3), 3.38 (t, 1H, J=9.4, 9.4 Hz, H-4), 2.21 (s, 1H, 3-
OH), 1.35 (d, 3H, J=6.2 Hz, CH3-6), 1.23 (s, 9H, CH3-Piv); 13C-NMR (CDCl3, 100 MHz): δ
178.1 (C=O Piv), 138.1 (Cq), 133.9 (Cq), 132.1, 129.2, 128.7, 128.3, 128.2, 127.8
(CHarom), 86.0 (C-1), 81.7 (C-4), 75.2 (CH2 Bn), 74.0 (C-2), 71.1 (C-3), 68.7 (C-5), 39.2
(Cq Piv), 27.2 (CH3 Piv), 18.1 (CH3-6); HRMS: [M+Na]+ calculated for C24H30O5SNa
453.17062, found 453.17055.
Phenyl 2,4-di-O-benzyl-1-thio-α-L-rhamnopyranoside (16) Compound 152c (0.108 g,
0.194 mmol) was dissolved in a 1:1 DCM/HFIP mixture (2 mL) and TES (0.09 mL, 0.58
mmol) was added. The mixture was cooled to 0°C and 0.97 mL of a 0.2M HCl/HFIP
solution was added. After TLC and TLC/MS analysis showed complete conversion of
the starting material in a lower running spot, the reaction was quenched with sat.
aq. NaHCO3 and diluted with DCM. The aqueous layer was washed with DCM and the
combined organic layers were washed with a sat. aq. NaCl solution, dried over
MgSO4 and concentrated. Silica gel column purification afforded compound 16 in
76% yield (0.064 g, 0.147 mmol). TLC: Rf 0.78 (PE/EtOAc, 2/1, v/v); [α]D20 -116.0 (c 1,
DCM); IR (neat, cm-1): 694, 736, 1026, 1066, 1082, 1583, 2873, 3030, 3061; 1H-NMR
(CDCl3, 400 MHz): δ 7.36 – 7.23 (m, 15H, CHarom), 5.56 (s, 1H, H-1), 4.91 (d, 1H, J=11.1
Hz, CHH Bn), 4.74 (d, 1H, J=11.7 Hz, CHH Bn), 4.67 (d, 1H, J=11.1 Hz, CHH Bn), 4.53 (d,
1H, J=11.7 Hz, CHH Bn), 4.16 (dq, 1H, J=9.4, 6.2, 6.2, 6.2 Hz, H-5), 4.00 – 3.95 (m, 2H,
H-2, H-3), 3.40 (t, 1H, J=9.1, 9.1 Hz, H-4), 2.37 (bs, 1H, 3-OH), 1.34 (d, 3H, J=6.2 Hz,
13
CH3-6); C-NMR (CDCl3, 100 MHz): δ 138.5, 137.5, 134.5 (Cq), 131.6, 129.2, 128.7,
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128.6, 128.3, 128.2, 128.1, 127.9, 127.5 (CHarom), 85.1 (C-1), 82.5 (C-4), 80.1 (C-2),
75.3 (CH2Bn), 72.5 (CH2Bn), 72.2 (C-3), 68.7 (C-5), 18.1 (CH3-6); HRMS: [M+Na]+
calculated for C26H28O4SNa 459.16005, found 459.15943.
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Tolyl
4,6-di-O-acetyl-2-O-benzyl-3-O-(2-naphthylmethyl)-1-thio-
α
-D-
mannopyranoside (18) Tolyl 4,6-O-benzylidene-2-O-benzyl-3-O-(2-naphthylmethyl)-
1-thio-α-D-mannopyranoside (1.37 g, 2.28 mmol) was dissolved in DCM/MeOH (3
mL/ 12 mL) and p-toluenesulfonic acid monohydrate (0.043 g, 0.228 mmol) was
added. The reaction was stirred for 5 days after which it was neutralized with Et3N.
The crude was dissolved in pyridine (12 mL), cooled to 0°C, followed by addition of
1.3 mL Ac2O. The reaction was stirred overnight after which it was quenched with
EtOH and concentrated. The crude mixture was diluted with EtOAc, washed with 1M
HCl, sat. aq. NaCl, dried over MgSO4 and concentrated. Column purification
(PE/EtOAc) gave compound 18 in 70% yield (0.969 g, 1.61 mmol). 1H-NMR(CDCl3, 400
MHz): δ 7.87 – 7.79 (m, 3H, CHarom), 7.74 (s, 1H CHarom), 7.53 – 7.48 (m, 1H CHarom),
7.48 – 7.37 (m, 2H CHarom), 7.37 – 7.21 (m, 7H CHarom), 7.12 – 7.05 (m, 2H CHarom),
5.54 – 5.43 (m, 2H, H-1, H-4), 4.84 – 4.51 (m, 4H, CH2 Bn/Nap), 4.39 – 4.30 (m, 1H, H-
5), 4.25 (dd, 1H, J=12.1, 6.0 Hz, H-6), 4.17 – 4.06 (m, 1H, H-6), 4.05 – 3.98 (m, 1H, H-
2), 3.84 (dd, 1H, J=9.6, 2.9 Hz, H-3), 2.32 (s, 3H, CH3 Tol), 2.07 – 2.01 (m, 6H, 2x CH3
13
Ac); C-NMR(CDCl3, 101 MHz): δ 170.8, 169.8 (C=O Ac), 138.0, 137.7, 135.3, 133.3,
133.1 (Cq), 132.2, 129.9 (CHarom), 129.9 (Cq), 128.4, 128.3, 128.0, 127.8, 127.8, 126.5,
126.3, 126.1, 125.7, 118.8 (CHarom), 86.1 (C-1), 77.0 (C-3), 75.5 (C-2), 72.2, 71.8 (CH2
OBn/ONap), 69.9 (C-5), 68.1 (C-4), 63.0 (C-6), 21.2, 21.0, 20.9 (CH3 Tol, Ac); HRMS:
[M+NH4]+ calculated for C35H40NO7S 618.25200, found 618.25193.
