Glycosylations of tertiary alcohols: Synthesis of fully protected disaccharides with sterically demanding groups attached to the sugar core

Article abstract of DOI:10.1055/s-0029-1217403

Modified gluco- and galactopyranosides with sterically demanding groups in the 4-position were synthesized. Glycosylation studies of these tertiary alcohols with glycosyl trichloroacetimidates and glycosyl phosphates were performed. Despite steric hindran

Full text of DOI:10.1055/s-0029-1217403

2596
PAPER
Glycosylations of Tertiary Alcohols: Synthesis of Fully Protected
Disaccharides with Sterically Demanding Groups Attached to the Sugar Core
Glycosylations of
n
T
ertiary
A
lco
n
hols ika Holkenbrink, Jordi Bertrán Vicente, Daniel B. Werz*
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: dwerz@gwdg.de
Received 18 February 2009; revised 17 April 2009
contrast to C-branched monosaccharide units which have
Abstract: Modified gluco- and galactopyranosides with sterically
demanding groups in the 4-position were synthesized. Glycosyla-
recently attracted some interest,8 the glycoside formation
with tertiary hydroxy acceptors by chemical means has
tion studies of these tertiary alcohols with glycosyl trichloroacet-
imidates and glycosyl phosphates were performed. Despite steric
not been investigated except for the less sterically encum-
hindrance the modified disaccharide moieties could be assembled in bered tert-butyl alcohol, 1-adamantanol, and cholesterol
derivatives as substrates.7 For the glycosylation of hin-
moderate yields.
dered and deactivated phenols the Kahne protocol using
sulfoxides as glycosyl donors proved to be the best
choice.9 Disaccharides with sterically demanding groups
attached to the sugar core have not been prepared so far.
Key words: carbohydrates, glycosylation, steric hindrance, glyco-
sides
Carbohydrates play an important role in a large number of
biological processes such as cell–cell recognition, immu-
nological response, metastasis, information transfer, and
viral infection.1 In bacteria carbohydrate oligomers or
polymers constitute often a major part of the bacterial cell
wall2 or are used as important points of attachment when
interacting with other cells.3 In contrast to mammalian
carbohydrates the variety of different monosaccharide
units found in plants, fungi, and microorganisms is enor-
mous.4 Besides the so-called ten mammalian monosac-
charide units even highly deoxygenated units or examples
with quaternary stereocenters (e.g., 1–3) are found in
these species (Figure 1).5
In order to achieve this goal, we prepared several pyrano-
side building blocks with an alkyl or an alkynyl moiety di-
rectly attached to the carbon with the free hydroxy group.
These monosaccharide units with tertiary hydroxy groups
were obtained by reaction of the corresponding ketone
with organolithium species such as MeLi, BuLi, and lithi-
ated alkynes, respectively. Alkynes were chosen for sev-
eral reasons. On the one hand they would allow a further
functionalization by Huisgen 1,3-dipolar cycloaddition10
or in the case of terminal alkynes by Sonogashira cou-
pling.11 On the other hand, the stiff alkyne unit presents a
moiety with limited steric bulk that could be of advantage
during the glycosylation reaction of a tertiary hydroxy
functionality.
OH
OH
OH
OH
Me
Me
Starting point of our investigations was the glucopyrano-
side ketone 4, which was synthesized from commercially
available methyl glucopyranoside in four steps.12 Nucleo-
philic attack of several organolithium species to the ke-
tone 4 afforded the monosaccharide units with tertiary
hydroxy groups in moderate to good yields (55–80%) as
depicted in Scheme 1. In all cases diastereomeric mix-
tures of the gluco- and the galacto-configured sugar deriv-
atives 5–8 were obtained that could be easily separated by
silica gel column chromatography or preparative HPLC
using a reversed-phase column. In the case of lithiated
alkynes the equatorial attack seems to be slightly favored
over the axial attack; however, for the small MeLi
axial attack is preferred. The identity of the diastereomers
5a/b–8a/b (gluco vs. galacto configuration) was unequiv-
ocally determined by extensive 2D-NMR spectroscopic
techniques as well as NOESY investigations. The major
NOE correlation effects for the determination of the con-
figuration at C-4 are depicted in Figure 2 exemplarily for
6a and 6b as well as for 8a and 8b. In the case of 8b we
found a strong NOE correlation between H-2 and the pro-
ton of the hydroxy group, whereas no NOE could be ob-
served in the case of the other diastereomer 8a. Due to
Me
HO
Me
HO
Me
MeO
O
O
O
NH2
HO
Me
OMe
1
2
3
Figure 1 Examples 1–3 of microbial monosaccharide units with
quaternary stereocenters
However, nature uses only very rarely tertiary hydroxy
groups to form glycosidic bonds.5b In such cases com-
monly C-methyl derivatives are utilized. Such methyl-
substituted species have also been used in biochemical
studies elucidating the substrate scope of glycosyltrans-
ferases.6 From a synthetic chemical point of view we were
interested in the question whether glycosylations of tertia-
ry alcohols with geminal sterically demanding groups are
still possible.7 Therefore, we envisioned a manipulation of
the core structure of glycosyl acceptors by attaching fur-
ther sterically demanding alkyl or alkynyl moieties direct-
ly to the carbon atoms of the six-membered ring. In
SYNTHESIS 2009, No. 15, pp 2596–2604
x
x.
x
x
.
2
0
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Advanced online publication: 22.06.2009
DOI: 10.1055/s-0029-1217403; Art ID: T04209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Glycosylations of Tertiary Alcohols
2597
OBn
R
O
HO
BnO
OBn
OBn
HO
O
O
BnO
HO
BnO
OMe
BnO
5a (R = Me)
6a (R = n-Bu)
OBn
H BnO
H BnO
O
OMe
OMe
O
RLi, THF
+
no NOE
strong NOE
6b
BnO
–78 °C, 2.5 h
6a
BnO
OBn
HO
OMe
TMS
4
O
R
BnO
strong NOE
OBn
H
BnO
OH
OMe
BnO
H
O
O
56%, dr = 67:33 (R = Me)
55%, dr = 47:53 (R = n-Bu)
5b (R = Me)
HO
BnO
6b (R = n-Bu)
BnO
TMS
BnO
BnO
R
OMe
OMe
no NOE between OH and H-2
OBn
8b
8a
O
HO
Figure 2 Most important NOE effects for determination of the ste-
reochemistry of 6a and 6b as well as 8a and 8b
BnO
BnO
OMe
7a (R = Ph)
8a (R = TMS)
OBn
O
OBn
OH
RC≡CH, n-BuLi, THF
O
+
R1
O
BnO
–78 °C, 3 h
BnO
BnO
OBn
BnO
HO
OMe
O
OMe
O
(R2O)n
4
O
5a–8b
OBn
O
O
TMSOTf
CH2Cl2
R
R1
BnO
+
BnO
BnO
BnO
OMe
7b (R = Ph)
8b (R = TMS)
(R2O)n
OMe
74%, dr = 42:58 (R = Ph)
80%, dr = 30:70 (R = TMS)
OLG
14–24
9–13
Scheme 1 Nucleophilic attack of lithiated species to glucose ketone
4
Scheme 2 Glycosylation reaction of sterically hindered glycosyl ac-
ceptors 5a–8b with glycosyl donors 9–13 (LG = leaving group).
strongly overlapping signals such a clear-cut analysis was using mannosyl phosphate 9 a product 14 could be ob-
not possible for 7a/7b. However, with the transformation tained in significant yield (Table 1, entry 1). In other cas-
of the hydroxy unit into an acetate moiety we could solve es, MS spectrometric and NMR spectroscopic
this stereochemical problem in an analogous way as done investigations have shown that product formation takes
for 8a/8b.
place slowly; however, due to the almost same polarity of
the sterically hindered acceptor and the formed disaccha-
ride a separation of these two species by conventional col-
umn chromatography was almost impossible.
