Surface-tethered iterative carbohydrate synthesis: A spacer study

Article abstract of DOI:10.1021/jo400095u

Comparative study of Surface-Tethered Iterative Carbohydrate Synthesis (STICS) using HPLC-assisted experimental setup clearly demonstrates benefits of using longer spacer-anchoring systems. The use of mixed self-assembled monolayers helps provide the requ

Full text of DOI:10.1021/jo400095u

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pubs.acs.org/joc
Surface-Tethered Iterative Carbohydrate Synthesis: A Spacer Study
N. Vijaya Ganesh,† Kohki Fujikawa,† Yih Horng Tan,†,‡ Swati S. Nigudkar,† Keith J. Stine,†,‡,*
and Alexei V. Demchenko*,†
‡
†Department of Chemistry and Biochemistry and Center for Nanoscience, University of MissouriSt. Louis, St. Louis, Missouri
63121, United States
S
* Supporting Information
ABSTRACT: Comparative study of Surface-Tethered Iterative
Carbohydrate Synthesis (STICS) using HPLC-assisted experimental
setup clearly demonstrates benefits of using longer spacer-anchoring
systems. The use of mixed self-assembled monolayers helps provide
the required space for glycosylation reaction around the immobilized
glycosyl acceptor. Both extension of the spacer length and using
mixed self-assembled monolayers help promote the reaction, and the
beneficial effects may include moving the glycosyl acceptor further
out into solution and providing additional conformational flexibility.
It is possible that surface-immobilized glycosyl acceptors with a
longer spacer (C8−O−C8)-lipoic acid have a higher tendency to
mimic a solution-phase reaction environment than acceptors with
shorter spacers.
moiety, is transferred into another vessel (C) containing an
appropriate solvent, wherein excess reagent is rinsed off.
Subsequently, the stick is dipped into the vessel (D) containing
a certain reagent to remove a strategically placed temporary
substituent P. This transformation results in the formation of
the second-generation glycosyl acceptor. To conclude the cycle,
the stick is then briefly placed in a thick-wall container
connected to the vacuum (E). Upon completion of this
sequence, again, a hydroxyl-modified stick is available for
consequent glycosylation. To repeat the cycle, coupling−
washing−deprotection−drying steps are performed once again.
At the end of the synthesis, the oligosaccharide can be either
cleaved off from the stick or deprotected directly on the stick to
be used for immunoassay or molecular recognition studies.
Whereas it is common that reactions on solid supports are
performed multiple times to ensure their completeness, we
intentionally performed each reaction only once to elucidate
the scope of the STICS approach. For instance, the lipoic acid
anchor/linker-glycosyl acceptor scaffold provided the best
yields (∼60%) in comparison to those using other anchoring
and glycosylation approaches used in our original STICS
study.19 This result clearly illustrates the need for significant
improvement for the STICS approach to become attractive on
a practical basis. Although quantitative conversion yields can be
achieved by repeating this reaction 2−3 times, this time and
material investment would be hardly justified and would not
serve the needs to reduce drawbacks of the solid-phase
synthesis.
INTRODUCTION
■
Organic synthesis on solid phases represents an active area of
research.1,2 The end of the last century has witnessed heated
interest in the area of solid phase-supported synthesis of
carbohydrates, and as a result, dramatic improvements have
emerged. Early efforts to synthesize oligosaccharides and
glycoconjugates using a manual approach3−7 have evolved
into the development of an automated oligosaccharide
synthesizer by Seeberger et al.8−16 Both manual and automated
polymer-supported synthesis is very attractive because it allows
for the rapid synthesis of oligosaccharide sequences without the
necessity of purifying (and characterizing) the intermediates.
Another important advantage of oligosaccharide synthesis on
solid-phase support is the ease of excess reagent removal
(usually achieved by filtration).17,18 In spite of remarkable
progress, solid-phase techniques still suffer from significant
limitations: long reaction times, large reagent excess, limited
use of molecular sieves, large volumes of waste solvent,
cumbersome analysis of intermediates, lower stereoselectivity,
loss and poisoning of resin, reagent trapping, etc.
To investigate whether these limitations could be addressed
by using a nanoporous gold surface instead of polymer support,
recently we developed a new technique that we named STICS
(surface-tethered iterative carbohydrate synthesis).19 As illus-
trated in Scheme 1, at the basis of the concept is a surface
functionalized “stick” made of chemically stable high surface
area material that would simplify the transformation of the solid
support-bound molecules between the reaction vessels. The
glycosyl acceptor-anchored stick (A) is placed in the reaction
vessel (B), containing sufficient quantities of the glycosyl
donor, promoter and molecular sieves. Upon completion of the
reaction, the stick, functionalized by a protected terminal sugar
Received: January 23, 2013
© XXXX American Chemical Society
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Scheme 1. STICS Concept Outline and Focus of This Study
Figure 1. Series of lipoic acid anchor/extended linker/glycosyl acceptor scaffold molecules 1−3.
We hypothesized that one way to improve reaction yields is
by lengthening the linker group20 that will extend the glycosyl
acceptor further away from the nanoporous gold (NPG)
surface and create more reaction space and the prospect for
improved reactivity and higher yields. The distancing from the
surface should be especially helpful for those molecules
immobilized along the ligament sections of positive curvature
as the carbohydrate groups become further apart as they project
out into the solution. The typical diameters of the pores and
ligaments of the NPG used in these studies falls in the range of
50−200 nm.21 This may help to reduce the gap between
relatively slow surface or polymer-bound reactions and fast
reactions in solution. In other words, the STICS would
approach being solution-like in terms of efficiency, reactivity,
and yields. Regions of negative curvature where ligaments meet
are not as favorable as reaction spaces but overall account for a
smaller amount of the available surface.
(SAM) on the surface of the nanoporous gold plates used in
STICS. The latter conclusion was drawn from the fact that no
desorption of the glycosyl acceptor from the surface was
detected during either the glycosylation or deprotection steps.
This application of lipoic acid-based anchor would help to
avoid another potential drawback of polythiolated compounds,
such as previously investigated tripod and adamantane
anchors,19 in which about 30% of the mercapto groups may
remain unbound to the surface and hence may potentially
interact with thiophilic reagents used in STICS. While it is not
guaranteed that all sulfurs of a lipoic acid anchor are involved in
gold−thiolate bonds,22 with two points of attachment such
accommodation is easier to achieve. All anchors bearing a
cleavable lipoic acid ester should allow for convenient cleavage
under basic conditions when needed.
As a part of ongoing research program in our laboratories,
herein we report the synthesis and study of a series of lipoic
acid anchor/extended linker/glycosyl acceptor scaffold mole-
cules 1−3 depicted in Figure 1. The purpose of this study is to
test our hypothesis that the spacer length has a significant effect
on the outcome of glycosylation on the surface of the
nanoporous gold. The spacer moieties were based on 1,4-
As the anchor we chose to continue with commercially
available lipoic acid, as that gave the best results so far. In the
previous study, lipoic acid was connected directly to the
glycosyl acceptor. Lipoic acid was proven sufficient for the
formation of a chemically resistant self-assembled monolayer
B
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a
butanediol, 1,8-octanediol, and the dimer of the latter, 9-
oxaheptadecane-1,17-diol. This will allow us to extend the
acceptor molecule away from the surface by O(CH2)4 (in
scaffold 1), O(CH2)8 (in scaffold 2), and O(CH2)8O(CH2)8
(in scaffold 3) in comparison to the original study wherein the
acceptor was conjugated to lipoic acid directly.