Tolyl 4,6-di-O-acetyl-2-O-benzyl-1-thio-α-D-mannopyranoside (19) Compound 18
(0.117 g, 0.195 mmol) was dissolved in 1:1 DCM/HFIP (2 mL) and 0.09 mL TES was
added. The solution was treated with 0.97 mL 0.2M HCl/HFIP. After 33 min the
reaction was quenched by addition of sat. aq. NaHCO3. The mixture was diluted DCM
and the organic layer is washed with sat. aq. NaCl, dried over MgSO4 and
concentrated. Purification by column chromatography (hexanes/EtOAc) gave 19 in
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86% yield (0.077 g, 0.168 mmol). TLC: Rf 0.56 (PE/EtOAc, 2/1, v/v); [α]D20 +61.6 (c 1,
DCM); IR (neat, cm-1): 781, 1051, 1101, 1226, 1739, 2924, 3477; 1H-NMR (CDCl3, 400
MHz): δ 7.39 – 7.27 (m, 6H, CHarom), 7.12 (d, 2H, J=8.0 Hz, CHarom), 5.57 (s, 1H, H-1),
5.14 (t, 1H, J=9.9, 9.9 Hz, H-4), 4.74 (d, 1H, J=11.6 Hz, CHH Bn), 4.53 (d, 1H, J=11.6 Hz,
CHH Bn), 4.42 (ddd, 1H, J=9.9, 5.8, 2.0 Hz, H-5), 4.27 (dd, 1H, J=12.1, 5.9 Hz, H-6),
4.12 (dd, 1H, J=12.1, 2.1 Hz, H-6), 4.01 (dd, 1H, J=3.5, 1.1 Hz, H-2), 3.90 (s, 1H, H-3),
2.39 (s, 1H, 3-OH), 2.33 (s, 3H, CH3 STol), 2.12 (s, 3H, CH3 Ac), 2.05 (s, 3H, CH3 Ac);
13C-NMR(CDCl3, 100 MHz): δ 13C-NMR (CDCl3, 100 MHz): δ 170.8 (C=O Ac), 138.2
(Cq), 137.1 (Cq), 132.5, 130.0 (CHarom), 129.6 (Cq), 128.7, 128.3, 128.1 (CHarom), 85.3
(C-1), 79.3 (C-2), 72.4 (CH2 Bn), 70.3 (C-3), 69.9 (C-4), 69.2 (C-5), 62.9 (C-6), 21.2 (CH3
STol), 21.1, 20.9 (CH3 Ac); HRMS: [M+Na]+ calculated for C24H28O7SNa 483.14480,
found 483.14387.
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Phenyl 4,6-di-O-acetyl-2,3-di-O-(2-naphthylmethyl)-1-thio-α-D-mannopyranoside
(20) 4,6-O-benzylidene-1-thio-α-D-mannopyranoside (1.08 g, 3 mmol) was
coevaporated twice with anhydrous toluene before being dissolved in DMF (15 mL).
The mixture was cooled to 0°C, after which sodium hydride (60% dispersion in
mineral oil, 0.48 g, 12 mmol) was added. The mixture was stirred for 10 minutes
followed by addition of 2-naphthylmethylbromide (2.65 g, 12 mmol). When TLC
analysis showed complete consumption of the starting material, the reaction was
quenched with sat. aq. NaHCO3. The mixture was diluted with EtOAc, the layers were
separated and the aqueous layer was extracted with EtOAc. The combined organic
layers were washed with sat. aq. NaCl, dried over MgSO4 and concentrated. The
crude was dissolved in DCM/MeOH (7.5 mL/ 7.5 mL), followed by addition of p-
toluenesulfonic acid monohydrate (0.057 g, 0.3 mmol). The reaction was stirred for
overnight after which it was neutralized with Et3N and concentrated. The compound
was purified by column chromatography (Pent/EtOAc). The diol was dissolved in 10
mL pyridine, cooled to 0°C and 1.67 mL Ac2O was added. After stirring for 6 days, the
reaction was quenched with EtOH, diluted with EtOAc and washed with 1M HCl.
Column purification (Pent/EtOAc) gave compound 20 in 57% yield (1.09 g, 1.71
mmol). 1H-NMR(CDCl3, 400 MHz): δ 7.84 – 7.61 (m, 8H, CHarom), 7.49 – 7.41 (m, 4H,
CHarom), 7.41 – 7.32 (m, 4H, CHarom), 7.26 – 7.17 (m, 3H, CHarom), 5.59 (d, 1H, J=1.6 Hz,
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H-1), 5.55 (t, 1H, J=9.6, 9.6 Hz, H-4), 4.87 – 4.72 (m, 2H, CH2 ONap), 4.70 – 4.54 (m,
2H, CH2 ONap), 4.39 – 4.24 (m, 2H, H-5, H-6), 4.14 (dd, 1H, J=11.8, 1.8 Hz, H-6), 4.09
13
– 4.01 (m, 1H, H-2), 3.86 (dd, 1H, J=9.6, 3.0 Hz, H-3), 2.02 (m, 6H, 2x CH3 Ac); C-
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NMR(CDCl3, 101 MHz): δ 170.7, 169.7 (C=O Ac), 135.2, 135.1, 133.5, 133.2, 133.1,
133.0, 133.0 (Cq), 131.5, 129.0, 128.2, 128.2, 127.9, 127.9, 127.7, 127.7, 126.8, 126.4,
126.2, 126.1, 126.0, 125.9, 125.6 (CHarom), 85.8 (C-1), 77.0 (C-3), 75.4 (C-2), 72.2, 71.9
(CH2 Nap), 70.0 (C-5), 68.0 (C-4), 62.8 (C-6), 20.9, 20.8 (CH3 Ac); HRMS: [M+NH4]+
calculated for C38H40NO7S 654.25200, found 654.25266.
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Phenyl 4,6-di-O-acetyl-1-thio-β-D-mannopyranoside (12) Compound 20 (0.127 g,
0.199 mmol) was dissolved in 1:1 DCM/HFIP (2.0 mL) and 0.16 mL TES was added.
The mixture was treated with 3.0 mL 0.2M HCl/HFIP was added. After 20 min the
reaction was quenched by addition of sat. aq. NaHCO3. The mixture was diluted DCM
and the organic layer is washed with sat. aq. NaCl, dried over MgSO4 and
concentrated. Purification by column chromatography (Tol/EtOAc) gave 12 in 68%
yield (0.048 g, 0.135 mmol). Spectroscopic data are in full accord with those
reported previously.
Phenyl 4,6-di-O-acetyl-3-O-(2-naphthylmethyl)-2-O-p-methoxybenzyl-1-thio-α-D-
mannopyranoside (21) Phenyl 4,6-O-Benzylidene-3-O-(2-naphthylmethyl)-1-thio- α-
D-mannopyranoside (5.17 g, 10.32 mmol) was coevaporated twice with anhydrous
toluene before being dissolved in DMF (25 mL). The mixture was cooled to 0°C, after
which sodium hydride (60% dispersion in mineral oil, 1.2 g, 30 mmol) was added.
The mixture was stirred for 10 minutes followed by addition of para-
methoxybenzylchloride (4.1 mL, 30 mmol). When TLC analysis showed complete
consumption of the starting material, the reaction was quenched with sat. aq.
