Imposing the trans/gauche conformation on a sialic acid donor with a 5-N,7-O-oxazinanone group: effect on glycosylation stereoselectivity

Article abstract of DOI:10.1016/j.tet.2007.12.026

A 5-N,7-O-oxazinanone derivative of a thiosialic acid ester has been synthesized and investigated for the effect of conformational restriction on glycosylation. The cyclic group is found to be powerfully disarming, but to have no beneficial effect on reac

Full text of DOI:10.1016/j.tet.2007.12.026

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2042e2047
www.elsevier.com/locate/tet
Imposing the trans/gauche conformation on a sialic acid donor with a
5-N,7-O-oxazinanone group: effect on glycosylation stereoselectivity
*
David Crich , Baolin Wu
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
Received 6 November 2007; received in revised form 7 December 2007; accepted 10 December 2007
Available online 15 December 2007
Abstract
A 5-N,7-O-oxazinanone derivative of a thiosialic acid ester has been synthesized and investigated for the effect of conformational restriction
on glycosylation. The cyclic group is found to be powerfully disarming, but to have no beneficial effect on reaction stereoselectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
by compounds such as 4,6-O-benzylidene-protected mannosyl
triflate 2 in b-mannosylation, the corresponding a-selective
glucosyl triflate 2,5,6 the 2-N,3-O-carbamate fused glycos-
amine 4 as an a-selective glycosyl donor,7e9 the 2,3-O-car-
bonate fused thioglycoside 5, a b-selective glucosyl donor
not dependent on neighboring participation group,9 and the
3,4-O-carbonate fused rhamnopyranose 6, as a b-selective
donor.10
The Takahashi group also reported on the use of 5-N,4-O-
oxazolidinone protected sialic acids, including donor 7 and
acceptors 8 and 9 and achieved an elegant synthesis of a-
(2/8)-oligosialosides by this method.11 A similar study on
the stereoselective synthesis of a-(2/3) and a-(2/6) linked
galactosyl sialosides was reported by De Meo and Farris.12
The 1-adamantanylthio sialoside 10 was developed later in
this laboratory to address the poor selectivities encountered
with donor 1 when coupling with secondary sugar acceptors.
This improved donor could be activated by NIS/TfOH in ni-
trile solvents at ꢀ78 ꢁC to afford coupled products with excel-
lent a-selectivity in high yields.13 Inspired by these beneficial
cyclic structures in sugar chemistry, we became interested in
exploring alternative cyclic protected donors and especially
in the use of the 5-N,7-O-oxazinanone derivative 11, which
was designed to mimic a benzylidene acetal. We describe
here the synthesis of donor 11 and its application in sialylation
reactions under diphenyl sulfoxide (Ph2SO) and triflic
anhydride (Tf2O) promotion conditions.
Sialic acid residues such as N-acetylneuraminic acid
(Neu5Ac), normally incorporated into complex glycolipids
or glycoproteins at the terminal positions of the oligosaccha-
ride chains, are involved in a wide range of biological
processes.1 In these complex oligosaccharides, N-acetylneur-
aminic acid is typically linked a-(2,3) or a-(2,6) to galactoside
residues, or is polymerized in the form of a-(2,8) or a-(2,9)
linkages. Several challenges are associated with sialylation
reactions arising from a number of factors: (i) frequent low
yields due to the sterically encumbered C2-position. (ii) H3
protons on ring C3 have the tendency to undergo 2,3-elimina-
tion during the coupling processes. (iii) The contra-thermo-
dynamic equatorial nature of the glycosidic bond that
necessitates the overriding of the anomeric effect. Many inno-
vative methodologies and strategies including chemical, enzy-
matic, and chemoenzymatic synthesis have been developed for
a-sialoside installation.2 Recently, we directed our efforts to
the a-sialylation field and have investigated sialoside donors
13 based on the knowledge that fused structures in sugar
donors have shown beneficial effects on either reactivities or
selectivities in glycoslation reactions.4 This is exemplified
* Corresponding author. Tel.: þ1 313 577 1915; fax: þ1 313 577 8822.
E-mail address: dcrich@chem.wayne.edu (D. Crich).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.026

D. Crich, B. Wu / Tetrahedron 64 (2008) 2042e2047
2043
AcO
Ac
OBn
O
SPh
Ph
O
OAc
Ph
O
O
O
AcO
O
BnO
O
BnO
CO2Me
N
BnO
OTf
O
OTf
O
2
3
1
OAc
OBn
O
O
SPh
O
O
AcO
SAr
BnO
SPh
O
O
O
OBn
NR
R = H, or Ac
4
O
O
O
O
6
5
HO
HO
CO2Me
CO2Me
OAc
OH
HN
ClAcO
BnO
HO
SPh
BnO
OAcCl
O
O
OC8H17
HN
OC8H17
O
CO2Me
HN
O
O
O
O
O
O
8
9
7
SPh
O
AcO
Ac
CO2Me
O
S
OAc
O
N
AcO
O
H
OTBS
O
CO2Me
N
O
O
O
10
11
2. Results and discussion
final transformation is that the employment of 4-nitrophenyl
chloroformate, a classical carbamate ring closure reagent,3,7,11
was ineffective, providing 11 in only 30% yield, along with a
significant amount of an unidentified byproduct.