Scheme 3. Synthesis of Lipoic Acid Derived Acceptor 3
RESULTS AND DISCUSSION
Synthesis of glycosyl acceptors molecules 1 and 2 both followed
the same pathway as depicted in Scheme 2. First,
■
Scheme 2. Synthesis of Lipoic Acid Derived Glycosyl
a
Acceptors 1 and 2
a
a
Conditions: (a) BnBr, NaH, THF/DMF, 0 °C → rt, 16 h; (b) TsCl,
Conditions: (a) Hg(CN)2/HgBr2, ClCH2CH2Cl, 4 Å molecular
pyridine, DMAP, 0 °C → rt, 16 h; (c) NaH, THF, 60 °C, 24 h; (d) H2,
Pd/C, MeOH, rt, 8 h; (e) TMSOTf, CH2Cl2, 3 Å molecular sieves, rt,
2 h; (f) TBDPSCl, pyridine, 50 °C, 6 h; (g) NaOMe, MeOH, rt, 5 h;
(h) TrCl, DMAP, pyridine, 80 °C, 8 h; (i) BnBr, NaH, DMF, 0 °C, 5
h; (j) TBAF, THF, rt, 4 h; (k) lipoic acid, EDC, DMAP, CH2Cl2, rt, 8
h; (l) 10% TFA/CH2Cl2, rt, 2 h.
sieves, rt, 36 h; (b) NaOMe, MeOH (and THF for 6b), rt, 5 h; (c)
TrCl, pyridine, DMAP, 80 °C, 6 h; (d) BnBr, NaH, DMF, 0 °C, 5 h;
(e) TBAF/THF, THF, rt, 3 h; (f) lipoic acid, EDC, DMAP, CH2Cl2,
rt, 8 h; (g) 10% TFA/CH2Cl2, rt, 2 h.
benzobromoglucose 423 was glycosidated with acceptors
5a24/5b25,26 under the Helferich conditions (Hg(CN)2/
HgBr2) to afford the corresponding glycosides 6a/6b in
89%/92% yield, respectively. After that, compounds 6a/6b
were sequentially deacylated under Zemplen conditions
(NaOMe), tritylated (TrCl/pyridine), and benzylated (BnBr/
NaH) to afford compounds 7a/7b in 62%/74% yield over three
steps. The latter compounds were desilylated (Bu4NF) to
afford alcohols 8a27/8b in 93%/88% yields. The latter was
esterified with lipoic acid in the presence of EDC and the
resulting compounds were detritylated (dilute trifluoroacetic
acid) to give the target glycosyl acceptors 1 and 2 in 96% and
75% yield, respectively.
The synthesis of glycosyl acceptor 3 began from the
commercially available 1,8-octanediol 9 as depicted in Scheme
3. Monobenzylation of 9 (BnBr/NaH) afforded alcohol 1028
(53% yield), which was then treated with TsCl in pyridine to
afford tosylate 1129 in 91% yield. Reaction of 10 with 11 in the
presence of NaH in THF at reflux produced dimeric product
12 in 87% yield. The latter was then hydrogenated (H2, Pd/C)
to afford diol 13 in 98% yield. Glycosylation of diol 13 with
glycosyl donor 1430 was catalyzed by TMSOTf and afforded
mono glycosylated product 15 in 70% yield. After that,
glycoside 15 was silylated (TBDPSCl in pyridine) and the
resulting product 16 (91%) was sequentially deacylated by
Zemplen (NaOMe in MeOH), tritylated (TrCl, DMAP,
pyridine), and benzylated (BnBr, NaH in DMF) to afford
fully protected compound 17 in 82% yield over three steps.
Then, compound 17 was desilylated (95%) and the liberated
hydroxyl in compound 18 was coupled with lipoic acid followed
by detritylation afford the target glycosyl acceptor 3 in 88%
yield over two steps.
Having obtained different thiolated glycosyl acceptors 1−3,
we turned our attention to studying their immobilization on the
nanoporous gold chips using CH2Cl2 as solvent. The
quantitative estimation of the amount of sugar molecules
absorbed on the surface to form self-assembled monolayers
(SAMs) was determined by weighing the NPG chips using a
microbalance before and after immobilization. The loading and
unloading study on the nanoporous gold surface was aimed at
examining the ease of recovery of sugar from the gold chips.
Accordingly, the loading and unloading of the sugar portion
from the nanoporous surface was conducted and it was
estimated to be quantitative recovery of the protected sugar
used in monolayer formation. The average increase in mass
upon loading of 1−3 on a NPG plate (8.0 mm × 8.0 mm ×
0.25 mm) was found to be 0.75−0.80 mg. The mass of an NPG
plate of these dimensions is typically 80 mg. Using a specific
surface area of 8.2 m2 g−1 for 72 h dealloyed NPG material,31
this corresponds to a total estimated surface of 0.66 m2. The
molar masses of 1-3 are 668.9, 725.0, and 853.2 g mol−1,
respectively. The loaded masses of 0.75−0.80 mg for 1-3
correspond to a loading of 0.94−1.1 μmol per plate, in the
same range as found in our prior reported study.19 The loading
is equivalent to a surface coverage of 1.44−1.66 μmol m−2, or
0.87−1.00 × 1018 molecules m−2.
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During our initial experimentation, glycosylation of pure
monolayers of glycosyl acceptors 1−3 with imidate donor was
not successful. At this point, we assumed that overcrowding of
sugar molecules of same length in the monolayer prevents any
glycosidation reaction to occur. Hence, we decided to test the
possibility of forming mixed monolayers with a similarly
structured compound, i.e., the methyl ester of lipoic acid
derivative 1932,33 as the additive. Our goal in using mixed SAMs
was to achieve less steric crowding around the acceptor sugar
and its bulky protecting groups and thereby facilitate the
glycosylation reaction by allowing better access for the donor
and promoter to the reactive hydroxyl group. It is also likely
that in a mixed SAM, the conformation flexibility of the
protected sugars would be increased and they would be more
likely to display a reactive conformation. After comparative
study of different monolayer ratios between acceptor 1−3 and
additive 19 (1/1, 2/3, 1/4, and 4/1 mol/mol) we determined
that the monolayer ratio of 2/3 gives comparatively better
disaccharide formation than others.
occupy less area on the gold surface than 1−3, since it lacks the
large protected sugar unit.
Modified NPG chips 1a−3a were used in glycosylations
using our recently developed HPLC-assisted automated
technology for oligosaccharide synthesis.27 This experimental
setup based on an unmodified HPLC instrument was executed
as follows. The Omnifit SolventPlus chromatography glass
column was loaded with freshly activated molecular sieves (3 Å
beads) and gold chips modified by SAMs (approximately size
4.0 mm × 4.0 mm × 0.25 mm, quantity, ∼0.20 mg each)
separated by a pad of cotton (Scheme 5). The use of molecular
Scheme 5. Outline of the HPLC-Assisted Experimental
Setup for Glycosylation of SAM-Modified NPG Chips
Hence, for the present study, freshly prepared nanoporous
gold chips were immersed in a solution containing the desired
ratio of one of the glycosyl acceptors 1−3 (0.0422 mmol) and
additive 19 (0.0636 mmol) in CH2Cl2 (10 mL) for 10 h.
