Synthesis of Sialyl LewisX Glycomimetics Bearing a Bicyclic 3- O,4- C-Fused Galactopyranoside Scaffold

Article abstract of DOI:10.1021/acs.joc.9b01075

Reported herein is the synthesis of sialyl Lewis^X analogues bearing a trans-bicyclo[4.4.0] dioxadecane-modified 3-O,4-C-fused galactopyranoside scaffold that locks the carboxylate pharmacophore in either the axial or equatorial position. This novel series of bicyclic galactopyranosides are prepared through a stereocontrolled intramolecular cyclization reaction that has been evaluated both experimentally and by density functional theory calculations. The cyclization precursors are obtained from β-d-galactose pentaacetate in a nine-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu(I) catalyzed formation of the acetylenic α-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin antagonists for the axially configured analogues as compared to their equatorial counterparts.

Full text of DOI:10.1021/acs.joc.9b01075

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Article
Synthesis of Sialyl LewisX Glycomimetics Bearing a
Bicyclic 3-O, 4-C-Fused Galactopyranoside Scaffold
Ryan Daniel Simard, Mathieu Joyal, Laura Gillard, Gianna Di Censo, Wael Maharsy, Janie
Beauregard, Pina Colarusso, Kamala D. Patel, Michel Prévost, Mona Nemer, and Yvan Guindon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01075 • Publication Date (Web): 15 May 2019
Downloaded from http://pubs.acs.org on May 15, 2019
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Page 1 of 20
The Journal of Organic Chemistry
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Synthesis of Sialyl LewisX Glycomimetics Bearing a Bicyclic 3-O, 4-C-
Fused Galactopyranoside Scaffold
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Ryan D. Simard†,‡, Mathieu Joyal§, Laura Gillard†, Gianna Di Censo†, Wael Maharsy§, Janie
Beauregard§, Pina Colarusso∥, Kamala D. Patel∥*, Michel Prévost†*, Mona Nemer§*, and Yvan
Guindon†,‡,§*
†Bio-organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7,
Canada
‡Department of Chemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada
§Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
∥Live Cell Imaging Laboratory, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1,
Canada
ABSTRACT: Reported herein is the synthesis of sialyl LewisX analogues bearing a trans-bicyclo[4.4.0] dioxadecane modified
3-O, 4-C-fused galactopyranoside scaffold that locks the carboxylate pharmacophore in either the axial or equatorial position.
This novel series of bicyclic galactopyranosides are prepared through a stereocontrolled intramolecular cyclization reaction
that has been evaluated both experimentally and by DFT calculations. The cyclization precursors are obtained from β-D-
galactose pentaacetate in a 9-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu(I) catalyzed
formation of the acetylenic α-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin
antagonists for the axially configured analogues as compared to their equatorial counterparts.
INTRODUCTION
HO
a) Sialyl LewisX (sLeX)
OH
Fuc
The design of small-molecule antagonists requires a fine
balance between plasticity and pre-organization to mimic
the bioactive conformation of endogenous ligands. This
strategy is particularly effective with complex carbohydrate
ligands to minimize entropic penalties upon receptor
binding.1 Analogues of sialyl LewisX (sLeX) interfere with the
recruitment of immune cells along the endothelial
vasculature at sites of inflammation.2-4 These antagonists
compete with the binding of the sLeX tetrasaccharide
(Figure 1a), present at the surface of leukocytes on
glycoprotein ligands ESL-1 and PSGL-1, to the selectins (E
and P).5-6 Interfering with these adhesion events offers
novel approaches to control the excessive influx of immune
cells characteristic of several inflammatory diseases.7
Moreover, metastatic cancers that take advantage of this
extravasation mechanism could be prevented from
adhering and translocating to distal sites.8 GMI-1070
(Figure 1b), an E-selectin antagonist, is currently in Phase
III evaluation for treatment of vascular occlusions in
patients with sickle cell disease.9
OH
Me
HO
O
OH
O
OH
NHAc
HO
AcHN
O
OH
O
O
O
O
HO
OH
CO2H
OH
OH
NeuAc
Gal
GlcNAc
O
b) Rivipansel (GMI-1070)
NH
HO
OH
O
O
OH
Me
O
N
O
O
O
O
H
HO OH
O
NH
NH
O
O
NH
NaO3S
SO3Na
SO3Na
O
O
HN
OBz
CO2Na
c) Guindon et al. 2012
d) This work:
HO
HO
OH
OH
OH
OH
Me
HO
O
Me
O
O
O
O
O
O
O
O
OiPr
OiPr
OR2
O
BzO
OiPr
OiPr
OH
Ph
O
Y
O
O
O
OR1
OBz
X
H
CO2H
The bound conformations of sLeX to E- and P-selectin are
well defined by molecular modeling and NMR methods.10-14
A significant chemical modification in sLeX glycomimetics is
the replacement of the GlcNAc moiety with a functionalized
cyclohexyl (Figure 1b) or tartrate diester tether (Figure
1c).4, 15
Y = H, X = CO2H Y = CO2H, X = H
1:
2:
3:
4:
R1 = Bz; R2 = H
R1 = R2 = Bz
R1 = Bz; R2 = H
R1 = R2 = Bz
Figure 1. Sialyl LewisX and glycomimetics thereof
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In both cases, the fucose and galactose saccharides are planned Grignard addition to ketone
Page 2 of 20
resulted
8
1
2
3
4
5
6
7
8
forced to adopt a gauche relationship that favorably orients
their pharmacophoric hydroxyls in the receptor.16 The
conformational bias of the tartrate esters has been
suggested to originate from stereoelectronic effects (gauche
effect and dipole-dipole minimization).17
predominantly in elimination of the C2-O-benzoate, while
the C3-O-alkylation of diol 9 was difficult, likely due to the
sterically hindered quaternary center at C4.
We developed a strategy capitalizing on the installation of
an alkyne at C4 (11) from protected galactoside 12. This
alkyne could then be extended to an acetylenic keto-ester
through a Cu(I) catalyzed addition of benzyl chlorooxalate.
Diastereoselective reduction of the ketone moiety would
lead to the two C9 diastereoisomers. After alkyne reduction
and subsequent mesylation (10), intramolecular cyclization
could then afford the bicyclic intermediate 6 with axial or
equatorial ester orientations. This approach unveiled an
intriguing stereocontrolled cyclization giving rise to the
axial isomer from both mesylate diastereomers. The origin
of selectivity for this reaction, which is proposed to follow
Curtin-Hammett kinetics, was studied experimentally and
computationally.
Several reports have also highlighted the importance of
orienting the carboxylate of the NeuAc moiety, which is
central to this study.18-19 Analogues exploiting the pre-
organization of the carboxylic acid fragment may benefit
from enhanced binding. A gain in affinity was demonstrated
when the sialic acid was simplified with derivatives of lactic
acid bearing a cyclohexyl or benzyl substituent.13 Structure
overlap of bound sLeX with bicyclic galactopyranoside
scaffolds suggested that an axially configured carboxylate
could mimic the bound orientation. In contrast, equatorially
configured glycomimetics were expected to bind less
favorably to the receptor.20 Formation of a bicyclic system
would lock the carboxylic acid moiety in either an axial (1
and 2, Figure 1d) or equatorial (3 and 4, Figure 1d)
configuration allowing this significance to be determined.
The preparation of these bicyclic compounds in a
stereospecific manner represented a major synthetic
challenge. Careful consideration of the ring junctions to
preserve the pharmacophoric hydroxyl at C4 of galactose
necessitated a 3-O, 4-C-fusion to be envisioned.
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RESULTS AND DISCUSSION
The reaction sequence to generate the targeted bicyclic
scaffolds began with construction of the quaternary center
at C4 (Scheme 2). The C6-O-TDBPS protected intermediate
12 was first prepared from known thiogalactoside 1330
through benzylidene removal followed by silylation of the
primary alcohol. Albright-Goldman oxidation with acetic
anhydride and DMSO, and subsequent treatment with
ethynyl magnesium bromide led to an unsatisfactory 3:2
ratio of C4 diastereomers 11a,b. Gratifyingly, treatment
with lithium TMS-acetylide provided the equatorial alkyne
15 in a diastereomeric ratio of 20:1 with a 93% isolated
yield. The equatorial selectivity was confirmed by NOE
correlations of E-olefin 16, which was formed through a
Red-Al reduction in 75% yield.31-32 High stereoselectivity
likely originates from a preferred bottom face attack on the
carbonyl to avoid electrostatic clashing of the carbonyl-
complexed lithium acetylide with the top face
substituents.33-34
The
synthesis
of
functionalized
trans-
bicyclo[4.4.0]galactopyranoside 5 (Scheme 1), to our
knowledge, has not been reported. Annulated pyranosides
have been recently described, however, relying mainly on
ring closing metathesis (RCM) reactions.21-27 A series of
gluco- and galacto- cis- and trans-oxabicyclo[4.4.0]decane
derivatives, featuring a 4-C, 6-O-fused ring scaffold, were
elegantly described by Crich et al.28-29 Taking these
strategies into consideration, formation of the bicyclic
galactopyranoside 6 was planned from the RCM of diene 7.
Scheme 1. Retrosynthetic analysis of trans-bicyclo-
[4.4.0]-galactopyranoside 5
Scheme 2. Stereoselective alkynylation reaction at
C4
CO2Bn
R
MgBr
OBn
O
O
HO
HO
HO
OBn
O
OBn
O
TfO
SEt
SEt
R
O
SEt
Ph
1. TsOH, MeOH/CH2Cl2
2. TBDPSCl, Imidazole,
DMF
O
HO
OTBDPS
OBz
OBz
OBz
CO2Bn
O
O
4
Grignard
Vinylation
Regioselective
O-alkylation
CO2Bn
SEt
8
7
9
O
PMBO
OPMB
O
(89% two steps)
SEt
OPMB
(ref 30)
Ring-Closing
Metathesis
PMBO
12
13
Ac2O, DMSO, 65 °C
(93%)
6
5
OR
O
3
1
SEt
Intramolecular
Cyclization
HO
RO
OTBDPS
O
HO
7
2
4
RO
O
OBz
CHCMgBr, THF,
MS 3Å, -78 °C
X
HO
SEt
OTBDPS
OTBDPS
SEt
H
O
4
O
O
8
OH
10
O
Y
O
9
MsO
9
SEt
SEt
PMBO
PMBO
O
OBz
OBn
CO2H
(85%, 3:2 dr)
OPMB
OPMB
O
6
5
11a:
11b:
X = OH, Y = CCH
X = CCH, Y = OH
14
OBn
O
Alkynylation
&
TMSCCLi,
THF, -78 °C
(93%, 20:1 dr)
BnO
Cl
Reduction
O
Li
TMS
HO
HO
OTBDPS
OTBDPS
H
8 HO
Red-Al, Et2O,
0 °C
O
O
HO
OTBDPS
OTBDPS
PMBO
SEt
PMBO
SEt
4
TMS
O
TMS
O
PMBO
NOE
Oxidation &
Alkynylation
OPMB
OPMB
SEt
SEt
PMBO
15
H7
12
11
H5
(75%)
OPMB
OPMB
H3
16
Unfortunately, the elaboration of either the C4 vinyl (9)
or the C3-O-allylic fragments (8) were unsuccessful. The
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The Journal of Organic Chemistry
The reaction sequence from alcohol 12 (oxidation,
hydroxyester 20b gave a 4:1 ratio in favor of the R-isomer
22a, in a 72% yield. This suggested that the reduction with
(R)-BINAL-H formed the S-configured alcohol. In addition,
these results reinforced the necessity for a protecting group
on the C4 tertiary alcohol to avoid spirocycle formation.
1
2
3
4
5
6
7
8
alkynylation, and deprotection) could be performed in
tandem to generate galactoside 11a in an 81% overall yield
(Scheme 3). In order to avoid formation of unwanted
spirocyclic compounds during the planned intramolecular
cyclization, protection of the C4 hydroxyl was evaluated.
This tertiary hydroxyl was inert to standard protection
conditions. By capitalizing on the alkoxide generated in situ
during the alkynylation reaction, treatment with TMSCl
provided the fully protected galactoside 17 in 87% overall
Table 1. Asymmetric reduction of acetylenic α-
ketoesters
R1O
OTBDPS
R1O
HO
9
OTBDPS
O
O
O
9
(R) PMBO
SEt
SEt
yield.
A
Cu(I)-catalyzed alkynylation with benzyl
PMBO
OBn
O
O
OPMB
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OPMB
chlorooxalate31 generated propargylic α-keto esters 18 or
19 in moderate to good yields (81 and 66%).
OBn
a
18:
R1 = H
R1O
OTBDPS
HO
19:
R1 = TMS
9
O
(S) PMBO
OBn
SEt
O
Scheme 3. Tandem alkynylation sequence and
sidechain extension at C4
OPMB
20:
21:
R1 = H
R1 = TMS
b
Yieldc
(%)
Ratiob
(a : b)
1. Ac2O, DMSO, 65 °C
2. TMSCCLi, THF, -78 °C;
NH4Cl(aq) or TMSCl, 0 °C
Reducing
Agenta
Ketone
Alcohol
Entry
HO
PMBO
R1O
PMBO
OTBDPS
OTBDPS
O
O
1
2
3d
18
18
19
18
19
(R)-BINAL-H
(S)-BINAL-H
(S)-BINAL-H
LiAlH(tBuO)3
LiAlH(tBuO)3
20
20
21
20
21
1 : 9
9 : 1
2 : 1
1 : 1
1 : 1
85
82
SEt
SEt
3. K2CO3, MeOH, 1 h
OPMB
OPMB
12
Yield over three steps:
n.d.
94
11a:
(81%)
(87%)
R1 = H
17:
R1 = TMS
4
5
97
O
CuCl cat.,
NEt3, THF
Cl
aConditions: BINAL-H (3 equiv) or LiAlH(OtBu)3 (1.1 equiv), THF
(0.1 M), -78 °C, 3 h. bDetermined by 1H NMR analysis of crude
reaction mixture. cIsolated yield. dPartial C4-O-TMS cleavage
observed. n.d.: not determined.
R1O
OTBDPS
HO
9
BnO
O
O
(R) PMBO
OBn
SEt
O
O
OPMB
R1O
OTBDPS
a
Table 1
O
R1O
OTBDPS
HO
SEt
PMBO
9
O
O
OPMB
Scheme
4.
Assignment
of
α-hydroxyester
(S) PMBO
OBn
OBn
SEt
O
OPMB
configuration and preparation of cyclization
precursors
20:
21:
18:
19:
(81%)
(66%)
R1 = H
R1 = TMS
R1 = H
b
R1 = TMS
O
OBn
H
Stereoselective reduction of the α-ketoester was first
1. TrisylNHNH2,
Et2O, Reflux
BnO
O
(R)
20a
or
20b
H
(S)
examined with chiral reducing agents (Table 1). Treatment
of ketone 18, bearing a free hydroxyl at C4, with (R)-BINAL-
H at -78 °C furnished propargylic-α-hydroxyester 20b in a
9:1 ratio in favor of the S-diastereoisomer (entry 1).36 (S)-
BINAL-H afforded the R-configured alcohol 20a in a similar
yield and ratio (entry 2). The initially planned
intramolecular SN2 displacement of the latter would
generate the axial carboxylic product 5b. Poor
stereoselection was observed when treating C4-O-TMS
protected ketone 19 with (S)-BINAL-H, suggesting
unfavorable clashing of the silyl group with the chiral
reagent (entry 3). Alternatively, reduction in the presence
of LiAlH(tBuO)3 gave an expected 1:1 mixture of alcohols 20
and 21 from ketones 18 and 19 respectively (entries 4 and
5).
O
O
9
9
OTBDPS
OTBDPS
2. MsCl, pyr.,
CH2Cl2, 40 °C
O
O
SEt
SEt
PMBO
PMBO
OPMB
OPMB
22a
4:1 dr from
22b
20a
8:1 dr from
(72%)
(76%)
20b
HO
(R) PMBO
TMSO
OTBDPS a) TMSOTf, 2,6-Lut.
OTBDPS
HO
HO
9
b) PPTS, MeOH
O
O
(R) PMBO
OBn
SEt
OPMB
SEt
O
O
OPMB
OBn
20a
21a
(87%)
c) TrisylNHNH2,
Et2O, Reflux
OBn
OBn
d) MsCl, NEt3,
CH2Cl2
O
O
OMs
PO
OH
PO
(R)
(R)
OTBDPS
OTBDPS
The absolute configuration of acetylenic α-hydroxyesters
20a and 20b was determined through diimide reduction of
the internal alkyne to the cis-olefin, followed by a
chemoselective mesylation of the C9 secondary alcohol
(Scheme 4). Displacement of the mesylate by the tertiary
alcohol at C4 formed mixtures of 5-membered spirocycles
22a and 22b. Treatment of α-hydroxyester 20a gave an 8:1
ratio in favor of the S-isomer 22b, thus suggesting reduction
with (S)-BINAL-H indeed formed the R-configured alcohol
as the major product. The stereochemical assignment is
supported by 2D NOE correlations between the C9 proton
and either the C6 or CH2 protons of the C3-O-PMB ether
moiety (See SI). Using the same reaction conditions, α-
O
O
e) DDQ, CH2Cl2,
H2O
SEt
SEt
HO
24a
PMBO
OH
OPMB
23a
(72%)
P = TMS
(68%)
OBn
O
OMs
PO
HO
OTBDPS
HO
(S)
a, b
c
d, e
OTBDPS
O
21b
23b
(S) PMBO
OBn
SEt
O
O
SEt
(92%)
(87%)
(74%)
HO
OPMB
OH
20b
24b
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Bis-protection of the α-hydroxy esters 20a and 20b was Remarkably, the silyl group migration could be
1
2
3
4
5
6
7
8
carried out in the presence of TMSOTf and 2,6-lutidine at
low temperature, with subsequent removal of the
secondary TMS moeity under mildly acidic conditions.
Through thermal decomposition of trisylhydrazide,37-38 the
alkynes were reduced to the corresponding cis-alkenes 23a
and 23b (68 and 87% yields). The sterically congested
nature of the disubstituted alkyne prevented complete
saturation to the alkane under conventional hydrogenation
conditions. Subsequent treatment with MsCl and NEt3
followed by oxidative cleavage of the 2,3-di-O-PMB ethers
using DDQ formed the cyclization precursors 24a (9R) and
24b (9S) in 72 and 74% yields.
suppressed by switching the solvent to toluene, and with
heating at 100 oC, the desired axial bicycle 25b was formed
in a 69% yield with an excellent 15:1 ratio (entry 4). When
these conditions were carried out using S-mesylate 24b
(entry 5), a 7:1 ratio also in favor of the axial isomer was
observed. Gratifyingly, an enhanced axial selectivity was
observed from a 1:1 mixture of mesylates 24a,b (entry 6),
suggesting that stereoselective reduction of the acetylenic
ketoesters was not required. Under extended refluxing in
toluene, the α,β-unsaturated ester 27 was obtained in 64%
yield (entry 7).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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The intriguing preference for the cyclized axial
galactopyranoside 25b from different mesylate mixtures
prompted us to seek computational insight (Gaussian 09)39
into the origin of this induction (Scheme 5). At the
M062x/6-31G*/6-311+G** level of theory,40-41 cyclization
of simplified mesylates 28a and 28b, in the presence of
NMe3 as the base, was found to proceed through lowest SN2
transition structures TS B and TS C.
With the mesylate precursors 24a,b in hand, the targeted
intramolecular cyclization reaction to access bicyclic
galactosides 25a,b was investigated (Table 2). A first
cyclization attempt using mesylate 24a with a mild base in
refluxing dichloromethane (entry 1) resulted in an
inseparable 1:2 mixture of spirocycles 26a and 26b in 35%
yield. Seemingly, an isomerization of the mesylate and
migration of the silyl ether to the less hindered C3 hydroxyl
had occurred. An intriguing observation was that either C9
epimer cyclized in refluxing acetonitrile (entries 2 and 3) to
provide spirocycles favoring the R-diastereomer 26a in
high yield, in a 3:1 or 5:1 ratio.