The preparation of donor 11 started from the known thio-
glycoside 12,14 from which hydrolytic removal of acetyl group
followed by selective acylation of the amine group with
FmocOSu gave the intermediate carbamate. Further treatment
with 2,2-dimethoxypropane in the presence of catalytic p-tol-
uenesulfonic acid afforded thioglycoside 13 in 31% overall
yield for the three steps.15 Treatment of 13 with TBSCl in
DMF smoothly furnished TBS ether 14 in 81% yield.16 The
silyl ether protecting group was selected over the more com-
mon acyl group to avoid the extra disarming property of the
ester function.17 Removal of the Fmoc group with piperidine
followed by 4-N,7-O-oxazinanone ring formation with 1,10-
carbonyldiimidazole in THF at reflux delivered the sialoside
donor 11 in 66% overall yield (Scheme 1).18 Establishment of
the oxazinanone moiety in donor 11 was confirmed by chem-
ical shift (d 151.4e151.7) of the carbamate carbon, which was
distinct from that of the alternative five-membered oxazolidi-
none expected to resonate around d 160.0.11,4 Of note in the
With access to the 4-N,7-O-oxazinanone donor 11 estab-
lished, we next investigated its coupling to a range of acceptors.
To our surprise, promotion systems such as NIS/TfOH, which
were adopted for activation of the 4-N,3-O-oxalidinone pro-
tected donors 1, 7, and 10 were ineffective toward donor 11
with the starting material recovered completely in repeated
experiments. The BSP/TTBP/Tf2O6,19 promotion system, de-
veloped in this laboratory for glycosylation of thioglycoside
donors also failed to activate 11. Accordingly we turned our
attention to the more potent activation system Ph2SO/Tf2O,
initially developed by Gin and co-workers20 for dehydrativegly-
cosylation and later extended by van Boom and co-workers to
the glycosylation of thioglycosides,21 and applied to thiosialo-
side activation in this laboratory.22 Fortunately, following our
previous protocol, treatment of sialoside donor 11 with Ph2SO
(3 equiv)/Tf2O (1.2 equiv) in the presence of the hindered
non-nucleophilic base 2,4,6-tri-tert-butylpyrimidine (TTBP)
followed by subsequent addition of 1-butanol smoothly gave
the coupled product 15 in excellent yield and moderate selectiv-
ity (Table 1, entry 1). Coupling to the tertiary alcohol 1-adman-
tanol and to the protected secondary alcohol threonine favored
the b-sialosides (Table 1, entries 2 and 5), and similar results
were obtained in the case of secondary carbohydrate acceptors
(Table 1, entries 3 and 4). The anomeric stereochemistry of all
coupling products was assigned based on the 3JC1,H-3ax coupling
constants.23 While it is not clear whether the b-selectivity ob-
served in the majority of these couplings is the result of the pres-
ence of the oxazinanone ring, or of the enforced use of the
diphenyl sulfoxide activation system, as was the case with donor
1,3 it is clear that the cyclic protecting group is highly disarming.
Thus, the failureto activate 11 by the NIS or BSP methods stands
AcO OAc
OAc
i) MsOH, reflux
ii) FmocOSu,
O
O
SPh
SPh
OH
O
MeO OMe
iii)
CO2Me
O
AcHN
CO2Me
FmocHN
AcO
12
HO
13
31% (for 3 steps)
TBSCl, imidazole
DMF, 81%
SPh
CO2Me
O
O
O
N
O
i) piperidine, 100%
ii) CDI, THF, reflux,
48 h, 66%
SPh
OH
O
H
OTBS
O
CO2Me
O
FmocHN
O
OTBS
14
11
Scheme 1. Synthesis of sialoside donor 11.

2044
D. Crich, B. Wu / Tetrahedron 64 (2008) 2042e2047
Table 1
Ph2SO/Tf2O promoted coupling of donor 1
in aqueous THF at room temperature was found to complicate
the reaction, affording undesired byproducts or more complex
mixtures.3,7
Acceptor
Coupled
product
% Yielda
(a/b ratiob)
3. Conclusion
O
The 5-N,7-O-oxazinanone group is powerfully disarming
in sialic acid donors owing to the combination of its innate
electron-withdrawing effect and the imposition of the tg con-
formation on the C6eC7 bond.
O
CO2Me
O
N
O
H
OTBS
1
BuOH
85 (1.4:1)
O
O
15
4. Experimental section
O
O
O
CO2Me
4.1. General methods
N
O
H
OTBS
2
93 (b only)
HO
1H and 13C NMR spectra were recorded at 500 and
125 MHz, respectively, with chemical shifts reported down-
field from tetramethylsilane. All solvents were dried by stan-
dard procedures. Commercial reagents were used without
purification. Air and/or moisture-sensitive reactions were
carried out under an atmosphere of argon or nitrogen using
oven-dried glassware. High-resolution mass spectra were
recorded with electrospray ionization.