Resultantly, we obtained gold chips loaded with a SAM
containing the glycosyl acceptor and the additive 1a−3a
(Scheme 4). It is known that the surface composition of SAMs
sieves represents a deviation from the experimental setup
reported previously for polymer-supported synthesis. This is
because we noticed that performing glycosylation using SAM-
modified NPG under a strictly anhydrous condition has a
dramatic effect on the yield of glycosylation. The loaded
column was then connected to the HPLC and a solution of
glycosyl donor in CH2Cl2 (78 mM) was then first circulated
through the packed column containing molecular sieves and
NPG chips for 30 min (flow rate 1.0 mL/min, 8 atm) in the
absence of promoter. This step helps to remove traces of
moisture in the stock solution of the glycosyl donor. After that,
promoter was added to the stock solution. After 2 h of
continuous recirculation of reagents, the system was purged
with CH2Cl2 to wash off any impurities that may be remaining
on the NPG surface. Then, NPG chips loaded with disaccharide
derivatives were carefully removed from the column and the
sugar content was cleaved off by soaking the plates in a 1 M
solution of NaOMe in MeOH for 16 h.
Scheme 4. Loading Mixed SAMs: Synthesis of NPG-
Immobilized Glycosyl Acceptors 1a−3a
Following this general experimental setup, we conducted
comparative studies of immobilized acceptors 1a−3a (Scheme
6). Glycosylation with glycosyl donor 14 followed by
deprotection/cleavage and acetylation afforded the correspond-
ing disaccharides 20−22 in yields ranging between 60 and 90%.
The yield calculation was based on TLC and NMR analysis of
the oligosaccharide mixtures cleaved off from the surface. More
precise calculations were deemed impractical given the use of a
mixed SAM of glycosyl acceptor 1−3 and methyl lipoic ester 19
since this introduces some uncertainty as to the exact percent of
the SAM composed of the glycosyl acceptor. More detailed
studies seeking to estimate the surface bound ratios of glycosyl
acceptor and additives such as the lipoic ester (19) on the NPG
surface with aid of surface analytical methods are currently
underway. If the exact number of immobilized acceptor sugar
units on the NPG chips used could be determined, then yields
could be based on the mass of disaccharide obtained. The best
yield was obtained for the synthesis of disaccharide 22 from
acceptor 3a equipped with the longest C8−O−C8 spacer. In
this case, practically no monosaccharide derived from the
immobilized glycosyl acceptor was detected. In contrast, in the
as prepared from solution does not necessarily match the
composition of the solution from which they are prepared in
terms of ratio of the two components; therefore, the 2:3 ratio is
the solution molar ratio and may differ from that actually on the
gold surface.34 The typical mass loading onto a 8.0 mm × 8.0
mm × 0.25 mm NPG plate for the mixed SAM of this ratio is
0.35−0.40 mg per plate, and this lower mass than found for the
loading of the pure glycosyl acceptors is expected since 19 has a
lower molar mass of 220.4 g mol−1. The lipoic ester 19 should
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Scheme 6. Comparative Glycosylations of Immobilized Glycosyl Acceptors 1a−3a with Donor 14 Using HPLC-Assisted
Experimental Setup
mL). The organic phase was separated, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (acetone−toluene gradient elution) to
afford the title compound (0.160 g, 96%) as a white foam. Analytical
data for 1: Rf = 0.50 (acetone/toluene, 1/5, v/v); 1H NMR (300 MHz,
CDCl3) δ 1.41−1.50 (m, 2H, −CH2−), 1.62−1.80 (m, 9H, 4 ×
−CH2−, −CH−), 1.83−1.95 (m, 1H, −CH2−), 2.29 (t, 2H, J = 7.3
Hz, −CH2COO−), 2.39−2.50 (m, 1H, −CH2−), 3.06−3.21 (m, 2H,
−CH2−), 3.33−3.38 (m, 1H, H-5), 3.40 (dd, 1H, J2,3 = 8.8 Hz, H-2),
3.51−3.62 (m, 3H, H-4, OCH2−, OH), 3.66 (dd, 1H, J3,4 = 9.0 Hz, H-
3), 3.71 (dd, 1H, J5,6a = 4.6 Hz, J6a,6b = 11.7 Hz, H-6a), 3.86 (dd, 1H,
J5,6b = 2.6 Hz, H-6b), 3.93 (m, 1H, OCH2−), 4.09 (t, 2H, J = 5.9 Hz,
case of the synthesis of disaccharides 20 (60%) and 21 (75%) a
notable amount of monosaccharide was detected (30% and
15%, respectively).
CONCLUSIONS
■
As evidenced from comparative glycosylations, the glycosyl
acceptor with longer spacer has a higher tendency to mimic a
solution-phase reaction environment than that of acceptors
with shorter spacers. The use of mixed SAMs helps to provide
the required space for reaction around the immobilized
acceptor. Extension of the spacer length could in principle
have a number of effects to promote reaction with the donor,
including moving the acceptor sugar further out into solution
and providing additional conformational flexibility through
which the acceptor sugar is more likely to adopt a reactive
orientation. Another strategy other than the use of mixed SAMs
that could be considered to potentially improve reactivity
would be the use of a SAM anchor molecule which in itself has
a larger surface footprint to accommodate the dimensions of
the protected sugar. However, such a strategy may not
significantly increase the ultimate amount of product recovered.
In principle, the gold chip is loaded with the disaccharide
derivative that can be subjected to further oligosaccharide
elongation via alternating deprotection/glycosylation steps.
Additionally, as shown in our previous study,27 all steps
including glycosylation, deprotection, and cleavage from the
solid support can be monitored using a standard HPLC
detection system set to record changes in the UV absorbance of
the solution eluting off the column.
2
−CH2OCO−), 4.43 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.75 (dd, 2H, J =
11.0 Hz, CH2Ph), 4.83 (dd, 2H, 2J = 11.0 Hz, CH2Ph), 4.86 (dd, 2H,
2J = 10.9 Hz, CH2Ph), 7.24−7.31 ppm (m, 15H, aromatic); 13C NMR
(75 MHz, CDCl3): δ, 24.6, 25.4, 26.2, 28.7, 34.0, 34.6, 38.4, 40.2, 56.3,
62.0, 63.9, 69.4, 74.9, 75.0 (×2), 75.7, 77.5, 82.3, 84.5, 103.6, 127.6,
127.7, 127.8 (×2), 127.9, 128.0 (×2), 128.1 (×2), 128.4 (×4), 128.5
(×2), 137.9, 138.3, 138.5, 173.5 ppm; HR-FAB MS [M + Na]+ calcd
for C39H50O8S2Na 733.2845, found 733.2827.
8-(tert-Butyldiphenylsilyloxy)oct-1-yl 2,3,4,6-Tetra-O-benzo-
yl-β-D-glucopyranoside (6b). A solution of 2,3,4,6-tetra-O-benzoyl-
α-D-glucopyranosyl bromide (4,23 2.0 g, 3.03 mmol) in ClCH2CH2Cl
(10 mL) was added to a suspension of 8-(tert-butyldiphenylsilyloxy)-
octan-1-ol (5b,25,26 1.28 g, 3.33 mmol), Hg(CN)2 (0.766 g, 3.03
mmol), HgBr2 (0.546 g, 1.50 mmol), and molecular sieves (4 Å, 3.0 g)
in ClCH2CH2Cl (20 mL), and the resulting mixture was stirred under
argon for 36 h at rt. After that, the solids were filtered off through a
pad of Celite and washed successively with CH2Cl2. The combined
filtrate (∼100 mL) was washed with 10% aq Na2S2O3 (2 × 50 mL),
5% aq NaHCO3 (50 mL), water (50 mL), and brine (30 mL). The
organic phase was separated, dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (ethyl acetate−hexane gradient elution) to afford the title
compound (2.67 g, 92%) as a white foam. Analytical data for 6b: Rf
EXPERIMENTAL SECTION
■
= 0.50 (ethyl acetate/hexane, 1/3, v/v); [α]22 +13.4 (c = 1.0,
4-[5-(1,2-Dithiolan-3-yl)pentanoyl]oxybut-1-yl 2,3,4-tri-O-
benzyl-β-D-glucopyranoside (1). Lipoic acid (0.048 g, 0.235
mmol) was added to a solution of compound 8a27 (0.180 g, 0.235
mmol), EDC hydrochloride (0.050 g, 0.259 mmol), and DMAP (0.014
g, 0.117 mmol) in CH2Cl2 (5.0 mL), and the resulting mixture was
stirred under argon for 8 h at rt. After that, a 10% aq TFA (5.0 mL)
was added dropwise, and the resulting mixture was stirred for 1 h at rt.