For the glycosylation studies (Scheme 2) we tested first a
variety of glycosyl phosphates.13 The reactions were per-
formed either at –40 °C or at 0 °C using a stoichiometric
amount of activating TMSOTf. However, only in one case
Table 1 Glycosylations of Tertiary Hydroxy Groups to Form Disaccharides
Entry Acceptor
Donor
Disaccharide
Yield Yield
(%)a (%)b
BnO
BnO
BnO
OBz
O
OBn
Me
BnO
BnO
BnO
OBz
O
OBn
O
O
Me
c
1
2
5a
6a
9
14
71
59
–
–
HO
BnO
O
BnO
BnO
OP(O)(OBu)2
BnO
OMe
OMe
OMe
NH
CCl3
Bu OBn
O
Bu
OBn
O
O
O
c
BnO
10
15
HO
BnO
BnO
Me
AcO
O
Me
O
BnO
AcO
OMe
AcO
AcO
OAc
OAc
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

2598
A. Holkenbrink et al.
PAPER
Table 1 Glycosylations of Tertiary Hydroxy Groups to Form Disaccharides (continued)
Entry Acceptor
Donor
Disaccharide
Yield Yield
(%)a (%)b
OAc
Me
OAc
OAc
NH
CCl3
O
HO
OBn
O
O
3
6b
10
16
35
75
Bu
BnO
O
OBn
O
Me
AcO
O
Bu
BnO
BnO
HO
OMe
AcO
BnO
OAc
OMe
AcO OAc
O
OAc
OBn
AcO
AcO
O
O
c
OBn
O
O
AcO
AcO
4
5
7b
7b
11
12
17
18
53
27
–
O
Ph
Ph
CCl3
NH
BnO
Ph
AcO
BnO
BnO
BnO
OMe
OMe
OMe
OAc
HO
OAc
OBn
O
AcO
AcO
O
O
OBn
O
AcO
AcO
62
86
AcO
Ph
O
CCl3
O
BnO
AcO
BnO
BnO
BnO
NH
OMe
OAc
Me
NH
CCl3
O
HO
OBn
OAc
OAc
O
O
6
7
7b
10
19
38
O
OBn
O
Ph
Me
AcO
BnO
O
BnO
Ph
BnO
OMe
AcO
BnO
OAc
O
OMe
TMS
TMS
NH
CCl3
OBn
O
OBn
8a
10
20
62
73
O
BnO
O
Me
AcO
O
HO
BnO
BnO
Me
AcO
O
OMe
AcO
BnO
OAc
AcO
OMe
OBn
OAc
AcO OAc
O
HO
AcO
AcO
OAc
O
O
OBn
O
AcO
AcO
8
9
8b
8b
8b
11
12
13
21
22
23
53
35
56
71
92
86
O
CCl3
TMS
TMS
TMS
O
BnO
TMS
AcO
BnO
BnO
BnO
NH
OMe
OMe
OAc
HO
OAc
OBn
O
AcO
AcO
O
O
OBn
O
O
AcO
AcO
AcO
TMS
O
CCl3
NH
BnO
AcO
BnO
BnO
BnO
OMe
OMe
OMe
OAc
O
HO
OAc
OBn
AcO
AcO
O
O
O
OBn
O
AcO
AcO
Cl3CCOHN
10
Cl3CCOHN
O
CCl3
NH
BnO
TMS
BnO
BnO
BnO
OMe
OAc
Me
OAc
OAc
NH
CCl3
O
HO
OBn
O
O
11
8b
10
24
48
77
O
OBn
O
TMS
Me
AcO
O
BnO
BnO
TMS
BnO
OMe
AcO
BnO
OAc
OMe
a Yield of isolated product.
b Yield based on recovered starting material (acceptor).
c Yield based on recovered starting material was not determined.
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

PAPER
Glycosylations of Tertiary Alcohols
2599
The use of peracetylated trichloroacetimidates14 as dis-
armed donors proved to be more successful. We tested a
variety of glycosyl trichloroacetimidates such as the ones Variant II: To a solution of ketone 4 (1.0 equiv) in THF (0.1 mol/L)
reduced pressure. The crude product was purified by column chro-
matography on silica gel and HPLC, respectively.
was slowly added n-BuLi or MeLi (1.7 and 1.3 equiv, respectively)
at –78 °C and the reaction mixture was stirred for 2.5 h at the same
temperature. Workup was performed as described above.
derived from rhamnose (10), galactose (11), glucose (12)
and glucosamine (13). These electron-poor building
blocks reacted with the respective sterically hindered ac-
ceptors to afford disaccharides 15–24 in moderate yield
(27–62%) after activation with the Lewis acid TMSOTf.
Methyl 2,3,6-Tri-O-benzyl-4-methyl-a-D-glucopyranoside (5a)
and Methyl 2,3,6-Tri-O-benzyl-4-methyl-a-D-galactopyrano-
side (5b)15
Following variant II, MeLi (1.6 M in hexane, 1.8 mL, 2.8 mmol)
and 4 (1.0 g, 2.2 mmol) in THF (40 mL) afforded 589 mg (56%) of
5a and 5b as a diastereomeric mixture (dr 67:33). The diastereomers
could be separated as colorless oils after column chromatography
(silica gel, pentane–EtOAc, 10:1).
A catalytic amount (0.15 equiv) of activating TMSOTf
was sufficient, stoichiometric amounts did not increase
the yield. In most cases we could recover a large amount
of the acceptor. Therefore, we provide in Table 1 next to
the product yield also the yield based on recovered start-
ing material. The latter values are in the range of 62–92%.
Even with the commonly relatively unreactive 4-hydroxy
group of galactose disaccharide formation took place. The
use of an higher excess of donor (up to 2.5 equiv) did not
lead to a significant increase of the yield. With the per-
acetylated donors the separation by silica gel column
chromatography was much more convenient due to big
differences in polarity of the respective donor, acceptor
and disaccharide.
5a
[a]D +45.3 (c = 0.17, CHCl3); Rf = 0.33 (hexane–EtOAc, 3:1).
IR (film): 3428, 2919, 1721, 1453, 1277, 1071 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.17 (s, 3 H, 7-CH3), 2.49 (s, 1 H,
OH), 3.39 (s, 3 H, OCH3), 3.41 (dd, J = 3.8, 10.1 Hz, 1 H, 2-H),
3.57 (dd, J = 7.1, 9.9 Hz, 1 H, 6-Ha), 3.71 (dd, J = 5.1, 9.9 Hz, 1 H,
6-Hb), 3.79 (d, J = 10.1 Hz, 1 H, 3-H), 3.88 (dd, J = 5.1, 7.1 Hz,
1 H, 5-H), 4.51 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.56 (d,
J = 12.0 Hz, 1 H, CHaHbPh), 4.59 (d, J = 3.8 Hz, 1 H, 1-H), 4.61 (d,
J = 12.2 Hz, 1 H, CHaHbPh), 4.77 (d, J = 12.2 Hz, 1 H, CHaHbPh),
4.79 (d, J = 11.7 Hz, 1 H, CHaHb-Ph), 4.94 (d, J = 11.7 Hz, 1 H,
CHaHbPh), 7.25–7.40 (m, 15 H, C6H5).
In summary, we have investigated the glycosylation reac-
tion of carbohydrate derivatives with tertiary hydroxy
groups. As acceptors we prepared gluco and galacto de-
rivatives with further alkyl and alkynyl groups attached to
position 4 of the pyranose system. As glycosyl donors gly-
cosyl trichloroacetimidates as well as glycosyl phosphates
were used. The glycosylation reaction of tertiary alcohols
itself proceeds much slower and in lower yields than with
the corresponding secondary alcohols; however, the syn-
thesis of the corresponding disaccharides with quaternary
carbons at the glycosidic bond could be obtained in mod-
erate yields. These results may be important for a specific
modification of medically relevant oligosaccharides and
could lead to promising tools for probing protein binding
domains.
13C NMR (125 MHz, CDCl3): d = 15.7, 54.9, 68.8, 70.8, 73.2, 73.4,
74.1, 75.5, 78.5, 83.4, 97.8, 127.4, 127.5, 127.6, 127.6, 127.7,
127.9, 128.2, 128.3, 128.3, 137.7, 138.1, 139.0.
ESI-HRMS: m/z [M + Na]+ calcd for C29H34O6 + Na: 501.22476;
found: 501.22470.
5b
[a]D +30.0 (c = 1.0, CHCl3); Rf = 0.27 (hexane–EtOAc, 3:1).
IR (film): 2927, 1722, 1453, 1274, 1071 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.16 (s, 3 H, 7-CH3), 2.69 (br s,
1 H, OH), 3.39 (s, 3 H, OCH3), 3.56 (d, J = 9.6 Hz, 1 H, 3-H), 3.65–
3.75 (m, 2 H, 5-H, 6-Ha), 3.76–3.84 (m, 1 H, 6-Hb), 3.89 (dd,
J = 3.7, 9.6 Hz, 1 H, 2-H), 4.56–4.67 (m, 4 H, CH2Ph), 4.69 (d,
J = 3.7 Hz, 1 H, 1-H), 4.76 (d, J = 12.0 Hz, 1 H, CHaHbPh), 5.00 (d,
J = 11.0 Hz, 1 H, CHaHbPh), 7.23–7.38 (m, 15 H, C6H5).
All reactions were performed in flame-dried glassware under argon.