O
O
16
OMe
O
O
O
OMe
O
O
O
N
O
O
CO2Me
H
HO
OTBS
3
81 (b only)
O
O
O
O
17
O
4.2. Methyl [phenyl 3,5-dideoxy-8,9-isopropylidene-5-
(9-fluorenylmethoxycarbonylamino)-2-thio-D-glycero-b-D-
galacto-non-2-ulopyranoside]onate (13)
O
O
O
O
O
O
O
O
A mixture of methyl (phenyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-2-thio-D-glycerol-b-D-galacto-non-2-
ulopyranoside)onate 12 (2.0 g, 2.9 mmol) and methanesulfonic
acid (1.4 mL, 23.2 mmol) in MeOH (30 mL) was heated at
60 ꢁC for 24 h. The reaction mixture was then cooled down to
room temperature and concentrated under vacuum, affording
a residue, which was redissolved in acetonitrile (20 mL) and wa-
ter (3 mL) followed by neutralization with triethylamine until
the pH was 7e8. 9-Fluorenylmethyl succinimidyl carbonate
(1.2 g, 3.5 mmol) was added to the above solution at room tem-
perature. After being stirred for 3 h, the solvent was removed un-
der vacuum to give a residue, which was diluted with ethyl
acetate (100 mL). The organic layer was washed with 0.5 M
HCl solution, aq NaHCO3, brine, dried over anhydrous Na2SO4,
and concentrated. The crude residue was used for the next step
without purification. To a stirred solution of the residue in
DMF (8 mL) was added p-toluenesulfonic acid monohydrate
(0.1 g, 0.5 mmol) followed by 2,2-dimethoxypropane (3 mL,
8.4 mmol). The resulting reaction mixture was stirred at room
temperature for 30 min, and then diluted with ethyl acetate
(100 mL). The organic layer was washed twice with water, aq
NaHCO3, brine, dried over anhydrous Na2SO4, and concen-
trated. The residue was purified by chromatography on silica
gel (hexane/ethyl acetate, 1:1) to give the title compound 13
O
CO2Me
O
4
63 (b only)
N
O
O
H
OTBS
HO
O
O
O
18
OMe
O
O
N
H
OBn
OMe
O
O
O
O
5
CO2Me
80 (b only)
O
N
N
H
OBn
O
H
OTBS
HO
O
O
19
a
Isolated yields after chromatography.
Determined by 1H NMR analysis on the crude reaction mixture, the ano-
meric stereochemistry is assigned based on the 3JC1,H-3ax coupling constant.
b
in contrast to the activation of 1 and other ester protected thiosi-
alosides by these systems, and signals the importance of the con-
formational restriction imposed on 11 by the fused ring. We
suggest that the disarming effect of the oxazinanone ring is
due to the superposition of the most electron-withdrawing tg
conformation of the C6eC7 bond with the presence of elec-
tron-withdrawing carbonyl group. This conformational effect
on reactivity is closely related to that determined by Bols to be
at the heart of the benzylidene effect in donors such as 2 and 3.24
Hydrolysis of the oxazinanones was realized with the use of
lithium hydroxide in hot aqueous ethanol (Scheme 2). The use
of either sodium methoxide in methanol or sodium hydroxide
1
(0.52 g, 0.9 mmol, 31%). [a]1D4 ꢀ190.0 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3) d 7.75 (d, J¼7.5 Hz, 2H), 7.52e
7.58 (m, 4H), 7.27e7.40 (m, 7H), 5.05 (d, J¼7.5 Hz, 1H),
4.41e4.51 (m, 2H), 4.30 (d, J¼10.5 Hz, 1H), 4.20 (t,
J¼6.5 Hz, 1H), 4.13 (t, J¼7.5 Hz, 1H), 4.03e4.08 (m, 1H),

D. Crich, B. Wu / Tetrahedron 64 (2008) 2042e2047
2045
O
O
O
O
LiOH (30 equiv),
H2O, EtOH,
80 °C, 82%
O
CO2Me
O
HO
H2N
N
O
CO2H
O
H
OTBS
OH
O
O
16
20
OMe
OMe
O
O
O
O
O
O
O
LiOH (30 equiv),
H2O, EtOH,
80 °C, 83%
O
O
O
O
HO
H2N
O
O
N
O
CO2Me
H
CO2H
OTBS
OH
O
O
17
21
Scheme 2. Hydrolysis of oxazinanone groups in compounds 16 and 17.
3.94e4.01 (m, 2H), 3.74 (q, J¼9.0 Hz, 1H), 3.65 (br s, 2H), 3.43
(s, 3H), 3.00 (br s, 1H), 2.78 (dd, J¼4.5, 13.5 Hz, 1H), 2.08 (dd,
J¼11.5, 13.5 Hz, 1H), 1.95 (br s, 1H), 1.41 (s, 3H), 1.40 (s, 3H);
13C NMR (125 MHz, CDCl3) d 168.6, 157.6, 143.7, 143.5,
141.3, 136.2, 127.7, 129.6, 128.7, 127.8, 127.2, 125.0, 120.1,
109.0, 90.2, 74.6, 72.8, 70.4, 67.7, 67.2, 67.1, 54.6, 52.4, 47.1,
41.1, 26.9, 25.5; ESIHRMS calcd for C34H37NO9SNa
[MþNa]þ: 658.2082, found 658.2083.
room temperature, the resulting reaction mixture was stirred at
room temperature for 1 h, and then diluted with ethyl acetate
(50 mL). The organic layer was washed twice with water, dried
over anhydrous Na2SO4, and concentrated to afford the residue.