The mixture was then diluted with CH2Cl2 (∼50 mL) and washed
with water (3 × 50 mL), 5% aq NaHCO3 (50 mL), and brine (30
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.97 (s, 9H, tert-butyl),
1.01−1.14 (m, 8H, 4 × −CH2−), 1.33−1.49 (m, 4H, 2 × −CH2−),
a
3.45 (dt, 1H, J = 9.7, 6.2 Hz, OCH2 −), 3.52 (t, 2H, J = 6.6 Hz,
b
−CH2OSi), 3.83 (m, 1H, J = 9.7, 6.2 Hz, OCH2 −), 4.05−4.10 (m,
1H, H-5), 4.43 (dd, 1H, J5,6a = 5.2 Hz, J6a,6b = 12.1 Hz, H-6a), 4.56
(dd, 1H, J5,6b = 3.3 Hz, H-6b), 4.75 (d, 1H, J1,2 = 7.9 Hz, H-1), 5.45
(dd, 1H, J2,3 = 9.7 Hz, H-2), 5.60 (dd, 1H, J4,5 = 9.7 Hz, H-4), 5.83
(dd, 1H, J3,4 = 9.6 Hz, H-3), 7.18−7.95 ppm (m, 30H, aromatic); 13
C
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NMR (75 MHz, CDCl3) δ 19.2, 25.6, 25.7, 26.8 (×3), 29.1, 29.2, 29.3,
32.5, 63.2, 63.9, 69.8, 70.3, 71.9, 72.1, 72.9, 101.3, 127.5 (×5), 128.3
(×6), 128.4 (×2), 128.8 (×2), 129.3, 129.5 (×2), 129.6, 129.7 (×5),
129.8 (×2), 133.0, 133.1, 133.2, 133.4, 134.1, 135.5 (×5), 165.0, 165.2,
165.8, 166.1 ppm; HR-FAB MS [M + Na]+ calcd for C58H62O11SiNa
985.3959, found 985.3961.
(×4), 128.8 (×6), 137.8, 138.5, 138.6, 143.9 (×3) ppm; HR-FAB MS
[M + Na]+ calcd for C54H60O7Na 843.4237, found 843.4250.
8-[5-(1,2-Dithiolan-3-yl)pentanoyl]oxyoct-1-yl 2,3,4-tri-O-
benzyl-β-D-glucopyranoside (2). The title compound was obtained
from 8b in 75% yield (two steps) as a white foam as described in the
synthesis of compound 1. Analytical data for 2: Rf = 0.50 (acetone/
1
toluene, 1/9, v/v); H NMR (300 MHz, CDCl3) δ 1.31 (s, 8H, 4 ×
8-(tert-Butyldiphenylsilyloxy)oct-1-yl 2,3,4-Tri-O-benzyl-6-
O-triphenylmethyl-β-D-glucopyranoside (7b). NaOMe (1 mL,
0.5 M solution) was added to a solution of 6b (2.51 g, 2.61 mmol) in
MeOH (30 mL) until pH ∼9, and the resulting mixture was stirred
under argon for 5 h at rt. After that, the reaction mixture was
neutralized with Dowex (H+), and the resin was filtered off and rinsed
successively with MeOH. The combined filtrate was concentrated in
vacuo and dried. The crude residue was dissolved in pyridine (15 mL),
trityl chloride (2.17 g, 7.79 mmol) and DMAP (0.063 g, 0.519 mmol)
were added, and the resulting mixture was stirred under argon for 10 h
at 80 °C. After that, the volatiles were removed in vacuo, and the
residue was coevaporated with toluene (3 × 50 mL). The resulting
residue was diluted with CH2Cl2 (∼50 mL) and washed with water (3
× 50 mL) and brine (30 mL). The organic phase was separated, dried
over MgSO4, and concentrated in vacuo. The residue was filtered
through a pad of silica gel (ethyl acetate−toluene elution) and
concentrated in vacuo. The crude residue was dissolved in DMF (40
mL), NaH (60% dispersion in oil, 0.624 g, 15.6 mmol) was added
portionwise, and the resulting mixture was stirred under argon for 30
min at 0 °C. Then BnBr (1.11 mL, 9.35 mmol) was added, and the
resulting reaction mixture was stirred for 5 h at rt. The reaction
mixture was neutralized with AcOH/MeOH (1/10, v/v), diluted with
CH2Cl2 (80 mL), and washed with water (2 × 50 mL) and brine (30
mL). The organic phase was separated, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate−hexane gradient elution)
to afford the title compound (2.04 g, 74%) as a pale-yellow foam.
Analytical data for 7b: Rf = 0.50 (ethyl acetate/hexane, 1/9, v/v);
[α]22D +4.5 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.99 (s,
9H, tert-butyl), 1.15−1.52 (m, 10H, 5 × −CH2−), 1.62−1.68 (m, 2H,
−CH2−), 3.16 (dd, 1H, J5,6a = 3.9 Hz, J6a,6b = 10.1 Hz, H-6a), 3.31−
−CH2−), 1.42−1.51 (m, 2H, −CH2−), 1.53−1.79 (m, 8H, 4 ×
−CH2−), 1.83−1.92 (m, 2H, −CH2−), 2.31 (t, 2H, J = 7.4 Hz,
−CH2COO−), 2.40−2.51 (m, 1H, −CH2−), 3.06−3.22 (m, 2H,
−CH2−), 3.31−3.39 (m, 1H, H-5), 3.41 (dd, 1H, J2,3 = 8.8 Hz, H-2),
a
3.49−3.62 (m, 3H, H-4, OCH2 −, OH), 3.67 (dd, 1H, J3,4 = 9.0 Hz,
H-3), 3.70 (dd, 1H, J5,6a = 4.6 Hz, J6a,6b = 11.5 Hz, H-6a), 3.86 (dd,
b
1H, J5,6b = 2.5 Hz, H-6b), 3.92 (m, 1H, OCH2 -), 4.04 (t, 2H, J = 6.7
Hz, −CH2OCO−), 4.43 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.67 (dd, 2H, 2J =
10.9 Hz, CH2Ph), 4.75 (dd, 2H, 2J = 11.0 Hz, CH2Ph), 4.80 (dd, 2H,
2J = 10.9 Hz, CH2Ph), 7.25−7.35 ppm (m, 15H, aromatic); 13C NMR
(75 MHz, CDCl3) δ 24.9, 26.0, 26.2, 28.8, 28.9, 29.3, 29.4, 29.9, 34.3,
34.7, 38.6, 40.4, 56.5, 62.2, 64.6, 70.5, 75.0, 75.1, 75.3, 75.9, 77.8, 82.5,
84.6, 103.8, 127.8, 127.9, 128.0 (×3), 128.1 (×2), 128.2 (×3), 128.3,
128.5 (×2), 128.7 (×2), 138.1, 138.5, 138.7, 173.8 ppm; HR-FAB MS
[M + Na]+ calcd for C43H58O8S2Na 789.3471, found 789.3463.