Scheme 5. Relative free energies (kcal/mol) for the
intramolecular cyclization reaction at 80 oC in
toluene, relative to 28b at the M062x/6-31G*/6-
311+G** level of theory and corrected with Truhlar’s
quasiharmonic entropic correction45-47
Table 2. Intramolecular cyclization to access trans-
bicyclo[4.4.0]galactopyranoside 25
SiMe3
Mesylate
24a : 24b
Temp
(°C)
Yieldc
(%)
Ratioa,b
O
SMe
O
OH
Entry
Solvent
Me
OH
(a : b)
OMs
H
OBn
OBn
OBn
O
O
O
(S)
MsO
CO2Me
TS A
9
O
OMs
PO
(R)
O
OTBDPS
OTBDPS
OTBDPS
+
O
O
O
SEt
SEt
SEt
TMSO
TMSO
HO
OH
OH
OH
TMSO
Me
TMSO
Me
TS A (24.1)
24a (R) 24b (S) P = TMS
or
26a
26b
O
O
HO
OMs
SMe
HO
OMs
SMe
(S)
(R)
1d
2
20 : 1
20 : 1
1 : 20
40
85
85
CH2Cl2
MeCN
MeCN
1 : 2
35
84
77
OH
OH
O
O
fast
:
k1 and k-1
OMe
OMe
28a (1.7)
3 : 1
5 : 1
28b (0.0)
3
NMe3
k2 : slow
k3 : slow
NMe3
OBn
TMSO
OTBDPS
TMSO
OTBDPS
9
O
OMs
PO
TMSO
BnO
O
TMSO
O
Me
O
O
Me
O
SEt
OTBDPS
H
+
O
O
SEt
O
O
H
O
SMe
OH
O
SMe
MeO
MsO
O
OH
H
SEt
MsO
H
H
HO
OH
BnO
H
OH
NMe3
H
H
OH
25a
25b
O
OMe
NMe3
TS B (38.7)
TS C (32.4)
4
5
6
20 : 1
1 : 20
1 : 1
100 e
100 e
100 e
Toluene
Toluene
Toluene
1 : 15
1 : 7
69
58
65
1 : 13
OBn
TMSO
OTBDPS
9
O
OMs
PO
O
SEt
OTBDPS
O
O
H
OH
O
SEt
HO
OBn
OH
27
7d
1 : 1
100
Toluene
-
64
aConditions: Solvent (0.1 to 0.2 M), DIPEA (3 equiv), 2 h.
TMSO
TMSO
Me
Me
bProduct ratio determined by 1H NMR analysis of crude mixture.
O
MeO
O
O
SMe
H
O
SMe
e
cIsolated yield. d16 h. Heating at 80 °C provided similar yields
O
OH
OH
H
and ratios, with longer reaction times than 2 h (approx. 9 h).
H
H
MeO
O
29a (-20.3)
(Minor)
29b (-21.5)
(Major)
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The Journal of Organic Chemistry
The two TS are both significantly higher in energy than
Removal of the silyl ethers was achieved by using
HF∙NEt3, followed by hydrogenation of the endocyclic olefin
and debenzylation with Pearlman’s catalyst to form
exclusively the annulated galactopyranosides 5a
(equatorial) and 5b (axial). The stereochemical
configurations of the carboxylates were assigned using
the epimerization TS A.48 The rapid epimerization is
consistent with 1H NMR spectroscopy studies in deuterated
toluene, as well as experimental results that demonstrate
the interconversion between mesylates 24a,b at 40 °C, a
lower temperature than what is required for the cyclization.
This is also in agreement with precedents from the
literature for α-halo and hydroxyester interconversions.42-
44 The TS C leading to the major axial epimer 29b displays a
lower relative Gibbs free energy of 32.4 kcal/mol, in
comparison to that of TS B for the formation of equatorial
product 29a (38.7 kcal/mol). Presumably, minimization of
the allylic strain to prevent steric clashing between the ester
and the C4-O-TMS group in TS C produces this difference in
energy.
1
2
3
4
5
6
7
8
9
1
3
their characteristic H NMR JH,H coupling constants and
NOE correlation data between H3 and H9 (See SI).
Although the synthetic route achieved exclusive access to
the axially configured bicyclic galactopyranoside, we sought
to develop a method that could access both diastereomers
selectively. By exploiting the observation that the olefin
geometry could migrate under basic conditions during the
intramolecular cyclization, removal of the silyl ethers of
benzoylated isomer 30b in presence of TBAF (~5% wt.
H2O) also resulted in migration of the double bond to
provide α,β-unsaturated ester 31 in 81% yield. Notably, the
hydrogenation occurred exclusively from the bottom face of
the bicycle to give equatorial galactopyranoside 5a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is noteworthy that this steric clash is also present in the
equatorial product 29a, which is 1.2 kcal/mol higher in
energy than 29b. A thermodynamic equilibrium between
these two products could therefore also furnish the
observed selectivity in favor of 29b. The reversibility
barrier through TS A or TS B is, however, quite substantial
at 80 oC (53.9 kcal/mol). Moreover, resubmitting the
isolated equatorial galactopyranoside 25a in the reaction
conditions only led to the corresponding decomposition
product 27. The yield of bicyclic galactoside 25b is greater
than 50%, independent of the diastereomeric composition
of mesylates 24a,b, and both epimers form the α,β-
unsaturated product 27. Thus, the observed selectivity is
not due to selective decomposition of the minor galactoside.
Taken together, we propose that the cyclization occurs
through a Curtin-Hammett scenario, where it is the relative
free energy of the cyclization transition states (TS B and TS
C) that is at the origin of the observed selectivity.49
The novel selectin antagonists were generated through
coupling of the C2-O-benzoate protected galactoside 30b
with our previously reported15 fucosylated acyclic tether 33
(Scheme 7). Gratifyingly, in the presence of NIS and TMSOTf,
glycoside 34 was obtained in excellent yield (87%) and β-
selectivity (>20 : 1 dr).
Scheme 7. Completion of the synthesis of selectin
antagonists
bearing
the
trans-
bicyclo[4.4.0]galactopyranoside scaffold
BnO
OBn
OBn
Me
O
BnO
OBn
O
O
OBn
Me
O
OiPr
OiPr
O
Bicyclic galactopyranosides 25a and 25b were then
benzoylated (Scheme 6), a necessary step to favor β-anomer
formation in the planned glycosylation through anchimeric
participation.
33
O
HO
TMSO
O
TMSO
OiPr
OiPr
OTBDPS
O
OTBDPS
O
O
SEt
O
H
H
O
O
NIS, TMSOTf
3Å MS, -35 °C, 2 h
(87%, >20:1 dr)
OBz
OBz
O
H
H
BnO
O
BnO
30b
34
Scheme
6.
Deprotection
of
the
bicyclic
intramolecular cyclization products
HF•NEt3
(94%)
TBAF
(96%)
1. HF•NEt3, THF
2. Pd(OH)2, H2,
THF
HO
O
TMSO
OH
O
BnO
Me
BnO
OBn
OTBDPS
OBn
O
BnO
O
O
SEt
OBn
OBn
O
SEt
O
H
O
Me
O
O
HO
(60% two steps)
OBz
OR1
Olefin
Migration
H9
H3
5a
H
O
O
O
HO
OiPr
OiPr
HO
OiPr
OiPr
OR1
OR1
BzCl, pyr.,
CH2Cl2
(74%)
25a:
30a:
R1 = H
R1 = Bz
O
O
O
H
O
O
Pd(OH)2,
H2, THF
(69%)
O
O
OBz
OBz
O
O
H
H
BnO
OBn
37:
38:
R1 = H
R1 = Bz
35:
36:
R1 = H
R1 = Bz
BzCl,
pyr.
(94%)
BzCl,
pyr.
(87%)
TMSO
O
HO
OTBDPS
OH
O
Pd(OH)2,
H2, THF
TBAF, THF
(81%)
O
Pd(OH)2,
H2, THF
SEt
SEt
H
O
O
OR1
OBz
H
O
H
HO
OH
HO
OH
BnO
OBn
31
BzCl, pyr.,
CH2Cl2
(93%)
OH
25b:
30b:
R1 = H
R1 = Bz
OH
Me
O
Me
O
O
O
O
O
O
O
HO
OiPr
OiPr
OR1
O
HO
O
OiPr
OiPr
OR1
O
HF•NEt3, THF
(83%)
HO
O
O
H9
O
O
OBz
OBz
HO
O
HO
O
H3
Pd(OH)2,
H2,THF
OH
OH
O
H9
H3
HO
O
O
SEt
1:
2:
3:
4:
R1 = H (87%)
R1 = Bz (53%)
R1 = H (85%)
R1 = Bz (93%)
SEt
H
H9
HO
OBz
(88%)
OBz
H
O
H3
BnO
O
32b
5b
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By capitalizing on the desilylation strategy described
activation of other adhesion molecules (integrins) are also
noted.
The evaluation of our molecules under flow conditions
1
2
3
4
5
6
7
8
above, protected glycoside 34 was treated with either
HF∙NEt3 or TBAF to access both deprotected axial and
isomerized unsaturated esters 35 and 37 in excellent yields.
We have previously reported the increased bioactivity of
selectin antagonists bearing a C4-O-benzoate group.4 The
incorporation of the benzoate at C4 was not compatible
with our synthetic design due to its propensity to eliminate
at the cyclization step. Nonetheless, the mono-protection of
primary alcohols 35 and 37 with BzCl to afford the 2,6-O-
dibenzoylated compounds 36 and 38, was successful (87
and 94% yields). The tri-benzoylated products were not
observed due to the encumbered C4 quaternary center. The
C6-O-benzoates may provide new hydrophobic interactions
within the binding pocket. The final global deprotection
step using Pearlman’s catalyst provided the target
glycomimetics 1-4 in good to excellent yields (53-93%).
was done using a parallel plate flow chamber to mimic the
hydrodynamic conditions found in the vasculature (Figure
3). Isolated primary human umbilical endothelial cells
(HUVEC) were assembled into the flow chamber.53-54 To
mobilize P-Selectin, stored in Weibel-Palade bodies of the
endothelial cells, histamine was used as the inflammatory
stimulus. Neutrophils alone or neutrophils containing
compounds 2, 4, or sLeX were perfused across the
endothelial cells. Most interestingly, compound 2 and sLeX
interfered with neutrophil interactions and firm adhesion,
while compound 4 was inactive in this assay. The higher
binding affinity noted for the axially oriented carboxylate
was less pronounced in the static adhesion assay,
potentially pointing to differences in P-Selectin/PSGL-1
affinity between the two assays. These preliminary results
suggest that it is indeed the axial carboxylate that better
mimics the bioactive conformation of sLeX.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Extensive biological evaluation of our selectin
antagonists is underway and will be reported in due time.
However, preliminary results obtained with 2,6-O-
dibenzoylated sLeX analogue 2 bearing the axial carboxylic
acid and its equatorial isomer 4 show promising antagonist
activity. We first evaluated their ability to disrupt adhesion
of tagged human leukocytes to immobilized P-Selectin
(Figure 2).4, 50 The native ligand, sLeX, had an EC50 of 2.2 mM
in this assay, whereas both analogues 2 and 4 displayed
markedly lower EC50 values of 20 uM and 40 uM,
respectively.
Figure 3. Effect of compounds 2, 4, and sLeX on total
neutrophil interactions on histamine-treated ECs.
Neutrophils alone or neutrophils containing 10 μM of
compounds 2, 4, or sLeX were perfused across endothelial cells
and their rolling or firm adhesion behavior recorded for 10
minutes. Data were normalized for each experiment and time
point and then expressed as percent histamine. Data for total
interactions at 3, 5, 7 and 9 minutes (A-D) are shown as the
mean (±SEM) for 4 to 6 data points from 5 or 6 independent
Figure 2. P-Selectin cell-based adhesion assay. HL-60
cells tagged with Leukotracker were bound to P-SelFc coated
Elisa plates. Compounds 2, 4, and sLeX were dissolved in TrisCa
buffer and added at concentrations of 0.001 mM to 5 mM or 10
mM. The number of adhered cells decreased in a dose-
dependent way. Inhibition was calculated as the 100% minus
binding observed in the wells. Results are the mean (±SEM) of
three independent experiments. *p<0.05.
experiments.
p
values represent t-test comparison to
a
hypothetical value of 100% and exact values are shown.
CONCLUSIONS
In summary,
a
synthesis featuring
a
highly
diastereoselective intramolecular cyclization was designed
to generate sLeX analogues bearing a trans-bicyclo[4.4.0]
dioxadecane modified 3-O, 4-C-fused galactopyranoside
scaffold with a locked (axial or equatorial) carboxylate
pharmacophore. The importance of the carboxylate
pharmacophore, as well as the effects of pre-organization to
mimic the bioactive conformation, were examined in
preliminary biological evaluations which highlight their
potential as P-selectin antagonists. We are now studying
A remarkable feature of selectin-ligand interactions in the
rolling adhesion of leukocytes, is the effect of shear stress
on the strength of adhesive bond formation.51-52 At low
shear stress, leukocytes detach frequently, however, higher
shear stress enables cells to decrease rolling and adhere
firmly. With a further increase in shear stress, cell-rolling
and adhesion is prevented. At the molecular level, changes
in catch-bond strength, the conformation of PSGL-1, and the
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The Journal of Organic Chemistry
25
different carboxylate bioisosteres to further improve the (Hexanes/EtOAc, 70:30); [α]D
-2.0 (c 1.2, CHCl3);
1
2
3
4
5
6
7
8
biological activity of this class of glycomimetics.
C40H50O7SSi; MW = 702.9780 gmol-1; IR (neat, cm-1) νmax
3494, 2931, 1723, 1508, 1252; 1H NMR (500 MHz, CDCl3) δ
(ppm) 7.72 – 7.63 (m, 4H), 7.45 – 7.23 (m, 10H), 6.88 (d, J =
8.6 Hz, 4H), 4.79 (d, J = 10.0 Hz, 1H), 4.70 (d, J = 9.8 Hz, 1H),
4.67 (d, J = 3.0 Hz, 2H), 4.37 (d, J = 9.7 Hz, 1H), 4.06 (t, J = 2.9
Hz, 1H), 3.96 – 3.84 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.66
(appt, J = 9.4 Hz, 1H), 3.48 (dd, J = 9.0, 3.2 Hz, 1H), 3.40 (t, J
= 5.9 Hz, 1H), 2.83 – 2.59 (m, 2H), 2.53 (d, J = 2.6 Hz, 1H),
1.28 (t, J = 7.5 Hz, 3H), 1.05 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 159.52, 159.45, 135.8, 135.7, 133.4, 133.2,
130.6, 130.2, 130.1, 129.9, 129.6, 127.9, 127.86, 127.84,
114.0, 113.9, 85.0, 82.3, 78.1, 77.8, 75.5, 71.9, 67.0, 63.2,
55.42, 55.38, 26.9, 24.5, 19.3, 15.2; HRMS calcd for
C40H50O7SSiNa [M+Na+] 725.2944, found 725.2946 (-1.1
ppm).
EXPERIMENTAL SECTION
General Comments. All reactions requiring anhydrous
conditions were carried out under an atmosphere of
nitrogen or argon in flame-dried glassware using standard
syringe techniques. All anhydrous solvents were dried with
4 Å molecular sieves prior to use. The 4 Å molecular sieves
(1−2 mm beads) were activated by being heated at 180 °C
for 48 h under vacuum prior to being added to new bottles
of solvent purged with nitrogen. Commercially available
reagents were used as received. Flash chromatography was
performed on silica gel 60 (0.040−0.063 mm) using forced
flow (flash chromatography) of the indicated solvent
system or an automated flash purification system.
Analytical thin-layer chromatography (TLC) was carried
out on precoated (0.25 mm) silica gel aluminum plates.
Visualization was performed with UV short wavelength
and/or revealed with potassium permanganate solutions.
1H NMR spectra were recorded at room temperature on a
500 MHz NMR spectrometer. The data are reported as
follows: chemical shift in parts per million referenced to
residual solvent (CDCl3 δ 7.26 ppm, CD3OD δ 3.31 ppm),
multiplicity (s = singlet, d = doublet, dd = doublet of
doublets, ddd = doublet of doublets of doublets, t = triplet,
td = triplet of doublets, m = multiplet, app = apparent),
coupling constants (hertz), and integration. 13C{1H} NMR
spectra were recorded at room temperature using 126 MHz.
The data are reported as follows: chemical shift in parts per
million referenced to residual solvent (CDCl3 δ 77.16 ppm,
CD3OD δ 49.00 ppm). Infrared spectra were recorded on a
Fourier transform infrared spectrophotometer with single
reflection diamond ATR module, and signals are reported in
cm−1. Mass spectra were recorded through electrospray
ionization positive ion mode. A Hybrid Quadrupole-
Orbitrap mass analyzer was used for HRMS measurements.
Optical rotations were measured at room temperature from
the sodium D line (589 nm) using CDCl3 as solvent unless
otherwise noted and calculated using the formula: [α]D =
(100)αobs/(l·c)), where c = (g of substrate/100 mL of
solvent) and l = 1 dm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
6-O-(tert-butyldiphenylsilyl)-2,3-di-O-(p-
methoxybenzyl)-1-thio-β-D-xylo-hexopyranosid-4-ulose
(14). To a solution of 12 (3.00 g, 4.27 mmol, 1.00 equiv) in
DMSO (5.0 mL, 0.85 M), acetic anhydride (3.51 mL, 37.1
mmol, 8.70 equiv) was added. The solution was stirred at 65
°C in an oil bath for 2 h. The reaction mixture was cooled to
25 °C before water (20 mL) was added, and the aqueous
layer was extracted with Et2O (2 x 30 mL). The combined
organic layers were washed with brine (2 x 20 mL), dried
over MgSO4, filtered, and concentrated in vacuo. Purification
by flash chromatography (Hexanes/Et2O, 60:40) provided
14 (2.8 g, 93%) as a colorless oil: Rf = 0.42 (Hexanes/ Et2O,
25
50:50); [α]D +17 (c 2.7, CHCl3); C40H48O7SSi; MW =
700.9620 gmol-1; IR (neat, cm-1) νmax 2930, 1736, 1612,
1512, 1247; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 (dd, J =
8.0, 1.5 Hz, 4H), 7.48 – 7.29 (m, 10H), 6.88 (dd, J = 10.2, 8.6
Hz, 4H), 4.86 (d, J = 11.1 Hz, 1H), 4.80 (d, J = 9.4 Hz, 1H), 4.76
(d, J = 10.2 Hz, 1H), 4.70 (d, J = 10.2 Hz, 1H), 4.55 (d, J = 11.1
Hz, 1H), 4.14 (dd, J = 11.3, 3.3 Hz, 1H), 4.09 (d, J = 9.4 Hz,
1H), 4.00 – 3.86 (m, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.69 (dd,
J = 9.5, 8.6 Hz, 1H), 2.99 – 2.58 (m, 2H), 1.34 (t, J = 7.4 Hz,
3H), 1.07 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
200.8, 159.6, 135.8, 135.7, 133.4, 133.2, 130.2, 129.94,
129.92, 129.87, 129.83, 129.6, 127.83, 127.80, 113.94,
113.88, 85.4, 84.8, 83.1, 81.7, 77.4, 75.1, 73.6, 62.1, 55.38,
55.35, 26.8, 24.8, 19.3, 15.1; HRMS calcd for C40H48O7SSiNa
[M+Na+]: 723.2788, found 723.2784 (+0.2 ppm).