Purification by a short silica gel column (hexane/ethyl acetate,
1:1) give amino alcohol intermediate (0.28 g, 0.53 mmol),
which was dissolved in dry THF (15 mL), followed by addition
of 1,10-carbonyldiimidazole (0.19 g, 1.2 mmol). The resulting
reaction mixture was heated at reflux for 48 h, then cooled
down to room temperature and concentrated under reduced
pressure. The residue was purified by chromatography on silica
gel (hexane/ethyl acetate, 3:1) to afford donor 11 (0.19 g,
0.35 mmol, 66%) as a white solid. Mp 163e164 ꢁC; [a]D16
4.3. Methyl [phenyl 3,5-dideoxy-8,9-isopropylidene-5-(9-
fluorenylmethoxycarbonylamino)-4-O-tert-butyldimethylsilyl-
2-thio-D-glycero-b-D-galacto-non-2-ulopyranoside]onate (14)
1
ꢀ63.8 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) d 7.31e
A mixture of compound 13 (0.34 g, 0.54 mmol), tert-butyldi-
methylsilyl chloride (0.12 g, 0.80 mmol) and imidazole (0.72 g,
1.08 mmol) in dry DMF (1 mL) was stirred at room temperature
for 20 h, and then diluted with ethyl acetate (50 mL). The or-
ganic layer was washed twice with water, aq NaHCO3, brine,
dried over anhydrous Na2SO4, and concentrated. The residue
was purified by chromatography on silica gel (hexane/ethyl ac-
etate, 2:1) to give title compound 14 (0.33 g, 0.44 mmol, 81%).
[a]2D0 ꢀ99.5 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.77
(d, J¼7.5 Hz, 2H), 7.56e7.61 (m, 4H), 7.26e7.42(m, 7H), 4.81(d,
J¼7.5 Hz, 1H), 4.51e4.55 (m, 1H), 4.42e4.46 (m, 2H), 4.39
(d, J¼10.5 Hz, 1H), 4.13e4.21 (m, 3H), 4.07 (dd, J¼5.5,
8.5 Hz, 1H), 3.96 (t, J¼9.0 Hz, 1H), 3.77 (t, J¼7.0 Hz, 1H),
3.60e3.67 (m, 2H), 3.43 (s, 3H), 2.68 (dd, J¼4.5, 13.5 Hz,
1H), 2.06 (dd, J¼11.5, 13.5 Hz, 1H), 1.45 (s, 3H), 1.43 (s,
3H), 0.86 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 168.6, 157.3, 143.8, 143.7, 141.4, 136.2,
129.9, 129.6, 128.7, 127.8, 127.2, 127.1, 125.0, 124.9, 120.1,
108.8, 90.3, 74.9, 72.9, 70.3, 67.8, 67.2, 66.9, 54.9, 52.4, 47.2,
42.1, 26.9, 25.7, 25.6, 17.9, ꢀ4.3, ꢀ4.7; ESIHRMS calcd for
C40H51NO9SiSNa [MþNa]þ: 772.2946, found 772.2934.
7.38 (m, 5H), 5.26 (s, 1H), 4.76 (dd, J¼6.0, 10.5 Hz, 1H),
4.53 (t, J¼5.0 Hz, 1H), 4.45 (q, J¼6.0 Hz, 1H), 4.01e4.05
(m, 2H), 3.56 (s, 3H), 3.31 (t, J¼10.5 Hz, 1H), 2.57 (dd,
J¼4.5, 14.0 Hz, 1H), 1.99 (dd, J¼11.0, 14.0 Hz, 1H), 1.37 (s,
3H), 1.34 (s, 3H), 0.91 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H);
13C NMR (125 MHz, CDCl3) d 168.0, 151.5, 135.3, 129.7,
129.3, 129.1, 109.7, 90.0, 75.0, 69.8, 66.1, 65.4, 55.1, 52.6,
40.2, 26.4, 25.7, 25.6, 17.9, ꢀ4.1, ꢀ4.6; ESIHRMS calcd for
C26H39NO8SiSNa [MþNa]þ: 576.2058, found 576.2050.
4.5. General procedure for sialylation with donor 11
A solution of donor 11 (50 mg, 0.09 mmol, 1 equiv), di-
phenyl sulfoxide (55 mg, 0.27 mmol, 3 equiv), TTBP (45 mg,
˚
0.18 mmol, 2 equiv), and activated 4 A molecular sieves in an-
hydrous CH2Cl2 (2 mL) was stirred at room temperature for 1 h
under an argon atmosphere, and then cooled down to ꢀ78 ꢁC,
followed by addition of Tf2O (18 mL, 0.11 mmol, 1.2 equiv).