NaHCO3. The mixture was diluted with EtOAc, washed with sat. aq. NaCl, dried over
MgSO4 and concentrated. After column purification (Pent/EtOAc) the compound was
dissolved in DCM/MeOH (15 mL/ 15 mL), followed by addition of p-toluenesulfonic
acid monohydrate (0.06 g, 0.30 mmol). The reaction was stirred overnight after
which it was neutralized with Et3N and concentrated. The compound was purified by
column chromatography (Pent/EtOAc) to yield the diol in 89% yield (2.97 g, 5.57
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mmol). The diol (1.425 g, 2.67 mmol) was dissolved in 15 mL pyridine, cooled to 0°C
and 1.5 mL Ac2O was added. After stirring for 3 days, the reaction was quenched
with EtOH and concentrated. The crude was taken up in EtOAc, washed with 1M HCl
and sat. aq. NaCl, dried over MgSO4 and concentrated. Column purification
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(hexanes/EtOAc) gave compound 21 in 75% yield (1.23 g, 1.99 mmol). H-
NMR(CDCl3, 400 MHz): δ 7.83 (m, 3H, CHarom), 7.73 (s, 1H CHarom), 7.48 (m, 1H,
CHarom), 7.47 – 7.36 (m, 4H, CHarom), 7.25 (m, 6H, CHarom), 6.78 (d, 2H, J=8.2 Hz,
CHarom), 5.55 (s, 1H, H-1), 5.47 (t, 1H, J=9.7, 9.7 Hz, H-4), 4.71 – 4.61 (m, 2H, CH2
ONap/OPMB), 4.58 (m, 2H, CH2 ONap/OPMB), 4.37 – 4.21 (m, 2H, H-5, H-6), 4.12 (d,
1H, J=11.7 Hz, H-6), 4.01 (s, 1H, H-2), 3.83 (dd, 1H, J=9.6, 2.9 Hz, H-3), 3.73 (s, 3H, CH3
OMe), 2.06 – 2.00 (m, 6H, 2x CH3 Ac); 13C-NMR(CDCl3, 101 MHz): δ 170.8, 169.8 (C=O
Ac), 159.3, 135.3, 133.7, 133.3, 133.0, 131.5 (Cq), 129.7, 129.1, 128.2, 128.0, 127.8,
127.7, 126.4, 126.3, 126.1, 125.6, 113.8 (CHarom), 85.8 (C-1), 77.0 (C-3), 75.0 (C-2),
71.8, 71.8 (CH2 ONap/OPMB), 70.0 (C-5), 68.1 (C-4), 62.9 (C-6), 55.3 (CH3 OMe), 21.0,
20.8 (CH3 Ac); HRMS: [M+NH4]+ calculated for C35H40NO8S 634.24691, found
634.24718.
Phenyl 4,6-di-O-acetyl-3-O-(2-naphthylmethyl)-1-thio-α-D-mannopyranoside (22)
Compound 21 (0.127 g, 0.202 mmol) was dissolved in 1:1 DCM/HFIP (2 mL) and 0.1
mL 0.2M HCl/HFIP was added. After 5 min the reaction was quenched by addition of
sat. aq. NaHCO3. The mixture was diluted DCM and the organic layer is washed with
sat. aq. NaCl, dried over MgSO4 and concentrated. Purification by column
chromatography (Tol/EtOAc) gave 22 in 80% yield (0.080 g, 0.162 mmol). TLC: Rf 0.35
(PE/EtOAc, 2/1, v/v); [α]D20 +132.4 (c 1, DCM); IR (neat, cm-1): 742, 1041, 1099, 1224,
1
1367, 1739, 2893, 3057, 3460; H-NMR (CDCl3, 500 MHz): δ 7.88 – 7.82 (m, 3H,
CHarom), 7.76 (s, 1H, CHarom), 7.55 – 7.47 (m, 2H, CHarom), 7.50 – 7.37 (m, 3H, CHarom),
7.33 – 7.23 (m, 3H, CHarom), 5.63 (d, 1H, J=1.4 Hz, H-1), 5.35 (t, 1H, J=9.7, 9.7 Hz, H-4),
4.86 (d, 1H, J=12.2 Hz, CHH Bn), 4.72 (d, 1H, J=12.2 Hz, CHH Bn), 4.37 (ddd, 1H, J=9.9,
5.7, 2.2 Hz, H-5), 4.30 (s, 1H, H-2), 4.24 (dd, 1H, J=12.2, 5.8 Hz, H-6), 4.05 (dd, 1H,
J=12.2, 2.3 Hz, H-6), 3.86 (dd, 1H, J=9.3, 3.2 Hz, H-3), 2.85 (s, 1H, 2-OH), 2.01 (s, 6H,
13
2x CH3 Ac); C-NMR (CDCl3, 125 MHz): δ 170.9, 169.9 (C=O Ac), 134.7 (Cq), 133.3
(Cq), 133.3 (Cq), 133.2, 131.7, 129.2, 128.6, 128.1, 127.9, 127.8, 127.0, 126.5, 126.4,
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125.7 (CHarom), 86.9 (C-1), 77.1 (C-3), 72.2 (CH2 Nap), 69.6 (C-5), 69.5 (C-2), 67.6 (C-4),
62.7 (C-6), 21.0, 20.9 (CH3 Ac); HRMS: [M+Na]+ calculated for C27H28O7SNa
519.14480, found 519.14406.
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Phenyl 4-O-acetyl-3-O-Benzyl-2-O-p-methoxybenzyl-6-O-tert-butyldimethylsilyl-1-
thio-β-D-glucopyranoside (23) Phenyl 3-O-Benzyl-2-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (2.41 g, 5 mmol) was coevaporated once with anhydrous toluene.