Compounds from Scheme 2: Ethyl 6-O-(tert-
butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-1-thio-β-D-
galactopyranoside (12). To a solution of ethyl 4,6-O-
Ethyl
4-C-trimethylsilylethynyl-6-O-(tert-
butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-1-thio-β-D-
galactopyranoside (15). A solution of n-butyl lithium (2.5 M
in hexane, 0.64 mL, 1.2 equiv) was added dropwise over 10
min to a solution of ethynyltrimethylsilane (232 μL, 1.68
mmol, 1.25 equiv) in anhydrous THF (6.7 mL, 0.25 M) at -78
°C and stirred for 30 min. The ketone 14 (940 mg, 1.34
mmol, 1.00 equiv), dissolved in anhydrous THF (6.7 mL,
0.20 M), was then cannulated dropwise into the reaction
mixture and stirred for 1 h at -78 °C. After addition of a
saturated solution of NH4Cl (20 mL), the reaction was
warmed to 25 °C for 30 min, and the aqueous layer was
extracted with Et2O (2 x 20 mL). The combined organic
layers were washed with brine (20 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography (Hexanes/Et2O, 50:50) provided 15 (1.0 g,
93%) as a colorless oil: Rf = 0.43 (Hexanes/Et2O, 50:50);
benzylidene-2,3-di-O-(4-methoxybenzyl)-1-thio-β-D-
[30]
galactopyranoside 13
(56.0 g, 101 mmol, 1.00 equiv) in
CH2Cl2/MeOH (1:1) (0.61 mL, 0.17 M), TsOH (13.5 g, 70.9
mmol, 0.70 equiv) was added. The reaction mixture was
stirred for 16 h at 25 °C. After addition of NEt3 (12.7 ml, 91.2
mmol, 0.90 equiv), the solution was stirred for 30 minutes
before the volatiles were removed in vacuo. To the crude
diol in anhydrous DMF (304 mL, 0.33 M) at 0 °C, imidazole
(13.8 g, 202 mmol, 2.00 equiv), and TBDPSCl (26.3 mL, 101
mmol, 1.00 equiv) were added. The reaction was warmed to
25 °C and stirred for 6 h. Water (200 mL) was added, and
the aqueous layer was extracted with Et2O (2 x 200 mL). The
combined organic layers were washed with brine (2 x 200
mL), dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (Hexanes/EtOAc,
70:30) provided 12 (63 g, 89%) as a colorless oil: Rf = 0.4
25
[α]D +1.7 (c 0.9, CHCl3); C45H58O7SSi2; MW = 799.1820
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gmol-1; IR (neat, cm-1) νmax 3451, 2947, 1613, 1514, 1249; 1H
NMR (500 MHz, CDCl3) δ (ppm) 7.77 – 7.69 (m, 4H), 7.44 –
7.25 (m, 10H), 6.86 (dd, J = 8.7, 7.2 Hz, 4H), 4.98 (d, J = 10.3
Hz, 1H), 4.83 (d, J = 10.4 Hz, 1H), 4.79 (d, J = 10.0 Hz, 1H),
4.65 (d, J = 10.1 Hz, 1H), 4.49 (d, J = 9.3 Hz, 1H), 4.22 (dd, J =
11.3, 5.8 Hz, 1H), 4.14 (dd, J = 11.3, 1.9 Hz, 1H), 3.81 (s, 3H),
3.80 (s, 3H), 3.69 – 3.59 (m, 2H), 3.59 – 3.52 (m, 1H), 2.87
(dq, J = 12.7, 7.4 Hz, 1H), 2.75 (dq, J = 12.7, 7.5 Hz, 1H), 1.34
(t, J = 7.4 Hz, 3H), 1.06 (s, 9H), 0.14 (s, 9H) (Labile protons
were not observed due to exchange with deuterated solvent);
13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 159.54, 159.48,
135.77, 135.74, 133.25, 133.21, 130.7, 130.5, 130.04,
130.02, 129.9, 127.89, 127.87, 113.93, 113.91, 105.3, 91.4,
86.1, 84.8, 81.4, 78.3, 77.4, 76.0, 75.5, 71.4, 64.4, 55.45,
55.43, 26.9, 24.3, 19.4, 15.3, -0.1; HRMS calcd for
C45H58O7SSi2Na [M+Na+]: 821.3339, found 821.3325 (-1.7
ppm).
layers were washed with brine (60 mL), dried over MgSO4,
filtered, and concentrated in vacuo. H NMR spectroscopic
analysis of the unpurified product indicated the formation
of a 3:2 mixture of C4 diastereomers. Purification by flash
chromatography (Hexanes/Et2O, 60:40) did not allow
separation of the diastereomers and provided a 3:2 ratio of
11a,b (3.6 g, 84.9%) as a pale-yellow oil.
1
1
2
3
4
5
6
7
8
General Procedure A: Optimized oxidation,
alkylation, and deprotection (Scheme 3): To a solution of
12 (52.0 g, 74.0 mmol, 1.00 equiv) in DMSO (78 mL, 0.85 M),
acetic anhydride (60.8 mL, 644 mmol, 8.70 equiv) was
added. The reaction mixture was stirred at 65 °C in an oil
bath for 2 h. The reaction mixture was cooled to 25 °C before
water (150 mL) was added, and the aqueous layer was
extracted with Et2O (2 x 100 mL). The combined organic
layers were washed with brine (2 x 150 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude
mixture was co-evaporated with toluene (2 x 50 mL) to
ensure dryness. The mixture was then dissolved in
anhydrous THF (0.29 L, 0.25 M) and cannulated dropwise
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Ethyl
4-C-[(E)-2-(trimethylsilyl)vinyl]-6-O-(tert-
butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-1-thio-β-D-
galactopyranoside (16). To a solution of alkyne 15 (80 mg,
0.10 mmol, 1.0 equiv) in Et2O (1.0 mL, 0.10 M) at 0 °C, Red-
Al (60 wt. % in toluene) (98 μL, 0.25 mmol, 2.5 equiv) was
added dropwise. After stirring for 1 h, a saturated solution
of Rochelle salt (5 mL) was added to the reaction mixture
which was then warmed to 25 °C and stirred for 30 min. A
saturated NH4Cl solution (10 mL) was added, and the
aqueous layer was extracted with EtOAc (2 x 15 mL). The
combined organic layers were washed with brine (30 mL),
dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (Hexanes/Et2O,
into
a
freshly prepared solution of lithium
(trimethylsilyl)acetylide (0.48 M in THF, 182 mL, 1.20
equiv) at -78 °C. After stirring for 2 h, a saturated solution
of NH4Cl (350 mL) was added and the reaction was warmed
to 25 °C for 30 min. The aqueous layer was extracted with
Et2O (2 x 200 mL), and the combined organic layers were
washed with brine (400 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The crude mixture was dissolved in
methanol (0.44 L, 0.16 M) and potassium carbonate (15.0 g,
109 mmol, 1.50 equiv) was added. The reaction mixture was
stirred at 25 °C for 1 h before water (400 mL) was added
and the aqueous layer was extracted with Et2O (2 x 200 mL).
The combined organic layers were washed with brine (400
mL), dried over MgSO4, filtered, and concentrated in vacuo.
1H NMR spectroscopic analysis of the unpurified product
70:30) provided 16 (60 mg, 75%) as a colorless oil: Rf = 0.37
25
(Hexanes/Et2O, 50:50); [α]D
+1.7 (c 0.7, CHCl3);
C45H60O7SSi2; MW = 801.1980 gmol-1; IR (neat, cm-1) νmax
3462, 2958, 1610, 1513, 1240; 1H NMR (500 MHz, CDCl3) δ
(ppm) 7.72 (d, J = 6.5 Hz, 2H), 7.66 (d, J = 6.5 Hz, 2H), 7.46 –
7.30 (m, 8H), 7.17 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H),
6.81 (d, J = 8.7 Hz, 2H), 6.31 (d, J = 18.7 Hz, 1H), 5.86 (d, J =
18.6 Hz, 1H), 4.83 (d, J = 10.0 Hz, 1H), 4.65 (appt, J = 10.2 Hz,
2H), 4.52 (appt, J = 10.3 Hz, 2H), 3.90 (dd, J = 11.5, 5.3 Hz,
1H), 3.80 – 3.79 (m, 8H), 3.64 (s, 1H), 3.43 (d, J = 8.8 Hz, 1H),
3.36 (dd, J = 5.2, 1.9 Hz, 1H), 3.00 – 2.68 (m, 2H), 1.36 (t, J =
7.4 Hz, 3H), 1.03 (s, 9H), 0.05 (s, 9H); 13C{1H} NMR (126
MHz, CDCl3) δ (ppm) 159.44, 159.42, 145.8, 135.7, 135.6,
133.0, 131.9, 131.8, 130.7, 130.4, 130.1, 129.92, 129.90,
129.88, 127.9, 127.8, 113.9, 113.8, 84.7, 84.6, 80.3, 79.2,
78.5, 75.5, 75.4, 64.1, 55.43, 55.40, 26.8, 24.2, 19.2, 15.3, -
1.2; HRMS calcd for C45H60O7SSi2Na [M+Na+]: 823.3490,
found 823.3484 (-0.7 ppm).
indicated the formation of
a >20:1 ratio of C4
diastereomers. Purification by flash chromatography
(Hexanes/Et2O, 60:40) provided 11a (44 g, 81%) as a pale-
yellow oil. Rf = 0.31 (Hexanes/Et2O, 50:50); [α]D25 +17 (c 0.6,
CHCl3); C42H50O7SSi; MW = 727.0000 gmol-1; IR (neat, cm-1)
1
νmax 3451, 3282, 2932, 1613, 1585, 1514, 1249; H NMR
(500 MHz, CDCl3) δ (ppm) 7.83 – 7.63 (m, 4H), 7.49 – 7.35
(m, 6H), 7.32 (dd, J = 8.6, 3.3 Hz, 4H), 6.86 (dd, J = 8.6, 6.5 Hz,
4H), 4.95 (d, J = 10.5 Hz, 1H), 4.84 (d, J = 10.4 Hz, 1H), 4.81
(d, J = 9.9 Hz, 1H), 4.66 (d, J = 10.0 Hz, 1H), 4.49 (d, J = 9.7
Hz, 1H), 4.22 (dd, J = 11.4, 5.4 Hz, 1H), 4.13 (dd, J = 11.4, 2.0
Hz, 1H), 3.92 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.67 (appt, J
= 9.2 Hz, 1H), 3.60 (d, J = 8.8 Hz, 1H), 3.50 (dd, J = 5.6, 2.0 Hz,
1H), 2.87 (dq, J = 12.6, 7.4 Hz, 1H), 2.75 (dq, J = 12.6, 7.5 Hz,
1H), 2.44 (s, 1H), 1.35 (t, J = 7.4 Hz, 3H), 1.05 (s, 9H);13C{1H}
NMR (126 MHz, CDCl3) δ (ppm) 159.51, 159.48, 135.9,
135.8, 133.1, 133.0, 130.5, 130.4, 130.1, 129.89, 129.88,
127.87, 127.86, 127.84, 113.93, 113.85, 85.8, 84.8, 83.6,
81.2, 78.2, 76.0, 75.5, 74.5, 71.1, 64.4, 55.43, 55.42, 26.8,
24.4, 19.3, 15.3; HRMS calcd for C42H50O7SSiNa [M+Na+]:
749.2947, found 749.2944 (-0.4 ppm).
Compounds from Scheme 3: Ethyl 4-C-ethynyl-6-O-(tert-
butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-1-thio-β-D-
galactopyranoside (11a).
Alkylation using ethynyl magnesium bromide
(Scheme 2): Ethynylmagnesium bromide (0.50 M in THF,
29 mL, 2.5 equiv) was added dropwise to a solution of
ketone 14 (4.09 g, 5.83 mmol, 1.00 equiv) in anhydrous THF
(58 mL, 0.10 M) and 3Å molecular sieves (4.0 g) at -78 °C.
The reaction mixture was stirred for 1 h at -40 °C, after
which the solution was filtered with EtOAc, and a saturated
solution of NH4Cl (60 mL) was added. The reaction mixture
was stirred at 25 °C for 15 min, and the aqueous layer was
extracted with EtOAc (2 x 30 mL). The combined organic
Ethyl 4-C-ethynyl-6-O-(tert-butyldiphenylsilyl)-2,3-di-O-
(p-methoxybenzyl)-4-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (17). Following General Procedure A for
11a, crude ketone 14 (46.0 g, 65.6 mmol, 1.00 equiv) was
dissolved in anhydrous THF (0.26 L, 0.25 M) and then
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The Journal of Organic Chemistry
cannulated dropwise into a freshly prepared solution of 128.87, 128.0, 127.9, 114.0, 113.9, 97.6, 85.0, 84.4, 82.9,
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5
6
7
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lithium (trimethylsilyl)acetylide (0.48 M in THF, 164 mL,
1.20 equiv) at -78 °C. After stirring for 2 h, TMSCl (16.7 mL,
131 mmol, 2.00 equiv) was added dropwise and the
reaction was warmed to 25 °C for 2 h. A saturated solution
of NH4Cl (350 mL) was added and the aqueous layer was
extracted with Et2O (2 x 200 mL). The combined organic
layers were washed with brine (400 mL), dried over MgSO4,
79.9, 78.0, 75.7, 75.6, 72.2, 68.9, 64.7, 55.44, 55.36, 26.7,
24.4, 19.2, 15.4; HRMS calcd for C51H56O10SSiNa [M+Na+]:
911.3261, found 911.3275 (+2.2 ppm).
Ethyl 4-C-(benzyloxycarbonyl-1-oxoprop-2-yn-3-yl)-6-O-
(tert-butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-4-O-
trimethylsilyl-1-thio-β-D-galactopyranoside (19). To
a
solution of CuCl (115 mg, 1.16 mmol, 0.300 equiv) in
anhydrous THF (39 mL, 0.030 M), NEt3 (1.62 mL, 11.6 mmol,
3.00 equiv) was added. The pale-brown solution was stirred
for 15 minutes before alkyne 17 (3.10 g, 3.88 mmol, 1.00
equiv) in anhydrous THF (10 mL, 0.39 M), and freshly
prepared benzyl chlorooxalate (1.54 g, 7.76 mmol, 2.00
equiv) in anhydrous THF (10 mL, 0.78 M) were added in
rapid succession. The reaction mixture was stirred for 2 h
at 25 °C before the light-orange mixture was poured into a
saturated solution of NaHCO3 (60 mL). The aqueous layer
was extracted with Et2O (2 x 30 mL). The combined organic
layers were washed with brine (100 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography (Hexanes/Et2O, 60:40) provided 19 (2.5 g,
66%) as a pale-yellow oil. Rf = 0.42 (Hexanes/Et2O, 50:50);
1
filtered, and concentrated in vacuo. H NMR spectroscopic
analysis of the unpurified product indicated the formation
of a >20:1 ratio of C4 diastereomers. Treatment with
potassium carbonate (13.6 g, 98.1 mmol, 1.50 equiv) in
methanol (0.39 L, 0.16 M) provided 17 (46 g, 89%) after
flash chromatography (Hexanes/Et2O, 60:40) as a pale-
yellow oil. Rf = 0.6 (Hexanes/Et2O 70:30); [α]D25 +27 (c 3.1,
CHCl3); C45H58O7SSi2; MW = 799.1820 gmol-1; IR (neat, cm-1)
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νmax 3283, 2932, 1613, 1513, 1246; H NMR (500 MHz,
CDCl3) δ (ppm) 7.78 – 7.68 (m, 4H), 7.47 – 7.36 (m, 6H), 7.31
(dd, J = 8.6, 3.9 Hz, 4H), 6.87 (dd, J = 8.6, 3.7 Hz, 4H), 4.91 (d,
J = 10.6 Hz, 1H), 4.83 (d, J = 10.5 Hz, 1H), 4.78 (d, J = 9.9 Hz,
1H), 4.67 (d, J = 9.9 Hz, 1H), 4.55 – 4.49 (m, 1H), 4.16 (dd, J
= 11.2, 2.0 Hz, 1H), 3.92 (dd, J = 11.2, 7.9 Hz, 1H), 3.82 (s,
3H), 3.81 (s, 3H), 3.57 – 3.49 (m, 3H), 2.89 (dq, J = 12.7, 7.4
Hz, 1H), 2.78 (dq, J = 12.7, 7.4 Hz, 1H), 2.35 (s, 1H), 1.38 (t, J
= 7.4 Hz, 3H), 1.10 (s, 9H), 0.06 (s, 9H); 13C{1H} NMR (126
MHz, CDCl3) δ (ppm) 159.4, 159.2, 135.82, 135.75, 134.9,
134.1, 133.8, 130.63, 130.56, 130.1, 130.0, 129.6, 127.689,
127.686, 113.9, 113.6, 87.2, 85.1, 84.4, 83.2, 78.2, 76.3, 75.5,
75.2, 72.4, 64.2, 55.4, 55.3, 26.9, 24.7, 19.3, 15.2, 2.1; HRMS
calcd for C45H58O7SSi2Na [M+Na+]: 821.3339, found
821.3359 (+3.1 ppm).
25
[α]D -13 (c 3.6, CHCl3); C54H64O10SSi2; MW = 961.3260
gmol-1; IR (neat, cm-1) νmax 2956, 2217, 1739, 1685, 1605,
1519, 1240; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.63 (dd, J =
17.9, 6.5 Hz, 4H), 7.40 – 7.28 (m, 13H), 7.18 (d, J = 8.6 Hz,
2H), 6.86 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 5.26 –
5.18 (m, 2H), 4.83 – 4.74 (m, 2H), 4.72 (d, J = 10.8 Hz, 1H),
4.64 (d, J = 10.0 Hz, 1H), 4.47 (d, J = 8.8 Hz, 1H), 3.93 (dd, J =
11.3, 2.7 Hz, 1H), 3.86 (dd, J = 11.3, 7.4 Hz, 1H), 3.80 (s, 3H),
3.76 (s, 3H), 3.60 – 3.45 (m, 3H), 2.84 (dq, J = 12.7, 7.4 Hz,
1H), 2.74 (dq, J = 12.7, 7.5 Hz, 1H), 1.35 (t, J = 7.4 Hz, 3H),
1.01 (s, 9H), 0.02 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 168.1, 159.5, 159.4, 158.0, 135.8, 135.7, 134.1, 133.6,
133.4, 130.6, 130.2, 130.1, 129.84, 129.79, 129.77, 129.2,
129.0, 128.9, 127.793, 127.788, 113.9, 113.7, 97.8, 85.6,
85.2, 83.9, 83.6, 78.1, 76.0, 75.4, 73.3, 68.9, 63.9, 55.4, 55.3,
26.9, 25.0, 19.3, 15.2, 1.9; HRMS calcd for C54H64O10SSi2Na
[M+Na+]: 983.3656, found 983.3680 (+2.9 ppm).
Ethyl 4-C-(benzyloxycarbonyl-1-oxoprop-2-yn-3-yl)-6-O-
(tert-butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-1-thio-
β-D-galactopyranoside (18). To a solution of CuCl (413 mg,
4.17 mmol, 0.300 equiv) in anhydrous THF (0.14 L, 0.030
M), NEt3 (5.81 mL, 41.7 mmol, 3.00 equiv) was added. The
pale-brown reaction mixture was stirred for 15 minutes
before a solution of alkyne 11a (11.1 g, 13.9 mmol, 1.00
equiv) in anhydrous THF (15 mL, 0.92 M) and freshly
prepared benzyl chlorooxalate (5.07 g, 27.8 mmol, 2.00
equiv) in anhydrous THF (15.0 mL, 1.85 M) were added in
rapid succession. The reaction mixture was stirred for 2 h
at 25 °C before the light-orange mixture was poured into a
saturated solution of NaHCO3 (150 mL). The aqueous layer
was extracted with Et2O (2 x 75 mL). The combined organic
layers were washed with brine (150 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography (Hexanes/Et2O, 60:40) provided 18 (11 g,
81%) as a pale-yellow oil. Rf = 0.30 (Hexanes/Et2O, 50:50);
[α]D25 -17 (c 2.8, CHCl3); C51H56O10SSi; MW = 889.1440 gmol-
1; IR (neat, cm-1) νmax 2932, 2209, 1740, 1689, 1613, 1514,
Compounds from Table 1. Ethyl 4-C-((1R)-
benzyloxycarbonyl-1-hydroxyprop-2-yn-3-yl)-6-O-(tert-
butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-1-thio-β-D-
galactopyranoside (20a). To a freshly prepared solution of
[36]
(S)-BINAL-H
in anhydrous THF (0.31 M, 1.9 mmol, 3.0
equiv), at -78 °C, acetylenic α-ketoester 18 (0.58 g, 0.65
mmol, 1.0 equiv) dissolved in THF (6.5 mL, 0.10 M) was
added dropwise. After stirring for 3 h, methanol (2 mL)
followed by a saturated solution of NH4Cl (10 mL) were
added. The aqueous layer was extracted with ethyl acetate
(2 x 10 mL) and the combined organic layers were washed
with brine (20 mL), dried over MgSO4, filtered, and
concentrated in vacuo. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a 9:1 ratio of
diastereomers. Purification by flash chromatography
(Hexanes/Et2O, 50:50) provided 20a (0.55 g, 96%) as a
white foam. Rf = 0.20 (Hexanes/Et2O, 50:50); [α]D25 +2.8 (c
3.4, CHCl3); C51H58O10SSi; MW = 891.1600 gmol-1; IR (neat,
1
1249; H NMR (500 MHz, CDCl3) δ (ppm) 7.74 – 7.64 (m,
4H), 7.46 – 7.30 (m, 13H), 7.26 (d, J = 8.6 Hz, 2H), 6.89 (d, J
= 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 5.24 (s, 2H), 4.88 – 4.78
(m, 3H), 4.69 (d, J = 10.0 Hz, 1H), 4.47 (d, J = 9.8 Hz, 1H), 4.44
(s, 1H), 4.17 (dd, J = 11.6, 4.7 Hz, 1H), 4.01 (dd, J = 11.6, 2.2
Hz, 1H), 3.81 (s, 3H), 3.79 – 3.74 (m, 4H), 3.63 (d, J = 8.7 Hz,
1H), 3.48 (dd, J = 4.6, 2.2 Hz, 1H), 2.86 (dq, J = 12.7, 7.4 Hz,
1H), 2.75 (dq, J = 12.6, 7.5 Hz, 1H), 1.36 (t, J = 7.4 Hz, 3H),
1.03 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 168.5,
159.60, 159.56, 158.2, 135.8, 135.7, 134.1, 132.5, 132.4,
130.5, 130.3, 130.13, 130.09, 130.06, 129.7, 129.1, 128.89,
1
cm-1) νmax 3446, 2936, 1750, 1613, 1514, 1249; H NMR
(500 MHz, CDCl3) δ (ppm) 7.76 – 7.70 (m, 4H), 7.46 – 7.35
(m, 7H), 7.31 (d, J = 8.6 Hz, 2H), 7.29 – 7.21 (m, 4H), 7.21
(dd, J = 6.7, 3.4 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.83 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
8.7 Hz, 2H), 5.17 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), trimethylsilyl-1-thio-β-D-galactopyranoside (21a). To
Page 10 of 20
a
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4.87 – 4.75 (m, 3H), 4.72 (d, J = 10.5 Hz, 1H), 4.65 (d, J = 10.0
Hz, 1H), 4.46 (d, J = 9.8 Hz, 1H), 4.17 (dd, J = 11.4, 5.4 Hz,
1H), 4.09 – 4.01 (m, 1H), 3.97 (s, 1H), 3.81 (s, 3H), 3.79 (s,
3H), 3.67 (dd, J = 9.8, 8.8 Hz, 1H), 3.51 (d, J = 8.8 Hz, 1H),
3.43 (dd, J = 5.3, 2.0 Hz, 1H), 2.92 – 2.79 (m, 2H), 2.80 – 2.69
(m, 1H), 1.35 (t, J = 7.4 Hz, 3H), 1.03 (s, 9H); 13C{1H} NMR
(126 MHz, CDCl3) δ (ppm) 169.8, 159.47, 159.46, 135.8,
135.7, 134.6, 132.91, 132.87, 130.5, 130.3, 130.10 130.08,
130.06, 129.9, 128.9, 128.8, 128.5, 127.95, 127.88, 113.9,
113.8, 85.6, 85.4, 84.8, 81.4, 80.8, 78.1, 75.8, 75.5, 71.3, 68.4,
64.4, 61.5, 55.42, 55.39, 26.8, 24.3, 19.2, 15.4; HRMS calcd
for C51H58O10SSiNa [M+Na+]: 913.3418, found 913.3405 (-
0.8 ppm).