After 15 min, a solution of the acceptor (0.18 mmol, 2 equiv)
in CH2Cl2 (1 mL) was added. The reaction mixture was stirred
at ꢀ78 ꢁC for 30 min, and then warmed up to 0 ꢁC slowly over
1 h, and quenched with aq NaHCO3, diluted with CH2Cl2
(20 mL), and filtered through Celite. The organic layer was
washed with brine, dried over anhydrous Na2SO4, and concen-
trated. The crude product was purified by chromatography on
silica gel to afford the sialosides, eluting with toluene/ethyl
acetate or toluene/acetone systems.
4.4. Methyl [phenyl 5-amino-5-N,7-O-carbonyl-3,5-dideoxy-
8,9-isopropylidene-4-O-tert-butyldimethylsilyl-2-thio-D-
glycero-b-D-galacto-non-2-ulopyranoside]onate (11)
To a stirred solution of compound 14 (0.4 g, 0.53 mmol) in
dry DMF (4 mL) was added piperidine (0.8 mL, 7.7 mmol) at

2046
D. Crich, B. Wu / Tetrahedron 64 (2008) 2042e2047
4.6. Methyl [2-butyl 5-amino-5-N,7-O-carbonyl-3,5-dideoxy-
8,9-isopropylidene-4-O-tert-butyldimethylsilyl-D-glycerol-b-
D-galacto-non-2-ulopyranoside]onate (15b) and methyl
[2-butyl 5-amino-5-N,7-O-carbonyl-3,5-dideoxy-8,9-
isopropylidene-4-O-tert-butyldimethylsilyl-D-glycerol-a-
D-galacto-non-2-ulopyranoside]onate (15a)
3H), 1.43 (s, 3H), 1.38 (s, 3H), 1.29 (d, J¼6.0 Hz, 3H), 1.26
(s, 3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 168.4 (3JC1,H-3ax¼1.25 Hz), 151.6,
109.9, 109.2, 99.2, 97.9, 76.0, 75.5, 75.0, 74.9, 69.3, 66.3,
65.5, 63.9, 54.9, 54.5, 52.4, 41.6, 28.1, 26.4, 26.3, 25.8, 25.7,
18.4, 17.9, ꢀ4.1, ꢀ4.7; ESIHRMS calcd for C30H52NO13Si
[MþH]þ: 662.3202, found 662.3199.
Compound 15b: [a]D9 36.3 (c 0.25, CHCl3); 1H NMR
(500 MHz, CDCl3) d 5.19 (s, 1H), 4.60 (t, J¼5.5 Hz, 1H), 4.46
(m, 1H), 4.05e4.14 (m, 2H), 3.93 (dd, J¼5.5, 10.5 Hz, 1H),
3.84 (s, 3H), 3.73e3.77 (m, 1H), 3.49e3.52 (m, 1H), 3.32e
3.40 (m, 2H), 2.62 (dd, J¼4.5, 13.0 Hz, 1H), 1.76 (dd, J¼11.5,
13.0 Hz, 1H), 1.47e1.54 (m, 2H), 1.44 (s, 3H), 1.25e1.39 (m,
2H), 1.37 (s, 3H), 0.83e0.92 (m, 3H), 0.88 (s, 9H), 0.11
(s, 6H); 13C NMR (125 MHz, CDCl3) d 168.7 (3JC1,H-3ax¼0 Hz),
151.4, 110.0, 100.1, 75.7, 74.7, 70.3, 67.9, 66.1, 64.4, 54.4, 52.8,
40.2, 31.6, 26.4, 25.7, 25.6, 19.1, 17.9, 13.8, ꢀ4.2, ꢀ4.7;
ESIHRMS calcd for C24H44NO9Si [MþH]þ: 518.2780, found
517.2779. Compound 15a: [a]9D 27.6 (c 0.5, CHCl3); 1H NMR
(500 MHz, CDCl3) d 5.22 (s, 1H), 4.58 (dd, J¼4.5, 5.5 Hz,
1H), 4.50e4.53 (m, 1H), 4.07e4.14 (m, 2H), 3.98 (dd, J¼6.0,
10.5 Hz, 1H), 3.88e3.93 (m, 1H), 3.79 (s, 3H), 3.43e3.47 (m,
1H), 3.30e3.34 (m, 2H), 2.30 (dd, J¼4.5, 13.0 Hz, 1H), 1.66
(dd, J¼11.0, 13.0 Hz, 1H), 1.54e1.59 (m, 2H), 1.46 (s, 3H),
1.38 (s, 3H), 1.33e1.41 (m, 2H), 0.93 (t, J¼7.5 Hz, 3H), 0.89
(s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 167.9 (3JC1,H-3ax¼6.25 Hz), 151.7, 109.7, 99.8, 75.4,
75.1, 69.4, 65.41, 65.37, 63.8, 54.9, 52.7, 40.3, 31.5, 26.3,
26.1, 25.7, 19.3, 17.9, 13.9, ꢀ4.1, ꢀ4.6; ESIHRMS calcd for
C24H44NO9Si [MþH]þ: 518.2780, found 517.2773.