The solvents were dried by standard procedures and distilled. Pre-
parative HPLC was carried out with a conventional pump and an
UV detector (Jasco) on a reversed-phase column (LiChrospher, RP-
18). 1H and 13C NMR spectra were obtained with a Varian Mercury
300 MHz, Varian Unity 300 MHz, Varian Inova 500 MHz and
Varian Inova 600 MHz spectrometer using CHCl3 as internal stan-
dard. ESI-HRMS mass spectrometry was carried out on a FTICR in-
strument (Bruker). IR spectra were measured on a Bruker Vector 22
spectrometer. A PerkinElmer polarimeter model 241 was used for
the measurement of the optical rotation.
13C NMR (125 MHz, CDCl3): d = 22.2, 55.3, 69.4, 72.3, 73.2, 73.6,
74.1, 76.2, 78.0, 80.5, 98.2, 127.6, 127.7, 127.8, 127.8, 128.1,
128.2, 128.3, 128.4, 128.4, 137.9, 138.3.
ESI-HRMS: m/z [M + Na]+ calcd for C29H34O6 + Na: 501.22476;
found: 501.22515.
Methyl 2,3,6-Tri-O-benzyl-4-butyl-a-D-glucopyranoside (6a)
and Methyl 2,3,6-Tri-O-benzyl-4-butyl-a-D-galactopyranoside
(6b)
Following variant II, n-BuLi (2.5 M in hexane, 2.1 mL, 5.3 mmol)
and 4 (1.5 g, 3.2 mmol) in THF (20 mL) gave 438 mg (26%) of 6a
as a colorless oil after column chromatography (silica gel, pentane–
EtOAc, 5:1). The other diastereomer 6b [489 mg (29%)] could be
obtained as a colorless oil after a second column chromatography
(silica gel, toluene–acetone, 20:1).
Alkylation and Alkynylation of Glucopyranoside Ketone 4;
General Procedure
Variant I: To a solution of alkyne (1.3 equiv) in THF (0.1 mol/L)
was slowly added n-BuLi (1.3 equiv) at –78 °C and the reaction
mixture was stirred for 1 h at the same temperature. A solution of
ketone 4 (1.0 equiv) in THF (0.1 mol/l) was added dropwise and the
solution was stirred for 3 h at –78 °C. The reaction was quenched
with aq sat. NH4Cl (20 mL) and the aqueous layer was extracted
with EtOAc (3 × 0.2 mol/L). The combined organic layers were
washed with brine (40 mL), dried (Na2SO4), and concentrated under
6a
[a]D +18.1 (c = 2.58, CHCl3); Rf = 0.27 (hexane–EtOAc, 3:1).
IR (film): 3382, 3032, 2956, 1722, 1497, 1454, 1275, 1049 cm–1.
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

2600
A. Holkenbrink et al.
PAPER
1H NMR (600 MHz, CDCl3): d = 0.89 (t, J = 7.1 Hz, 3 H, 10-CH3),
1.21–1.33 (m, 3 H, 8-Ha, 9-CH2), 1.46–1.54 (m, 2 H, 7-Ha, 8-Hb),
1.70–1.79 (m, 1 H, 7-Ha), 2.50 (br s, 1 H, OH), 3.41 (s, 3 H, OCH3),
3.53 (dd, J = 3.8, 10.0 Hz, 1 H, 2-H), 3.58 (dd, J = 7.6, 9.9 Hz, 1 H,
6-Ha), 3.73 (dd, J = 4.7, 9.9 Hz, 1 H, 6-Hb), 3.80 (d, J = 10.0 Hz,
1 H, 3-H), 3.92 (dd, J = 4.7, 7.6 Hz, 1 H, 5-H), 4.51 (d, J = 11.9 Hz,
1 H, CHaHbPh), 4.55 (d, J = 11.9 Hz, 1 H, CHaHbPh), 4.62 (d,
J = 3.8 Hz, 1 H, 1-H), 4.64 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.75 (d,
J = 11.8 Hz, 1 H, CHaHbPh), 4.76 (d, J = 12.1 Hz, 1 H, CHaHbPh),
4.92 (d, J = 11.8 Hz, 1 H, CHaHbPh), 7.25–7.38 (m, 15 H, C6H5).
7b
[a]D –30.4 (c = 1.08, CHCl3); Rf = 0.22 (hexane–EtOAc, 3:1).
IR (film): 2929, 1722, 1494, 1454, 1271, 1053 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.44 (s, 3 H, OCH3), 3.82 (dd,
J = 3.6, 9.6 Hz, 1 H, 2-H), 3.93 (dd, J = 6.9, 11.1 Hz, 1 H, 6-Ha),
4.04–4.10 (m, 2 H, 5-H, 6-Hb), 4.05 (d, J = 9.6 Hz, 1 H, 3-H), 4.59
(d, J = 12.1 Hz, 1 H, CHaHbPh), 4.64 (d, J = 12.1 Hz, 1 H, CHaHb-
Ph), 4.64 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.71 (d, J = 3.6 Hz, 1 H,
1-H), 4.80 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.96 (d, J = 10.6 Hz,
1 H, CHaHbPh), 5.04 (d, J = 10.6 Hz, 1 H, CHaHbPh), 7.19–7.45 (m,
20 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 14.1, 23.8, 26.1, 29.6, 55.1, 69.0,
72.5, 73.3, 73.4, 75.1, 75.6, 77.8, 84.6, 97.8, 127.5, 127.6, 127.8,
128.0, 128.3, 128.4, 137.8, 138.2, 139.1.
13C NMR (125 MHz, CDCl3): d = 55.4, 69.7, 71.8, 71.9, 73.6, 73.6,
76.3, 76.5, 81.5, 85.9, 88.4, 98.4, 122.0, 127.6, 127.6, 127.8, 127.9,
128.1, 128.3, 128.3, 128.4, 128.4, 128.4, 128.7, 131.7, 137.9, 138.1,
138.2.
ESI-HRMS: m/z [M + Na]+ calcd for C32H40O6 + Na: 543.27171;
found: 543.27186.
ESI-HRMS: m/z [M + Na]+ calcd for C36H36O6 + Na: 587.24041;
found: 587.24049.
6b
[a]D +30.7 (c = 0.3, CHCl3); Rf = 0.18 (hexane–EtOAc, 3:1).
IR (film): 3388, 2934, 1723, 1496, 1454, 1274, 1054 cm–1.
Methyl 2,3,6-Tri-O-benzyl-4-trimethylsilylethynyl-a-D-glu-
copyranoside (8a) and Methyl 2,3,6-Tri-O-benzyl-4-trimethyl-
silylethynyl-a-D-galactopyranoside (8b)16
Following variant I, trimethylsilylacetylene (0.41 mL, 2.9 mmol)
and n-BuLi (2.5 M in hexane, 1.2 mL, 3.0 mmol) in THF (20 mL)
and 4 (1.0 g, 2.2 mmol) in THF (20 mL) afforded 996 mg (80%) of
8a and 8b as a diastereomeric mixture (dr 30:70). The diastereomers
could be obtained as colorless oils after column chromatography
(silica gel, pentane–EtOAc, 5:1) and HPLC separation on reversed
phase RP-18 (MeOH–H2O, 85:15).
1H NMR (600 MHz, CDCl3): d = 0.78 (t, J = 6.8 Hz, 3 H, 10-CH3),
0.95–1.18 (m, 4 H, 8-CH2, 9-CH2), 1.28–1.41 (m, 1 H, 7-Ha), 1.73–
1.87 (m, 1 H, 7-Hb), 2.71 (s, 1 H, OH), 3.40 (s, 3 H, OCH3), 3.66
(dd, J = 5.9, 10.8 Hz, 1 H, 6-Ha), 3.77 (dd, J = 2.8, 10.8 Hz, 1 H, 6-
Hb), 3.80 (d, J = 9.4 Hz, 1 H, 3-H), 3.85 (dd, J = 2.8, 5.9 Hz, 1 H, 5-
H), 3.96 (dd, J = 3.7, 9.4 Hz, 1 H, 2-H), 4.52 (d, J = 12.2 Hz, 1 H,
CHaHbPh), 4.57 (d, J = 12.2 Hz, 1 H, CHaHbPh), 4.63 (d,
J = 11.0 Hz, 1 H, CHaHbPh), 4.63 (d, J = 12.2 Hz, 1 H, CHaHbPh),
4.68 (d, J = 3.7 Hz, 1 H, 1-H), 4.76 (d, J = 12.2 Hz, 1 H, CHaHbPh),
5.00 (d, J = 11.0 Hz, 1 H, CHaHbPh), 7.23–7.38 (m, 15 H, C6H5).
8a
[a]D +48.0 (c = 0.61, CHCl3); Rf = 0.35 (hexane–EtOAc, 3:1).
13C NMR (125 MHz, CDCl3): d = 13.9, 23.3, 26.3, 35.3, 55.4, 69.1,
69.9, 73.3, 73.7, 75.7, 76.2, 77.0, 78.6, 98.1, 127.7, 127.8, 127.8,
127.9, 128.2, 128.3, 128.4, 128.5, 138.0, 138.4, 138.5.