vigorously stirred solution of 20a (0.45 g, 0.51 mmol, 1.0
equiv) in anhydrous dichloromethane (5.1 mL, 0.10 M) at -
40 °C, 2,6-lutidine (175 μL, 1.51 mmol, 3.00 equiv) and
TMSOTf (228 μL, 1.26 mmol, 2.50 equiv) were added. The
reaction vessel was sealed with a Teflon cap and kept at -20
°C for 16 h. Water (10 mL) was then slowly added, and the
solution was diluted with dichloromethane (5 mL) and
warmed to 25 °C. The organic layer was collected and
washed with a HCl solution (1 M, 5 mL), a saturated solution
of NaHCO3 (10 mL), followed by brine (10 mL). The organic
layer was dried over MgSO4, filtered, and concentrated in
vacuo. The crude viscous oil was then dissolved in
dichloromethane (8 mL, 0.07 M) and methanol (1.0 mL, 0.49
M), and a solution of PPTS (0.10 M in methanol, 0.51 mL,
0.10 equiv) was added dropwise. After stirring for 2 h, a
saturated solution of NaHCO3 (10 mL) was added. The
aqueous layer was extracted with Et2O (2 x 10 mL) and the
combined organic layers were washed with brine (20 mL),
dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (Hexanes/Et2O,
50:50) provided 21a (0.42 g, 87%) as a clear oil. Rf = 0.35
(Hexanes/Et2O, 50:50); C54H66O10SSi2; MW = 963.3420
gmol-1; IR (neat, cm-1) νmax 3466, 2956, 1749, 1514, 1249; 1H
NMR (500 MHz, CDCl3) δ (ppm) 7.69 (dd, J = 11.8, 6.5 Hz,
4H), 7.44 – 7.31 (m, 7H), 7.34 – 7.19 (m, 8H), 6.84 (dd, J =
15.4, 8.6 Hz, 4H), 5.23 (d, J = 12.0 Hz, 1H), 5.00 (d, J = 12.0
Hz, 1H), 4.75 (d, J = 10.4 Hz, 1H), 4.71 (dd, J = 10.3, 6.9 Hz,
3H), 4.63 (d, J = 10.0 Hz, 1H), 4.47 (d, J = 9.5 Hz, 1H), 4.04
(dd, J = 11.2, 2.0 Hz, 1H), 3.89 (dd, J = 11.3, 8.2 Hz, 1H), 3.80
(s, 3H), 3.80 (s, 3H), 3.54 – 3.44 (m, 2H), 3.42 (d, J = 9.1 Hz,
1H), 2.86 (dq, J = 12.9, 7.4 Hz, 1H), 2.81 – 2.68 (m, 2H), 1.36
(t, J = 7.4 Hz, 3H), 1.05 (s, 9H), -0.04 (s, 9H); 13C{1H} NMR
(126 MHz, CDCl3) δ (ppm) 169.6, 159.4, 159.2, 135.83,
135.75, 134.5, 134.1, 133.7, 130.52, 130.50, 130.13, 130.09,
129.74, 129.71, 129.0, 128.82, 128.77, 127.762, 127.760,
113.9, 113.6, 86.9, 85.11, 85.08, 84.1, 82.1, 78.1, 76.2, 75.3,
72.6, 68.5, 64.1, 61.5, 55.42, 55.37, 26.9, 24.8, 19.4, 15.2, 2.0;
HRMS calcd for C54H66O10SSi2Na [M+Na+]: 985.3813, found
985.3803 (-0.4 ppm).
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Ethyl 4-C-((1S)-benzyloxycarbonyl-1-hydroxyprop-2-yn-3-
yl)-6-O-(tert-butyldiphenylsilyl)-2,3-di-O-(p-
methoxybenzyl)-1-thio-β-D-galactopyranoside
(20b).
Following a similar procedure as in 20a, to a solution of (R)-
[36]
BINAL-H
in anhydrous THF (0.31 M, 1.4 mmol, 3.0
equiv), acetylenic α-ketoester 18 (0.41g, 0.46 mmol, 1.0
equiv) dissolved in THF (4.6 mL, 0.10 M) was added
dropwise. 1H NMR spectroscopic analysis of the unpurified
product indicated the formation of a 9:1 ratio of
diastereomers. Purification by flash chromatography
(Hexanes/Et2O, 50:50) provided 20b (0.35 g, 85%) as a
white foam. Rf = 0.20 (Hexanes/Et2O, 50:50); [α]D25 +5.0 (c
1.5, CHCl3); C51H58O10SSi; MW = 891.1600 gmol-1; IR (neat,
1
cm-1) νmax 3443, 2932, 1749, 1613, 1514, 1249; H NMR
(500 MHz, CDCl3) δ (ppm) 7.76 – 7.66 (m, 4H), 7.47 – 7.36
(m, 7H), 7.34 – 7.24 (m, 6H), 7.25 – 7.19 (m, 2H), 6.87 (d, J =
8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.16 (d, J = 12.1 Hz, 1H),
5.05 (d, J = 12.1 Hz, 1H), 4.83 (m, 2H), 4.79 (d, J = 10.0 Hz,
1H), 4.74 (d, J = 10.5 Hz, 1H), 4.65 (d, J = 10.0 Hz, 1H), 4.44
(d, J = 9.7 Hz, 1H), 4.17 (dd, J = 11.4, 5.1 Hz, 1H), 4.08 (s, 1H),
4.02 (dd, J = 11.4, 1.9 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.68
(dd, J = 9.8, 8.8 Hz, 1H), 3.50 (d, J = 8.8 Hz, 1H), 3.39 (dd, J =
5.0, 1.7 Hz, 1H), 2.92 – 2.81 (m, 2H), 2.80 – 2.69 (m, 1H), 1.35
(t, J = 7.4 Hz, 3H), 1.04 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 169.7, 159.45, 159.43, 135.8, 135.7, 134.6,
132.85, 132.78, 130.5, 130.2, 130.1, 130.0, 129.95, 129.93,
128.9, 128.8, 128.5, 127.92, 127.87, 113.9, 113.8, 85.6, 85.4,
84.8, 81.4, 80.6, 78.0, 75.7, 75.5, 71.3, 68.4, 64.5, 61.5, 55.39,
55.36, 26.7, 24.2, 19.2, 15.3; HRMS calcd for C51H58O10SSiNa
[M+Na+]: 913.3418, found 913.3427 (+1.6 ppm).
Ethyl 4-C-((1S)-benzyloxycarbonyl-1-hydroxyprop-2-yn-3-
yl)-6-O-(tert-butyldiphenylsilyl)-2,3-di-O-(p-
methoxybenzyl)-4-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (21b). Following a similar procedure as
in 21a, to solution of 20b (0.48 g, 0.54 mmol, 1.0 equiv) in
anhydrous dichloromethane (5.4 mL, 0.10 M), 2,6-lutidine
(189 μL, 1.63 mmol, 3.00 equiv) and TMSOTf (246 μL, 1.35
mmol, 2.50 equiv) were added. The crude oil was then
dissolved in dichloromethane (8 mL, 0.07 M) and methanol
(1.1 mL, 0.49 M), and a solution of PPTS (0.10 M in
methanol, 0.54 mL, 0.10 equiv) was added dropwise.
Purification by flash chromatography (Hexanes/Et2O,
50:50) provided 21b (0.48 g, 92%) as a clear oil. Rf = 0.35
(Hexanes/Et2O, 50:50); C54H66O10SSi2; MW = 963.3420
gmol-1; IR (neat, cm-1) νmax 3466, 2956, 1749, 1514, 1249; 1H
NMR (500 MHz, CDCl3) δ (ppm) 7.74 – 7.65 (m, 4H), 7.46 –
7.34 (m, 7H), 7.35 – 7.19 (m, 8H), 6.85 (d, J = 8.7 Hz, 2H),
6.81 (d, J = 8.6 Hz, 2H), 5.23 (d, J = 12.0 Hz, 1H), 4.96 (d, J =
12.0 Hz, 1H), 4.79 – 4.68 (m, 4H), 4.62 (d, J = 9.9 Hz, 1H),
4.46 (d, J = 9.6 Hz, 1H), 4.06 (dd, J = 11.2, 2.0 Hz, 1H), 3.88
(dd, J = 11.2, 8.1 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.52 –
3.45 (m, 2H), 3.39 (d, J = 9.1 Hz, 1H), 2.91 – 2.81 (m, 1H),
Non-selective reduction of acetylenic α-ketoesters 18
and 19 (entries 4 and 5): To a solution of the
corresponding acetylenic α-ketoester dissolved in
anhydrous THF (0.1 M) at -78 °C, a solution of LiAlH(OtBu)3
(1.0 M in THF, 1.1 equiv) was added dropwise. After stirring
for 15 min, methanol followed by a saturated solution of
NH4Cl were added. The aqueous layer was extracted with
Et2O and the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
1H NMR spectroscopic analysis of the unpurified product
indicated the formation of a 1:1 ratio of diastereomers.
Purification by flash chromatography (Hexanes/Et2O,
60:40) provided acetylenic α-hydroxyesters 20a,b or 21a,b
as an inseparable mixture of diastereomers (94-97%).
Compounds from Scheme 4: Ethyl 4-C-((1R)-
benzyloxycarbonyl-1-hydroxyprop-2-yn-3-yl)-6-O-(tert-
butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-4-O-
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2.81 – 2.72 (m, 2H), 1.36 (t, J = 7.4 Hz, 3H), 1.06 (s, 9H), -0.02 of an 8:1 ratio of diastereomers. Purification by flash
(s, 9H);13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 169.5, 159.4,
159.2, 135.8, 135.7, 134.5, 134.1, 133.6, 130.51, 130.45,
130.11, 130.09, 129.74, 129.70, 129.0, 128.8, 128.7, 127.78,
127.75, 113.9, 113.6, 86.9, 85.1, 85.0, 84.0, 82.0, 78.1, 76.1,
75.3, 72.6, 68.5, 64.1, 61.5, 55.4, 55.3, 26.9, 24.7, 19.4, 15.2,
2.0; HRMS calcd for C54H66O10SSi2Na [M+Na+]: 985.3813,
found 985.3800 (-0.8 ppm).
chromatography (Hexanes/Et2O, 50:50) provided an 8:1
diastereomeric ratio of 22a (50 mg, 76%) as a clear oil. Rf =
0.30 (Hexanes/Et2O, 50:50); C51H58O9SSi; MW = 875.3571
gmol-1; IR (neat, cm-1) νmax 3070, 2931, 1760, 1728, 1613,
1514, 1248; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.66 – 7.59
(m, 4H), 7.50 – 7.31 (m, 5H), 7.25 – 7.18 (m, 8H), 7.10 (d, J =
8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H),
6.02 (dd, J = 6.0, 2.0 Hz, 1H), 5.40 (dd, J = 6.0, 2.4 Hz, 1H),
5.04 (t, J = 2.2 Hz, 1H), 4.83 (d, J = 12.4 Hz, 1H), 4.78 (d, J =
12.4 Hz, 1H), 4.57 (d, J = 9.9 Hz, 1H), 4.48 (d, J = 10.4 Hz, 1H),
4.44 (d, J = 9.8 Hz, 1H), 4.40 (d, J = 10.0 Hz, 1H), 4.37 (d, J =
10.4 Hz, 1H), 3.80 (s, 3H), 3.82 – 3.75 (m, 1H), 3.77 (s, 3H),
3.69 (dd, J = 10.4, 4.2 Hz, 1H), 3.66 (appt, J = 8.8 Hz, 1H), 3.54
(dd, J = 5.7, 4.8 Hz, 1H), 3.30 (d, J = 9.1 Hz, 1H), 2.79 (dq, J =
12.6, 7.4 Hz, 1H), 2.68 (dq, J = 12.6, 7.4 Hz, 1H), 1.29 (t, J =
7.4 Hz, 3H), 1.02 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 169.7, 159.4, 159.3, 135.8, 133.6, 133.4, 130.8, 130.5,
130.2, 130.0, 129.9, 129.8, 128.4, 128.3, 128.1, 128.05,
128.03, 127.83, 127.81, 113.9, 113.6, 94.4, 85.3, 84.9, 83.5,
81.2, 79.4, 75.3, 75.2, 66.6, 63.0, 55.43, 55.39, 27.0, 24.6,
19.3, 15.2; HRMS calcd for C51H58O9SSiNa [M+Na+]:
897.3469, found 897.3469 (+0.7 ppm).
1
2
3
4
5
6
7
8
Ethyl 4-O,4-C-((1R)-benzyloxycarbonylprop-2-en-1,3-diyl)-
6-O-(tert-butyldiphenylsilyl)- 2,3-di-O-(p-methoxybenzyl)-1-
thio-β-D-galactopyranoside (22a). To a solution of 20b (25
mg, 28 μmol, 1.0 equiv) in Et2O (0.9 mL, 0.03 M), 2,4,6-
triisopropylbenzenesulfonyl hydrazide (50 mg, 0.17 mmol,
6.0 equiv) was added. The reaction mixture was refluxed in
an oil bath for 16 h. After cooling to 25 °C, a saturated
solution of NaHCO3 (5 mL) was added to the reaction
mixture, and the aqueous layer was extracted with Et2O (2
x 5 mL), washed with brine (10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude viscous oil
was then dissolved in dichloromethane (0.20 mL, 0.14 M)
and pyridine (77 μL, 0.36 M) at 0 °C, methanesulfonyl
chloride (3.00 μL, 38.8 μmol, 2.00 equiv) was added
dropwise. The reaction mixture was warmed to 40 °C and
stirred for 3 h before water (2 mL) was added, and the
aqueous layer was extracted with dichloromethane (2 x 2
mL), washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a 4:1 ratio of
diastereomers. Purification by flash chromatography
(Hexanes/Et2O, 50:50) provided a 6:1 diastereomeric ratio
of 22a (18 mg, 72%) as a clear oil. Rf = 0.29 (Hexanes/Et2O,
50:50); C51H58O9SSi; MW = 875.3571 gmol-1; IR (neat, cm-1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 4-C-((1R,Z)-benzyloxycarbonyl-1-hydroxyprop-2-en-
3-yl)-6-O-(tert-butyldiphenylsilyl)-2,3-di-O-(p-
methoxybenzyl)-4-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (23a). To a solution of 21a (740 mg, 768
μmol, 1.00 equiv) in Et2O (15 mL, 0.050 M), 2,4,6-
triisopropylbenzenesulfonyl hydrazide (1.15 g, 3.84 mmol,
5.00 equiv) was added. The reaction mixture was refluxed
for 16 h. After cooling to 25 °C, a saturated solution of
NaHCO3 (15 mL) was added to the reaction mixture, and the
aqueous layer was extracted with Et2O (2 x 15 mL), washed
with brine (15 mL), dried over MgSO4, filtered, and
1
νmax 3069, 2931, 1759, 1733, 1613, 1514, 1249; H NMR
(500 MHz, CDCl3) δ (ppm) 7.67 – 7.60 (m, 4H), 7.44 – 7.33
(m, 11H), 7.33 – 7.27 (m, 2H), 7.12 (d, J = 8.7 Hz, 2H), 6.83
(dd, J = 8.7, 7.9 Hz, 4H), 5.86 (dd, J = 5.9, 1.8 Hz, 1H), 5.35
(dd, J = 2.7, 1.8 Hz, 1H), 5.33 (dd, J = 5.9, 2.8 Hz, 1H), 5.01 –
4.92 (m, 2H), 4.79 (d, J = 9.9 Hz, 1H), 4.65 (d, J = 10.5 Hz, 1H),
4.62 (d, J = 9.9 Hz, 1H), 4.43 (d, J = 9.7 Hz, 1H), 4.39 (d, J =
10.6 Hz, 1H), 4.03 (dd, J = 11.6, 6.7 Hz, 1H), 3.84 (dd, J = 11.6,
3.8 Hz, 1H), 3.794 (s, 3H), 3.790 (s, 3H), 3.71 (dd, J = 9.8, 9.1
Hz, 1H), 3.51 – 3.45 (m, 1H), 3.31 (d, J = 9.1 Hz, 1H), 2.86 –
2.77 (m, 1H), 2.77 – 2.67 (m, 1H), 1.31 (t, J = 7.4 Hz, 3H), 1.02
(s, 9H);13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 169.5, 159.4,
159.3, 135.80, 135.78, 134.1, 133.8, 130.7, 130.6, 130.1,
129.73, 129.70, 129.5, 128.8, 128.6, 128.39, 128.37, 128.32,
128.31, 127.77, 127.75, 113.9, 113.8, 94.7, 85.8, 85.0, 84.3,
81.3, 79.8, 75.6, 75.5, 66.7, 63.8, 55.43, 55.41, 26.9, 24.7,
19.3, 15.2; HRMS calcd for C51H58O9SSiNa [M+Na+]:
897.3469, found 897.3452 (-1.3 ppm).
concentrated
in
vacuo.
Purification
by
flash
chromatography (Hexanes/Et2O, 50:50) provided 23a
(0.50 g, 67%) as a white foam. Rf = 0.17 (Hexanes/Et2O,
25
40:60); [α]D +2.6 (c 0.3, CHCl3); C54H68O10SSi2; MW =
965.3580 gmol-1; IR (neat, cm-1) νmax 3448, 2070, 2955,
1740, 1613, 1514, 1249; 1H NMR (500 MHz, CDCl3) δ (ppm)
7.69 (d, J = 6.5 Hz, 2H), 7.64 (d, J = 6.6 Hz, 2H), 7.42 – 7.24
(m, 13H), 7.18 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 6.79
(d, J = 8.7 Hz, 2H), 5.49 (dd, J = 12.6, 1.1 Hz, 1H), 5.36 (dd, J
= 12.6, 9.0 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 5.14 – 5.08 (m,
1H), 5.08 (d, J = 12.2 Hz, 1H), 4.78 (d, J = 9.8 Hz, 1H), 4.75 (d,
J = 10.8 Hz, 1H), 4.66 (d, J = 10.8 Hz, 1H), 4.62 (d, J = 9.8 Hz,
1H), 4.47 (d, J = 9.8 Hz, 1H), 3.91 (dd, J = 11.3, 2.7 Hz, 1H),
3.85 (dd, J = 11.3, 7.2 Hz, 1H), 3.81 (d, J = 9.0 Hz, 1H), 3.79
(s, 3H), 3.78 (s, 3H), 3.75 (dd, J = 7.7, 2.7 Hz, 1H), 3.59 (appt,
J = 9.4 Hz, 1H), 2.89 – 2.65 (m, 3H), 1.32 (t, J = 7.4 Hz, 3H),
1.03 (s, 9H), 0.01 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 173.2, 159.5, 159.1, 138.5, 135.9, 135.8, 135.3, 134.1,
133.7, 130.9, 130.5, 130.1, 129.8, 129.69, 129.67, 128.74,
128.72, 128.66, 128.5, 127.73, 127.71, 113.9, 113.6, 85.7,
84.9, 83.8, 80.9, 79.4, 75.7, 75.1, 67.7, 67.1, 63.9, 55.43,
55.36, 27.0, 24.7, 19.4, 15.2, 2.9; HRMS calcd for C54H68O-
10SSi2Na [M+Na+]: 987.3964, found 987.3948 (-1.8 ppm).