The diol was dissolved in DMF (25 mL) and cooled to 0°C. Imidazole (0.35 g, 5.2
mmol) was added followed by TBS-Cl (0.78 g, 5.2 mmol). After 100 minutes the
reaction was quenched with MeOH and concentrated. The crude was dissolved in 25
mL pyridine and cooled to 0°C. Ac2O (1.9 mL) was added and the reaction was stirred
for 5 days. The reaction was quenched with EtOH and concentrated. The crude was
taken up in EtOAc, washed with 1M HCl and sat. aq. NaCl, dried over MgSO4 and
concentrated. Column purification (hexanes/EtOAc) gave compound 23 in 77% yield
(2.45 g, 3.83 mmol). 1H-NMR(CDCl3, 400 MHz): δ 7.62 – 7.54 (m, 2H, CHarom), 7.38 –
7.18 (m, 10H, CHarom), 6.90 – 6.82 (m, 2H, CHarom), 4.99 (t, 1H, J=9.7, 9.7 Hz, H-4),
4.86 – 4.73 (m, 2H, CHH OBn/OPMB), 4.69 – 4.56 (m, 3H, H-1, CHH OBn/OPMB), 3.78
(s, 3H, CH3 OMe), 3.73 – 3.59 (m, 3H, H-3, H-6), 3.52 (t, 1H, J=9.6, 9.1 Hz, H-2), 3.44
(ddd, 1H, J=9.9, 4.8, 3.3 Hz, H-5), 1.90 (s, 3H, CH3 Ac), 0.90 (s, 9H, CH3 tBu), 0.89 (s,
3H, CH3 Me), 0.06 (s, 3H, CH3 Me); 13C-NMR(CDCl3, 101 MHz): δ 169.6 (C=O Ac),
159.5, 138.3, 133.9 (Cq), 131.9 131.8 (CHarom), 130.2 (Cq), 130.0, 129.0, 128.5, 127.9,
127.8, 127.5, 113.9 (CHarom), 87.6 (C-1), 84.3 (C-3), 80.3 (C-2), 79.2 (C-5), 75.5, 75.1
(CH2 OBn/OPMB), 70.2 (C-4), 62.9 (C-6), 55.3 (CH3 OMe), 26.0 (CH3 tBu), 20.9 (CH3
Ac), 18.4 (Cq tBu), -5.2, -5.4 (CH3 Me); [M+NH4]+ calculated for C35H50O7SSiN
656.30718, found 656.30769.
Phenyl
4-O-acetyl-3-O-Benzyl-6-O-tert-butyldimethylsilyl-1-thio-β-D-
glucopyranoside (24) Compound 23 (0.130 g, 0.203 mmol) was dissolved in 1:1
DCM/HFIP (2 mL) and 0.033 mL TES was added. The solution was treated with 0.1 mL
of a 0.2M HCl/HFIP solution. After 6 min the reaction was quenched by addition of
sat. aq. NaHCO3. The mixture was diluted DCM and the organic layer is washed with
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chromatography (Tol/EtOAc) gave 24 in 48% yield (0.0738 g, 0.142 mmol). TLC: Rf
20
0.33 (PE/EtOAc, 6/1, v/v); [α]D -22.2 (c 1, DCM); IR (neat, cm-1): 734, 1026, 1228,
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1741, 2856, 2926, 3288; H NMR (CDCl3, 400 MHz): δ 7.61 – 7.51 (m, 2H, CHarom),
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7.37 – 7.20 (m, 8H, CHarom), 4.93 (t, 1H, J=9.8, 9.8 Hz, H-4), 4.82 (d, 1H, J=11.8 Hz,
CHH Bn), 4.68 (d, 1H, J=11.8 Hz, CHH Bn), 4.50 (d, 1H, J=9.3 Hz, H-1), 3.74 – 3.61 (m,
2H, H-6), 3.60 – 3.43 (m, 3H, H-2, H-3, H-5), 2.46 (s, 1H, 2-OH), 1.96 (s, 3H, CH3 Ac),
0.90 (s, 9H, CH3 tBu), 0.07 (s, 3H, CH3 Me), 0.05 (s, 3H, CH3 Me); 13C-NMR (CDCl3, 100
MHz): δ 169.7 (C=O), 138.4 (Cq), 133.0 (CHarom), 131.6 (Cq), 129.1, 128.6, 128.3,
128.0, 127.9 (CHarom), 88.1 (C-1), 83.3 (C-3), 79.6 (C-5), 74.8 (CH2 Bn), 72.4 (C-2), 69.9
(C-4), 63.0 (C-6), 26.0 (CH3 tBu), 21.0 (CH3 Ac), 18.5 (Cq tBu), -5.1, -5.3 (CH3 Me);
HRMS: [M+Na]+ calculated for C27H38O6SSiNa 541.20506, found 541.20484.
Phenyl
4-O-acetyl-3-O-(2-Naphthylmethyl)-2-O-p-methoxybenzyl-6-O-tert-
(25) Phenyl 3-O-(2-
butyldimethylsilyl-1-thio-α-D-mannopyranoside
Naphthylmethyl)-2-O-p-methoxybenzyl-1-thio-α-D-mannopyranoside (0.37 g, 0.7
mmol) was coevaporated once with anhydrous toluene. The diol was dissolved in
DMF (3.5 mL) and cooled to 0°C. Imidazole (0.05 g, 0.7 mmol) was added followed by
TBS-Cl (0.11 g, 0.72 mmol). After 20 minutes the reaction was quenched with MeOH
and concentrated. The crude was taken up in Et2O, washed with H2O and sat. aq.
NaCl, dried over MgSO4 and concentrated. The compound was dissolved in pyridine
(3 mL) and cooled to 0°C, followed by addition of 1 mL Ac2O. The reaction was stirred
overnight after which it was quenched with EtOH. The mixture was concentrated,
taken up in EtOAc, washed with 1M HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried
over MgSO4 and concentrated. Purification by column chromatography gave
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compound 25 in 95% yield (0.457 g, 0.66 mmol). H-NMR(CDCl3, 500 MHz): δ 7.75 –
7.70 (m, 3H, CHarom), 7.66 (s, 1H, CHarom), 7.44 – 7.35 (m, 4H, CHarom), 7.21 – 7.08 (m,
6H, CHarom), 6.69 (d, 2H, J=8.5 Hz, CHarom), 5.43 (s, 1H, H-1), 5.28 (t, 1H, J=9.6, 9.6 Hz,
H-4), 4.60 (d, 1H, J=12.4 Hz, CHH OPMB/OBn), 4.56 – 4.43 (m, 3H, CHH OPMB/OBn,
CH2 OPMB/OBn), 4.10 (bm, 1H, H-5), 3.91 (s, 1H, H-2), 3.76 – 3.67 (m, 2H, H-3, H-6),
3.63 (m, 4H, CH3 OMe, H-6), 1.94 (s, 3H, CH3 Ac), 0.86 – 0.77 (m, 9H, CH3 tBu), -0.05
(s, 6H, 2x CH3 Me); 13C-NMR(CDCl3, 126 MHz): δ 169.9 (C=O Ac), 159.3, 135.5, 134.3,
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133.3, 133.0 (Cq), 131.8 (CHarom), 129.9 (Cq), 129.6, 129.0, 128.2, 128.0, 127.8, 127.5,
126.5, 126.2, 126.0, 125.7, 113.8 (CHarom), 85.9 (C-1), 77.2 (C-3), 75.4 (C-2), 73.3 (C-
5), 71.7, 71.7 (CH2 ONap/OPMB), 68.8 (C-4), 63.3 (C-6), 55.2 (CH3 OMe), 26.0 (CH3
tBu), 21.1 (CH3 Ac), 18.4 (Cq tBu), -5.2, -5.3 (CH3 Me); [M+NH4]+ calculated for
C39H52O7SSiN 706.32283, found 706.32349.