IR (film): 3381, 2927, 1497, 1454, 1369, 1251, 1057 cm–1.
ESI-HRMS: m/z [M + NH4]+ calcd for C32H44NO6: 538.31642;
found: 538.31631.
1H NMR (600 MHz, CDCl3): d = 0.16 [s, 9 H, Si(CH3)3], 3.38 (s,
3 H, OCH3), 3.67 (dd, J = 3.7, 10.0 Hz, 1 H, 2-H), 3.70 (dd, J = 5.9,
9.0 Hz, 1 H, 6-Ha), 3.84–3.92 (m, 2 H, 5-H, 6-Hb), 3.86 (d,
J = 10.0 Hz, 3-H), 4.53 (d, J = 11.6 Hz, 1 H, CHaHbPh), 4.56 (d,
J = 11.6 Hz, 1 H, CHaHbPh), 4.57 (d, J = 3.7 Hz, 1 H, 1-H), 4.63 (d,
J = 12.2 Hz, 1 H, CHaHbPh), 4.77 (d, J = 12.2 Hz, 1 H, CHaHbPh),
4.89 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.96 (d, J = 12.0 Hz, 1 H,
CHaHbPh), 7.23–7.44 (m, 15 H, C6H5).
Methyl 2,3,6-Tri-O-benzyl-4-phenylethynyl-a-D-glucopyrano-
side (7a) and Methyl 2,3,6-Tri-O-benzyl-4-phenylethynyl-a-D-
galactopyranoside (7b)
Following variant I, using phenylacetylene (0.26 mL, 2.4 mmol)
and n-BuLi (2.5 M in hexane, 0.94 mL, 2.4 mmol) in THF (20 mL)
and 4 (0.84 g, 1.8 mmol) in THF (20 mL) gave 750 mg (74%) of 7a
and 7b as a diastereomeric mixture (dr 42:58). The diastereomers
could be obtained as colorless oils after column chromatography
(silica gel, pentane–EtOAc, 4:1) and HPLC separation using a re-
versed phase column RP-18 (MeOH–H2O, 80:20).
13C NMR (125 MHz, CDCl3): d = –0.1, 55.3, 69.9, 70.1, 73.5, 73.8,
74.3, 75.1, 77.7, 82.2, 92.4, 98.4, 102.7, 127.3, 127.4, 127.7, 127.8,
127.8, 128.3, 128.3, 128.4, 128.4, 137.6, 138.2, 139.3.
ESI-HRMS: m/z [M + Na]+ calcd for C33H40O6Si + Na: 583.24864;
found: 583.24860.
7a
[a]D +56.7 (c = 1.23, CHCl3); Rf = 0.22 (hexane–EtOAc, 3:1).
8b
[a]D +2.0 (c = 0.4, CHCl3); Rf = 0.35 (hexane–EtOAc, 3:1).
IR (film): 2924, 1454, 1369, 1198, 1055 cm–1.
IR (film): 3425, 3032, 2930, 1724, 1497, 1454, 1354, 1251, 1197,
1060 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.43 (s, 3 H, OCH3), 3.54 (s, 1 H,
OH), 3.76–3.85 (m, 2 H, 2-H, 5-H), 3.96–4.07 (m, 3 H, 3-H, 6-
CH2), 4.60 (d, J = 12.0 Hz, 1 H, CHaHbPh,), 4.63 (d, J = 12.0 Hz,
1 H, CHaHbPh), 4.67 (d, J = 3.4 Hz, 1 H, 1-H), 4.68 (d, J = 12.0 Hz,
1 H, CHaHbPh), 4.82 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.96 (d,
J = 11.9 Hz, 1 H, CHaHbPh), 5.02 (d, J = 11.9 Hz, 1 H, CHaHbPh),
7.24–7.51 (m, 20 H, C6H5).
1H NMR (600 MHz, CDCl3): d = 0.14 [s, 9 H, Si(CH3)3], 3.31 (d,
J = 1.1 Hz, 1 H, OH), 3.43 (s, 3 H, OCH3), 3.74 (dd, J = 3.7, 9.6 Hz,
1 H, 2-H), 3.85 (dd, J = 7.5, 11.4 Hz, 1 H, 6-Ha), 3.97 (d,
J = 9.6 Hz, 1 H, 3-H), 3.98–4.01 (m, 2 H, 5-H, 6-Hb), 4.56 (d,
J = 12.1 Hz, 1 H, CHaHbPh), 4.62 (d, J = 12.3 Hz, 1 H, CHaHbPh),
4.64 (d, J = 12.3 Hz, 1 H, CHaHbPh), 4.68 (d, J = 3.7 Hz, 1 H, 1-H),
4.78 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.91 (d, J = 10.4 Hz, 1 H,
CHaHbPh), 4.99 (d, J = 10.4 Hz, 1 H, CHaHbPh), 7.25–7.43 (m,
15 H, C6H5).
13C NMR (125 MHz, CDCl3): d = 55.3, 70.1, 70.2, 73.5, 73.8, 74.5,
75.4, 78.1, 82.6, 86.4, 87.3, 98.3, 122.5, 127.4, 127.6, 127.6, 127.7,
127.7, 128.1, 128.2, 128.3, 128.4, 128.4, 131.9, 137.5, 138.2, 139.1.
ESI-HRMS: m/z [M + Na]+ calcd for C36H36O6 + Na: 587.24041;
found: 587.24052.
13C NMR (125 MHz, CDCl3): d = –0.3, 55.4, 69.6, 71.4, 71.8, 73.6,
73.6, 76.1, 76.5, 81.4, 90.9, 98.3, 104.8, 127.6, 127.6, 127.8, 127.8,
128.0, 128.3, 128.3, 128.3, 128.4, 138.0, 138.2, 138.2.
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

PAPER
Glycosylations of Tertiary Alcohols
2601
ESI-HRMS: m/z [M + Na]+ calcd for C33H40O6Si + Na: 583.24864;
found: 583.24857.
4.57 (d, J = 2.4 Hz, 1 H, 1-H), 4.57–4.60 (m, 2 H, CHaHbPh, CHaH-
bPh), 4.68 (d, J = 11.7 Hz, 1 H, CHaHbPh), 4.83 (d, J = 11.1 Hz,
1 H, CHaHbPh), 5.01–5.09 (m, 3 H, 2¢-H, 4¢-H, CHaHbPh), 5.25 (dd,
J = 3.2, 10.2 Hz, 1 H, 3¢-H), 5.38 (d, J = 1.7 Hz, 1 H, 1¢-H), 7.20–
7.38 (m, 15 H, C6H5).
Glycosylation of Tertiary Alcohols 5–8; General Procedure
Variant I: Glycosyl donor as well as glycosyl acceptor were azeo-
troped with toluene (3 × 1 mL), dried in high vacuum for 1 h,
and dissolved in CH2Cl2 (0.3 mol/mL). The solution was cooled to
–40 °C, TMSOTf was added and stirred for 2 h at the same temper-
ature. Pyridine (1 mL) was added and the solvents were removed
under reduced pressure. The crude product was purified by column
chromatography on silica gel.
13C NMR (75 MHz, CDCl3): d = 13.9, 17.4, 20.7, 20.8, 20.8, 23.6,
26.2, 27.9, 55.0, 66.9, 68.8, 69.4, 70.7, 71.0, 72.7, 73.1, 73.4, 74.9,
80.0, 80.9, 81.6, 92.2, 97.1, 127.0, 127.2, 127.3, 127.4, 127.9,
128.1, 128.2, 128.2, 128.4, 137.7, 138.3, 139.3, 169.9, 170.0, 170.1.
ESI-HRMS: m/z [M + K]+ calcd for C44H56O13 + K: 831.33525;
found: 831.33503.
Variant II: In contrast to variant I, the solution was cooled to 0 °C
and TMSOTf was used in stoichiometric and catalytic amounts, re-
spectively.
Methyl 2,3,4-Tri-O-acetyl-a-L-rhamnopyranosyl-(1→4)-2,3,6-
tri-O-benzyl-4-butyl-a-D-galactopyranoside (16)
Following variant II, glycosyl acceptor 6b (38.7 mg, 74.3 mmol),
glycosyl donor 10 (45.0 mg, 104 mmol) and TMSOTf (17.0 mL,
94.0 mmol) were reacted in CH2Cl2 (2 mL). Column chromatogra-
phy (pentane–EtOAc, 7:1) of the crude product gave 20.7 mg (35%;
75% based on recovered starting material) of 16 as a colorless oil;
[a]D +2.8 (c = 0.25, CHCl3); Rf = 0.11 (hexane–EtOAc, 3:1).
Methyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-a-D-mannopyranosyl-
(1→4)-2,3,6-tri-O-benzyl-4-methyl-a-D-glucopyranoside (14)
Following variant II, glycosyl acceptor 5a (55.0 mg, 115 mmol),
glycosyl donor 9 (105 mg, 141 mmol) and TMSOTf (25.0 mL,
138 mmol) were reacted in CH2Cl2 (5 mL). Column chromatogra-
phy (pentane–EtOAc, 7:1; pentane–EtOAc, 12:1 → 10:1) of
the crude product gave 82.5 mg (71%) of 14 as a colorless oil;
[a]D –25.5 (c = 1.0, CHCl3); Rf = 0.27 (hexane–EtOAc, 3:1).
IR (film): 2933, 1748, 1455, 1369, 1224, 1040 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 6.8 Hz, 3 H, 10-CH3),
1.04–1.32 (m, 5 H, 7-Ha, 8-CH2, 9-CH2), 1.12 (d, J = 6.3 Hz, 3 H,
6¢-CH3), 1.37–1.51 (m, 1 H, 7-Hb), 1.96 [s, 6 H, O(CO)CH3], 2.04
[s, 3 H, O(CO)CH3], 3.39 (s, 3 H, OCH3), 3.61 (dd, J = 7.0,
10.7 Hz, 1 H, 6-Ha), 3.72 (dd, J = 2.7, 10.7 Hz, 1 H, 6-Hb), 3.87 (d,
J = 9.9 Hz, 1 H, 3-H), 3.90 (dd, J = 6.3, 9.8 Hz, 1 H, 5¢-H), 3.97
(dd, J = 2.7, 7.0 Hz, 1 H, 5-H), 4.07 (dd, J = 3.8, 9.9 Hz, 1 H, 2-H),
4.43 (d, J = 10.8 Hz, 1 H, CHaHbPh), 4.47 (d, J = 12.0 Hz, 1 H,
CHaHbPh), 4.65 (d, J = 3.8 Hz, 1 H, 1-H), 4.67 (d, J = 12.0 Hz, 1 H,
CHaHbPh), 4.70 (d, J = 11.7 Hz, 1 H, CHaHbPh), 4.90 (d,
J = 11.7 Hz, 1 H, CHaHbPh), 4.97 (d, J = 10.8 Hz, 1 H, CHaHbPh),
5.00 (dd, J = 9.8, 10.0 Hz, 1 H, 4¢-H), 5.27 (dd, J = 3.2, 10.0 Hz,
1 H, 3¢-H), 5.37 (d, J = 1.6 Hz, 1 H, 1¢-H), 5.51 (m, 1 H, 2¢-H),
7.14–7.38, 7.41–7.48 (m, 15 H, C6H5).
IR (film): 2920, 1724, 1497, 1453, 1364, 1268, 1073 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.35 (s, 3 H, 7-CH3), 3.44 (s, 3 H,
OCH3), 3.46–3.50 (m, 2 H, 2-H, 6¢-Ha), 3.59 (dd, J = 1.5, 10.6 Hz,
1 H, 6-Ha), 3.73 (dd, J = 4.1, 10.6 Hz, 1 H, 6-Hb), 3.78–3.82 (m,
2 H, 5-H, 6¢-Hb), 3.88 (dd, J = 7.1, 8.4 Hz, 1 H, 5¢-H), 3.93 (d,
J = 9.9 Hz, 1 H, 3-H), 3.97 (dd, J = 8.4, 9.5 Hz, 1 H, 4¢-H), 4.02
(dd, J = 2.7, 9.5 Hz, 1 H, 3¢-H), 4.45 (d, J = 11.7 Hz, 1 H, CHaHb-
Ph), 4.45 (d, J = 10.8 Hz, 1 H, CHaHbPh), 4.48 (d, J = 12.2 Hz, 1 H,
CHaHbPh), 4.53 (d, J = 11.7 Hz, 1 H, CHaHbPh), 4.54 (d,
J = 12.2 Hz, 1 H, CHaHbPh), 4.55 (d, J = 12.0 Hz, 1 H, CHaHbPh),
4.58 (d, J = 3.7 Hz, 1 H, 1-H), 4.65 (d, J = 12.0 Hz, 1 H, CHaHbPh),
4.69 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.72 (d, J = 12.0 Hz, 1 H,
CHaHbPh), 4.80 (d, J = 11.2 Hz, 1 H, CHaHbPh), 4.83 (d,
J = 10.8 Hz, 1 H, CHaHbPh), 5.12 (d, J = 11.2 Hz, 1 H, CHaHbPh),
5.61 (dd, J = 2.1, 2.7 Hz, 1 H, 2¢-H), 5.78 (d, J = 2.1 Hz, 1 H, 1¢-H),
6.98–7.04 (m, 3 H, C6H5), 7.12–7.35 (m, 29 H, C6H5), 7.50–7.54
(m, 1 H, C6H5), 7.92–7.95 (m, 2 H, C6H5).
13C NMR (125 MHz, CDCl3): d = 13.7, 17.5, 20.7, 20.7, 20.7, 23.2,
26.3, 29.0, 55.3, 66.6, 68.8, 69.6, 69.8, 70.7, 70.8, 73.3, 73.9, 76.1,
77.5, 79.0, 81.7, 92.7, 98.2, 127.4, 127.5, 127.6, 127.9, 128.2,
128.3, 128.3, 128.4, 138.0, 138.2, 138.5, 169.4, 169.8, 169.9.
ESI-HRMS: m/z [M + Na]+ calcd for C44H56O13 + Na: 815.36131;
found: 815.36143.
13C NMR (125 MHz, CDCl3): d = 11.8, 55.0, 68.7, 69.0, 69.9, 71.5,
72.0, 73.1, 73.2, 73.3, 74.1, 75.0, 75.2, 78.2, 79.2, 79.7, 83.6, 94.1,
97.3, 126.9, 126.9, 127.3, 127.4, 127.4, 127.5, 127.8, 127.9, 128.0,
128.0, 128.1, 128.1, 128.2, 128.2, 128.2, 128.3, 128.4, 129.8, 129.9,
132.8, 137.9, 138.1, 138.3, 138.4, 138.5, 165.2.
Methyl 2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl-(1→4)-
2,3,6-tri-O-benzyl-4-phenylethynyl-a-D-galactopyranoside (17)
Following variant II, acceptor 7b (42.0 mg, 74.4 mmol), donor 11
(49.0 mg, 99.5 mmol), and TMSOTf (17.0 mL, 94.0 mmol) were re-
acted in CH2Cl2 (3 mL). Column chromatography (pentane–EtOAc,
5:1) of the crude product gave 35 mg (53%) of 17 as a colorless oil;
[a]D –28.0 (c = 0.25, CHCl3); Rf = 0.11 (hexane–EtOAc, 3:1).
ESI-HRMS: m/z [M + Na]+ calcd for C63H66O12 + Na: 1037.44465;
found: 1037.44470.
Methyl 2,3,4-Tri-O-acetyl-a-L-rhamnopyranosyl-(1→4)-2,3,6-
tri-O-benzyl-4-butyl-a-D-glucopyranoside (15)
IR (film): 2931, 1750, 1494, 1454, 1370, 1227, 1041 cm–1.
Following variant II, glycosyl acceptor 6a (49.3 mg, 94.7 mmol),
glycosyl donor 10 (54.0 mg, 124 mmol) and TMSOTf (22.0 mL,
122 mmol) were reacted in CH2Cl2 (3 mL). Column chromatogra-
phy (pentane–EtOAc, 3:1) of the crude product afforded 44.5 mg
(59%) of 15 as a colorless oil; [a]D –8.2 (c = 0.11, CHCl3); Rf = 0.17
(hexane–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 1.53 [s, 3 H, O(CO)CH3], 1.82 [s,
3 H, O(CO)CH3], 1.95 [s, 3 H, O(CO)CH3], 2.12 [s, 3 H,
O(CO)CH3], 3.41 (s, 3 H, OCH3), 3.72–4.34 (m, 8 H, 2-H, 3-H, 5-
H, 5¢-H, 6-CH2, 6¢-CH2), 4.51 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.53