Ethyl 4-O,4-C-((1S)-benzyloxycarbonylprop-2-en-1,3-diyl)-
6-O-(tert-butyldiphenylsilyl)- 2,3-di-O-(p-methoxybenzyl)-1-
thio-β-D-galactopyranoside (22b). Following a similar
procedure as in 22a, to a solution of 20a (60 mg, 67 μmol,
1.0 equiv) in Et2O (2.0 mL, 0.03 M), 2,4,6-
triisopropylbenzenesulfonyl hydrazide (0.12 g, 0.40 mmol,
6.0 equiv) was added. The crude oil was then dissolved in
dichloromethane (0.67 mL, 0.10 M) and pyridine (0.19 mL,
0.35 M) and methanesulfonyl chloride (10 μL, 0.13 mmol,
4-C-((1S,Z)-benzyloxycarbonyl-1-hydroxyprop-2-en-3-yl)-
6-O-(tert-butyldiphenylsilyl)-2,3-di-O-(p-methoxybenzyl)-4-
1
2.0 equiv) was added dropwise. H NMR spectroscopic
O-trimethylsilyl-1-thio-β-D-galactopyranoside
(23b).
analysis of the unpurified product indicated the formation
Following a similar procedure as in 23a, to a solution of 21b
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Page 12 of 20
(423 mg, 439 μmol, 1.00 equiv) in Et2O (9 mL, 0.05 M), 2,4,6-
C39H54O10S2Si2Na [M+Na+]: 825.2589, found 825.2586 (-0.4
ppm).
Ethyl
methanesulfonyloxyprop-2-en-3-yl)-6-O-(tert-
butyldiphenylsilyl)-4-O-trimethylsilyl-1-thio-β-D-
1
2
3
4
5
6
7
8
triisopropylbenzenesulfonyl hydrazide (655 mg, 2.20
mmol, 5.00 equiv) was added. Purification by flash
chromatography (Hexanes/Et2O, 50:50) provided 23b
(0.37 g, 87%) as a white foam. Rf = 0.21 (Hexanes/Et2O,
4-C-((1S,Z)-benzyloxycarbonyl-1-
25
40:60); [α]D +35 (c 0.8, CHCl3); C54H68O10SSi2; MW =
galactopyranoside (24b). Following a similar procedure as
in 24a, to a solution of 23b (320 mg, 331 mmol, 1.00 equiv)
in anhydrous dichloromethane (3.3 mL, 0.10 M),
triethylamine (116 μL, 829 μmol, 2.50 equiv) and
methanesulfonyl chloride (51.3 μL, 663 μmol, 2.00 equiv)
were added dropwise. The crude residue was dissolved in a
20:1 solution of dichloromethane and water (6.5 mL, 0.05
M) and DDQ (163 mg, 717 μmol, 2.20 equiv) was added.
Purification by flash chromatography (Hexanes/EtOAc,
50:50) provided 24b (0.19 g, 74%) as a clear oil. Rf = 0.23
965.3580 gmol-1; IR (neat, cm-1) νmax 2931, 1734, 1614,
1514, 1249; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.69 (d, J =
6.5 Hz, 2H), 7.65 (d, J = 6.6 Hz, 2H), 7.45 – 7.26 (m, 9H), 7.24
(s, 4H), 7.15 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.78
(d, J = 8.6 Hz, 2H), 5.45 (dd, J = 12.4, 8.6 Hz, 1H), 5.29 (d, J =
12.3 Hz, 1H), 5.18 (dd, J = 8.9, 3.5 Hz, 1H), 5.11 (d, J = 12.1
Hz, 1H), 5.05 (d, J = 12.1 Hz, 1H), 4.81 (d, J = 9.8 Hz, 1H), 4.68
(d, J = 10.6 Hz, 1H), 4.62 (d, J = 9.8 Hz, 1H), 4.57 (d, J = 10.6
Hz, 1H), 4.49 (d, J = 9.6 Hz, 1H), 3.88 – 3.74 (m, 2H), 3.80 (s,
3H), 3.78 (s, 3H), 3.66 (dd, J = 7.0, 2.7 Hz, 1H), 3.61 (t, J = 9.3
Hz, 1H), 3.55 (d, J = 9.1 Hz, 1H), 3.06 (d, J = 3.8 Hz, 1H), 2.89
– 2.70 (m, 2H), 1.33 (t, J = 7.4 Hz, 3H), 1.02 (s, 9H), 0.03 (s,
9H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 173.0, 159.5,
159.3, 136.8, 135.8, 135.8, 135.3, 133.7, 133.5, 130.4, 130.2,
130.1, 130.0, 129.81, 129.77, 129.72, 128.7, 128.6, 127.79,
127.77, 127.6, 113.9, 113.6, 85.3, 84.9, 84.3, 81.3, 79.4, 75.9,
75.1, 67.4, 66.7, 63.8, 55.4, 55.3, 26.9, 25.1, 19.2, 15.3, 3.0;
HRMS calcd for C54H68O10SSi2Na [M+Na+]: 987.3964, found
987.3960 (-0.4 ppm).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
(EtOAc/Hex 1:1); [α]D +23 (c 1.4, CHCl3); C39H54O10S2Si2;
MW = 803.1410 gmol-1; IR (neat, cm-1) νmax 3505, 2931,
1751, 1360; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.68 (dd, J =
14.9, 6.5 Hz, 4H), 7.47 – 7.34 (m, 7H), 7.31 – 7.24 (m, 2H),
7.22 (d, J = 7.7 Hz, 2H), 6.46 (d, J = 9.8 Hz, 1H), 5.50 (dd, J =
12.2, 9.8 Hz, 1H), 5.40 (d, J = 12.2 Hz, 1H), 5.10 (d, J = 12.1
Hz, 1H), 4.98 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 3.88
(dd, J = 11.6, 3.0 Hz, 1H), 3.81 (dd, J = 11.6, 7.0 Hz, 1H), 3.64
– 3.50 (m, 3H), 3.05 (s, 3H), 2.83 – 2.68 (m, 2H), 2.62 (s, 2H),
1.33 (t, J = 7.4 Hz, 3H), 1.05 (s, 9H), 0.07 (s, 9H);13C{1H} NMR
(126 MHz, CDCl3) δ (ppm) 167.4, 137.7, 135.82, 135.75,
134.7, 133.6, 133.4, 129.9, 129.8, 128.8, 128.7, 128.6, 127.9,
127.8, 123.4, 86.3, 84.3, 81.1, 77.2, 73.4, 70.8, 67.9, 63.6,
39.4, 26.9, 25.2, 19.3, 15.4, 3.0; HRMS calcd for
C39H54O10S2Si2Na [M+Na+]: 825.2589, found 825.2586 (-0.4
ppm).
Ethyl
4-C-((1R,Z)-benzyloxycarbonyl-1-
methanesulfonyloxyprop-2-en-3-yl)-6-O-(tert-
butyldiphenylsilyl)-4-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (24a). To a solution of 23a (250 mg, 259
mmol, 1.00 equiv) in anhydrous dichloromethane (2.6 mL,
0.10 M) at 0 °C, triethylamine (90.2 μL, 647 μmol, 2.50
equiv) and methanesulfonyl chloride (40.1 μL, 518 μmol,
2.00 equiv) were added dropwise. The reaction mixture was
warmed to 25 °C and stirred for 30 min. before water (5 mL)
was added, and the aqueous layer was extracted with
dichloromethane (2 x 5 mL), washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The crude
residue was dissolved in a 20:1 solution of dichloromethane
and water (5.2 mL, 0.05 M) and DDQ (129 mg, 569 μmol,
2.20 equiv) was added. The reaction mixture was stirred for
30 min. before being refluxed for 30 min. After cooling to 25
°C, a saturated solution of NaHCO3 (10 mL) was added to the
reaction mixture, and the aqueous layer was extracted with
ethyl acetate (2 x 10 mL), washed with brine (10 mL), dried
over MgSO4, filtered, and concentrated in vacuo. Purification
by flash chromatography (Hexanes/EtOAc, 50:50) provided
24a (0.15 g, 72 %) as a clear oil. Rf = 0.4 (Hexanes/EtOAc,
Compounds in Table 2: Ethyl 3-O,4-C-((1S)-
benzyloxycarbonylprop-2-en-1,3-diyl)-6-O-(tert-
butyldiphenylsilyl)-4-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (25b). To a 1:1 mixture of 24a and 24b
(4.00 g, 4.98 mmol, 1.00 equiv) in anhydrous toluene (16
mL, 0.20 M), diisopropylethylamine (2.60 mL, 14.9 mmol,
3.00 equiv) was added. The reaction mixture was warmed
to 100 °C for 2 h. The dark brown solution was then cooled
to room temperature and a saturated solution of NaHCO3
(20 mL) was added. The aqueous layer was extracted with
ethyl acetate (2 x 20 mL), and the combined organic layers
were washed with brine (40 mL), dried over MgSO4, filtered,
1
and concentrated in vacuo. H NMR spectroscopic analysis
of the unpurified product indicated the formation of a 13:1
ratio
of
diastereomers.
Purification
by
flash
chromatography (Hexanes/ Et2O, 50:50) provided 25b (2.3
g, 65%) as a clear oil. Note: 41 mg of 25a was recovered as
an inseparable mixture with an unknown decomposition
product. Rf = 0.31 (Hexanes/ Et2O, 50:50); [α]D25 -51 (c 0.3,
CHCl3); C38H50O7SSi2; MW = 707.0410 gmol-1; IR (neat, cm-1)
25
50:50): [α]D -50 (c 1.1, CHCl3); C39H54O10S2Si2 MW =
803.1410 gmol-1; IR (neat, cm-1) νmax 3503, 2956, 1757,
1733, 1363; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.66 (dd, J =
12.6, 6.5 Hz, 4H), 7.43 – 7.32 (m, 11H), 6.35 (d, J = 7.4 Hz,
1H), 5.50 – 5.44 (m, 2H), 5.24 (d, J = 12.0 Hz, 1H), 5.16 (d, J
= 12.0 Hz, 1H), 4.07 (d, J = 9.7 Hz, 1H), 3.89 (dd, J = 11.2, 3.9
Hz, 1H), 3.80 (d, J = 8.8 Hz, 1H), 3.77 (dd, J = 11.3, 6.3 Hz,
1H), 3.60 (dd, J = 9.7, 8.9 Hz, 1H), 3.46 (dd, J = 6.2, 4.0 Hz,
1H), 2.95 (s, 3H), 2.73 – 2.65 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H),
1.05 (s, 9H), 0.08 (s, 9H) (Labile protons were not observed
due to exchange with deuterated solvent); 13C{1H} NMR (126
MHz, CDCl3) δ (ppm) 167.8, 137.1, 135.8, 135.7, 134.4,
133.6, 133.3, 129.9, 129.8, 129.04, 128.95, 128.87, 127.9,
127.8, 123.0, 86.0, 83.5, 80.4, 75.7, 74.4, 70.4, 68.7, 63.3,
39.0, 27.0, 24.7, 19.3, 15.5, 2.8; HRMS calcd for
1
νmax 3483, 2931, 1749, 1251; H NMR (500 MHz, CDCl3) δ
(ppm) 7.65 (ddd, J = 6.8, 3.4, 1.7 Hz, 4H), 7.44 – 7.33 (m,
11H), 6.33 (dd, J = 10.2, 2.7 Hz, 1H), 6.08 (dd, J = 10.2, 3.4
Hz, 1H), 5.27 (d, J = 12.2 Hz, 1H), 5.20 (d, J = 12.2 Hz, 1H),
4.88 (t, J = 3.1 Hz, 1H), 4.29 (d, J = 9.2 Hz, 1H), 3.97 (dd, J =
10.9, 6.0 Hz, 1H), 3.81 (td, J = 9.4, 1.7 Hz, 1H), 3.73 (dd, J =
10.9, 4.9 Hz, 1H), 3.65 (d, J = 9.6 Hz, 1H), 3.33 (dd, J = 6.0, 4.9
Hz, 1H), 2.76 – 2.61 (m, 2H), 2.50 (d, J = 1.8 Hz, 1H), 1.27 (t,
J = 7.5 Hz, 3H), 1.06 (s, 9H), 0.02 (s, 9H); 13C{1H} NMR (126
MHz, CDCl3) δ (ppm) 169.5, 135.79, 135.76, 135.3, 133.4,
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The Journal of Organic Chemistry
133.3, 129.93, 129.91, 129.1, 128.8, 128.7, 128.6, 128.5,
acetate (2 x 2 mL), and the combined organic layers were
washed with brine , dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash
1
2
3
4
5
6
7
8
127.88, 127.86, 86.2, 81.1, 80.7, 73.4, 68.8, 67.5, 67.4, 63.0,
27.0, 23.9, 19.3, 15.4, 2.2; HRMS calcd for C38H50O7SSi2Na
[M+Na+]: 729. 2713, found 729.2717 (-0.1 ppm).
chromatography (Hexanes/Et2O, 50:50) provided 27 (0.17
25
g, 64%) as a clear oil. Rf = 0.18 (Hexanes/Et2O, 50:50); [α]D
Ethyl 4-O,4-C-((1R)-benzyloxycarbonylprop-2-en-1,3-diyl)-
6-O-(tert-butyldiphenylsilyl)-3-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (26a) and Ethyl 4-O,4-C-((1S)-
benzyloxycarbonylprop-2-en-1,3-diyl)-6-O-(tert-
+28 (c 0.9, CHCl3); C38H50O7SSi2; MW = 707.0410 gmol-1; IR
1
(neat, cm-1) νmax 3410, 2931, 1724, 1652, 1428, 1252; H
NMR (500 MHz, CDCl3) δ (ppm) 7.71 – 7.59 (m, 4H), 7.52 –
7.30 (m, 11H), 6.04 (dd, J = 5.0, 3.0 Hz, 1H), 5.28 (d, J = 12.4
Hz, 1H), 5.22 (d, J = 12.3 Hz, 1H), 4.33 (d, J = 9.6 Hz, 1H), 3.93
– 3.82 (m, 2H), 3.78 (dd, J = 11.0, 5.8 Hz, 1H), 3.47 (d, J = 9.1
Hz, 1H), 3.26 (t, J = 5.6 Hz, 1H), 2.84 (d, J = 1.9 Hz, 1H), 2.82
– 2.61 (m, 2H), 2.26 – 2.09 (m, 2H), 1.29 (t, J = 7.4 Hz, 3H),
1.06 (s, 9H), -0.04 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 162.0, 143.9, 135.81, 135.76, 133.4, 133.2, 130.0,
129.97, 128.7, 128.4, 128.3, 127.91, 127.903, 127.895,
110.1, 85.4, 83.0, 82.6, 70.6, 67.8, 66.9, 62.9, 31.2, 27.0, 23.6,
19.3, 15.3, 2.3; HRMS calcd for C38H50O7SSi2Na [M+Na+]:
729.2713, found 729.2724 (+2.1 ppm).
butyldiphenylsilyl)-3-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (26b). To a solution of 24a (62.0 mg,
77.2 μmol, 1.00 equiv) in acetonitrile (0.77 mL, 0.10 M),
diisopropylethylamine (404 μL, 232 μmol, 3.00 equiv) was
added. The reaction mixture was refluxed for 2 h. The dark
brown solution was then cooled to room temperature and
water (2 mL) was added. The aqueous layer was extracted
with Et2O (2 x 2 mL), and the combined organic layers were
washed with brine (4 mL), dried over MgSO4, filtered, and
concentrated in vacuo. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a 3.4:1 ratio
of inseparable diastereomers. Purification by flash
chromatography (Hexanes/EtOAc, 70:30) provided 26a
and 26b as a 3.2:1 mixture of diastereomers (46 mg, 84%)
as a clear oil. Rf = 0.30 (Hexanes/EtOAc 60:40);
C38H50O7SSi2; MW = 707.0410 gmol-1; IR (neat, cm-1) νmax
3532, 3070, 2957, 1760, 1731, 1428, 1249; HRMS calcd for
C35H42O7SSiNa [M–TMS+Na+]: 657.2318, found 657.2303 (-
1.5 ppm).
26a: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.69 – 7.60 (m,
4H), 7.48 – 7.31 (m, 7H), 7.27 (d, J = 1.9 Hz, 3H), 7.24 – 7.18
(m, 1H), 5.90 (dd, J = 6.0, 1.6 Hz, 1H), 5.35 (dd, J = 6.0, 2.8 Hz,
1H), 5.27 (dd, J = 2.8, 1.7 Hz, 1H), 5.00 (d, J = 12.2 Hz, 1H),
4.95 (d, J = 12.2 Hz, 1H), 4.30 (d, J = 9.8 Hz, 1H), 4.04 (dd, J =
11.6, 6.6 Hz, 1H), 3.88 (dd, J = 11.6, 3.7 Hz, 1H), 3.71 – 3.61
(m, 1H), 3.58 (dd, J = 6.6, 3.8 Hz, 1H), 3.43 (d, J = 8.7 Hz, 1H),
2.83 – 2.64 (m, 2H), 2.24 (d, J = 2.2 Hz, 1H), 1.31 (t, J = 7.4
Hz, 3H), 1.02 (s, 9H), 0.07 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3) δ (ppm) 169.5, 135.83, 135.78, 134.1, 133.8, 129.86,
129.69, 129.4, 128.6, 128.5, 128.36, 128.33, 127.82, 127.74,
127.73, 94.7, 86.04, 85.98, 81.5, 78.1, 71.2, 66.6, 64.0, 26.9,
24.1, 19.3, 15.5, 0.6;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compounds in Scheme 6: Ethyl 2-O-benzoyl-3-O,4-C-
((1R)-benzyloxycarbonylprop-2-en-1,3-diyl)-6-O-(tert-
butyldiphenylsilyl)-4-O-trimethylsilyl-1-thio-β-D-
galactopyranoside (30a). To a crude mixture of 25a (41 mg,
58 μmol, 50.0% purity, 1.0 equiv) in dichloromethane (0.28
mL, 0.10 M), pyridine (6.9 μL, 85 μmol, 3.0 equiv) and
benzoyl chloride (4.9 μL, 424 μmol, 1.5 equiv) were added.
After stirring for 16 h at 25 °C, a saturated solution of
NaHCO3 (2 mL) was added. The aqueous layer was
extracted with Et2O (2 x 2 mL), and the combined organic
layers were washed with brine (4 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography (Hexanes/Et2O, 70:30) provided 30a (17
mg, 72%) as a white foam. Rf = 0.33 (Hexanes/Et2O, 70:30);
[α]D25 +11 (c 0.3, CHCl3); C45H54O8SSi2 MW = 811.1490 gmol-
1; IR (neat, cm-1) νmax 3049, 2957, 1765, 1731, 1452, 1267;
1H NMR (500 MHz, CDCl3) δ (ppm) 8.03 (dd, J = 8.3, 1.4 Hz,
2H), 7.75 – 7.64 (m, 4H), 7.62 – 7.51 (m, 1H), 7.48 – 7.35 (m,
9H), 7.30 (apps, 4H), 6.31 (dd, J = 10.3, 2.8 Hz, 1H), 6.10 (dd,
J = 10.3, 1.8 Hz, 1H), 5.62 (t, J = 9.8 Hz, 1H), 5.15 (s, 2H), 4.83
(t, J = 2.4 Hz, 1H), 4.51 (d, J = 9.5 Hz, 1H), 4.03 (dd, J = 10.8,
6.3 Hz, 1H), 3.78 (dd, J = 10.8, 4.7 Hz, 1H), 3.62 (d, J = 10.0
Hz, 1H), 3.48 (dd, J = 6.3, 4.7 Hz, 1H), 2.76 (dq, J = 12.3, 7.4
Hz, 1H), 2.67 (dq, J = 12.3, 7.5 Hz, 1H), 1.21 (t, J = 7.5 Hz, 3H),
1.07 (s, 9H), 0.03 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 167.9, 165.4, 135.8, 135.7, 135.3, 133.5, 133.2, 133.0,
130.5, 130.0, 129.9, 129.4, 128.66, 128.64, 128.62, 128.47,
128.45, 128.41, 127.91, 127.89, 83.3, 81.6, 81.5, 76.0, 69.8,
68.3, 67.1, 62.9, 27.0, 22.9, 19.3, 15.0, 2.4; HRMS calcd for
C45H54O8SSi2Na [M+Na+]: 833.2976, found 833.2984 (+1.7
ppm).