1,17-Bis(benzyloxy)-9-oxaheptadecane (12). NaH (60% dis-
persion in mineral oil, 0.203 g, 5.08 mmol) was added to a solution of
8-benzyloxyoctan-1-ol (10,28 1.0 g, 4.23 mmol) in THF (10 mL), and
the resulting mixture was stirred under argon for 30 min at 60 °C.
Then, a solution of 8-(benzyloxy)oct-1-yl tosylate (11,29 1.98 g, 5.08
mmol) in THF (20 mL) was added dropwise, and the resulting
solution was stirred for 24 h at rt. After that, MeOH (∼30 mL) and
CH2Cl2 (∼40 mL) were added, and the resulting mixture was washed
with water (2 × 30 mL) and brine (20 mL). The organic phase was
separated, dried over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (ethyl acetate−
hexanes gradient elution) to afford the title compound (2.0 g, 87%) as
a colorless oil. Analytical data for 12: Rf = 0.50 (ethyl acetate/hexane,
1/9, v/v); [α]21 −1.9 (c = 1.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.31 (s, 16H, 8 × −CH2−), 1.50−1.63 (m, 8H, 4 ×
−CH2−), 3.37 (t, 4H, 2 × OCH2−), 3.45 (t, 4H, 2 × OCH2−), 4.49
(s, 4H, 2 × CH2Ph), 7.23−7.33 ppm (m, 10H, aromatic); 13C NMR
(75 MHz, CDCl3) δ 26.3 (×4), 29.6 (×4), 29.9 (×4), 70.6 (×2), 71.1
(×2), 73.0 (×2), 127.6 (×3), 127.7 (×3), 128.5 (×4), 138.8 (×2)
ppm; HR-FAB MS [M + Na]+ calcd for C30H46O3Na 477.3345, found
477.3337.
a
3.35 (m, 1H, H-5), 3.44−3.59 (m, 6H, H-2, 3, 6b, OCH2 b-,
−CH2OSi), 3.73 (dd, 1H, J4,5 = 8.9 Hz, H-4), 3.98 (m, 1H, OCH2 -
), 4.36 (d, 1H, J1,2 = 7.3 Hz, H-1), 4.45 (dd, 2H, 2J = 10.3 Hz, CH2Ph),
2
2
4.77 (dd, 2H, J = 10.8 Hz, CH2Ph), 4.81 (dd, 2H, J = 11.0 Hz,
CH2Ph), 6.77−7.62 ppm (m, 40H, aromatic); 13C NMR (75 MHz,
CDCl3) δ 19.2, 25.7, 26.3, 26.5, 26.9 (×3), 29.4, 29.5, 32.6, 62.4, 64.0,
69.8, 74.5, 74.8, 75.0, 75.9, 77.9, 82.5, 84.7, 86.3, 103.6, 126.9 (×2),
127.5 (×3), 127.6 (×2), 127.7 (×5), 127.8 (×3), 128.0 (×2), 128.1
(×2), 128.2 (×2), 128.3, 128.4 (×2), 128.8 (×3), 129.4, 129.6 (×4),
134.1, 134.8 (×4), 135.1 (×2), 135.5 (×3), 137.8, 138.6 (×2), 143.9
(×3) ppm; HR-FAB MS [M + Na]+ calcd for C70H78O7SiNa
1081.5415, found 1081.5392.
9-Oxaheptadecane-1,17-diol (13). Pd/C (10%, 0.060 g) was
added to a solution of 12 (0.600 g, 1.32 mmol) in MeOH (15 mL),
and the resulting mixture was stirred under a pressure of hydrogen gas
for 8 h at rt. The solid was filtered off through a pad of Celite and
washed successively with MeOH (5 × 10 mL). The combined filtrate
was concentrated in vacuo to afford the title compound (0.355 g, 98%)
8-Hydroxyoct-1-yl 2,3,4-Tri-O-benzyl-6-O-triphenylmethyl-
β-D-glucopyranoside (8b). TBAF (2.10 mL, 2.08 mmol) was
added to a solution of 7b (1.10 g, 1.03 mmol) in THF (20 mL), and
the resulting mixture was stirred under argon for 3 h at rt. The reaction
mixture was then diluted with CH2Cl2 (∼40 mL) and washed with
water (50 mL) and brine (30 mL). The organic phase was separated,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (ethyl acetate−
toluene gradient elution) to afford the title compound (0.750 g, 88%)
as a white foam. Analytical data for 8b: Rf = 0.50 (ethyl acetate/
hexane, 1/4, v/v); [α]24D +3.2 (c = 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.37 (s, 6H, 3 × −CH2−), 1.46−1.62 (m, 5H, 2 × −CH2−,
as a white amorphous solid. Analytical data for 13: Rf = 0.50 (ethyl
1
acetate/hexane, 3/2, v/v); [α]21 −2.3 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3 + D2O) δ 1.32 (s, 16H, 8 × −CH2−), 1.51−1.59
(m, 8H, 4 × −CH2−), 3.39 (t, 4H, J = 6.7 Hz, 2 × OCH2−), 3.62 (t,
4H, 2 × −CH2OH); 13C NMR (75 MHz, CDCl3) δ 25.6 (×2), 26.0
(×2), 29.3 (×4), 29.6 (×2), 32.6 (×2), 62.8 (×2), 70.8 (×2) ppm;
HR-FAB MS [M + H]+ calcd for C16H35O3 275.2586, found 275.2582.
17-Hydroxy-9-oxaheptadec-1-yl 2,3,4,6-Tetra-O-benzoyl-β-
D-glucopyranoside (15). A mixture of glycosyl trichloroacetimidate
1430 (2.70 g, 3.65 mmol), alcohol 13 (1.00 g, 3.65 mmol), and freshly
activated molecular sieves (3 Å, 3.0 g) in CH2Cl2 (60 mL) was stirred
under argon for 1 h at rt. TMSOTf (0.20 mL, 1.10 mmol) was added,
and the resulting mixture was stirred for 1 h at rt. After that, the solid
was filtered off, and the residue was rinsed with CH2Cl2 (4 × 20 mL).