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Phenyl 4-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-(2-Naphthylmethyl)-1-thio-α-D-
mannopyranoside (26) Compound 25 (0.1337 g, 0.194 mmol) was dissolved in 1:1
DCM/HFIP (2 mL) and 0.194 mL TES was added. The solution was treated with 0.095
mL of a 0.2M HCl/HFIP solution. After 3 min the reaction was quenched by addition
of sat. aq. NaHCO3. The mixture was diluted DCM and the organic layer is washed
with sat. aq. NaCl, dried over MgSO4 and concentrated. Purification by column
chromatography (Tol/EtOAc) gave 26 in 61% yield (0.07 g, 0.123 mmol). TLC: Rf 0.48
20
(PE/EtOAc, 7/1, v/v); [α]D +92.0 (c 1, DCM); IR (neat, cm-1): 740, 777, 835, 1051,
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1085, 1228, 1369, 1741, 2854, 2926, 3057, 3640; H-NMR (CDCl3, 500 MHz): 7.83 –
7.77 (m, 3H, CHarom), 7.72 (s, 1H, CHarom), 7.45 – 7.42 (m, 4H, CHarom), 7.38 (dd, 1H,
J=8.5, 1.6 Hz, CHarom), 7.24 – 7.19 (m, 3H, CHarom), 5.53 (d, 1H, J=1.7 Hz, H-1), 5.23 (t,
1H, J=9.5, 9.5 Hz, H-4), 4.81 (d, 1H, J=12.2 Hz, CHH Nap), 4.67 (d, 1H, J=12.2 Hz, CHH
Nap), 4.27 – 4.22 (m, 1H, H-2), 4.18 (ddd, 1H, J=9.3, 6.2, 2.6 Hz, H-5), 3.79 (dd, 1H,
J=9.2, 3.2 Hz, H-3), 3.69 (dd, 1H, J=11.4, 6.2 Hz, H-6), 3.61 (dd, 1H, J=11.4, 2.6 Hz, H-
6), 2.74 (s, 1H, 2-OH), 1.96 (s, 3H, CH3 Ac), 0.82 (s, 9H, CH3 tBu), -0.03 (s, 3H, CH3
Me), -0.04 (s, 3H, CH3 Me); 13C-NMR(CDCl3, 125 MHz): δ 170.0 (C=O Ac), 134.9 (Cq),
133.8 (Cq), 133.3 (Cq), 133.2 (Cq), 131.8, 130.5, 129.1, 129.0, 128.6, 128.1, 128.0,
127.9, 127.6, 126.9, 126.5, 126.3, 125.8 (CHarom), 87.2 (C-1), 77.3 (C-3), 72.8 (C-5),
72.0(CH2 Nap), 69.6 (C-2), 68.3 (C-4), 63.1 (C-6), 26.0 (CH3 tBu), 21.1 (CH3 Ac), 18.5
(Cq tBu), -5.2, -5.3 (CH3 Me); HRMS: [M+Na]+ calculated for C31H40O6SSiNa 591.22071,
found 591.22003.
Phenyl 4-O-acetyl-3-O-Benzyl-2-O-p-methoxybenzyl-6-O-tert-butyldiphenylsilyl-1-
thio-β-D-glucopyranoside (27) Phenyl 3-O-Benzyl-2-O-p-methoxybenzyl-1-thio-β-D-
glucopyranoside (1.23 g, 2.55 mmol) was coevaporated twice with anhydrous
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toluene. The diol was dissolved in DMF (13 mL) and cooled to 0°C. Imidazole (0.17 g,
2.55 mmol) was added followed by TBDPS-Cl (0.69 mL, 2.66 mmol). After 15 minutes
the icebath was removed and the reaction was stirred overnight. The reaction was
quenched with MeOH, concentrated, dissolved in Et2O and washed twice with H2O.
The organic layer was washed with sat. aq. NaCl, dried over MgSO4 and
concentrated. The crude was dissolved in 15 mL pyridine and cooled to 0°C. Ac2O
(1.2 mL) was added and the reaction was stirred until all starting material was
converted in a higher running spot. The reaction was quenched with EtOH and
concentrated. The crude was taken up in EtOAc, washed with 1M HCl and sat. aq.
NaCl, dried over MgSO4 and concentrated. Column purification (hexanes/EtOAc)
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gave compound 27 in 78% yield (1.53 g, 2.00 mmol). H-NMR(CDCl3, 400 MHz): δ
7.75 – 7.64 (m, 5H, CHarom), 7.64 – 7.57 (m, 2H, CHarom), 7.46 – 7.17 (m, 16H, CHarom),
6.92 – 6.83 (m, 2H, CHarom), 5.08 (t, 1H, J=9.6, 9.5 Hz, H-4), 4.80 (m, 2H, CHH
OBn/OPMB), 4.70 – 4.57 (m, 3H, H-1, CHH OBn/OPMB), 3.80 (s, 3H, CH3 OMe), 3.70
(d, 2H, J=3.7 Hz, H-6), 3.65 – 3.50 (m, 2H, H-2, H-3), 3.46 (dt, 1H, J=10.0, 3.7, 3.7 Hz,
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H-5) 1.75 (s, 3H, CH3 Ac), 1.06 (s, 9H, CH3 tBu); C-NMR (CDCl3, 101 MHz): δ 169.5
(C=O Ac), 159.6, 138.3 (Cq), 135.8, 135.8, 134.9 (CHarom), 133.9, 133.3, 133.2 (Cq),
132.0 (CHarom), 130.3 (Cq), 130.1, 129.8, 129.7, 129.1, 128.6, 128.0, 127.9, 127.8,
127.8, 127.6, 114.0 (CHarom), 87.7 (C-1), 84.4 (C-3), 80.5 (C-5), 79.2 (C-2), 75.5, 75.2
(CH2 Bn/PMB), 69.8 (C-4), 63.1 (C-6), 55.4 (CH3 OMe), 26.9 (CH3 tBu), 20.8 (CH3 Ac),
19.3 (Cq tBu); [M+NH4]+ calculated for C45H54O7SSiN 780.33848, found 780.33936.