26b: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.69 – 7.61 (m,
4H), 7.48 – 7.32 (m, 7H), 7.27 (dd, J = 2.8, 2.2 Hz, 3H), 7.24 –
7.18 (m, 1H), 6.00 (dd, J = 6.1, 1.9 Hz, 1H), 5.41 (dd, J = 6.1,
2.5 Hz, 1H), 5.17 (d, J = 12.4 Hz, 1H), 5.05 (d, J = 12.4 Hz, 1H),
5.01 (t, J = 2.2 Hz, 1H), 4.35 (d, J = 9.8 Hz, 1H), 3.80 (dd, J =
10.9, 5.7 Hz, 1H), 3.79 – 3.72 (m, 1H), 3.75 – 3.67 (m, 1H),
3.66 – 3.63 (m, 1H), 3.46 (d, J = 8.8 Hz, 1H), 2.85 – 2.64 (m,
2H), 2.20 (d, J = 2.3 Hz, 1H), 1.29 (t, J = 7.4 Hz, 3H), 1.03 (s,
9H), 0.01 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
169.3, 135.8, 135.7, 133.6, 133.4, 129.86, 129.82, 129.4,
128.7, 128.6, 128.5, 128.4, 128.3, 127.82, 127.80, 94.4, 85.9,
85.4, 81.6, 78.1, 70.9, 66.5, 63.2, 26.9, 24.1, 19.3, 15.4, 0.6.
Ethyl 2-O-benzoyl-3-O,4-C-((1S)-benzyloxycarbonylprop-
2-en-1,3-diyl)-6-O-(tert-butyldiphenylsilyl)-4-O-
trimethylsilyl-1-thio-β-D-galactopyranoside
(30b).
Ethyl 3-O,4-C-(benzyloxycarbonylprop-1-en-1,3-diyl)-6-O-
(tert-butyldiphenylsilyl)-4-O-trimethylsilyl-1-thio-β-D-
Following a similar procedure as in 30a, to a solution of 25b
(280 mg, 396 μmol, 1.00 equiv) in dichloromethane (4.0 mL,
0.10 M), pyridine (96 μL, 1.2 mmol, 3.0 equiv) and benzoyl
chloride (69 μL, 0.59 mmol, 1.5 equiv) were added.
Purification by flash chromatography (Hexanes/Et2O,
70:30) provided 30b (0.30 g, 93%) as a white foam. Rf =
galactopyranoside (27). To a 1:1 mixture of 24a and 24b
(30 mg, 18.7 μmol, 1.00 equiv) in anhydrous toluene (0.37
mL, 0.10 M), diisopropylethylamine (19.5 μL, 112 μmol,
3.00 equiv) was added. The reaction mixture was warmed
to 100 °C for 16 h. The dark brown solution was then cooled
to room temperature and a saturated solution of NaHCO3 (2
mL) was added. The aqueous layer was extracted with ethyl
25
0.40 (Hexanes/Et2O, 70:30); [α]D -58 (c 0.8, CHCl3);
C45H54O8SSi2 MW = 811.1490 gmol-1; IR (neat, cm-1) νmax
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1
3071, 2958, 1754, 1726, 1552, 1339; H NMR (500 MHz,
CDCl3) δ (ppm) 8.20 – 8.07 (m, 2H), 7.75 – 7.62 (m, 4H), 7.58
– 7.51 (m, 1H), 7.55 – 7.35 (m, 8H), 7.35 – 7.25 (m, 3H), 7.28
– 7.23 (m, 2H), 6.40 (dd, J = 10.3, 2.8 Hz, 1H), 6.07 (dd, J =
10.3, 3.5 Hz, 1H), 5.54 (t, J = 9.8 Hz, 1H), 5.15 (d, J = 2.1 Hz,
2H), 4.83 (t, J = 3.1 Hz, 1H), 4.53 (d, J = 9.5 Hz, 1H), 4.05 (d, J
= 10.2 Hz, 1H), 4.03 (d, J = 10.9 Hz, 1H), 3.79 (dd, J = 10.9,
4.8 Hz, 1H), 3.45 (dd, J = 6.1, 4.8 Hz, 1H), 2.76 (dq, J = 12.4,
7.5 Hz, 1H), 2.68 (dq, J = 12.4, 7.4 Hz, 1H), 1.22 (t, J = 7.5 Hz,
3H), 1.08 (s, 9H), 0.08 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 169.3, 165.9, 135.81, 135.76, 135.4, 133.5,
133.2, 132.9, 130.5, 130.2, 129.95, 129.93, 128.82, 128.80,
128.75, 128.6, 128.4, 128.3, 127.90, 127.89, 83.2, 81.0, 78.8,
73.3, 69.2, 68.5, 67.0, 63.0, 27.0, 23.1, 19.3, 15.0, 2.2; HRMS
calcd for C45H54O8SSi2Na [M+Na+]: 833.2976, found
833.2971 (-0.6 ppm).
Hz, 1H), 5.64 (t, J = 9.7 Hz, 1H), 5.18 (s, 2H), 4.92 (td, J = 2.4,
1
2
3
4
5
6
7
8
0.7 Hz, 1H), 4.62 (d, J = 9.8 Hz, 1H), 4.08 (dd, J = 12.2, 6.7 Hz,
1H), 3.95 (dd, J = 12.2, 3.2 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H),
3.56 (dd, J = 6.7, 3.2 Hz, 1H), 2.88 – 2.67 (m, 2H), 1.63 (s, 2H),
1.26 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 168.8, 165.4, 135.0, 133.2, 130.2, 130.1, 129.8,
128.83, 128.75, 128.53, 128.49, 128.42, 83.8, 79.8, 79.7,
75.5, 68.7, 67.8, 67.2, 60.7, 23.7, 15.0; HRMS calcd for
C26H28O8SNa [M+Na+]: 523.1403, found 523.1399 (+0.4
ppm).
9
Ethyl 2-O-benzoyl-3-O,4-C-((1S)-benzyloxycarbonylprop-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-en-1,3-diyl)-1-thio-β-D-galactopyranoside
(32b).
Following a similar procedure as in 32a, to a solution of 30b
(39.0 mg, 48.1 μmol, 1.00 equiv) in anhydrous THF (0.14
mL, 0.33 M), triethylamine trihydrofluoride (157 μL, 962
μmol, 20.0 equiv) was added. Purification by flash
chromatography (Hexanes/EtOAc, 20:80) provided 32b
(20 mg, 83%) as a white foam. Rf = 0.43 (Hexanes/EtOAc,
10:90); [α]D25 -124 (c 1.6, CHCl3); C26H28O8S; MW = 500.5620
gmol-1; IR (neat, cm-1) νmax 3468, 3064, 2967, 1749, 1721,
1452, 1267; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.20 – 8.01
(m, 2H), 7.69 – 7.50 (m, 1H), 7.49 – 7.38 (m, 2H), 7.35 – 7.28
(m, 3H), 7.26 – 7.18 (m, 2H), 6.18 (dd, J = 10.2, 2.3 Hz, 1H),
6.13 (dd, J = 10.2, 3.2 Hz, 1H), 5.61 (t, J = 9.7 Hz, 1H), 5.13 (d,
J = 12.2 Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H), 4.91 (dd, J = 3.2,
2.3 Hz, 1H), 4.67 (d, J = 9.7 Hz, 1H), 4.17 (d, J = 9.7 Hz, 1H),
4.06 (dd, J = 12.2, 6.2 Hz, 1H), 3.96 (dd, J = 12.2, 3.2 Hz, 1H),
3.52 (dd, J = 6.3, 3.2 Hz, 1H), 2.87 – 2.68 (m, 2H), 2.36 (s, 2H),
1.26 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 168.8, 165.9, 135.2, 133.1, 130.22, 130.20, 129.1,
128.8, 128.7, 128.5, 128.4, 128.2, 84.0, 79.5, 78.4, 73.2, 68.7,
67.2, 66.7, 60.8, 24.0, 15.1; HRMS calcd for C26H28O8SNa
[M+Na+]: 523.1403, found 523.1395 (-0.4 ppm).
Ethyl 2-O-benzoyl-3-O,4-C-(benzyloxycarbonylprop-1-en-
1,3-diyl)-1-thio-β-D-galactopyranoside (31). To a solution of
30b (22.0 mg, 27.1 μmol, 1.00 equiv) in anhydrous THF (0.3
mL, 0.09 M), TBAF (81 μL, 1.0 M in THF, 3.0 equiv) was
added dropwise. The reaction mixture was stirred for 1 h
before being diluted with EtOAc (2 mL) and a saturated
solution of NH4Cl (2 mL) was added. The aqueous layer was
extracted with EtOAc (2 x 2 mL), and the organic layers
were combined, washed with brine (5 mL), dried over
MgSO4, filtered and concentrated in vacuo. Purification by
flash chromatography (Hexanes/EtOAc, 20:80) provided
31 (11 mg, 81%) as a clear oil. Rf = 0.41 (Hexanes/EtOAc,
10:90); [α]D25 +29 (c 0.3, CHCl3); C26H28O8S; MW = 500.5620
gmol-1; IR (neat, cm-1) νmax 3475, 3065, 2963, 1724, 1452,
1268;1H NMR (500 MHz, CDCl3) δ (ppm) 8.11 – 8.01 (m, 2H),
7.62 – 7.55 (m, 1H), 7.48 – 7.39 (m, 2H), 7.25 – 7.11 (m, 5H),
6.14 (dd, J = 5.1, 2.8 Hz, 1H), 5.66 (dd, J = 10.1, 9.4 Hz, 1H),
5.19 (d, J = 12.7 Hz, 1H), 5.05 (d, J = 12.6 Hz, 1H), 4.70 (d, J =
10.1 Hz, 1H), 4.06 (dd, J = 12.3, 6.1 Hz, 1H), 3.94 (dd, J = 12.4,
3.0 Hz, 1H), 3.89 (dd, J = 9.4, 1.4 Hz, 1H), 3.45 (dd, J = 6.1, 3.0
Hz, 1H), 2.87 – 2.67 (m, 2H), 2.32 (ddd, J = 18.7, 2.9, 1.1 Hz,
1H), 2.25 (ddd, J = 18.7, 5.1, 1.6 Hz, 1H), 1.86 (s, 2H), 1.27 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ (ppm)
165.4, 161.6, 143.8, 135.5, 133.3, 130.1, 130.0, 129.9, 128.5,
128.1, 127.8, 108.9, 83.9, 81.4, 79.9, 68.8, 68.2, 66.7, 61.1,
31.6, 24.1, 15.0; HRMS calcd for C26H28O8SNa [M+Na+]:
523.1403, found 523.1396 (-0.1 ppm).
Ethyl 2-O-benzoyl-3-O,4-C-((1R)-carboxyprop-1,3-diyl)-1-
thio-β-D-galactopyranoside (5a). To a solution of 32a (11.0
mg, 22.0 μmol, 1.00 equiv) in THF (1.8 mL, 0.01 M),
palladium hydroxide (20 wt. %) on carbon (10.8 mg, 15.4
μmol, 0.70 equiv) was added. The reaction mixture was
degassed and flushed with a hydrogen filled balloon. After
stirring at 25 °C under a standard hydrogen atmosphere for
16 h, the reaction mixture was filtered through Celite,
washed with methanol, and concentrated in vacuo.
Purification by reverse phase C18 (H2O/MeOH, 60:40)
provided 5a (6.5 mg, 72%) as a clear film. [α]D25 +35 (c 0.1,
MeOH); C19H24O8S; MW = 412.4530 gmol-1; IR (neat, cm-1)
νmax 3360, 2934, 1715, 1604, 1424, 1277; 1H NMR (500 MHz,
CD3OD) δ (ppm) 8.00 (dd, J = 8.3, 1.4 Hz, 2H), 7.59 (t, J = 7.5
Hz, 1H), 7.50 – 7.43 (m, 2H), 5.42 (t, J = 9.7 Hz, 1H), 4.71 (d,
J = 9.9 Hz, 1H), 3.89 (dd, J = 11.2, 3.6 Hz, 1H), 3.85 – 3.75 (m,
2H), 3.68 (d, J = 9.6 Hz, 1H), 3.51 (dd, J = 6.6, 3.5 Hz, 1H),
2.81 (dq, J = 12.4, 7.5 Hz, 1H), 2.73 (dq, J = 12.6, 7.5 Hz, 1H),
1.94 – 1.79 (m, 3H), 1.65 (td, J = 13.0, 5.5 Hz, 1H), 1.23 (t, J =
7.4 Hz, 3H) (Labile protons were not observed due to
exchange with deuterated solvent); 13C{1H} NMR (126 MHz,
CD3OD) δ (ppm) 179.2, 167.5, 134.2, 131.5, 130.8, 129.4,
84.9, 83.7, 82.5, 81.1, 70.9, 70.5, 61.3, 32.1, 25.5, 24.7, 15.3;
HRMS calcd for C19H24O8SNa [M+Na+]: 435.1090, found:
435.1081 (-0.7 ppm).
Ethyl 2-O-benzoyl-3-O,4-C-((1R)-benzyloxycarbonylprop-
2-en-1,3-diyl)-1-thio-β-D-galactopyranoside (32a). To a
solution of 30a (35.0 mg, 43.1 μmol, 1.00 equiv) in
anhydrous THF (0.14 mL, 0.33 M), triethylamine
trihydrofluoride (129 μL, 863 μmol, 20.0 equiv) was added.
The reaction mixture was stirred for 3 h before being
diluted with EtOAc (2 mL) and a saturated solution of NH4Cl
(2 mL) was added. The aqueous layer was extracted with
EtOAc (2 x 2 mL), and the organic layers were combined,
washed with brine (5 mL), dried over MgSO4, filtered and
concentrated
in
vacuo.
Purification
by
flash
chromatography (Hexanes/EtOAc, 20:80) provided 32a (15
mg, 69%) as a white foam. Rf = 0.45 (Hexanes/EtOAc,
10:90); [α]D25 +90 (c 0.2, CHCl3); C26H28O8S; MW = 500.5620
gmol-1; IR (neat, cm-1) νmax 3467, 3064, 2929, 1723, 1452,
1
1266; H NMR (500 MHz, CDCl3) δ (ppm) 8.12 – 8.02 (m,
Ethyl 2-O-benzoyl-3-O,4-C-((1S)-carboxyprop-1,3-diyl)-1-
2H), 7.57 (t, J = 7.4 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.35 – 7.30
(m, 5H), 6.25 (dd, J = 10.1, 2.4 Hz, 1H), 5.99 (dd, J = 10.1, 2.4
thio-β-D-galactopyranoside (5b). Following
a similar
procedure as in 5a, to a solution of 32b (22.0 mg, 43.9 μmol,
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The Journal of Organic Chemistry
1.00 equiv) in THF (0.9 mL, 0.05 M), palladium hydroxide 78.0, 77.9, 77.7, 77.6, 77.4, 75.9, 74.8, 73.3, 73.2, 72.5, 70.5,
1
2
3
4
(20 wt. %) on carbon (21.6 mg, 30.7 μmol, 0.70 equiv) was
added. Purification by reverse phase C18 (H2O/MeOH,
60:40) provided 5b (16 mg, 88%) as a clear film. [α]D25 +11
(c 0.3, MeOH); C19H24O8S; MW = 412.4530 gmol-1; IR (neat,
69.1, 68.8, 67.4, 66.9, 62.8, 27.1, 21.8, 21.71, 21.66, 21.6,
19.3, 16.6, 2.2; HRMS calcd for C80H94O18Si2Na [M+Na+]:
1421.5876, found 1421.5832 (-2.7 ppm).
(2R,3R)-2-O-(2-O-benzoyl-3-O,4-C-((1S)-
1
cm-1) νmax 3375, 3070, 2930, 1712, 1592, 1401, 1275; H
5
benzyloxycarbonylprop-2-en-1,3-diyl)-β-D-
NMR (500 MHz, CD3OD) δ (ppm) 8.12 – 8.05 (m, 2H), 7.62 –
7.53 (m, 1H), 7.50 – 7.42 (m, 2H), 5.37 (t, J = 9.8 Hz, 1H), 4.68
(d, J = 9.9 Hz, 1H), 4.34 (d, J = 9.7 Hz, 1H), 4.24 – 4.18 (m,
1H), 3.88 – 3.73 (m, 2H), 3.42 (dd, J = 6.2, 3.2 Hz, 1H), 2.85 –
2.66 (m, 2H), 2.30 – 2.19 (m, 1H), 2.13 – 2.05 (m, 1H), 1.71
– 1.58 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H) (Labile protons were
not observed due to exchange with deuterated solvent);
13C{1H} NMR (126 MHz, CD3OD) δ (ppm) 178.8, 168.0,
133.9, 132.1, 131.0, 129.3, 85.4, 83.8, 77.9, 76.0, 71.2, 70.9,
61.4, 29.2, 24.9, 23.1, 15.3; HRMS calcd for C19H24O8SNa
[M+Na+]: 435.1090, found 435.1083 (-0.3 ppm).
6
7
8
9
galactopyranosyl)-3-O-(2,3,4-tri-O-benzyl-α-L-
fucopyranosyl)-tartaric acid diisopropyl ester (35). To a
solution of 34 (55.0 mg, 39.3 μmol, 1.00 equiv) in anhydrous
THF (0.12 mL, 0.33 M), triethylamine trihydrofluoride (157
μL, 962 μmol, 20.0 equiv) was added. The reaction mixture
was stirred for 3 h before a second addition of triethylamine
trihydrofluoride (157 μL, 962 μmol, 20.0 equiv) was added
dropwise. After 2 h, the reaction mixture was diluted with
EtOAc (2 mL) and a saturated solution of NH4Cl (2 mL) was
added. The aqueous layer was extracted with EtOAc (2 x 2
mL), and the organic layers were combined, washed with
brine (5 mL), dried over MgSO4, filtered and concentrated in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compounds from Scheme 7: (2R,3R)-2-O-(2-O-benzoyl-
3-O,4-C-((1S)-benzyloxycarbonylprop-2-en-1,3-diyl)-6-O-
(tert-butyldiphenylsilyl)-4-O-trimethylsilyl-β-D-
vacuo.