(d, J = 11.8 Hz, 1 H, CHaHbPh), 4.60 (d, J = 3.6 Hz, 1 H, 1-H), 4.66
(d, J = 12.1 Hz, 1 H, CHaHbPh), 4.76 (d, J = 11.8 Hz, 1 H, CHaHb-
Ph), 4.87 (d, J = 10.5 Hz, 1 H, CHaHbPh), 4.95 (d, J = 10.5 Hz, 1 H,
CHaHbPh), 5.03 (dd, J = 3.5, 9.9 Hz, 1 H, 3¢-H), 5.19 (d, J = 7.9 Hz,
1 H, 1¢-H), 5.26 (dd, J = 7.9, 9.9 Hz, 1 H, 2¢-H), 5.34 (dd, J = 0.5,
3.5 Hz, 1 H, 4¢-H), 7.18–7.43 (m, 20 H, C6H5).
IR (film): 2930, 1748, 1454, 1372, 1224, 1044 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, J = 6.8 Hz, 3 H, 10-CH3),
1.18 (d, J = 6.2 Hz, 3 H, 6¢-CH3), 1.21–1.33 (m, 3 H, 8-Ha, 9-CH2),
1.38–1.53 (m, 1 H, 8-Hb), 1.64–1.78 (m, 1 H, 7-Ha), 1.79–1.95 (m,
1 H, 7-Hb), 1.96 [s, 3 H, O(CO)CH3], 2.04 [s, 3 H, O(CO)CH3],
2.05 [s, 3 H, O(CO)CH3], 3.41 (s, 3 H, OCH3), 3.60 (dd, J = 2.4,
6.3 Hz, 1 H, 2-H), 3.62 (dd, J = 4.0, 9.9 Hz, 1 H, 6-Ha), 3.89 (dd,
J = 0.6, 9.9 Hz, 1 H, 6-Hb), 3.95–4.02 (m, 2 H, 3-H, 5-H), 4.04 (dd,
J = 6.2, 9.7 Hz, 1 H, 5¢-H), 4.54 (d, J = 11.7 Hz, 1 H, CHaHbPh),
13C NMR (125 MHz, CDCl3): d = 20.4, 20.5, 20.6, 50.3, 61.6, 67.0,
68.4, 70.2, 71.1, 73.3, 73.5, 73.8, 76.8, 77.2, 79.2, 82.1, 82.8, 90.6,
98.2, 98.6, 121.2, 127.3, 127.4, 127.7, 127.8, 128.1, 128.2, 128.3,
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

2602
A. Holkenbrink et al.
PAPER
128.4, 128.5, 129.3, 131.6, 138.3, 138.4, 138.6, 170.0, 170.1, 170.3,
170.3.
ESI-HRMS: m/z [M + K]+ calcd for C48H52O13 + K: 875.30395;
found: 875.30353.
ESI-HRMS: m/z [M + Na]+ calcd for C50H54O15 + Na: 917.33549;
found: 917.33513.
Methyl 2,3,4-Tri-O-acetyl-a-L-rhamnopyranosyl-(1→4)-2,3,6-
tri-O-benzyl-4-trimethylsilylethynyl-a-D-glucopyranoside (20)
Following variant II, acceptor 7b (25.3 mg, 45.1 mmol), donor 10
(39.0 g, 89.7 mmol), and TMSOTf (16.0 mL, 88.5 mmol) were react-
ed in CH2Cl2 (2 mL). Column chromatography (pentane–EtOAc,
7:1 → 5:1) of the crude product yielded 23.0 mg (62%; 73% based
on recovered starting material) of 20 as a colorless oil; [a]D +21.1
(c = 0.19, CHCl3); Rf = 0.19 (hexane–EtOAc, 3:1).
Methyl 2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-(1→4)-
2,3,6-tri-O-benzyl-4-phenylethynyl-a-D-galactopyranoside (18)
Following variant II, glycosyl acceptor 7b (48.3 mg, 86.0 mmol),
glycosyl donor 12 (56.0 mg, 114 mmol), and TMSOTf (20.0 mL,
111 mmol) were reacted in CH2Cl2 (3 mL). Column chromatogra-
phy (pentane–EtOAc, 7:1 → 5:1 → 3:1) of the crude product gave
20.9 mg (27%; 62% based on recovered starting material) of 18 as
a colorless oil; [a]D –21.7 (c = 0.12, CHCl3); Rf = 0.09 (hexane–
EtOAc, 3:1).
IR (film): 2926, 1749, 1607, 1454, 1372, 1223, 1045 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.11 [s, 9 H, Si(CH3)3], 1.11 (d,
J = 6.3 Hz, 3 H, 6¢-CH3), 1.96 [s, 3 H, O(CO)CH3], 2.02 [s, 3 H,
O(CO)CH3], 2.08 [s, 3 H, O(CO)CH3], 3.40 (s, 3 H, OCH3), 3.68
(dd, J = 3.6, 9.8 Hz, 1 H, 2-H), 3.77 (dd, J = 8.0, 10.5 Hz, 1 H, 6-
Ha), 3.89 (d, J = 9.8 Hz, 1 H, 3-H), 3.91 (dd, J = 1.7, 8.0 Hz, 1 H, 5-
H), 3.96 (dd, J = 1.7, 10.5 Hz, 1 H, 6-Hb), 4.01 (dd, J = 6.3, 9.9 Hz,
1 H, 5¢-H), 4.53 (d, J = 11.9 Hz, 1 H, CHaHbPh), 4.60 (d,
J = 3.6 Hz, 1 H, 1-H), 4.61–4.63 (m, 2 H, CHaHbPh, CHaHbPh),
4.65 (d, J = 11.9 Hz, 1 H, CHaHbPh), 4.88 (d, J = 11.5 Hz, 1 H,
CHaHbPh), 4.99 (d, J = 11.5 Hz, 1 H, CHaHbPh), 5.02 (dd, J = 9.9,
10.1 Hz, 1 H, 4¢-H), 5.16 (dd, J = 2.2, 3.3 Hz, 1 H, 2¢-H), 5.22 (dd,
J = 3.3, 10.1 Hz, 1 H, 3¢-H), 5.59 (d, J = 2.2 Hz, 1 H, 1¢-H), 7.19–
7.39 (m, 15 H, C6H5).
IR (film): 2928, 1754, 1494, 1454, 1370, 1226, 1040 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 [s, 3 H, O(CO)CH3], 1.85 [s,
3 H, O(CO)CH3], 1.97 [s, 3 H, O(CO)CH3], 1.99 [s, 3 H,
O(CO)CH3], 3.41 (s, 3 H, OCH3), 3.62 (ddd, J = 2.4, 5.0, 9.9 Hz,
1 H, 5¢-H), 3.71 (dd, J = 8.3, 10.8 Hz, 1 H, 6-Ha) 3.72 (dd, J = 3.6,
9.9 Hz, 1 H, 2-H), 3.98–4.15 (m, 4 H, 5-H, 6-Hb, 6¢-CH2), 4.02 (d,
J = 9.9 Hz, 1 H, 3-H), 4.48 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.52 (d,
J = 11.5 Hz, 1 H, CHaHbPh), 4.60 (d, J = 3.6 Hz, 1 H, 1-H), 4.65 (d,
J = 11.5 Hz, 1 H, CHaHbPh), 4.73 (d, J = 12.0 Hz, 1 H, CHaHbPh),
4.87 (d, J = 10.6 Hz, 1 H, CHaHbPh), 4.95 (d, J = 10.6 Hz, 1 H,
CHaHbPh), 4.98 (dd, J = 9.6, 9.9 Hz, 1 H, 4¢-H), 5.10 (dd, J = 7.9,
9.6 Hz, 1 H, 2¢-H), 5.24 (d, J = 7.9 Hz, 1 H, 1¢-H), 5.25 (dd, J = 9.6,
9.6 Hz, 1 H, 3¢-H), 7.20–7.42 (m, 20 H, C6H5).
13C NMR (125 MHz, CDCl3): d = –0.6, 17.4, 20.7, 20.7, 20.8, 55.1,
67.6, 69.0, 69.7, 70.1, 70.7, 71.5, 73.2, 73.4, 74.6, 77.5, 79.3, 82.1,
94.9, 96.4, 97.5, 97.8, 126.9, 127.0, 127.3, 127.5, 127.9, 127.9,
128.2, 128.4, 137.7, 138.5, 139.3, 169.7, 169.9, 170.0.
13C NMR (125 MHz, CDCl3): d = 20.4, 20.4, 20.5, 20.6, 55.3, 62.0,
68.7, 70.2, 70.8, 71.2, 73.0, 73.3, 73.4, 73.7, 76.7, 76.8, 79.2, 82.0,
82.8, 90.4, 98.1, 98.2, 121.2, 127.3, 127.3, 127.7, 127.8, 128.0,
128.1, 128.2, 128.2, 128.4, 128.5, 129.3, 131.6, 138.3, 138.3,
138.6,169.4, 169.7, 170.2, 170.4.
ESI-HRMS: m/z [M + NH4]+ calcd for C45H60NO13Si + NH4:
850.3828; found: 850.3832.
Methyl 2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl-(1→4)-
2,3,6-tri-O-benzyl-4-trimethylsilylethynyl-a-D-galactopyrano-
side (21)
ESI-HRMS: m/z [M + Na]+ calcd for C50H54O15 + Na: 917.33549;
found: 917.33634.