The combined filtrate (∼140 mL) was washed with 20% aq NaHCO3
(80 mL), water (80 mL), and brine (30 mL). The organic phase was
separated, dried over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (ethyl acetate −
toluene gradient elution) to afford the title compound (2.17 g, 70%) as
a white foam. Analytical data for 15: Rf = 0.50 (ethyl acetate/toluene,
1/3, v/v); [α]21D +4.7 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
OH), 1.74−1.83 (m, 2H, −CH2−), 3.27 (dd, 1H, J5,6a = 4.0 Hz, J6a,6b
=
10.1 Hz, H-6a), 3.42−3.48 (m, 1H, H-5), 3.52−3.69 (m, 6H, H-2, 3,
a
6b, OCH2 b-, −CH2OH), 3.84 (dd, 1H, J4,5 = 8.9 Hz, H-4), 4.10 (m,
1H, OCH2 -), 4.48 (d, 1H, J1,2 = 7.3 Hz, H-1), 4.56 (dd, 2H, 2J = 10.3
2
2
Hz, CH2Ph), 4.88 (dd, 2H, J = 10.8 Hz, CH2Ph), 4.92 (dd, 2H, J =
10.9 Hz, CH2Ph), 6.87−7.56 ppm (m, 30H, aromatic); 13C NMR (75
MHz, CDCl3) δ 25.6, 26.2, 29.3, 29.4, 29.8, 32.7, 62.4, 62.9, 69.7, 74.5,
74.8, 75.0, 75.9, 77.9, 82.5, 84.7, 86.3, 103.6, 126.9 (×2), 127.6 (×2),
127.7 (×6), 127.9 (×2), 128.0 (×2), 128.1 (×3), 128.2 (×3), 128.3
F
dx.doi.org/10.1021/jo400095u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
b
δ 1.05−1.24 (m, 8H, 4 × −CH2−), 1.31 (s, 10H, 5 × −CH2−), 1.41−
1.57 (m, 6H, 3 × −CH2−), 3.30−3.41 (m, 4H, 2 × −CH2O), 3.53 (dt,
Hz, OCH2 -), 4.45 (d, 1H, J1,2 = 7.2 Hz, H-1), 4.53 (dd, 2H, 2J = 10.3
2
2
Hz, CH2Ph), 4.84 (dd, 2H, J = 10.8 Hz, CH2Ph), 4.90 (dd, 2H, J =
11.0 Hz, CH2Ph), 6.84−7.50 ppm (m, 30H, aromatic); 13C NMR (75
MHz, CDCl3) δ 25.7, 26.2 (×2), 26.4, 29.4, 29.5 (×3), 29.8 (×2),
29.9, 32.8, 62.5, 63.0 (×2), 69.9, 70.9, 74.6, 74.9, 75.1, 76.0, 78.0, 82.6,
84.8, 86.4, 103.7, 127.0 (×2), 127.7 (×2), 127.8 (×5), 127.9 (×2),
128.1 (×2), 128.2 (×5), 128.3 (×3), 128.4 (×2), 128.5 (×2), 128.9
(×5), 137.9, 138.7 (×2), 144.0 (×3) ppm; HR-FAB MS [M + Na]+
calcd for C62H76O8Na 971.5438, found 971.5444.
a
1H, J = 9.7, 6.1 Hz, OCH2 −), 3.62 (t, 2H, J = 6.6 Hz, −CH2OH),
b
3.91 (m, 1H, OCH2 -), 4.12−4.18 (m, 1H, H-5), 4.50 (dd, 1H, J5,6a
=
5.2 Hz, J6a,6b = 12.1, H-6a), 4.63 (dd, 1H, J5,6b = 3.3 Hz, H-6b), 4.83 (d,
1H, J1,2 = 7.8 Hz, H-1), 4.99 (s, 1H, OH), 5.53 (dd, 1H, J2,3 = 7.9 Hz,
H-2), 5.67 (dd, 1H, J4,5 = 9.7 Hz, H-4), 5.91 (dd, 1H, J3,4 = 9.6 Hz, H-
3), 7.27−8.03 ppm (m, 20H, aromatic); 13C NMR (75 MHz, CDCl3)
δ 25.6, 25.7, 25.9, 26.0, 29.1, 29.2, 29.3 (×2), 29.4, 29.6, 29.7, 32.7,
62.9, 63.2, 69.8, 70.3, 70.9, 71.8, 72.0, 72.9, 79.1, 101.2, 128.2, 128.3
(×3), 128.5 (×3), 128.7 (×3), 128.9, 129.3 (×2), 129.5, 129.7 (×4),
129.8 (×2), 133.0, 133.1, 133.2, 133.4, 165.0, 165.2, 165.8, 166.1 ppm;
HR-FAB MS [M + Na]+ calcd for C50H60O12Na 875.3982, found
875.3999.
17-[5-(1,2-Dithiolan-3-yl)pentanoyl]oxy-9-oxaheptadec-1-yl
2,3,4-Tri-O-benzyl-β-D-glucopyranoside (3). The title compound
was obtained from 18 in 88% yield (two steps) as a white foam as
described in the synthesis of compound 1. Analytical data for 3: Rf =
0.50 (acetone/toluene, 1/9, v/v); 1H NMR (300 MHz, CDCl3) δ 1.25
(s, 16H, 8 × −CH2−), 1.35−1.68 (s, 14H, 7 × −CH2−), 1.77−1.88
(m, 2H, −CH2−), 2.23 (t, 2H, −CH2COO−), 2.33−2.43 (m, 1H,
−CH2−), 2.98−3.14 (m, 2H, −CH2−), 3.26−3.37 (m, 6H, H-2, 5, 2 ×
17-tert-Butyldiphenylsilyloxy-9-oxaheptadec-1-yl 2,3,4,6-
Tetra-O-benzoyl-β-D-glucopyranoside (16). TBDPSCl (0.61 mL,
2.344 mmol) was added to a solution of compound 15 (1.00 g, 1.77
mmol) in pyridine (4.0 mL), and the resulting mixture was stirred
under argon for 7 h at 50 °C. After that, the reaction was diluted with
CH2Cl2 (∼30 mL) and washed with water (30 mL) and brine (10
mL). The organic phase was separated, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate−hexanes gradient elution)
to afford the title compound (1.16 g, 91%) as a white foam. Analytical
data for 16: Rf = 0.50 (ethyl acetate/hexanes, 1/5, v/v); [α]21D +2.8 (c
= 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.03 (s, 9H, tert-butyl),
1.07−1.20 (m, 6H, 3 × −CH2−), 1.23−1.37 (br s, 10H, 5 × −CH2−),
a
OCH2−), 3.42−3.47 (m, 2H, OCH2 -, OH), 3.48 (dd, 1H, J4,5 = 9.3
Hz, H-4), 3.59 (dd, 1H, J3,4 = 9.0 Hz, H-3), 3.66 (dd, 1H, J5,6a = 4.3
b
Hz, J6a,6b = 8.9, H-6a), 3.77−3.88 (m, 2H, H-6b, OCH2 -), 3.98 (t, 2H,
2
−CH2OCO−), 4.35 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.67 (dd, 2H, J =
10.9 Hz, CH2Ph), 4.75 (dd, 2H, 2J = 11.0 Hz, CH2Ph), 4.79 (dd, 2H,
2J = 10.9 Hz, CH2Ph), 7.18−7.27 ppm (m, 15H, aromatic); 13C NMR
(75 MHz, CDCl3) δ 24.6, 25.8, 26.0, 26.1 (×2), 28.6, 28.7, 29.2, 29.3
(×2), 29.4 (×2), 29.7 (×2), 34.1, 34.5, 38.4, 40.2, 56.3, 62.0, 64.4,
70.3, 70.9 (×2), 74.8, 74.9, 75.0, 75.6, 77.6, 82.3, 84.4, 103.7, 127.6
(×2), 127.8 (×2), 127.9, 128.0 (×3), 128.3 (×5), 128.4 (×2), 137.9,
138.4, 138.5, 173.5 ppm; HR-FAB MS [M + Na]+ calcd for
C51H74O9S2Na 917.4672, found 917.4674.
General Procedure for the Preparation of NPG Chips. The
NPG plates were prepared by dealloying cut pieces (typical dimension
8 mm × 8 mm × 0.25 mm) of 10 carat yellow gold sheet (Hoover and
Strong) in concentrated nitric acid for 72 h followed by successive
rinsing with water and methanol and drying in vacuo.31 The pieces
were then broken using the end of a spatula into four roughly equal
fragments (ca. 4 mm × 4 mm × 0.25 mm) that could fit into the
HPLC column.
General Procedure for the Formation of the Mixed SAM.
The freshly prepared nanoporous gold chips were allowed to stand in a
solution of glycosyl acceptor (0.030 g, 0.0422 mmol) and methyl lipoic
ester (0.014 g, 0.0636 mmol) in CH2Cl2 (10 mL) under argon for 10 h
at rt. After that, NPG chips were carefully removed, washed with
CH2Cl2 (4 × 5 mL), and dried in vacuo for 5 h. The loaded chips were
then transferred into the Omnifit column that was then connected
with HPLC system to be used in subsequent glycosidations.