Purification
by
flash
chromatography
(Hexanes/EtOAc, 20:80) provided 35 (40 mg, 94%) as a
clear oil. Rf = 0.35 (Hexanes/EtOAc, 30:70); [α]D25 -66 (c 0.8,
CHCl3); C61H68O18; MW = 1089.1970 gmol-1; IR (neat, cm-1)
νmax 3462, 3060, 2981, 1731, 1454, 1272; 1H NMR (500 MHz,
CDCl3) δ (ppm) 8.30 – 8.24 (m, 2H), 7.57 – 7.14 (m, 23H),
6.06 (dd, J = 10.1, 3.4 Hz, 1H), 5.88 (dd, J = 10.1, 2.7 Hz, 1H),
5.52 (d, J = 7.7 Hz, 1H), 5.43 (dd, J = 10.0, 7.7 Hz, 1H), 5.16
(d, J = 12.1 Hz, 1H), 5.08 (hept, J = 6.3 Hz, 1H), 5.00 – 4.89
(m, 3H), 4.88 (t, J = 3.0 Hz, 1H), 4.87 – 4.81 (m, 2H), 4.80 –
4.71 (m, 5H), 4.62 (d, J = 11.6 Hz, 1H), 4.50 (dd, J = 10.3, 2.8
Hz, 1H), 4.21 (q, J = 6.6 Hz, 1H), 4.10 (s, 1H), 4.00 (dd, J =
10.3, 3.9 Hz, 1H), 3.93 (d, J = 10.1 Hz, 1H), 3.89 (dd, J = 12.1,
8.9 Hz, 1H), 3.73 – 3.69 (m, 1H), 3.60 (d, J = 12.2 Hz, 1H),
3.50 (dd, J = 8.9, 2.4 Hz, 1H), 2.43 (s, 1H), 1.28 (d, J = 6.3 Hz,
3H), 1.24 (d, J = 6.2 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.06 (d,
J = 6.2 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ (ppm) 169.6, 168.6, 167.7, 166.4, 139.3,
138.8, 138.7, 135.3, 132.7, 130.7, 130.5, 128.8, 128.70,
128.67, 128.6, 128.5, 128.41, 128.39, 128.38, 128.33, 128.2,
128.1, 127.8, 127.54, 127.52, 127.3, 99.2, 99.1, 79.1, 77.5,
77.4, 76.6, 76.5, 75.9, 75.7, 74.9, 73.5, 73.3, 72.5, 71.0, 70.4,
69.6, 67.7, 67.0, 66.1, 59.7, 21.82, 21.77, 21.71, 21.67, 16.7;
HRMS calcd for C61H68O18Na [M+Na+]: 1111.4303, found
1111.4267 (-2.8 ppm).
galactopyranosyl)-3-O-(2,3,4-tri-O-benzyl-α-L-
fucopyranosyl)-tartaric acid diisopropyl ester (34). To a
stirring solution of 30b (80 mg, 99 μmol, 1.0 equiv) and
(2R,3R)-3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)-tartaric
acid diisopropyl ester 33 (128 mg, 197 μmol, 2.00 equiv) in
anhydrous THF (2 mL, 0.05 M), activated 3Å molecular
sieves (80 mg) were added. The reaction mixture was
stirred at 25 °C for 30 min. before being cooled to -35 °C and
N-iodosuccinimide (66.6 mg, 296 μmol, 3.00 equiv) and
TMSOTf (3.6 μL, 20 μmol, 0.20 equiv) were added
sequentially. The reaction mixture was stirred for 2 h at -35
°C and then filtered using Et2O and a saturated solution of
Na2S2O3 (~1 mL) was added dropwise to the dark brown
reaction mixture until it clarified. After warming to room
temperature, a saturated solution of NaHCO3 (4 mL) was
added. The aqueous layer was extracted with Et2O (2 x 5
mL) and the combined organic layers were washed with
brine (10 mL), dried over MgSO4, filtered and concentrated
in vacuo. Purification by flash chromatography
(Hexanes/Et2O, 50:50) provided 34 (0.12 g, 87%) as a pale-
yellow oil. Rf = 0.32 (Hexanes/Et2O, 5:50); [α]D25 -80 (c 2.7,
CHCl3); C80H94O18Si2; MW = 1399.7840 gmol-1; IR (neat, cm-
1
1) νmax 3065, 2933, 1729, 1454, 1362, 1269; H NMR (500
MHz, CDCl3) δ (ppm) 8.25 – 7.86 (m, 2H), 7.79 – 7.60 (m,
4H), 7.48 – 7.23 (m, 25H), 7.28 – 7.17 (m, 4H), 6.37 (dd, J =
10.3, 2.7 Hz, 1H), 6.02 (dd, J = 10.2, 3.4 Hz, 1H), 5.44 (dd, J =
10.5, 7.6 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 5.05 (d, J = 12.1
Hz, 1H), 4.89 (d, J = 11.5 Hz, 1H), 4.85 (d, J = 3.5 Hz, 1H), 4.82
(d, J = 6.3 Hz, 1H), 4.81 – 4.77 (m, 2H), 4.76 (d, J = 5.4 Hz,
1H), 4.73 (s, 1H), 4.71 – 4.56 (m, 3H), 4.55 (d, J = 11.6 Hz,
1H), 4.49 (d, J = 5.4 Hz, 1H), 4.38 (d, J = 5.4 Hz, 1H), 4.02 (q,
J = 6.5 Hz, 1H), 3.99 (dd, J = 10.7, 6.5 Hz, 1H), 3.92 (dd, J =
10.2, 2.6 Hz, 1H), 3.86 (dd, J = 10.2, 3.5 Hz, 1H), 3.85 (d, J =
10.4 Hz, 1H), 3.67 (dd, J = 10.7, 4.4 Hz, 1H), 3.51 (dd, J = 2.8,
1.3 Hz, 1H), 3.27 (dd, J = 6.6, 4.4 Hz, 1H), 1.13 (d, J = 6.3 Hz,
3H), 1.08 (s, 9H), 1.11 – 1.04 (m, 6H), 1.03 (d, J = 6.2 Hz, 3H),
0.94 (d, J = 6.4 Hz, 3H), 0.07 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 169.2, 168.3, 168.2, 165.8, 139.22, 139.19,
139.0, 135.73, 135.70, 135.4, 133.3, 133.0, 132.6, 130.9,
130.2, 130.0, 129.9, 129.1, 128.7, 128.7, 128.4, 128.38,
128.35, 128.34, 128.29, 128.27, 128.22, 128.0, 127.9,
127.89, 127.56, 127.53, 127.4, 127.3, 100.9, 99.8, 79.4, 78.2,
(2R,3R)-2-O-(2,6-di-O-benzoyl-3-O,4-C-((1S)-
benzyloxycarbonylprop-2-en-1,3-diyl)-β-D-
galactopyranosyl)-3-O-(2,3,4-tri-O-benzyl-α-L-
fucopyranosyl)-tartaric acid diisopropyl ester (36). To a
solution of 35 (21.0 mg, 19.3 μmol, 1.00 equiv) in
dichloromethane (0.19 mL, 0.10 M), pyridine (4.7 μL, 58
μmol, 3.0 equiv) and benzoyl chloride (3.4 μL, 29 μmol, 1.5
equiv) were added. After stirring for 16 h at 25 °C, a
saturated solution of NaHCO3 (2 mL) was added. The
aqueous layer was extracted with EtOAc (2 x 2 mL), and the
combined organic layers were washed with brine (5 mL),
dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (Hexanes/EtOAc,
70:30) provided 36 (20 mg, 87%) as a white foam. Rf = 0.15
(Hexanes/EtOAc, 70:30); [α]D25 -45 (c 0.6, CHCl3); C68H72O19;
MW = 1193.3050 gmol-1; IR (neat, cm-1) νmax 3473, 3038,
2979, 1727, 1453, 1270; 1H NMR (500 MHz, CDCl3) δ (ppm)
8.16 – 8.10 (m, 2H), 8.11 – 8.06 (m, 2H), 7.61 – 7.54 (m, 1H),
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The Journal of Organic Chemistry
Page 16 of 20
7.51 – 7.43 (m, 3H), 7.41 – 7.33 (m, 4H), 7.32 – 7.24 (m, (40.0 mg, 36.7 μmol, 1.00 equiv) in dichloromethane (0.37
1
2
3
4
5
6
7
8
12H), 7.22 – 7.14 (m, 6H), 6.24 (dd, J = 10.2, 2.6 Hz, 1H), 6.10
(dd, J = 10.2, 3.4 Hz, 1H), 5.51 (dd, J = 10.1, 7.2 Hz, 1H), 5.12
– 5.05 (m, 2H), 5.00 (d, J = 12.1 Hz, 1H), 4.97 – 4.81 (m, 6H),
4.80 – 4.68 (m, 2H), 4.72 – 4.65 (m, 2H), 4.61 (d, J = 11.7 Hz,
1H), 4.54 (d, J = 11.5 Hz, 1H), 4.44 – 4.43 (m, 2H), 4.06 – 3.97
(m, 2H), 3.91 (t, J = 2.9 Hz, 2H), 3.53 (dd, J = 6.7, 3.7 Hz, 1H),
3.50 – 3.45 (m, 1H), 2.52 (s, 1H), 1.17 (m, 9H), 1.12 (d, J =
6.3 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ (ppm) 168.6, 168.4, 167.8, 166.5, 166.0, 139.1,
139.0, 138.9, 135.2, 133.4, 133.0, 130.5, 130.1, 129.95,
129.93, 128.84, 128.75, 128.71, 128.67, 128.44, 128.42,
128.40, 128.38, 128.36, 128.3, 128.2, 127.8, 127.6, 127.49,
127.45, 127.4, 100.4, 99.8, 79.7, 78.5, 77.8, 77.7, 77.4, 75.5,
74.9, 74.8, 73.2, 73.0, 72.7, 70.9, 69.3, 69.1, 67.4, 67.2, 66.4,
62.6, 21.77, 21.75, 21.74, 21.72, 16.6; HRMS calcd for
C68H72O19Na [M+Na+]: 1215.4560, found 1215.4557 (-0.2
ppm).
mL, 0.10 M), pyridine (12 μL, 0.15 mmol, 4.0 equiv) and
benzoyl chloride (6.4 μL, 55 μmol, 1.5 equiv) were added.
Purification by flash chromatography (Hexanes/EtOAc,
70:30) provided 38 (41 mg, 94%) as a white foam. Rf = 0.11
(Hexanes/EtOAc, 70:30); [α]D25 -39 (c 0.7, CHCl3); C68H72O19;
MW = 1193.3050 gmol-1; IR (neat, cm-1) νmax 3480, 2981,
1
1724, 1453, 1269; H NMR (500 MHz, CDCl3) δ (ppm) 8.07
(ddd, J = 19.6, 8.2, 1.4 Hz, 4H), 7.55 (q, J = 7.2 Hz, 2H), 7.43
(td, J = 7.8, 6.2 Hz, 5H), 7.40 – 7.33 (m, 2H), 7.33 – 7.25 (m,
8H), 7.26 – 7.11 (m, 8H), 7.02 (t, J = 7.4 Hz, 1H), 6.00 (dd, J =
5.3, 2.7 Hz, 1H), 5.44 (dd, J = 10.0, 8.0 Hz, 1H), 5.30 – 5.20
(m, 2H), 5.04 (d, J = 12.6 Hz, 1H), 5.00 – 4.93 (m, 3H), 4.88
(d, J = 11.5 Hz, 1H), 4.83 – 4.74 (m, 2H), 4.72 – 4.65 (m, 2H),
4.64 – 4.54 (m, 3H), 4.52 – 4.45 (m, 2H), 4.10 (q, J = 6.4 Hz,
1H), 3.99 (dd, J = 10.2, 3.7 Hz, 1H), 3.90 (dd, J = 10.2, 2.7 Hz,
1H), 3.54 – 3.46 (m, 2H), 2.96 (d, J = 10.0 Hz, 1H), 2.50 (s,
1H), 2.18 (dd, J = 21.0, 4.0 Hz, 1H), 1.95 (d, J = 18.9 Hz, 1H),
1.23 – 1.14 (m, 12H), 1.00 (d, J = 6.4 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ (ppm) 168.2, 167.9, 166.4, 165.5, 161.6,
143.7, 138.76, 138.73, 138.7, 135.7, 133.4, 133.0, 130.5,
130.01, 129.96, 129.91, 128.8, 128.55, 128.53, 128.50,
128.44, 128.41, 128.3, 128.1, 128.0, 127.92, 127.85, 127.7,
127.6, 127.3, 109.5, 99.2, 99.0, 80.0, 78.3, 78.0, 77.4, 76.38,
76.36, 75.9, 74.9, 73.9, 72.8, 70.6, 69.5, 69.3, 68.1, 67.5, 66.6,
62.2, 31.3, 21.79, 21.78, 21.77, 21.73, 16.6; HRMS calcd for
C68H72O19Na [M+Na+]: 1215.4560, found 1215.4549 (-0.9
ppm).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2R,3R)-2-O-(2-O-benzoyl-3-O,4-C-
(benzyloxycarbonylprop-1-en-1,3-diyl)-β-D-
galactopyranosyl)-3-O-(2,3,4-tri-O-benzyl-α-L-
fucopyranosyl)-tartaric acid diisopropyl ester (37). To a
solution of 34 (100 mg, 71.4 μmol, 1.00 equiv) in anhydrous
THF (0.30 mL, 0.24 M), TBAF (0.21 mL, 1.0 M in THF, 3.0
equiv) was added dropwise. The reaction mixture was
stirred for 1 h before being diluted with EtOAc (2 mL) and a
saturated solution of NH4Cl (2 mL) was added. The aqueous
layer was extracted with EtOAc (2 x 2 mL), and the organic
layers were combined, washed with brine (5 mL), dried
over MgSO4, filtered and concentrated in vacuo. Purification
by flash chromatography (Hexanes/EtOAc, 50:50) provided
37 (75 mg, 96%) as a clear oil. Rf = 0.35 (Hexanes/EtOAc,
50:50); [α]D25 -54 (c 0.3, CHCl3); C61H68O18; MW = 1089.1970
gmol-1; IR (neat, cm-1) νmax 3473, 3038, 2979, 1729, 1454,
(2R,3R)-2-O-(2-O-benzoyl-3-O,4-C-((S)-carboxyprop-1,3-
diyl)-β-D-galactopyranosyl)-3-O-(α-L-fucopyranosyl)-
tartaric acid diisopropyl ester (1). To a solution of 35 (16.0
mg, 14.7 μmol, 1.00 equiv) in THF (1.2 mL, 0.010 M),
palladium hydroxide (20 wt. %) on carbon (15.5 mg, 22.0
μmol, 1.50 equiv) was added. The reaction mixture was
degassed and flushed with a hydrogen filled balloon. After
stirring at 25 °C under a standard hydrogen atmosphere for
16 h, the reaction mixture was filtered through Celite,
washed with methanol, and concentrated in vacuo.
Purification by reverse phase C18 (H2O/MeOH, 60:40)
provided 1 (9.3 mg, 87%) as a white powder. [α]D25 -108 (c
0.1, MeOH); C33H46O18; MW = 730.7130 gmol-1; IR (neat, cm-
1
1272; H NMR (500 MHz, CDCl3) δ (ppm) 8.30 (dd, J = 8.3,
1.4 Hz, 2H), 7.64 – 7.56 (m, 1H), 7.55 – 7.46 (m, 6H), 7.43 –
7.36 (m, 2H), 7.38 – 7.32 (m, 1H), 7.31 (dd, J = 4.2, 1.2 Hz,
4H), 7.31 – 7.26 (m, 1H), 7.24 – 7.17 (m, 3H), 7.16 – 7.06 (m,
4H), 6.82 – 6.76 (m, 1H), 5.91 (dd, J = 5.1, 2.7 Hz, 1H), 5.59
(d, J = 8.3 Hz, 1H), 5.31 (d, J = 12.6 Hz, 1H), 5.28 (dd, J = 10.1,
8.3 Hz, 1H), 5.12 (hept, J = 6.2 Hz, 1H), 5.04 – 4.92 (m, 4H),
4.88 – 4.82 (m, 4H), 4.80 (dd, J = 10.3, 2.8 Hz, 1H), 4.69 –
4.61 (m, 3H), 4.34 (d, J = 12.0 Hz, 1H), 4.17 (q, J = 6.5 Hz, 1H),
4.05 (dd, J = 10.3, 3.9 Hz, 1H), 3.84 (dd, J = 12.2, 9.7 Hz, 1H),
3.72 (d, J = 2.4 Hz, 1H), 3.56 – 3.48 (m, 2H), 2.29 (d, J = 10.2
Hz, 1H), 2.11 (s, 1H), 1.85 (ddd, J = 18.6, 5.2, 1.7 Hz, 1H), 1.61
(dd, J = 18.5, 2.9 Hz, 1H), 1.30 (d, J = 6.3 Hz, 3H), 1.27 (t, J =
6.6 Hz, 6H), 1.15 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.5 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 169.6, 168.2, 166.1,
161.7, 143.7, 139.4, 138.5, 138.2, 135.9, 132.8, 130.8, 130.4,
129.3, 128.9, 128.69, 128.67, 128.5, 128.4, 128.2, 128.1,
127.89, 127.85, 127.75, 127.64, 127.63, 109.7, 97.7, 97.6,
79.2, 78.7, 78.2, 77.4, 76.8, 75.1, 75.0, 74.6, 74.4, 73.3, 70.9,
70.4, 69.9, 67.73, 67.65, 66.4, 59.9, 31.0, 22.1, 21.80, 21.76,
21.67, 16.7; HRMS calcd for C61H68O18Na [M+Na+]:
1111.4303, found 1111.4288 (-0.9 ppm).
1
1) νmax 3392, 2982, 1758, 1718, 1592, 1277; H NMR (500
MHz, CD3OD) δ (ppm) 8.16 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.5
Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 5.36 (dd, J = 10.2, 7.8 Hz,
1H), 5.08 (hept, J = 6.3 Hz, 1H), 4.79 – 4.74 (m, 2H), 4.71 –
4.63 (m, 2H), 4.40 (d, J = 3.1 Hz, 1H), 4.31 (d, J = 10.3 Hz, 1H),
4.20 (d, J = 6.3 Hz, 1H), 4.08 (q, J = 6.5 Hz, 1H), 3.81 (dd, J =
11.8, 3.2 Hz, 1H), 3.74 – 3.65 (m, 2H), 3.62 (dd, J = 10.2, 3.9
Hz, 1H), 3.53 (dd, J = 3.2, 1.2 Hz, 1H), 3.39 (dd, J = 6.8, 3.2 Hz,
1H), 2.29 – 2.18 (m, 1H), 2.06 (d, J = 13.5 Hz, 1H), 1.67 (d, J
= 12.5 Hz, 1H), 1.59 (td, J = 13.4, 4.3 Hz, 1H), 1.29 (dd, J = 6.3,
5.2 Hz, 6H), 1.19 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H),
0.99 (d, J = 6.5 Hz, 3H) (Labile protons were not observed due
to exchange with deuterated solvent); 13C{1H} NMR (126
MHz, CD3OD) δ (ppm) 178.8, 170.7, 168.9, 168.4, 133.9,
131.9, 131.4, 129.2, 103.4, 103.2, 80.6, 79.1, 78.9, 76.4, 76.0,
73.5, 72.6, 71.6, 71.5, 70.7, 70.5, 69.9, 68.7, 60.9, 28.8, 23.0,
22.1, 21.99, 21.94, 21.8, 16.4; HRMS calcd for C33H46O18Na
[M+Na+]: 753.2582, found 753.2582 (+0.7 ppm).
(2R,3R)-2-O-(2,6-di-O-benzoyl-3-O,4-C-
(benzyloxycarbonylprop-1-en-1,3-diyl)-β-D-
galactopyranosyl)-3-O-(2,3,4-tri-O-benzyl-α-L-
fucopyranosyl)-tartaric acid diisopropyl ester (38).
Following a similar procedure as in 36, to a solution of 37
(2R,3R)-2-O-(2-O-benzoyl-3-O,4-C-((R)-carboxyprop-1,3-
diyl)-β-D-galactopyranosyl)-3-O-(α-L-fucopyranosyl)-
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The Journal of Organic Chemistry
25
tartaric acid diisopropyl ester (3). Following a similar
60:40) provided 4 (13 mg, 93%) as a white powder. [α]D
-
26 (c 0.8, MeOH); C40H50O19; MW = 834.8210 gmol-1; IR
1
2
3
4
5
6
7
8
procedure as in 1, to a solution of 37 (35.0 mg, 32.1 μmol,
1.00 equiv) in THF (0.64 mL, 0.050 M), palladium hydroxide
(20 wt. %) on carbon (33.8 mg, 48.2 μmol, 1.50 equiv) was
(neat, cm-1) νmax 3431, 2980, 1720, 1453, 1271; H NMR
1
(500 MHz, CD3OD) δ (ppm) 8.07 (dd, J = 8.3, 1.4 Hz, 4H), 7.66
– 7.56 (m, 2H), 7.54 – 7.44 (m, 4H), 5.45 (dd, J = 10.1, 7.9 Hz,
1H), 4.95 (hept, J = 6.2 Hz, 1H), 4.92 (d, J = 7.8 Hz, 1H), 4.79
– 4.72 (m, 1H), 4.68 (d, J = 3.8 Hz, 1H), 4.65 (dd, J = 11.9, 3.1
Hz, 1H), 4.62 (d, J = 4.0 Hz, 1H), 4.46 (dd, J = 11.9, 8.0 Hz,
1H), 4.33 (d, J = 4.1 Hz, 1H), 4.01 (appq, J = 6.6 Hz, 1H), 3.89
(dd, J = 10.8, 3.0 Hz, 1H), 3.87 (dd, J = 7.7, 2.7 Hz, 1H), 3.68
(d, J = 10.1 Hz, 1H), 3.64 (dd, J = 10.2, 3.1 Hz, 1H), 3.60 (dd, J
= 10.2, 3.8 Hz, 1H), 3.50 (dd, J = 3.1, 1.2 Hz, 1H), 1.98 – 1.86
(m, 3H), 1.73 (td, J = 13.4, 6.0 Hz, 1H), 1.19 (t, J = 6.3 Hz, 6H),
1.15 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H), 0.99 (d, J =
6.7 Hz, 3H) (Labile protons were not observed due to
exchange with deuterated solvent); 13C{1H} NMR (126 MHz,
CD3OD) δ (ppm) 179.0, 170.0, 169.2, 167.9, 167.7, 134.4,
134.3, 131.5, 131.4, 131.1, 130.7, 129.6, 129.4, 103.1, 103.0,
81.29, 81.26, 79.3, 79.1, 78.0, 73.5, 72.2, 71.6, 71.3, 70.6,
70.2, 70.0, 68.7, 64.0, 32.0, 25.4, 22.0, 21.90, 21.86, 21.85,
16.5; HRMS calcd for C40H50O19Na [M+Na+]: 857.2844, found
857.2846 (+0.9 ppm).
added. Purification by reverse phase C18 (H2O/MeOH,
25
60:40) provided 3 (20 mg, 85%) as a white powder. [α]D
-
45 (c 0.6, MeOH); IR (neat, cm-1) νmax 3374, 2981, 1726,
1603, 1277; C33H46O18; MW = 730.7130 gmol-1; 1H NMR (500
MHz, CD3OD) δ (ppm) 8.09 (d, J = 7.4, 2H), 7.61 (t, J = 7.4 Hz,
1H), 7.47 (t, J = 7.8 Hz, 2H), 5.39 (dd, J = 10.0, 7.8 Hz, 1H),
5.07 (hept, J = 6.3 Hz, 1H), 4.89 (d, J = 8.0 Hz, 1H), 4.86 – 4.80
(m, 1H), 4.80 (d, J = 3.5 Hz, 1H), 4.71 (d, J = 3.1 Hz, 1H), 4.41
(d, J = 3.0 Hz, 1H), 4.05 (appq, J = 6.5 Hz, 1H), 3.87 (dd, J =
10.9, 3.6 Hz, 1H), 3.83 (dd, J = 11.9, 3.3 Hz, 1H), 3.77 (dd, J =
11.8, 6.4 Hz, 1H), 3.67 – 3.61 (m, 3H), 3.52 – 3.47 (m, 2H),
1.95 – 1.81 (m, 3H), 1.64 (td, J = 12.8, 5.6 Hz, 1H), 1.34 – 1.26
(m, 6H), 1.24 (d, J = 6.1 Hz, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.00
(d, J = 6.7 Hz, 3H) (Labile protons were not observed due to
exchange with deuterated solvent); 13C{1H} NMR (126 MHz,
CD3OD) δ (ppm) 178.9, 170.4, 169.3, 168.4, 134.5, 131.3,
131.2, 129.4, 103.3, 102.6, 81.5, 81.1, 80.2, 79.2, 78.8, 73.5,
72.6, 71.5, 71.4, 70.7, 70.4, 69.8, 68.7, 60.9, 31.8, 25.4, 22.1,
21.99, 21.94, 21.88, 16.5; HRMS calcd for C33H46O18Na
[M+Na+]: 753.2582, found 753.2583 (+0.9 ppm).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
(2R,3R)-2-O-(2,6-di-O-benzoyl-3-O,4-C-((S)-carboxyprop-
1,3-diyl)-β-D-galactopyranosyl)-3-O-(α-L-fucopyranosyl)-
tartaric acid diisopropyl ester (2). Following a similar
procedure as in 1, to a solution of 36 (65.0 mg, 54.5 μmol,
1.00 equiv) in THF (2.2 mL, 0.030 M), palladium hydroxide
(20 wt. %) on carbon (57.4 mg, 817 μmol, 1.50 equiv) was
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org
1H NMR and 13C{1H} NMR spectra for all new
compounds along with proofs of structure.