Following variant II, glycosyl acceptor 8b (26.6 mg, 47.4 mmol),
glycosyl donor 11 (55.0 mg, 112 mmol), and TMSOTf (2.0 mL,
11.1 mmol) were reacted in CH2Cl2 (2 mL). Column chromatogra-
phy (pentane–EtOAc, 7:1 → 5:1) of the crude product gave 22.1 mg
(53%; 71% based on recovered starting material) of 21 as a color-
less oil; [a]D –22.4 (c = 0.17, CHCl3); Rf = 0.10 (hexane–EtOAc,
3:1).
Methyl 2,3,4-Tri-O-acetyl-a-L-rhamnopyranosyl-(1→4)-2,3,6-
tri-O-benzyl-4-phenylethynyl-a-D-galactopyranoside (19)
Following variant II, glycosyl acceptor 7b (46.0 mg, 81.5 mmol),
glycosyl donor 10 (46.0 g, 106 mmol), and TMSOTf (20.0 mL,
111 mmol) were reacted in CH2Cl2 (3 mL). Column chromatogra-
phy (pentane–EtOAc, 5:1) of the crude product gave 25.4 mg (38%;
86% based on recovered starting material) of 19 as a colorless oil;
[a]D –40.7 (c = 0.14, CHCl3); Rf = 0.09 (hexane–EtOAc, 3:1).
IR (film): 2931, 1751, 1497, 1454, 1370, 1226, 1074 cm–1.
IR (film): 2925, 1747, 1493, 1454, 1370, 1223, 1047 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.15 [s, 9 H, Si(CH3)3], 1.45 [s,
3 H, O(CO)CH3], 1.95 [s, 3 H, O(CO)CH3], 2.00 [s, 3 H,
O(CO)CH3], 2.11 [s, 3 H, O(CO)CH3], 3.39 (s, 3 H, OCH3), 3.68
(dd, J = 8.0, 12.3 Hz, 1 H, 6-Ha), 3.68 (dd, J = 3.7, 9.8 Hz, 1 H, 2-
H), 3.78 (dd, J = 6.8, 7.2 Hz, 1 H, 5¢-H), 3.91 (dd, J = 1.4, 12.3 Hz,
1 H, 6-Hb), 3.93 (d, J = 9.8 Hz, 1 H, 3-H), 3.97 (dd, J = 6.8,
11.2 Hz, 1 H, 6¢-Ha), 4.00 (dd, J = 1.4, 8.0 Hz, 1 H, 5-H), 4.03 (dd,
J = 7.2, 11.2 Hz, 1 H, 6¢-Hb), 4.48 (d, J = 12.1 Hz, 1 H, CHaHbPh),
4.48 (d, J = 11.8 Hz, 1 H, CHaHbPh), 4.55 (d, J = 3.7 Hz, 1 H, 1-H),
4.63 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.73 (d, J = 11.8 Hz, 1 H,
CHaHbPh), 4.80 (d, J = 10.3 Hz, 1 H, CHaHbPh), 4.87 (d,
J = 10.3 Hz, 1 H, CHaHbPh), 5.01 (dd, J = 3.5, 10.3 Hz, 1 H, 3¢-H),
5.11 (d, J = 8.0 Hz, 1 H, 1¢-H), 5.21 (dd, J = 8.0, 10.3 Hz, 1 H, 2¢-
H), 5.35 (d, J = 3.5 Hz, 1 H, 4¢-H), 7.21–7.39 (m, 15 H, C6H5).
1H NMR (300 MHz, CDCl3): d = 1.12 (d, J = 6.3 Hz, 3 H, 6¢-CH3),
1.87 [s, 3 H, O(CO)CH3], 1.93 [s, 3 H, O(CO)CH3], 2.03 [s, 3 H,
O(CO)CH3], 3.43 (s, 3 H, OCH3), 3.73 (dd, J = 7.8, 11.0 Hz, 1 H, 6-
Ha), 3.89 (dd, J = 6.3, 9.9 Hz, 1 H, 5¢-H), 3.93 (dd, J = 3.5, 10.0 Hz,
1 H, 2-H), 4.05 (d, J = 10.0 Hz, 1 H, 3-H), 4.02–4.09 (m, 1 H, 6-
Hb), 4.19 (dd, J = 1.6, 7.8 Hz, 1 H, 5-H), 4.55 (d, J = 12.1 Hz, 1 H,
CHaHbPh), 4.66 (d, J = 12.1 Hz, 1 H, CHaHbPh), 4.67 (d,
J = 3.5 Hz, 1 H, 1-H), 4.71 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.78 (d,
J = 10.4 Hz, 1 H, CHaHbPh), 4.88 (d, J = 12.0 Hz, 1 H, CHaHbPh),
4.91 (d, J = 10.4 Hz, 1 H, CHaHbPh), 4.97 (dd, J = 9.9, 10.2 Hz,
1 H, 4¢-H), 5.23 (dd, J = 3.3, 10.2 Hz, 1 H, 3¢-H), 5.53 (dd, J = 2.0,
3.3 Hz, 1 H, 2¢-H), 5.60 (d, J = 2.0 Hz, 1 H, 1¢-H), 7.17–7.39, 7.41–
7.48 (m, 20 H, C6H5).
13C NMR (125 MHz, CDCl3): d = –0.4, 20.4, 20.6, 20.6, 55.3, 61.2,
66.8, 68.3, 69.8, 70.0, 71.2, 73.3, 73.4, 73.8, 76.6, 76.9, 79.0, 82.0,
96.9, 98.2, 98.5, 98.7, 127.4, 127.4, 127.7, 127.8, 128.1, 128.2,
128.3, 128.4, 138.4, 138.4, 138.6, 170.0, 170.2, 170.2, 170.33.
13C NMR (125 MHz, CDCl3): d = 17.5, 20.7, 20.8, 55.4, 67.0, 69.5,
69.7, 69.8, 70.7, 73.4, 74.4, 76.7, 77.2, 77.2, 78.2, 82.4, 83.5, 89.7,
95.9, 98.6, 121.4, 127.5, 127.5, 127.6, 127.7, 128.1, 128.2, 128.3,
128.3, 128.4, 128.5, 129.1, 131.9, 138.0, 138.1, 138.5, 169.3, 169.9,
170.0.
ESI-HRMS: m/z [M + NH4]+ calcd for C47H62NO15Si + NH4:
908.38832; found: 908.38829.
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

PAPER
Glycosylations of Tertiary Alcohols
2603
Methyl 2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl-(1→4)-
2,3,6-tri-O-benzyl-4-trimethylsilylethynyl-a-D-galactopyrano-
side (22)
Methyl 2,3,4-tri-O-acetyl-a-L-rhamnopyranosyl-(1→4)-2,3,6-
tri-O-benzyl-4-trimethylsilylethynyl-a-D-galactopyranoside
(24)
Following variant II, glycosyl acceptor 8b (42.8 mg, 76.3 mmol),
glycosyl donor 12 (49.0 mg, 99.5 mmol), and TMSOTf (18.0 mL,
99.5 mmol) were reacted in CH2Cl2 (3 mL). Column chromatogra-
phy (pentane–EtOAc, 5:1 → 3:1) of the crude product afforded
23.6 mg (35%; 92% based on recovered starting material) of 22 as
a colorless oil; [a]D –32.2 (c = 0.09, CHCl3); Rf = 0.09 (hexane–
EtOAc, 3:1).
Following variant II, glycosyl acceptor 8b (17.7 mg, 32.0 mmol),
glycosyl donor 10 (26.0 g, 60.0 mmol) and TMSOTf (1.0 mL,
3.20 mmol) were reacted in CH2Cl2 (2 mL). Column chromatogra-
phy (pentane–EtOAc, 7:1 → 5:1) of the crude product gave 12.7 mg
(48%; 77% based on recovered starting material) of 24 as a color-
less oil; [a]D –12.6 (c = 0.69, CHCl3); Rf = 0.06 (hexane–EtOAc,
3:1).
IR (film): 2933, 1755, 1497, 1454, 1370, 1225, 1040 cm–1.