General Procedure for the HPLC-Assisted Glycosylation of
1a, 2a, and 3a with Glycosyl Donor 14: Synthesis of
Disaccharides 20−22. A solution of glycosyl donor 14 (pump A,
78 mM solution, 0.175 g in 3.0 mL of CH2Cl2) was passed through the
column containing NPG-bound glycosyl acceptor 1a, 2a, or 3a and 3A
molecular sieves in beads form) at a flow rate of 1.0 mL/min for 30
min with column output connects back to the same chamber A (i.e.,
recirculation mode). After 30 min, TMSOTf (50 μL) was injected into
the chamber A and continued circulation for 2 h at room temperature,
and then the flow was switched to pump B containing CH2Cl2 for 10
min (flow rate: 2 mL/min).
General Procedure Cleavage of Sugar from NPG Chips. A
solution of NaOCH3 in CH3OH (0.1 M, 2.0 mL) was added to a
reaction vessel containing NPG chips with disaccharides on it. The
vessel was kept in a shaker overnight, and then the reaction mixture
was neutralized with Dowex (H+) resin, filtered, and concentrated in
vacuo to afford the corresponding deprotected disaccharide. The crude
product was then acetylated as follows. To a stirred solution of crude
disaccharide (∼0.005 g, 0.0073 mmol) in pyridine (1 mL) was added
dropwise Ac2O (0.5 mL) in the presence of catalytic DMAP. The
reaction mixture was stirred under argon for 8 h at room temperature.
The reaction mixture was quenched with CH3OH (1 mL), and the
resulting mixture was concentrated under reduced pressure. The
residue was diluted with CH2Cl2 (20 mL), and washed with 1 N HCl
(2 × 10 mL), water (20 mL), satd aq NaHCO3 (20 mL), and water
1
1.41−1.60 (m, 8H, 4 × −CH2−), 3.32 (t, 2H, /2OCH2−), 3.37 (m,
2H, OCH2−), 3.53 (m, 1H, 1/2 OCH2−), 3.65 (t, 2H, −CH2OSi),
3.92 (m, 1H, 1/2 OCH2−), 4.12−4.18 (m, 1H, H-5), 4.50 (dd, 1H,
J5,6a = 5.2 Hz, J6a,6b = 12.1 Hz, H-6a), 4.64 (dd, 1H, J5,6b = 3.3 Hz, H-
6b), 4.83 (d, 1H, J1,2 = 7.8 Hz, H-1), 5.53 (dd, 1H, J2,3 = 7.9 Hz, H-2),
5.68 (dd, 1H, J4,5 = 9.7 Hz, H-4), 5.91 (dd, 1H, J3,4 = 9.6 Hz, H-3),
7.25−8.03 ppm (m, 30H, aromatic); 13C NMR (75 MHz, CDCl3) δ
19.2, 25.7 (×2), 26.0, 26.1, 26.8 (×3), 29.1, 29.2, 29.3 (×2), 29.4, 29.7
(×2), 32.5, 63.2, 63.9, 69.8, 70.3, 70.9 (×2), 71.8, 72.1, 72.9, 101.3,
127.5 (×5), 128.2 (×2), 128.3 (×3), 128.4 (×2), 128.8 (×2), 129.3,
129.4 (×2), 129.5, 129.7 (×6), 129.8 (×2), 133.1 (×2), 133.2, 133.4,
134.1, 135.5 (×5), 165.0, 165.2, 165.8, 166.1 ppm; HR-FAB MS [M +
Na]+ calcd for C66H78O12SiNa 1113.5160, found 1113.5194.
17-tert-Butyldiphenylsilyloxy-9-oxaheptadec-1-yl 2,3,4-Tri-
O-benzyl-6-O-triphenylmethyl-β-D-glucopyranoside (17). The
title compound was obtained from 16 in 82% yield (3 steps) as a white
foam as described in the synthesis of compound 7b. Analytical data for
17: Rf = 0.50 (ethyl acetate/hexane, 1/9, v/v); [α]21 +1.6 (c = 1.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 9H, tert-butyl),
1.22−1.40 (m, 16H, 8 × −CH2−), 1.50−1.58 (m, 6H, 3 × −CH2−),
1.68−1.78 (m, 2H, −CH2−), 3.23 (dd, 1H, J5,6a = 3.9 Hz, J6a,6b = 10.1
Hz, H-6a), 3.37 (t, 4H, 2 × OCH2−), 3.38−3.43 (m, 1H, H-5), 3.51−
a
3.60 (m, 4H, H-2, 3, 6b, OCH2 -), 3.64 (t, 2H, −CH2OSi), 3.81 (dd,
b
1H, J4,5 = 9.1 Hz, H-4), 4.05 (m, 1H, OCH2 -), 4.44 (d, 1H, J1,2 = 7.2
Hz, H-1), 4.52 (dd, 2H, 2J = 10.3 Hz, CH2Ph), 4.84 (dd, 2H, 2J = 10.8
Hz, CH2Ph), 4.89 (dd, 2H, 2J = 10.9 Hz, CH2Ph), 6.84−7.68 ppm (m,
40H, aromatic); 13C NMR (75 MHz, CDCl3) δ 19.2, 25.7 (×2), 26.1,
26.2, 26.3, 26.8 (×3), 29.3 (×2), 29.4, 29.5, 29.7, 29.8, 32.5, 62.4, 63.9,
69.8, 70.9 (×2), 74.5, 74.9, 75.0, 75.9, 77.9, 82.7, 84.7, 86.3, 103.6,
126.9 (×3), 127.5 (×5), 127.6 (×2), 127.7 (×5), 128.0 (×3), 128.1
(×3), 128.2 (×3), 128.3 (×3), 128.4 (×3), 128.8 (×4), 129.4 (×3),
134.1 (×2), 135.5 (×3), 137.8, 138.6 (×2), 143.9 (×3) ppm; HR-FAB
MS [M + Na]+ calcd for C78H94O8SiNa 1209.6616, found 1209.6655.
17-Hydroxy-9-oxaheptadec-1-yl 2,3,4-Tri-O-benzyl-6-O-tri-
phenylmethyl-β-D-glucopyranoside (18). The title compound
was obtained from 17 in 95% yield as a white foam as described in the
synthesis of compound 8b. Analytical data for 18: Rf = 0.50 (ethyl
1
acetate/hexane, 1/3, v/v); [α]21 +2.4 (c = 1.0, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 1.31 (s, 16H, 8 × −CH2−), 1.42−1.58 (m, 6H,
3 × −CH2−), 1.63−1.84 (m, 3H, −CH2−, OH), 3.23 (dd, 1H, J5,6a
=
3.9 Hz, J6a,6b = 10.1 Hz, H-6a), 3.37 (t, 4H, J = 6.5 Hz, 2 × OCH2−),
a
3.41−3.47 (m, 1H, H-5), 3.52−3.65 (m, 6H, H-2, 3, 6b, OCH2 -,
−CH2OH), 3.81 (dd, 1H, J4,5 = 9.0 Hz, H-4), 4.06 (dt, 1H, J = 9.4, 6.4
G
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(20 mL). The organic phase was separated, dried over MgSO4, and
concentrated in vacuo to afford corresponding disaccharides 20−22
(60−90%, TLC estimation).
