Novel galactosyl donor with 2-naphthylmethyl (NAP) as the non-participating group at C-2 position: Efficient synthesis of α-galactosyl ceramide

Article abstract of DOI:10.1016/j.tetlet.2010.06.071

Predominant α-linked products can be generated in glycosylation involving galactosyl trichloroacetimidate donors with 2-naphthylmethyl (NAP) as the non-participating group at C-2 position. The above-mentioned donor was successfully utilized for the synthe

Full text of DOI:10.1016/j.tetlet.2010.06.071

Tetrahedron Letters 51 (2010) 4411–4414
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel galactosyl donor with 2-naphthylmethyl (NAP) as the non-participating
group at C-2 position: efficient synthesis of
a-galactosyl ceramide
*
Sirajud D. Khaja, Vipin Kumar, Misbah Ahmad, Jun Xue, Khushi L. Matta
Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Predominant
donors with 2-naphthylmethyl (NAP) as the non-participating group at C-2 position. The above-mentioned
donor was successfully utilized for the synthesis of -galactosyl ceramide.
Ó 2010 Elsevier Ltd. All rights reserved.
a-linked products can be generated in glycosylation involving galactosyl trichloroacetimidate
Received 12 April 2010
Revised 10 June 2010
Accepted 14 June 2010
Available online 19 June 2010
a
Keywords:
Glycans
a-Galactosyl ceramide
2-Naphthylmethyl (NAP)
Oligosaccharides
1. Introduction
topyranosyl,9 -arabinofuranosyl,10 -sialyl linkages,11 and b-man-
a a
nopyranosyl12 still presents significant challenge as each case
requires a special strategy when applied to construct a complex car-
bohydrate structure.
Glycans, the vital endogenous biomolecules, found mostly in
conjugation with lipids (to form glycolipids) and proteins (to form
glycoproteins), are composed of various monosaccharide units
linked together through O-glycosidic linkages. They are crucially en-
gaged in various biochemicalpathways and biologicalprocessesviz.,
cell-cell communication, cell adhesion, immune response, molecu-
lar recognition, tissue repair, and microbial and viral pathogenesis.1
Therefore, practical and stereocontrolled synthesis of glycans occu-
pies great importance in carbohydrate chemistry where a glycosyl-
In general, a non-assisting functionality at C-2 position of glyco-
syl donors in most cases is a benzyl, a substituted benzyl or allyl
group for the introduction of 1,2-cis-glycosidic linkages. Invariably,
the use of these glycosyl donors leads to the formation of mixtures of
anomers.2f Time-consuming purification protocols are required for
the separation of these anomers which also results in the loss of
material. In order to find a better stereoselective glycosylation
methodology, we became interested in checking the influence of
2-naphthylmethyl (NAP) group as a non-participating group in
ation reaction involving a donor and an acceptor can yield a- as well
as b-isomers during the glycosidic bond formation.2 Despite the
enormous efforts put in by various groups for the development of
efficient and stereoselective glycosylation methodologies, not all
problems are completely answered.3 In carbohydrate chemistry,
generally it is believed that the glycosylation with glycosyl donors
possessing an O-acyloxyl group at C-2 usually afford 1,2-trans glyco-
side with quite high stereoselectivity by virtue of its neighboring
group participation.2k,n,4 But, some reports revealed unusual 1,2-
1,2-cis a-galactosyl bond formation as it is endowed with versatile
properties such as stability to variety of acidic and basic conditions,
selective introduction, and chemoselective removal.13 With the
intention of studying the stereoselectivity–structure relationship,
a variety of donors (with O-NAP group at C-2) and acceptors were
used for coupling together (Table 1). Herein, we describe the results
for the above-described coupling reactions and successful applica-
tion of our findings to the synthesis of biologically important
cis-glycosylation,5
a
-(1?3)-glycosylations,6 and 1,2-cis-galactosy-
lations7 with glycosyl donors having a C-2 ester capable of neighbor-
ing group participation.
a
-galactosyl ceramide 24.14 The synthesis of modified analogs of
this molecule is the focus of attention in numerous laboratories.14
Stereoselective synthesis of 1,2-cis glycosides is usually a more
difficult issue where no assistance by neighboring group participa-
tion is available.2f For instance, the stereoselective construction of
2. Results and discussion
certain 1,2-cis glycosyl linkages such as a a-galac-
-glucopyranosyl,8
Galactosyl imidates used for 1,2-cis galactosylations suffer from
certain drawbacks. For example, 2,3,4,6-tetra-O-benzyl-galactosyl
donor generates anomeric mixtures which are difficult to purify
* Corresponding author. Fax: +1 716 845 8768.
E-mail address: khushi.matta@roswellpark.org (K.L. Matta).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.071