4.9. 3-O-[Methyl 5-amino-5-N,7-O-carbonyl-3,5-dideoxy-
8,9-isopropylidene-4-O-tert-butyldimethylsilyl-D-glycerol-
b-D-galacto-non-2-ulopyranosylonate]-(2/3)-1,2:5,6-
di-isopropylidene-a-D-glucofuranose (18)
[a]1D8 8.9 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.82
(d, J¼3.5 Hz, 1H), 5.21 (s, 1H), 4.73 (dd, J¼5.5 Hz, 1H), 4.47e
4.52 (m, 2H), 4.43 (d, J¼3.5 Hz, 1H), 4.25 (d, J¼4.0 Hz, 1H),
4.02e4.23 (m, 6H), 3.82e3.89 (m, 1H), 3.82 (s, 3H), 3.29
(t, J¼10.0 Hz, 1H), 2.44 (dd, J¼4.5, 14.0 Hz, 1H), 1.71 (dd,
J¼11.0, 13.5 Hz, 1H), 1.47 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H),
1.36 (s, 3H), 1.31 (s, 3H), 1.25 (s, 3H), 1.21 (s, 3H), 0.89 (s,
9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 168.1 (3JC1,H-3ax¼3.75 Hz), 151.5, 111.8, 110.1, 109.7,
104.7, 98.5, 82.7, 81.1, 75.5, 75.10, 75.05, 71.4, 69.6, 68.0,
65.5, 65.0, 54.5, 52.8, 40.4, 26.7, 26.4, 26.1, 25.7, 25.6, 24.8,
17.9, ꢀ4.0, ꢀ4.6; ESIHRMS calcd for C32H54NO14Si
[MþH]þ: 704.3308, found 704.3312.
4.10. N-Benzoyl-O-[methyl 5-amino-5-N,7-O-carbonyl-3,5-
dideoxy-8,9-isopropylidene-4-O-tert-butyldimethylsilyl-D-
glycerol-b-D-galacto-non-2-ulopyranosylonate]-L-threonine
methyl ester (19)
4.7. Methyl [2-(1-adamantanyl) 5-amino-5-N,7-O-carbonyl-
3,5-dideoxy-8,9-isopropylidene-4-O-tert-butyldimethylsilyl-
D-glycerol-b-D-galacto-non-2-ulopyranoside]onate (16)
[a]9D 17.0 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.38e7.39 (m, 5H), 5.48 (d, J¼9.0 Hz, 1H), 5.22 (s, 1H),
5.13 (d, J¼1.5 Hz, 2H), 4.64 (t, J¼5.0 Hz, 1H), 4.49e4.52
(m, 1H), 4.41 (dd, J¼2.0, 9.5 Hz, 1H), 4.34e4.38 (m, 1H),
4.14e4.17 (m, 1H), 4.07 (dd, J¼6.5, 8.0 Hz, 1H), 3.88 (dd,
J¼6.0, 10.5 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.69e3.73
(m, 1H), 3.34 (t, J¼10.0 Hz, 1H), 2.29 (dd, J¼4.5, 13.0 Hz,
1H), 1.56 (dd, J¼11.0, 13.5 Hz, 1H), 1.45 (s, 3H), 1.37 (s,
3H), 1.12 (d, J¼6.0 Hz, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11
[a]1D6 15.1 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.22
(s, 1H), 4.57e4.59 (m, 1H), 4.50e4.54 (m, 1H), 4.22 (dd, J¼5.5,
10.5 Hz, 1H), 4.12e4.15 (m, 1H), 4.06e4.09 (m, 1H), 3.90 (dt,
4.5, 10.0 Hz, 1H), 3.77 (s, 3H), 3.18 (t, J¼10.0 Hz, 1H), 2.31
(dd, J¼4.5, 13.0 Hz, 1H), 2.10 (br s, 3H), 1.78e1.85 (m, 6H),
1.54e1.61 (m, 6H), 1.43e1.48 (m, 1H), 1.45 (s, 3H), 1.38
(s, 3H), 0.88 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 170.0 (3JC1,H-3ax¼2.5 Hz), 151.7, 109.5,
98.2, 78.3, 75.3, 75.1, 69.7, 65.3, 65.1, 55.0, 52.6, 43.2, 42.9,
36.0, 30.9, 26.4, 25.7, 17.9, ꢀ4.1, ꢀ4.6; ESIHRMS calcd for
C30H50NO9Si [MþH]þ: 596.3249, found 596.3233.
(s, 3H); 13C NMR (125 MHz, CDCl3) d 170.5 (3JC1,H-3ax
¼
2.5 Hz), 168.5, 156.4, 151.5, 136.0, 128.6, 128.4, 128.3,
109.8, 98.1, 78.1, 76.4, 75.2, 74.9, 70.1, 69.3, 67.5, 66.4,
65.4, 58.8, 54.4, 52.9, 52.6, 40.9, 26.3, 25.71, 25.66, 17.9,
16.0, ꢀ4.2, ꢀ4.7; ESIHRMS calcd for C33H51N2O13Si
[MþH]þ: 711.3155, found 711.3147.