4-Acetoxybut-1-yl O-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyra-
nosyl)-(1→6)-2,3,4-tri-O-benzyl-β-D-glucopyranoside (20). The
title compound was synthesized from glycosyl acceptor 1 and glycosyl
ASSOCIATED CONTENT
* Supporting Information
General experimental and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
donor 14 in 60% yield (TLC estimation). Analytical data for 20: Rf =
1
0.40 (acetone/toluene, 1/9, v/v); [α]21 −5.4 (c = 1.0, CHCl3); H
AUTHOR INFORMATION
Corresponding Author
*E-mail: kstine@umsl.edu, demchenkoa@umsl.edu.
Notes
■
D
NMR (300 MHz, CDCl3) δ 1.70−1.79 (m, 4H, 2 × −CH2−), 1.99,
2.00, 2.03, 2.04, 2.05 (5 s, 15H, 5 × −COCH3), 3.35−3.49 (m, 3H, H-
a
2, 3, 5), 3.50−3.59 (m, 1H, OCH2 -), 3.61−3.69 (m, 3H, H-4, 5′, 6a),
b
3.99 (m, 1H, OCH2 -), 4.05−4.15 (m, 4H, H-6b, 6′a, −CH2OAc),
The authors declare no competing financial interest.
4.24 (dd, 1H, J5′,6′b = 4.6 Hz, J6′a,6′b = 12.3 Hz, H-6′b), 4.36 (d, 1H, J1,2
2
= 7.8 Hz, H-1), 4.62 (d, 1H, J1′,2′ = 7.9 Hz, H-1′), 4.68 (dd, 2H, J =
ACKNOWLEDGMENTS
This work was supported by an award from the NIGMS
(GM090254).
10.9 Hz, CH2Ph), 4.82 (dd, 2H, 2J = 10.9 Hz, CH2Ph), 4.88 (dd, 2H,
2J = 10.9 Hz, CH2Ph), 4.99 (dd, 1H, J2′,3′ = 9.2 Hz, H-2′), 5.08 (dd,
■
1H, J4′,5′ = 9.5 Hz, H-4′), 5.16 (dd, 1H, J3′,4′ = 9.3 Hz, H-3′), 7.23−
7.33 ppm (m, 15H, aromatic); 13C NMR (75 MHz, CDCl3) δ 20.6
(×2), 20.7 (×2), 20.9, 25.4, 26.2, 61.9, 64.1, 68.3, 68.4, 69.3, 71.2, 71.8,
72.9, 74.8, 74.9, 75.7, 77.2, 77.9, 82.2, 84.5, 100.8, 103.4, 127.7 (×2),
127.9 (×3), 128.0 (×4), 128.4 (×5), 128.5, 137.8, 138.3, 138.4, 169.0,
169.4, 170.3, 170.7, 171.1 ppm; HR-FAB MS [M + Na]+ calcd for
C47H58O17Na 917.3572, found 917.3601.
REFERENCES
■
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1
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a
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b
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= 6.7 Hz, −CH2OAc), 3.97−4.01 (m, 1H, H-6′a), 4.05 (dd, 1H, J5,6b
=
2.3 Hz, J6a,6b = 12.5, H-6b), 4.17 (dd, 1H, J5′,6′b = 4.6 Hz, J6′a,6′b = 12.3
Hz, H-6′b), 4.29 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.55 (d, 1H, J1′,2′ = 7.9
Hz, H-1′), 4.61 (dd, 2H, 2J = 11.0 Hz, CH2Ph), 4.75 (dd, 2H, 2J = 10.9
Hz, CH2Ph), 4.77 (dd, 2H, 2J = 10.9 Hz, CH2Ph), 4.95 (dd, 1H, J2′,3′
9.3 Hz, H-2′), 5.00 (dd, 1H, J4′,5′ = 8.1 Hz, H-4′), 5.10 (dd, 1H, J3′,4′
=
=
9.2 Hz, H-3′), 7.15−7.26 ppm (m, 15H, aromatic); 13C NMR (75
MHz, CDCl3) δ 20.6 (×2), 20.7 (×2), 20.9, 25.8, 26.1, 28.5, 29.2, 29.3,
29.7, 61.9, 64.5, 68.3, 68.4, 70.1, 71.2, 71.8, 72.9, 74.8, 74.9, 75.7, 77.2,
77.9, 82.1, 84.5, 100.7, 103.5, 127.6, 127.7, 127.8 (×2), 127.9 (×3),
128.0 (×3), 128.3 (×3), 128.5 (×2), 137.8, 138.3, 138.4, 169.0, 169.3,
170.2, 170.6, 171.2 ppm; HR-FAB MS [M + Na]+ calcd for
C51H66O17Na 973.4198, found 973.4187.
17-Acetoxy-9-oxaheptadec-1-yl O-(2,3,4,6-Tetra-O-acetyl-β-
D-glucopyranosyl)-(1→6)-2,3,4-tri-O-benzyl-β-D-glucopyrano-
side (22). The title compound was synthesized from glycosyl donor
14 and glycosyl acceptor 3 in 90% yield (TLC estimation). Analytical
data for 22: Rf = 0.50 (acetone/toluene, 1/9, v/v); [α]22 −2.6 (c =
D
1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.24 (s, 16H, 8 ×
−CH2−), 1.42−1.58 (m, 8H, 4 × −CH2−), 1.92, 1.92, 1.95 1.97, 1.98
(5 s, 15H, 5 × −COCH3), 3.26−3.37 (m, 6H, H-2, 5, 2 × OCH2−),
a
3.38−3.49 (m, 2H, H-3, OCH2 -), 3.53−3.62 (m, 3H, H-4, 5′, 6a),
b
3.88 (m, 1H, OCH2 -), 3.94−3.96 (m, 1H, H-6b), 3.97 (t, 2H, J = 6.7
Hz, −CH2OCO−), 4.05 (dd, 1H, J5′,6′a = 2.3 Hz, J6′a,6′b = 12.2 Hz, H-
6′a), 4.17 (dd, 1H, J5′,6′b = 4.6 Hz, H-6′b), 4.29 (d, 1H, J1,2 = 7.8 Hz,
2
H-1), 4.55 (d, 1H, J1,2 = 7.9 Hz, H-1′), 4.61 (dd, 2H, J = 10.9 Hz,
CH2Ph), 4.75 (dd, 2H, 2J = 10.9 Hz, CH2Ph), 4.77 (dd, 2H, 2J = 11.0
Hz, CH2Ph), 4.95 (dd, 1H, J2′,3′ = 9.3 Hz, H-2′), 5.00 (dd, 1H, J4′,5′
=
9.6 Hz, H-4′), 5.06 (dd, 1H, J3′,4′ = 9.2 Hz, H-3′), 7.16−7.26 ppm (m,
15H, aromatic); 13C NMR (75 MHz, CDCl3) δ 20.6 (×2), 20.7 (×2),
20.9, 25.8, 26.1 (×2), 26.2, 28.5, 29.2, 29.3, 29.4 (×2), 29.7 (×3), 61.9,
64.6, 68.3, 68.4, 70.1, 70.9 (×2), 71.2, 71.7, 72.9, 74.8, 74.9, 75.7, 77.2,
77.9, 82.1, 84.5, 100.7, 103.5, 127.6, 127.7, 127.8, 127.9 (×4), 128.0,
128.1 (×2), 128.3 (×3), 128.5 (×2), 137.8, 138.3, 138.4, 169.0, 169.4,
170.2, 170.7, 171.2 ppm; HR-FAB MS [M + Na]+ calcd for C59H82O18
Na 1101.5399, found 1101.5404.
H
dx.doi.org/10.1021/jo400095u | J. Org. Chem. XXXX, XXX, XXX−XXX

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