4412
S. D. Khaja et al. / Tetrahedron Letters 51 (2010) 4411–4414
Table 1
Coupling results with different donors and acceptorsa
Entry
Donor (1.2 equiv)
Acceptor (1 equiv)
OBn
Product
Ph
Yield (%)
Ratio (a/b)
O
O
O
OBz
O
OH
OBz
NAPO
NAPO
BzO
1
4
68
9:1
6
O
OBz
OBn
O
7
BzO
OBz
O
NAPO
NAPO
BzO
2
3
5
5
6
88
82
Only
Only
a
O
OBz
O
OBn
8
OAc
O
OBz
O
AcO
HO
BzO
OAc
OAc
O
O
NAPO
a
AcO
NAPO
O
O
AcO
9
10
Ph
Ph
OBz
O
OPMB
O
BzO
O
O
O
NAPO
O
O
PMBO
NAPO
O
O
O
HO
4
5
68
6.2:1
11
12
OBz
O
BzO
HO
BzO
O
OBz
NAPO
O
BzO
NAPO
5
6
5
5
78
74
Only
Only
a
a
O
O
BzO
O
13
14
OAc
OBz
O
AcO
AcO
BzO
NAPO
OH
O
O
HO
OBn
O
NHAc
AcO
NAPO
O
OAc
O
AcO
AcO
15
O
HO
O
OBn
NHAc
AcO
16
a
All the reactions were conducted using TMSOTf (0.2 equiv) in CH2Cl2 and at ꢀ15 °C. The reactions were completed within 3–4 h.
after glycosylation.9c Furthermore, its 4,6-benzylidene derivative is
highly unstable and difficult to isolate and store.9c Inspired by the
past success of NAP group in glycosylation, we became interested
in exploring the applicability of NAP group being utilized as a
by activation of the resultant hemiacetal with trichloroacetonitrile
in the presence of DBU as a base,9c to afford the imidate 4 in 74%
yield over two steps (Scheme 1).
We first examined the use of compound 4 as a galactosyl donor
using benzyl 2,4-dibenzoyl-a-L-fucoside 6 as an acceptor, the reac-
non-participating group in
a
-glycosylations.15
We designed the synthesis of galactosyl donor 4 starting from
-galactose pentaacetate (1). Treatment of 1 with ethanethiol and
tion gave a moderate yield of dissacharide 7 with low a-selectivity
D
(Table 1, entry 1). The 1H NMR spectra of compound 7 showed a
doublet at d 5.63 for anomeric proton with J1,2 = 3.7 Hz which con-
BF3–OEt2 at 0 °C gave b-ethylthio galactoside,16 which on Zemplén
deacetylation17 provided crystalline b-thioethyl galactoside 2 in
92% yield over two steps. Benzylidene protection of b-galactoside
2 with benzaldehyde dimethylacetal and PTSA followed by naph-
thylmethylation13 of 2,3-hydroxyl groups provided compound 3
as a white solid in 78 % yield (for two steps). The removal of ano-
meric ethylthio group of 3 was accomplished using NBS,18 followed
firm the a-stereochemistry in the dissacharide 7. It was found (also
reported for similar imidate in the literature) that the imidate 4 is
very unstable and difficult to store.9c In order to increase the stabil-
ity and a-selectivity of the donor 4, the benzylidene protection was
replaced with dibenzoyl ester protection. The dibenzoyl ester pro-
tection at C-4 and C-6 makes donor 5 less reactive than donor 4