Modified methods for bioassays along with details
concerning the computational method, energies,
and Cartesian coordinates for all of the transition
structures and intermediate geometries
added. Purification by reverse phase C18 (H2O/MeOH,
25
60:40) provided 2 (24 mg, 53%) as a white powder. [α]D
-
41 (c 0.2, MeOH); C40H50O19; MW = 834.8210 gmol-1; IR
(neat, cm-1) νmax 3375, 2980, 1719, 1602, 1271; H NMR
1
(500 MHz, CD3OD) δ (ppm) 8.16 (dd, J = 8.3, 1.4 Hz, 2H), 8.05
(dd, J = 8.4, 1.3 Hz, 2H), 7.67 – 7.59 (m, 1H), 7.61 – 7.54 (m,
1H), 7.53 – 7.43 (m, 4H), 5.40 (dd, J = 10.3, 7.8 Hz, 1H), 4.94
(hept, J = 6.3 Hz, 1H), 4.84 (d, J = 7.8 Hz, 1H), 4.66 (d, J = 3.9
Hz, 1H), 4.66 – 4.60 (m, 2H), 4.56 (dd, J = 11.8, 3.3 Hz, 1H),
4.43 (dd, J = 11.8, 7.7 Hz, 1H), 4.38 (d, J = 10.3 Hz, 1H), 4.36
(d, J = 3.6 Hz, 1H), 4.22 (d, J = 6.3 Hz, 1H), 4.08 (appq, J = 6.4
Hz, 1H), 3.81 (dd, J = 7.7, 3.3 Hz, 1H), 3.68 (dd, J = 10.2, 3.2
Hz, 1H), 3.61 (dd, J = 10.2, 4.0 Hz, 1H), 3.54 (dd, J = 3.3, 1.2
Hz, 1H), 2.25 (m, 1H), 2.09 (dt, J = 14.7, 3.7 Hz, 1H), 1.78 –
1.69 (m, 1H), 1.68 (dd, J = 13.2, 4.5 Hz, 1H), 1.19 (d, J = 6.3
Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H), 1.10 (d, J = 6.3 Hz, 3H), 1.02
(d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H) (Labile protons
were not observed due to exchange with deuterated solvent);
13C{1H} NMR (126 MHz, CD3OD) δ (ppm) 178.7, 170.5,
168.9, 168.1, 167.8, 134.4, 133.9, 132.0, 131.4, 131.3, 130.7,
129.6, 129.2, 103.5, 103.1, 79.19, 79.16, 78.3, 76.3, 76.0,
73.5, 72.4, 71.6, 71.5, 70.6, 70.4, 69.9, 68.7, 63.8, 28.8, 23.0,
22.1, 21.89, 21.84, 21.82, 16.5; HRMS calcd for C40H50O19Na
[M+Na+]: 857.2844, found 857.2837 (-0.2 ppm).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: yvan.guindon@ircm.qc.ca.
*E-mail: michel.prevost@ircm.qc.ca.
*E-mail: kpatel@ucalgary.ca.
*E-mail: mnemer@uottawa.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Funding for this research has been granted from the
Canadian
Glycomics
Network
(Glyconet
http://doi.org/10.13039/501100009056), and in part
from Natural Sciences and Engineering Research Council,
NSERC, RGPIN-2015-06405. This research was enabled in
part by WestGrid (www.westgrid.ca) and Compute
Canada−Calcul Canada (www. computecanada.ca). In
memory of Donald Jobin (MSc 2004) for his synthetic work
towards these scaffolds.
(2R,3R)-2-O-(2,6-di-O-benzoyl-3-O,4-C-((R)-carboxyprop-
1,3-diyl)-β-D-galactopyranosyl)-3-O-(α-L-fucopyranosyl)-
tartaric acid diisopropyl ester (4). Following a similar
procedure as in 1, to a solution of 38 (19.2 mg, 16.1 μmol,
1.00 equiv) in THF (1.3 mL, 0.010 M), palladium hydroxide
(20 wt. %) on carbon (16.9 mg, 24.1 μmol, 1.50 equiv) was
added. Purification by reverse phase C18 (H2O/MeOH,
REFERENCES
1) Ernst, B.; Magnani, J. L., From carbohydrate leads
to glycomimetic drugs. Nat. Rev. Drug. Discov. 2009, 8, 661.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
2) Simanek, E. E.; McGarvey, G. J.; Jablonowski, J. A.; 17) Guindon, Y.; Ogilvie, W. W.; Bordeleau, J.; Cui, W. L.;
1
2
3
4
5
6
7
8
Wong, C.-H., Selectin−Carbohydrate Interactions: From
Natural Ligands to Designed Mimics. Chem. Rev. 1998, 98,
833.
Durkin, K.; Gorys, V.; Juteau, H.; Lemieux, R.; Liotta, D.;
Simoneau, B.; Yoakim, C., Opening of tartrate acetals using
dialkylboron bromide: evidence for stereoselectivity
downstream from ring fission. J. Am. Chem. Soc. 2003, 125,
428.
3) Magnani, J. L., The discovery, biology, and drug
development of sialyl Lea and sialyl Lex. Arch. Biochem.
Biophys. 2004, 426, 122.
18) Kranich, R.; Busemann, A. S.; Bock, D.; Schroeter-
Maas, S.; Beyer, D.; Heinemann, B.; Meyer, M.; Schierhorn, K.;
Zahlten, R.; Wolff, G.; Aydt, E. M., Rational design of novel,
potent small molecule pan-selectin antagonists. J. Med.
Chem. 2007, 50, 1101.
4) Calosso, M.; Tambutet, G.; Charpentier, D.; St-
Pierre, G.; Vaillancourt, M.; Bencheqroun, M.; Gratton, J. P.;
Prevost, M.; Guindon, Y., Acyclic tethers mimicking subunits
of polysaccharide ligands: selectin antagonists. ACS Med.
Chem. Lett. 2014, 5, 1054.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19) Titz, A.; Ernst, B., Mimetics of Sialyl Lewis X: The
Pre-Organization of the Carboxylic Acid is Essential for
Binding to Selectins. CHIMIA 2007, 61, 194.
5) Bevilacqua, M. P., Endothelial-leukocyte adhesion
molecules. Annu. Rev. Immunol. 1993, 11, 767.
20) Thoma, G.; Schwarzenbach, F.; Duthaler, R. O.,
Synthesis of a Sialyl Lewis x Mimic with Fixed Carboxylic
Acid Group: Chemical Approach toward the Elucidation of
the Bioactive Conformation of Sialyl Lewis x. J. Org. Chem.
1996, 61, 514.
6) Thoma, G.; Magnani, J. L.; Patton, J. T.; Ernst, B.;
Jahnke, W., Preorganization of the Bioactive Conformation
of Sialyl LewisX Analogues Correlates with Their Affinity to
E-Selectin. Angew. Chem. Int. Ed. 2001, 40, 1941.
7) Krishnamurthy, V. R.; Sardar, M. Y.; Ying, Y.; Song,
X.; Haller, C.; Dai, E.; Wang, X.; Hanjaya-Putra, D.; Sun, L.;
Morikis, V.; Simon, S. I.; Woods, R. J.; Cummings, R. D.;
Chaikof, E. L., Glycopeptide analogues of PSGL-1 inhibit P-
selectin in vitro and in vivo. Nat. Commun. 2015, 6, 6387.
21) Borowski, D.; Zweiböhmer, T.; Ziegler, T., 1,2-
Annulated Sugars: Synthesis of Polyhydroxylated 2,10-
Dioxadecalins with β-manno Configuration. Eur. J. Org.
Chem. 2016, 2016, 5248.
22) Doddi, V. R.; Kancharla, P. K.; Reddy, Y. S.; Kumar,
A.; Vankar, Y. D., Synthesis of fused pyran-
carbahexopyranoses as glycosidase inhibitors. Carbohydr.
Res. 2009, 344, 606.
8) Natoni, A.; Macauley, M. S.; O'Dwyer, M. E.,
Targeting Selectins and Their Ligands in Cancer. Front.
Oncol. 2016, 6, 93.
9) Chang, J.; Patton, J. T.; Sarkar, A.; Ernst, B.; Magnani,
J. L.; Frenette, P. S., GMI-1070, a novel pan-selectin
antagonist, reverses acute vascular occlusions in sickle cell
mice. Blood 2010, 116, 1779.
23) Ansari, A. A.; Rajasekaran, P.; Khan, M. M.; Vankar,
Y. D., Bicyclic hybrid sugars as glycosidase inhibitors:
synthesis and comparative study of inhibitory activities of
fused oxa-oxa, oxa-aza, and oxa-carbasugar hybrid
molecules. J. Org. Chem. 2014, 79, 1690.
10) Somers, W. S.; Tang, J.; Shaw, G. D.; Camphausen, R.
T., Insights into the Molecular Basis of Leukocyte Tethering
and Rolling Revealed by Structures of P- and E-Selectin
Bound to SLeX and PSGL-1. Cell 2000, 103, 467.
24) Lazzara, N. C.; Rosano, R. J.; Vagadia, P. P.; Giovine,
M. T.; Bezpalko, M. W.; Piro, N. A.; Kassel, W. S.; Boyko, W. J.;
Zubris, D. L.; Schrader, K. K.; Wedge, D. E.; Duke, S. O.;
Giuliano, R. M. Synthesis and Biological Evaluation of 6-
[(1R)-1-Hydroxyethyl]-2,4a(R),6(S),8a(R)-
tetrahydropyrano-[3,2- b]-pyran-2-one and Structural
Analogues of the Putative Structure of Diplopyrone. J. Org.
Chem. 2019, 84, 666.
11) Leppanen, A.; White, S. P.; Helin, J.; McEver, R. P.;
Cummings, R. D., Binding of glycosulfopeptides to P-selectin
requires stereospecific contributions of individual tyrosine
sulfate and sugar residues. J. Biol. Chem. 2000, 275, 39569.
12) Rinnbauer, M.; Ernst, B.; Wagner, B.; Magnani, J.;
Benie, A. J.; Peters, T., Epitope mapping of sialyl Lewis(x)
bound to E-selectin using saturation transfer difference
NMR experiments. Glycobiology 2003, 13, 435.
25) Mandhapati, A. R.; Yang, G.; Kato, T.; Shcherbakov,
D.; Hobbie, S. N.; Vasella, A.; Bottger, E. C.; Crich, D.
Structure-Based Design and Synthesis of Apramycin–
Paromomycin Analogues: Importance of the Configuration
at the 6′-Position and Differences between the 6′-Amino
and Hydroxy Series. J. Am. Chem. Soc. 2017, 139, 14611.
13) Kolb, H. C.; Ernst, B., Development of Tools for the
Design of Selectin Antagonists. Chem. Eur. J. 1997, 3, 1571.
14) Preston, R. C.; Jakob, R. P.; Binder, F. P.; Sager, C. P.;
Ernst, B.; Maier, T., E-selectin ligand complexes adopt an
extended high-affinity conformation. J. Mol. Cell. Biol. 2016,
8, 62.
26) Aboussafy, C. L.; Andersen Gersby, L. B.; Molinaro,
A.; Newman, M. A.; Lowary, T. L. A Convergent Route to
Enantiomers of the Bicyclic Monosaccharide Bradyrhizose
Leads to Insight into the Bioactivity of an Immunologically
Silent Lipopolysaccharide. J. Org. Chem. 2019, 84, 14.
15) Calosso, M.; Charpentier, D.; Vaillancourt, M.;
Bencheqroun, M.; St-Pierre, G.; Wilkes, B. C.; Guindon, Y., A
new approach to explore the binding space of
polysaccharide-based ligands: selectin antagonists. ACS
Med. Chem. Lett. 2012, 3, 1045.
27) Li, W.; Silipo, A.; Gersby, L. B.; Newman, M. A.;
Molinaro, A.; Yu, B. Synthesis of Bradyrhizose
Oligosaccharides Relevant to the Bradyrhizobium
O-Antigen. Angew. Chem. Int. Ed. 2017, 56, 2092.
16) Schwizer, D.; Patton, J. T.; Cutting, B.; Smiesko, M.;
Wagner, B.; Kato, A.; Weckerle, C.; Binder, F. P.; Rabbani, S.;
Schwardt, O.; Magnani, J. L.; Ernst, B., Pre-organization of the
core structure of E-selectin antagonists. Chem. Eur. J. 2012,
18, 1342.
28) Dharuman, S.; Crich, D., Determination of the
Influence of Side-Chain Conformation on Glycosylation
Selectivity using Conformationally Restricted Donors.
Chem. Eur. J. 2016, 22, 4535.
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
29) Amarasekara, H.; Dharuman, S.; Kato, T.; Crich, D.,
41) Zhao, Y.; Truhlar, D. G., Density functionals with
broad applicability in chemistry. Acc. Chem. Res. 2008, 41,
157.
1
2
3
4
5
6
7
8
Synthesis of Conformationally-Locked cis- and trans-
Bicyclo[4.4.0] Mono-, Di-, and Trioxadecane Modifications
3
of Galacto- and Glucopyranose; Experimental Limiting JH,H
42) Koh, K.; Durst, T., Stereoselective SN2 Reactions of
the (R)-Pantolactone Ester of Racemic .alpha.-Halo
Carboxylic Acids with Aryl Oxides. A Synthesis of (S)-2-
Aryloxy and (S)-2-Hydroxy Acids. J. Org. Chem. 1994, 59,
4683.
Coupling Constants for the Estimation of Carbohydrate Side
Chain Populations and Beyond. J. Org. Chem. 2018, 83, 881.
30) Misra, A. K.; Das, S. K.; Roy, N., Preparation
oftransDiequatorial 2,3-Pyruvate Acetals in a Di- and a
Trisaccharide Related to the K-Antigen from E. Coli
0101:K103:H−. Synth. Commun. 1998, 28, 1471.
43) Ben, R. N.; Durst, T., Synthesis of Optically Active α-
9
Amino Esters via Dynamic Kinetic Resolution:
A
31) Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C.;
Saucy, G., Synthetic studies on (2R,4'R,8'R)-.alpha.-
tocopherol. Facile syntheses of optically active, saturated,
acyclic isoprenoids via stereospecific [3,3] sigmatropic
rearrangements. J. Org. Chem. 1976, 41, 3497.
Mechanistic Study. J. Org. Chem. 1999, 64, 7700.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
44) Huerta, F. F.; Minidis, A. B. E.; Bäckvall, J.-E.,
Racemisation in asymmetric synthesis. Dynamic kinetic
resolution and related processes in enzyme and metal
catalysis. Chem. Soc. Rev. 2001, 30, 321.
32) Chan, K.-K.; Specian, A. C.; Saucy, G., Synthesis of
(2R,4'R,8'R)-α-tocopheryl acetate (vitamin E acetate) using
[3,3] sigmatropic rearrangement. J. Org. Chem. 1978, 43,
3435.
45) Zhao, Y.; Truhlar, D. G., Computational
characterization and modeling of buckyball tweezers:
density functional study of concave-convex pi...pi
interactions. Phys. Chem. Chem. Phys. 2008, 10, 2813.
33) Miljkovic, M.; Gligorijevic, M.; Satoh, T.; Miljkovic,
D., Synthesis of macrolide antibiotics. I. Stereospecific
addition of methyllithium and methylmagnesium iodide to
46) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar,
D. G., Use of solution-phase vibrational frequencies in
continuum models for the free energy of solvation. J. Phys.
Chem. B. 2011, 115, 14556.
methyl
α-D-xylo-hexopyranosid-4-ulose
derivatives.
Determination of the configuration at the branching carbon
atom by carbon-13 nuclear magnetic resonance
spectroscopy. J. Org. Chem. 1974, 39, 1379.
47) Legault, C. Y. CYLview, 1.0b, Université de
Sherbrooke, 2009, (http://www.cylview.org).
48) The rapid isomerization could also be attributed to
a base-induced protonation/deprotonation pathway and is
currently being investigated.
34) Miljkovic,
M.,
Carbohydrates:
Synthesis,
Mechanisms, and Stereoelectronic Effects, Springer, New
York, 2009.
49) Seeman, J. I., The Curtin-Hammett principle and the
Winstein-Holness equation: new definition and recent
extensions to classical concepts. J. Chem. Educ. 1986, 63, 42.
35) Guo, M.; Li, D.; Zhang, Z., Novel synthesis of 2-oxo-
3-butynoates by copper-catalyzed cross-coupling reaction
of terminal alkynes and monooxalyl chloride. J. Org. Chem.
2003, 68, 10172.
50) Ghoshal, P.; Rajendran, M.; Odo, N.; Ikuta, T.,
Glycosylation inhibitors efficiently inhibit P-selectin-
mediated cell adhesion to endothelial cells. PLoS One 2014,
9, e99363.
36) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M.,
Asymmetric synthesis via axially dissymmetric molecules.
6. Rational designing of efficient chiral reducing agents.
Highly enantioselective reduction of aromatic ketones by
binaphthol-modified lithium aluminum hydride reagents. J.
Am. Chem. Soc. 1984, 106, 6709.
51) Beste, M. T.; Hammer, D. A., Selectin catch-slip
kinetics encode shear threshold adhesive behavior of
rolling leukocytes. Proc. Natl. Acad. Sci. USA. 2008, 105,
20716.
37) Pasto, D. J.; Taylor, R. T., Reduction with Diimide,
Org. React. 1992, 40, 91.
52) Waldron, T. T.; Springer, T. A., Transmission of
allostery through the lectin domain in selectin-mediated
cell adhesion. Proc. Natl. Acad. Sci. USA. 2009, 106, 85.
38) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozepeikar,
B., 2,4,6-Tri-isopropylbenzenesulphonyl hydrazide:
A
53) Chakrabarti, S.; Patel, K. D., Regulation of matrix
metalloproteinase-9 release from IL-8-stimulated human
neutrophils. J. Leukoc. Biol. 2005, 78, 279.
convenient source of di-imide. Tetrahedron 1976, 32, 2157.
39) Frisch, M. J.; et al. Gaussian 09, revision A.02;
Gaussian, Inc.: Wallingford, CT, 2009.
54) Ganguly, A.; Zhang, H.; Sharma, R.; Parsons, S.;
Patel, K. D., Isolation of human umbilical vein endothelial
cells and their use in the study of neutrophil transmigration
under flow conditions. J. Vis. Exp. 2012, 66, e4032.
40) Zhao, Y.; Truhlar, D. G., The M06 suite of density
functionals
for
main
group
thermochemistry,
thermochemical kinetics, noncovalent interactions, excited
states, and transition elements: two new functionals and
systematic testing of four M06-class functionals and 12
other functionals. Theor. Chem. Acc. 2007, 120, 215.
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OH
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R1 = R2 = Bz
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O
O
HO
OiPr
OiPr
OR2
Y = CO2H, X = H
4
O
Conformationally
Locked
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R1 = R2 = Bz
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