IR (film): 1747, 1693, 1223, 1048 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.14 [s, 9 H, Si(CH3)3], 1.45 [s,
3 H, O(CO)CH3], 1.96 [s, 3 H, O(CO)CH3], 2.01 [s, 3 H,
O(CO)CH3], 2.03 [s, 3 H, O(CO)CH3], 3.38 (s, 3 H, OCH3), 3.57
(ddd, J = 2.4, 4.5, 9.9 Hz, 1 H, 5¢-H), 3.64 (dd, J = 9.4, 12.1 Hz,
1 H, 6-Ha), 3.65 (dd, J = 3.6, 9.8 Hz, 1 H, 2-H), 3.89–4.02 (m, 2 H,
5-H, 6-Hb), 3.92 (d, J = 9.8 Hz, 1 H, 3-H), 3.98 (dd, J = 2.4,
12.2 Hz, 1 H, 6¢-Ha), 4.18 (dd, J = 4.5, 12.2 Hz, 1 H, 6¢-Hb), 4.45 (d,
J = 12.1 Hz, 1 H, CHaHbPh), 4.48 (d, J = 11.8 Hz, 1 H, CHaHbPh),
4.54 (d, J = 3.6 Hz, 1 H, 1-H), 4.63 (d, J = 12.1 Hz, 1 H, CHaHbPh),
4.71 (d, J = 11.8 Hz, 1 H, CHaHbPh), 4.80 (d, J = 10.4 Hz, 1 H,
CHaHbPh), 4.87 (d, J = 10.4 Hz, 1 H, CHaHbPh), 5.00 (dd, J = 9.9,
10.0 Hz, 1 H, 4¢-H), 5.06 (dd, J = 8.0, 9.3 Hz, 1 H, 2¢-H), 5.15 (d,
J = 8.0 Hz, 1 H, 1¢-H), 5.23 (dd, J = 9.3, 10.0 Hz, 1 H, 3¢-H), 7.18–
7.42 (m, 15 H, C6H5).
1H NMR (300 MHz, CDCl3): d = 0.15 [s, 9 H, Si(CH3)3], 1.10 (d,
J = 6.3 Hz, 3 H, 6¢-CH3), 1.84 [s, 3 H, O(CO)CH3], 1.90 [s, 3 H,
O(CO)CH3], 2.02 [s, 3 H, O(CO)CH3], 3.40 (s, 3 H, OCH3), 3.64
(dd, J = 8.1, 11.0 Hz, 1 H, 6-Ha), 3.79–3.88 (m, 1 H, 5¢-H), 3.85
(dd, J = 3.4, 9.9 Hz, 1 H, 2-H), 3.92–3.99 (m, 1 H, 6-Hb), 3.94 (d,
J = 9.9 Hz, 1 H, 3-H), 4.07 (dd, J = 1.6, 8.1 Hz, 1 H, 5-H), 4.52 (d,
J = 12.0 Hz, 1 H, CHaHbPh), 4.63 (d, J = 3.4 Hz, 1 H, 1-H), 4.65 (d,
J = 12.0 Hz, 1 H, CHaHbPh), 4.67 (d, J = 11.9 Hz, 1 H, CHaHbPh),
4.72 (d, J = 10.2 Hz, 1 H, CHaHbPh), 4.84 (d, J = 10.2 Hz, 1 H,
CHaHbPh), 4.85 (d, J = 11.9 Hz, 1 H, CHaHbPh), 4.96 (dd, J = 9.9,
10.1 Hz, 1 H, 4¢-H), 5.19 (dd, J = 3.3, 10.1 Hz, 1 H, 3¢-H), 5.45 (dd,
J = 2.0, 3.3 Hz, 1 H, 2¢-H), 5.50 (d, J = 2.0 Hz, 1 H, 1¢-H), 7.22–
7.45 (m, 15 H, C6H5).
13C NMR (125 MHz, CDCl3): d = –0.4, 17.4, 20.7, 20.7, 20.8, 55.4,
67.0, 69.5, 69.6, 69.7, 70.7, 73.3, 73.4, 74.4, 76.7, 77.8, 82.2, 95.7,
95.8, 98.6, 99.8, 127.5, 127.5, 127.6, 127.7, 128.1, 128.4, 128.4,
128.4, 138.1, 138.1, 138.5, 169.3, 169.9, 170.0.
13C NMR (125 MHz, CDCl3): d = –0.4, 20.3, 20.6, 20.6, 20.6, 55.3,
61.8, 68.6, 70.0, 70.6, 70.9, 71.0, 73.3, 73.3, 73.8, 76.6, 76.8, 79.1,
81.9, 96.8, 98.0, 98.1, 98.7, 127.3, 127.4, 127.7, 127.8, 128.1,
128.1, 128.2, 128.2, 128.4, 138.4, 138.4, 138.6, 169.4, 169.7, 170.3,
170.4.
ESI-HRMS: m/z [M + Na]+ calcd for C45H56O13Si + Na: 855.33824;
found: 855.33812.
ESI-HRMS: m/z [M + NH4]+ calcd for C47H62NO15Si + NH4:
908.38832; found: 908.38878.
Acknowledgment
Methyl 3,4,6-Tri-O-acetyl-2-N-trichloroacetyl-b-D-glucosami-
no-(1→4)-2,3,6-tri-O-benzyl-4-trimethylsilylethynyl-a-D-galac-
topyranoside (23)
Following variant II, glycosyl acceptor 8b (73.8 mg, 132 mmol),
glycosyl donor 13 (125 mg, 210 mmol), and TMSOTf (38.0 mL,
210 mmol) were reacted in CH2Cl2 (3 mL). Column chromatogra-
phy (pentane–EtOAc, 5:1) of the crude product gave 72 mg (56%;
86% based on recovered starting material) of 23 as a colorless oil;
[a]D +3.8 (c = 0.24, CHCl3); Rf = 0.07 (hexane–EtOAc, 3:1).
Financial support from the Deutsche Forschungsgemeinschaft (Em-
my Noether Fellowship to D.B.W.) and the Fonds der Chemischen
Industrie (Liebig Fellowship to D.B.W.) is gratefully acknowled-
ged. J.B.V. thanks the European Union for an ERASMUS fel-
lowship. We thank Prof. Lutz F. Tietze for generous support of our
work and helpful discussions.
References
IR (film): 1754, 1521, 1228, 1041 cm–1.
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1H NMR (600 MHz, CDCl3): d = 0.17 [s, 9 H, Si(CH3)3], 1.93 [s,
3 H, O(CO)CH3], 2.02 [s, 3 H, O(CO)CH3], 2.07 [s, 3 H,
O(CO)CH3], 3.38 (s, 3 H, OCH3), 3.57 (ddd, J = 3.0, 4.0, 9.8 Hz,
1 H, 5¢-H), 3.63 (dd, J = 3.7, 13.4 Hz, 1 H, 2-H), 3.64 (dd, J = 8.1,
11.6 Hz, 1 H, 6-Ha), 3.97 (dd, J = 1.6, 11.6 Hz, 1 H, 6-Hb), 3.99–
4.03 (m, 2 H, 3-H, 6¢-Ha), 4.06 (dd, J = 1.6, 8.1 Hz, 1 H, 5-H), 4.18
(ddd, J = 8.6, 8.8, 10.3 Hz, 1 H, 2¢-H), 4.27 (dd, J = 4.0, 12.2 Hz,
1 H, 6¢-Hb), 4.50 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.53 (d,
J = 11.3 Hz, 1 H, CHaHbPh), 4.59 (d, J = 11.3 Hz, 1 H, CHaHbPh),
4.66 (d, J = 12.0 Hz, 1 H, CHaHbPh), 4.78 (d, J = 3.7 Hz, 1 H, 1-H),
4.80 (d, J = 9.7 Hz, 1 H, CHaHbPh), 4.84 (d, J = 9.7 Hz, 1 H, CHaH-
bPh), 4.91 (dd, J = 9.6, 10.3 Hz, 1 H, 3¢-H), 5.10 (dd, J = 9.6,
9.8 Hz, 1 H, 4¢-H), 5.28 (d, J = 8.8 Hz, 1 H, 1¢-H), 6.80 (d,
J = 8.6 Hz, 1 H, NH), 7.23–7.40 (m, 15 H, C6H5).
13C NMR (125 MHz, CDCl3): d = –0.3, 20.5, 20.6, 20.7, 54.8, 55.4,
61.8, 68.5, 69.8, 71.6, 72.2, 73.0, 73.5, 74.0, 77.6, 78.4, 82.3, 91.7,
95.1, 97.3, 98.1, 99.9, 127.5, 127.5, 127.6, 127.8, 128.3, 128.4,
128.4, 128.7, 128.9, 137.9, 138.2, 138.4, 162.1, 169.2, 170.4, 170.5.
(4) (a) Herget, S.; Toukach, P. V.; Ranzinger, R.; Hull, W. E.;
Knirel, Y. A.; von der Lieth, C.-W. BMC Struct. Biol. 2008,
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A.; von der Lieth, C.-W.; Seeberger, P. H. ACS Chem. Biol.
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ESI-HRMS: m/z [M + H]+ calcd for C47H57Cl3NO14Si + H:
992.26084; found: 992.25990.
Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York

2604
A. Holkenbrink et al.
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Synthesis 2009, No. 15, 2596–2604 © Thieme Stuttgart · New York