4.8. Methyl O-[methyl 5-amino-5-N,7-O-carbonyl-3,5-
dideoxy-8,9-isopropylidene-4-O-tert-butyldimethylsilyl-
D-glycerol-b-D-galacto-non-2-ulopyranosylonate]-(2/4)-
2,3-isopropylidene-a-L-rhamnopyranoside (17)
4.11. 2-(1-Adamantanyl) 5-amino-3,5-dideoxy-D-glycerol-b-
D-galacto-non-2-ulopyranosidic acid (20)
To a stirred solution of compound 16 (28 mg, 0.05 mmol) in
ethanol (2 mL) and water (2 mL) was added LiOH (34 mg,
1.5 mmol) at room temperature. The reaction mixture was then
heated at 80 ꢁC for 3 h, and cooled down to room temperature
followed by removal of the solvent under reduced pressure. The
residue was purified by chromatography on silica gel (ethyl
[a]2D0 1.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) d 5.23
(s, 1H), 4.80 (s, 1H), 4.52 (br s, 2H), 4.21e4.23 (m, 2H), 3.98e
4.04 (m, 3H), 3.76e3.80 (m, 2H), 3.73 (s, 3H), 3.51
(t, J¼10.0 Hz, 1H), 3.38e3.44 (m, 1H), 3.35 (s, 3H), 2.32 (dd,
J¼4.5, 13.5 Hz, 1H), 1.60 (dd, J¼11.0, 13.5 Hz, 1H), 1.44 (s,

D. Crich, B. Wu / Tetrahedron 64 (2008) 2042e2047
2047
Eds.; Harwood: Amsterdam, The Netherlands, 1996; pp 277e300; (e)
Hasegawa, A.; Kiso, M. Preparative Carbohydrate Chemistry; Hanessian,
S., Ed.; Dekker: New York, NY, 1997; pp 357e379; (f) Boons, G.-J.;
Demchenko, A. V. Chem. Rev. 2000, 100, 4539e4565; (g) Kiso, M.;
Ishida, H.; Ito, H. Carbohydrates in Chemistry and Biology; Ernst, B.,
acetate/isopropanol/water, 9:4:2) to give title compound 20
(17 mg, 82%). [a]D19 ꢀ19.0 (c 1.0, MeOH); 1H NMR
(500 MHz, MeOD) d 4.35 (br s, 1H), 4.00e4.17 (m, 4H), 3.45
(d, J¼8.0 Hz, 1H), 3.03 (t, J¼8.0 Hz, 1H), 2.45 (d, J¼11.0 Hz,
1H), 1.99e2.14 (m, 9H), 1.58e1.67 (m, 6H), 1.39 (s, 3H), 1.31
(s, 3H), 1.31e1.39 (m, 1H); 13C NMR (125 MHz, MeOD)
d 176.3, 109.3, 99.0, 76.4, 73.5, 70.9, 69.9, 67.6, 65.5, 53.5,
43.7, 42.4, 35.9, 31.2, 25.9, 24.1; ESIHRMS calcd for
C22H36NO8 [MþH]þ: 442.2435, found 442.2421.
Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000;
¨
pp 345e365; (h) Halcomb, R. L.; Chappell, M. D. Glycochemistry: Prin-
ciples, Synthesis, and Applications; Wang, P. G., Bertozzi, C. R., Eds.;
Dekker: New York, NY, 2001; pp 177e220; (i) Boons, G.-J.; Demchenko,
A. V. Carbohydrate-Based Drug Discovery; Wong, C.-H., Ed.; Wiley-
VCH: Weinheim, Germany, 2003; Vol. 1, pp 55e102; (j) Ress, D. K.;
Linhardt, R. J. Curr. Org. Synth. 2004, 1, 31e46.
3. Crich, D.; Li, W. J. Org. Chem. 2007, 72, 2387e2391.
´
4. Litjens, R. E. J. N.; van den Bos, L. J.; Codee, J. D. C.; Overkleeft, H. S.;
4.12. Methyl O-(5-amino-dideoxy-D-glycerol-b-D-galacto-
non-2-ulopyranosylonate)-(2/4)-2,3-isopropylidene-a-
L-rhamnopyranoside (21)
van der Marel, G. A. Carbohydr. Res. 2007, 342, 419e429.
5. Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926e4930.
6. Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015e9020.
7. Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001, 123, 9461e9462.
8. (a) Kerns, R. J.; Zha, C.; Benakli, K.; Liang, Y.-Z. Tetrahedron Lett. 2003,
44, 8069e8072; (b) Crich, D.; Vinod, A. U. Org. Lett. 2003, 5, 1297e
1300; (c) Wei, P.; Kerns, R. J. J. Org. Chem. 2005, 70, 4195e4198; (d)
Mendlik, M. T.; Tao, P.; Hadad, C. M.; Coleman, R. S.; Lowary, T. L.
J. Org. Chem. 2006, 71, 8059e8070.
9. Crich, D.; Jayalath, P. J. Org. Chem. 2005, 70, 7252e7259.
10. Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68, 8453e8458.
11. Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2006, 128,
7124e7125.