Phenyl
4-O-acetyl-3-O-Benzyl-6-O-tert-butyldiphenylsilyl-1-thio-β-D-
glucopyranoside (28) Compound 27 (0.0798 g, 0.104 mmol) was dissolved in 1:1
DCM/HFIP (1 mL) and 0.017 mL TES was added. The solution was treated with 0.05
mL of a 0.2M HCl/HFIP solution. After 18 min the reaction was quenched by addition
of sat. aq. NaHCO3. The mixture was diluted DCM and the organic layer is washed
with sat. aq. NaCl, dried over MgSO4 and concentrated. Purification by column
chromatography (Tol/EtOAc) gave 28 in 90% yield (0.06 g, 0.093 mmol). TLC: Rf 0.37
(PE/EtOAc, 6/1, v/v); [α]D20 -17.2 (c 1, DCM); IR (neat, cm-1): 740, 1028, 1112, 1228,
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1747, 2929, 2954, 3028, 3496; H-NMR (CDCl3, 500 MHz): δ 7.73 – 7.65 (m, 4H,
CHarom), 7.62 – 7.56 (m, 2H, CHarom), 7.44 – 7.20 (m, 15H, CHarom), 5.03 (t, 1H, J=9.5,
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9.5 Hz, H-4), 4.81 (d, 1H, J=11.8 Hz, CHH Bn), 4.67 (d, 1H, J=11.8 Hz, CHH Bn), 4.52 (d,
1H, J=9.2 Hz, H-1), 3.73 – 3.68 (m, 2H, H-6), 3.59 – 3.47 (m, 3H, H-2, H-3, H-5), 2.47
(d, 1H, J=1.4 Hz, 2-OH), 1.81 (CH3 Ac) 1.05 (s, 9H, CH3 tBu); 13C-NMR (CDCl3, 125
MHz): δ 169.5 (C=O Ac), 138.3 (Cq), 135.8, 135.8, 134.9 (CHarom), 133.3 (Cq), 133.2
(CHarom), 133.0 (Cq), 131.7, 129.8, 129.8, 129.2, 128.6, 128.3, 128.0, 127.9, 127.8,
127.8, 127.8 (CHarom), 88.2 (C-1), 83.3 (C-3), 79.5 (C-5), 74.7 (CH2 Bn), 72.5 (C-2), 69.4
(C-4), 63.0 (C-6), 26.8 (CH3 tBu), 20.9 (CH3 Ac), 19.3 (Cq tBu); HRMS: [M+Na]+
calculated for C37H42O6SSiNa 665.23636, found 665.23572.
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Phenyl
4-O-acetyl-3-O-(2-Naphthylmethyl)-2-O-p-methoxybenzyl-6-O-tert-
butyldiphenylsilyl-1-thio-α-D-mannopyranoside (29) Compound 21 (0.416 g, 0.6
mmol) was dissolved in MeOH and a catalytic amount of NaOMe was added. After
consumption of the starting material in a lower running spot the mixture was
neutralized with Amberlite-H+ resin, filtered and concentrated. The diol was
coevaporated once with anhydrous toluene, dissolved in DMF (5 mL) and cooled to
0°C. Imidazole (0.04 g, 0.6 mmol) was added followed by TBDPS-Cl (0.16 mL, 0.62
mmol). After overnight stirring the reaction was quenched with MeOH and
concentrated. The compound was dissolved in pyridine (4 mL) and cooled to 0°C,
followed by addition of 2 mL Ac2O. The reaction was stirred overnight after which it
was quenched with EtOH. The mixture was concentrated, taken up in Et2O, washed
with 1M HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried over MgSO4 and concentrated.
Purification by column chromatography gave compound 25 in 50% yield (0.25 g, 0.30
1
mmol). H NMR (CDCl3, 400 MHz): δ 7.86 – 7.77 (m, 3H, CHarom), 7.74 (s, 1H, CHarom),
7.66 (m, 4H, CHarom), 7.52 – 7.16 (m, 17H, CHarom), 6.80 – 6.73 (m, 2H, CHarom), 5.57
(d, 1H, J=1.8 Hz, H-1), 5.44 (t, 1H, J=9.7, 9.7 Hz, H-4), 4.73 – 4.53 (m, 4H, 2x CH2
ONap/OPMB), 4.29 – 4.20 (m, 1H, H-5), 4.05 – 3.99 (m, 1H, H-2), 3.85 (dd, 1H, J=11.4,
6.2 Hz, H-6), 3.79 (dd, 1H, J=9.4, 3.0 Hz, H-3), 3.75 – 3.64 (m, 4H, CH3 OMe, H-6), 1.86
(s, 3H, CH3 Ac), 1.03 (s, 9H, CH3 tBu); 13C-NMR(CDCl3, 101 MHz): δ 169.7 (C=O), 159.3
(Cq), 135.8, 135.7 (CHarom), 135.5, 134.7, 133.5, 133.4, 133.3, 133.1 (Cq), 131.3
(CHarom), 129.9 (Cq), 129.7, 129.6, 129.6, 129.1, 128.2, 128.0, 127.8, 127.7, 127.6,
127.4, 126.5, 126.2, 126.0, 125.8, 113.8 (CHarom), 86.0 (C-1), 77.2 (C-3), 75.4 (C-2),
73.3 (C-5), 71.8, 71.6 (CH2 ONap/OPMB), 68.3 (C-4), 63.5 (C-6), 55.3 (CH3 OMe), 26.8
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(CH3 tBu), 21.0 (CH3 Ac), 19.3 (Cq tBu); [M+NH4]+ calculated for C49H56O7SSiN
830.35413, found 830.35472.
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Phenyl 4-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-(2-Naphthylmethyl)-1-thio-α-D-
mannopyranoside (30) Compound 29 (0.0825 g, 0.101 mmol) was dissolved in 1:1
DCM/HFIP (1 mL) and 0.1 mL 0.2M HCl/HFIP was added. After 18 min the reaction
was quenched by addition of sat. aq. NaHCO3. The mixture was diluted DCM and the
organic layer is washed with sat. aq. NaCl, dried over MgSO4 and concentrated.
Purification by column chromatography (Tol/EtOAc) gave 30 in 88% yield (0.0614 g,
0.0886 mmol). TLC: Rf 0.23 (PE/EtOAc, 6/1, v/v); [α]D20 +71.8 (c 1, DCM); IR (neat, cm-
1
1): 740, 821, 1053, 1083, 1228, 1743, 2854, 2927, 3051, 3448; H-NMR (CDCl3, 500
MHz): δ 7.84 (d, 3H, J=7.8 Hz), 7.76 (s, 1H), 7.67 – 7.61 (m, 4H), 7.54 – 7.46 (m, 4H),
7.45 – 7.27 (m, 7H), 7.27 – 7.19 (m, 4H), 5.62 (d, 1H, J=1.6 Hz, H-1), 5.34 (t, 1H, J=9.5,
9.5 Hz, H-4), 4.85 (d, 1H, J=12.2 Hz, CHH Nap), 4.71 (d, 1H, J=12.2 Hz, CHH Nap), 4.31
(s, 1H, H-2), 4.29 – 4.23 (m, 1H, H-5), 3.84 – 3.75 (m, 2H, H-3, H-6), 3.64 (dd, 1H,
J=11.5, 2.1 Hz, H-6), 2.74 (s, 1H, 2-OH), 1.85 (s, 3H, CH3 Ac), 1.01 (s, 9H, CH3 tBu); 13C-
NMR (CDCl3, 125 MHz): δ 169.8 (C=O Ac), 135.9, 135.7, 134.8 (Cq), 134.1 (Cq), 133.5
(Cq), 133.3 (Cq), 133.3 (Cq), 133.3 (Cq), 131.4, 129.7, 129.7, 129.2, 128.6, 128.1, 127.9,
127.8, 127.7, 127.5, 127.0, 126.5, 126.3, 125.8 (CHarom), 87.2 (C-1), 77.3 (C-3), 72.8
(C-5), 71.9 (CH2 Nap), 69.7 (C-2), 67.8 (C-4), 63.3 (C-6), 26.8 (CH3 tBu), 21.0 (CH3 Ac),
19.3 (Cq tBu); HRMS: [M+Na]+ calculated for HRMS: [M+Na]+ calculated for
C41H44O6SSiNa 715.25201, found 715.25149.
Methyl
(3-O-benzyl-4-O-levulinoyl-2-O-(2-naphthylmethyl)-1-O-(N-
[phenyl]trifluoroacetimidoyl)-α/β-ᴅ-mannopyranosyl uronate) (31) Dibutyltinoxide
(5.98 g, 24 mmol, 1.2 eq.) was added to a solution of methyl 4,6-O-benzylidene-α-ᴅ-
mannopyranoside18 (5.65 g, 20 mmol) in toluene (100 mL) and refluxed overnight
under an argon atmosphere. The solution was concentrated to dryness in vacuo and
DMF (100 mL) was added under argon. Benzyl bromide (2.6 mL, 22 mmol, 1.1 eq.)
and CsF (3.65 g, 24 mmol, 1.2 eq.) were added to the reaction mixture. After stirring
overnight the reaction mixture was quenched with H2O and extracted first with Et2O
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and then EtOAc, dried over MgSO4, filtered and concentrated in vacuo. Purification
by column chromatography (PE/EtOAc, 5:1 to 1:2) yielded the title compound as a
yellow oil (6.7 g, 18 mmol, 89%). TLC: Rf 0.59 (PE/EtOAc, 1/1, v/v); Methyl 3-O-
benzyl-4,6-O-benzylidene-α-ᴅ-mannopyranoside (6.48 g, 17.4 mmol) was dissolved
in DMF (90 mL) and cooled to 0°C. 2-(Bromomethyl)naphthalene (4.62 g, 20.9 mmol,
1.2 eq.) and sodiumhydride (60% dispersion in oil, 867 mg, 20.9 mmol, 1.2 eq.) were
added and the solution left to stir for 3.5 hours. The reaction mixture was quenched
by dropwise addition of H2O and subsequently extracted with EtOAc. The organic
layer was washed with sat. aq. NaCl and dried with MgSO4. After filtration and
concentration in vacuo, the crude compound was purified by column
chromatography (PE/EtOAc, 9:1 to 4:1) to yield the title compound as a yellow oil
(8.41 g, 16.4 mmol, 94%). TLC: Rf 0.62 (PE/EtOAc, 4/1, v/v); To a solution of the
compound (7.3 g, 14.2 mmol) in acetic anhydride (70 mL), pTsOH•H2O (4.0 g, 21.0
mmol, 1.5 eq.) was added. The reaction mixture was allowed to stir for four days at
room temperature until TLC analysis showed substantial conversion to the desired
product. The reaction mixture was quenched by pouring it over ice and gradually
adding solid NaHCO3 until all ice had melted and CO2 evolution had stopped. The
aqueous mixture was extracted two times with EtOAc and the combined organic
layers where washed once with sat. aq. NaCl. The organic fraction was dried over
MgSO4, filtered and concentrated in vacuo, after which the residue was co-
evaporated once with toluene. Column chromatography purification (PE/EtOAc, 6:1
to 2:1) afforded the title compound as an orange oil (5.06 g, 9.44 mmol, 66%, α >> β
). TLC: Rf 0.36 (PE/EtOAc, 2/1, v/v); Methyl 4,6-di-O-acetyl-3-O-benzyl-2-O-(2-
naphthylmethyl)-α-ᴅ-mannopyranoside (5.06 g, 9.44 mmol) was dissolved in 4%
piperidine (1.85 mL, 18.9 mmol, 2 eq.) in THF (47 mL). After stirring for 3 days at
room temperature H2O was added and the mixture was extracted with EtOAc. The
organic layer was washed once with sat. aq. NaCl and subsequently dried over
MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography
(PE/EtOAc, 9:1 to 1:1) gave the hemiacetal as an yellow oil (4.1 g, 8.3 mmol, 88%, α :
β = 4.3 : 1). TLC: Rf 0.58 (PE/EtOAc, 1/1, v/v); TBDMSCl (1.5 g, 10 mmol, 2 eq.) and
imidazole (0.68 g, 10 mmol, 2eq.) were added to a solution of the hemiacetal (2.45 g,
4.95 mmol) in dry DCM (25 mL) under an argon atmosphere. After stirring for 6.5
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Page 28 of 37
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hours the reaction was quenched with H2O and extracted twice with EtOAc.