To a stirred solution of compound 18 (30 mg, 0.05 mmol) in
ethanol (2 mL) and water (2 mL) was added LiOH (33 mg,
1.5 mmol) at room temperature. The reaction mixture was
then heated at 80 ꢁC for 3 h, and cooled down to room temper-
ature followedby removal of the solvent under reduced pressure.
The residue was purified by chromatography on silica gel
(ethyl acetate/isopropanol/water, 9:4:2) to give title compound
21 (19 mg, 83%). [a]D19 ꢀ61.3 (c 1.0, MeOH); 1H NMR
(500 MHz, MeOD) d 4.65 (s, 1H), 4.53 (br s, 1H), 4.36 (br s,
1H), 4.16 (br s, 1H), 3.85e4.02 (m, 6H), 3.46 (d, J¼8.5 Hz, 1H),
3.37 (s, 3H), 3.05 (t, J¼9.0 Hz, 1H), 2.48 (d, J¼12.5 Hz, 1H),
1.95 (s, 1H), 1.55 (t, J¼12.0 Hz, 1H), 1.47 (s, 3H), 1.40
(s, 3H), 1.37 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H); 13C NMR
(125 MHz, MeOD) d 174.1, 109.6, 108.5, 100.1, 98.5, 76.7,
75.3, 73.7, 72.9, 70.7, 70.6, 67.5, 67.0, 65.6, 54.2, 53.2, 42.4,
26.7, 26.0, 24.9, 24.3, 17.2; ESIHRMS calcd for C22H37NO12Na
[MþNa]þ: 530.2208, found 530.2197.
12. Farris, M. D.; De Meo, C. Tetrahedron Lett. 2007, 48, 1225e1227.
13. Crich, D.; Li, W. J. Org. Chem. 2007, 72, 7794e7797.
14. (a) Marra, A.; Sinay, P. Carbohydr. Res. 1989, 187, 35e42; (b) Martin, R.;
¨
Witte, K. L.; Wong, C.-H. Bioorg. Med. Chem. 1998, 6, 1283e1292.
15. (a) Hasegawa, A.; Ogawa, H.; Ishida, H.; Kiso, M. Carbohydr. Res. 1992,
224, 175e184; (b) Castro-Palomino, J. C.; Tsvetkov, Y. E.; Schneider, R.;
Schmidt, R. R. Tetrahedron Lett. 1997, 38, 6837e6840; (c) Lecourt, T.;
Herault, A.; Pearce, A. J.; Sollogoub, M.; Sinay, P. Chem.dEur. J.
2004, 10, 2960e2971.
¨
16. Selective protection using tert-butyldiphenylsilyl chloride (TBDPSCl) only
afforded the desired product with very low conversion, regardless of
reaction temperature and concentration.
Acknowledgements
17. Miyazaki, T.; Sato, H.; Sakakibara, T.; Kajihara, Y. J. Am. Chem. Soc.
2000, 122, 5678e5694.
18. Ella-Menye, J.-R.; Sharma, V.; Wang, G. J. Org. Chem. 2005, 70, 463e469.
19. Crich, D.; Lim, L. B. Org. React. 2004, 64, 115e251.
20. (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997, 119,
7597e7598; (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122,
4269e4279; (c) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem.,
Int. Ed. 2001, 40, 414e417; (d) Haberman, J. M.; Gin, D. Y. Org. Lett.
2003, 5, 2539e2541.
We thank the NIH (GM 62160) for financial support of this
work.
References and notes
1. (a) Schauer, R. Sialic Acid: Chemistry, Metabolism and Function; Springer:
New York, NY, 1982; Vol. 10; (b) Varki, A. Glycobiology 1993, 3, 97e
103; (c) Mammen, M.; Chio, S.-K.; Whitesides, G. M. Angew. Chem.,
Int. Ed. 1998, 37, 2755e2794; (d) Simanek, E. E.; McGarvey, G. J.;
Jablonowski, J. A.; Wong, C.-H. Chem. Rev. 1998, 98, 833e862; (e)
Sialobiology and Other Novel Forms of Glycosylation; Inoue, Y., Lee,
Y. C., Troy, F. A., Eds.; Gakushin: Osaka, Japan, 1999.
´
21. Codee, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft, H. S.;
van Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A. Tetrahedron
2004, 60, 1057e1064.
22. Crich, D.; Li, W. Org. Lett. 2006, 8, 959e962.
23. (a) Haverkamp, J.; Spoormaker, T.; Dorland, L.; Vliegenthart, J. F. G.;
Schauer, R. J. Am. Chem. Soc. 1979, 101, 4851e4853; (b) Hori, H.;
Nakajima, T.; Nishida, Y.; Ohrui, H.; Meguro, H. Tetrahedron Lett.
1988, 29, 6317e6320.
2. (a) Kumar, V.; Remers, W. A. J. Org. Chem. 1978, 43, 3327e3331; (b)
Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503e1531; (c) Boons,
G.-J. J. Contemp. Org. Synth. 1996, 3, 173e200; (d) Hasegawa, A.
Modern Methods in Carbohydrate Synthesis; Khan, S. H., O’Neill, R. A.,
24. Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004, 126,
9205e9213.