Combined organic layers were washed with sat. aq. NaCl, dried over MgSO4, filtered
and concentrated in vacuo. Purification by column chromatography (PE/EtOAc, 15:1
to 2:1) yielded the silylether as an yellowish oil (2.59 g, 4.25 mmol, 86%, α : β = 1 :
4.5). TLC: Rf 0.49 (PE/EtOAc, 4/1, v/v); To a solution of the anomeric silylether (907
mg, 1.49 mmol) in MeOH (8 ml) a catalytic amount of NaOMe (8 mg, 0.15 mmol, 0.1
eq.) was added. After stirring overnight, the reaction mixture was neutralized with
Amberlite H+ which was subsequently filtered off. The filtrate was concentrated in
vacuo and tert-butyldimethylsilyl 3-O-benzyl-2-O-(2-naphthylmethyl)-α/β-ᴅ-
mannopyranoside was obtained as a colourless oil (770 mg, 1.47 mmol, 98%, α : β =
1 : 4.2). TLC: Rf 0.48 (PE/EtOAc, 1/1, v/v); Diol (3.7 g, 7.05 mmol) was dissolved in
EtOAc (25 mL) and H2O (10 mL) was added. To the biphasic system TEMPO (220 mg,
1.41 mmol, 0.2 eq.) and BAIB (5.68 g, 17.6 mmol, 2.5 eq.) were added. After stirring
vigorously for 4.5 hours at room temperature, the reaction was quenched by
addition of sat. aq. Na2S2O3. EtOAc (50 mL) was added and the layers separated. The
organic layer was dried with MgSO4, filtered and concentrated in vacuo. The residue
was co-evaporated with toluene once. The crude mannuronic acid was then
dissolved in DMF (22 mL) and put under an argon atmosphere at 0°C. Methyl iodide
(1.3 mL, 21.15 mmol, 3.0 eq.) and K2CO3 (2.92 g, 21.15 mmol, 3.0 eq.) were added
and the reaction was stirred overnight. The reaction was quenched with H2O and
extracted twice with EtOAc. The organic layers were collected and dried with MgSO4,
filtered and concentrated in vacuo. Purification by column chromatography
(PE/EtOAc, 10:1 to 2:1) afforded the mannuronic acid as a yellow solid (3.11 g, 5.63
mmol, 80%, α : β = 1 : 8.3). TLC: Rf 0.29 (PE/EtOAc, 4/1, v/v); Levulinic acid (1.08 g,
9.32 mmol, 2.8 eq.) and DIC (0.73 mL, 4.66 mmol, 1.4 eq.) were added to a 0°C
solution of methyl (tert-butyldimethylsilyl 3-O-benzyl-2-O-(2-naphthylmethyl)-α/β-
ᴅ-mannopyranosyl uronate) (1.84 g, 3.33 mmol) in dry DCM (8.5 mL). A catalytic
amount of DMAP (40 mg, 0.3 mmol, 0.1 eq.) was added and the reaction mixture
was allowed to reach room temperature. After 3 hours the reaction mixture was
filtered over Celite and the filtrate washed with sat. aq. NaHCO3 and sat. aq. NaCl.
The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Column
chromatography (PE/EtOAc, 6:1 to 2:1) afforded the compound as an amorphous
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The Journal of Organic Chemistry
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off-white solid (2.07 g, 3.18 mmol 95%, α : β = 1 : 10). TLC: Rf 0.45 (PE/EtOAc, 2/1,
v/v); Acetic acid (0.36 mL, 6.36 mmol, 2 eq.) was added to a 0°C solution of
compound Methyl (tert-butyldimethylsilyl 3-O-benzyl-4-O-levulinoyl-2-O-(2-
naphthylmethyl)-α/β-ᴅ- mannopyranosyl uronate) (2.07 g, 3.18 mmol) in dry THF
(30 mL). TBAF (1.0 M solution in THF, 4.8 mL, 4.8 mmol, 1.5 eq.) was added drop
wise over 5 minutes. The reaction mixture was stirred for 2.5 hours at room
temperature and subsequently diluted with EtOAc and washed once with H2O and
sat. aq. NaCl. The organic layer was dried over MgSO4, filtered and concentrated in
vacuo. Purification by column chromatography (Pentane/DCM/EtOAc, 4:1:1 to 1:1:2)
furnished the hemiacetal as a colourless oil (1.7 g, 3.17 mmol, 99%, α : β = 8.3 : 1).
TLC: Rf 0.18 (PE/EtOAc, 1/1, v/v); Trifluoro-N-phenylacetimidoyl chloride (0.82 mL,
5.4 mmol, 1.1 eq.) was added drop wise to a 0°C solution of the hemiacetal (2.6 g,
4.8 mmol) and Cs2CO3 (1.9 g, 5.86 mmol 1.2 eq.) in acetone (16 mL). After stirring
overnight at ambient temperature TLC analysis showed complete conversion of the
starting compound to a higher running spot. H2O was added and the mixture was
extracted two times with EtOAc. The organic fraction was washed with sat. aq. NaCl,
dried over MgSO4, filtered, and concentrated in vacuo. The crude compound was
purified using column chromatography (PE/EtOAc, 8:1 to 1:1) to yield the title
compound as a yellow oil (3.39 g, 4.79 mmol, 98%, α : β = 8.3 : 1). TLC: Rf 0.69 α, 0.63
β (PE/EtOAc, 1/1, v/v); IR (neat, cm-1): 1123, 1153, 1207, 1717, 1748; 1H-NMR (CDCl3,
400 MHz): δ 7.71-7.81 (m, 2.24H, CHarom), 7.44-7.50 (m, 3.36H, CHarom), 7.21-7.30 (m,
10.20H, CHarom), 7.11 (t, 1H, J = 7.6 Hz, CHarom NPh), 6.67-6.71 (m, 2.24H, CHarom
NPh), 6.47 (bs, 1H, H-1 α), 6.04 (bs, 0.12H, H-1 β), 5.74 (t, 0.12H, J = 6.4Hz, H-4 β),
5.61 (t, 1H, J = 7.6Hz, H-4 α), 4.97 (s, 0.24H, CH2 Bn/Nap β), 4.86 (d, 1H, J = 12.0 Hz,
CHH Bn/Nap α), 4.80 (d, 1H, J = 12.0 Hz, CHH Bn/Nap α), 4.68 (d, 0.12H, J = 12.4 Hz,
CHH Bn/Nap β), 4.60-4.63 (m, 1.12H, CHH Bn/Nap α, CHH Bn/Nap β), 4.55 (d, 1H, J =
12.0 Hz, CHH Bn/Nap α), 4.40 (d, 1H, J = 7.2 Hz, H-5 α), 4.14 (bs, 0.12H, H-5 β), 4.07
(bs, 0.12H, H-2 β), 3.89 (dd, 1H, J = 3.2, 7.6 Hz, H-3 α), 3.80-3.82 (m, 1.12H, H-2 α, H-
3 β), 3.69 (s, 3H, CH3 CO2Me α), 3.64 (s, 0.36H, CH3 CO2Me β), 2.69 (t, 2.24H, J = 6.4
Hz, CH2 Lev α,β), 2.46-2.62 (m, 2.24H, CH2 Lev α,β), 2.17 (s, 3H, CH3 Lev α), 2.16 (s,
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0.36H, CH3 Lev β); C-NMR (CDCl3, 100MHz): δ 206.2 (C=O Lev), 171.6, 168.0 (C=O
Lev, CO2Me), 143.2, 142.5, 142.2, 141.8, 137.9, 137.5, 135.2, 134.9, 133.2 (Cq), 128.8,
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