S. D. Khaja et al. / Tetrahedron Letters 51 (2010) 4411–4414
4413
Ph
versatile alternative to donor 4, furnishing the expected
a
-glyco-
O
AcO
AcO
OAc
O
sides with remarkable stereoselectivities (entries 2, 3, 5, and 6).
Presumably, the higher -selectivity may be attributed to the
HO
HO
OH
O
O
a
b
a
O
OAc
SEt
d
SEt
NAPO
low reactivity of donor 5 and non-participating nature of NAP
group at C-2 position. Also, the effect of remote participation by
4- and 6-benzoyl group for the enhancement of a-selectivity could
not be ruled out in this case. It is worth mentioning here that the
OAc
OH
NAPO
3
1
2
Ph
O
OBz
O
BzO
NAPO
c
O
3
similar glycosylation reaction when performed with imidate hav-
O
NAPO
ing benzyl group in the place of NAP gave a mixture of a:b products
NAPO
O
CCl3
with very high b-selectivity.19
NAPO
O
CCl3
5
NH
Having established the utility of novel galactosyl donor 5, we
initiated the synthesis of -galactosy ceramide 24 (KRN7000),
4
NH
a
using this novel galactosyl donor (Scheme 2). Our synthetic route
to galactosyl ceramide 24 started with the amidation reaction of
hexacosanoic acid and commercially available phytosphingosine.
Several attempts of N-acylation of sphingosine 17 with DCC and
DIC were unsuccessful. Finally, sphingosine 17 was coupled with
hexacosanoic acid using HOBT and EDC in DMF at 100 °C20 to ob-
tain the ceramide chain 18 in 92% yield. Compound 18 was silylat-
ed using TBSOTf and lutidine to yield the known TBS ether 1921 in
82% yield. The spectral data (1H and 13C NMR) of compound 19 ob-
tained were identical with the literature values.21 Chemoselective
deprotection of 19, to obtain free primary hydroxyl group, was car-
ried out using 10% aq TFA in THF at ꢀ10 to 10 °C to provide com-
pound 20 in 88% yield.20,21 Glycosylation of 20 with 5 using
Scheme 1. Preparation of donor 4 and 5. Reagents and conditions: (a) (i) DCM–
ethanethiol (2.5 equiv), BF3ꢁEt2O (1.5 equiv), 0 °C, 6 h, (ii) NaOMe (1 M), MeOH, rt,
20 h, 92% for two steps; (b) (i) PhCH(OMe)2 (2 equiv) , p-TsOH (0.1 equiv), rt, 6 h, (ii)
NAP-Br (2.8 equiv), NaH (4 equiv), THF, rt, 6 h, 78% for two steps; (c) (i) NBS
(1.4 equiv), acetone, 0 °C, 2 h, (ii) CCl3CN (10 equiv), DBU (0.5 equiv), CH2Cl2, 0 °C,
30 min, 74% for two steps; (d) (i) 60% HOAc, 60 °C, 5 h, (ii) BzCl (3 equiv), py, rt, 6 h,
(iii) NBS (1.4 equiv), acetone, 0 °C, 2 h, (iv) CCl3CN (10 equiv), DBU (0.5 equiv),
CH2Cl2, 0 °C, 30 min, 58%.
and hence, provides greater possibility of higher selectivity. Thus,
removal of benzylidine ring of 3, followed by conventional dib-
enzoylation, deprotection of anomeric ethylthio group, and finally
treatment with trichloroacetonitrile and DBU afforded the desired
galactosyl imidate 5 as a white crystalline solid in 58% yield over
four steps (Scheme 1). As prerequisite, the galactosyl donor 5
was found to be very stable with a long shelf-life. It was found to
be stable below 5 °C for over six months. Donor 5 was coupled ini-
TMSOTf in THF at ꢀ30 °C gave the desired product
a-galactosyl
ceramide 21 in 68 % yield. The stereoselectivity of the glycosylation
was readily determined by 1H and 13C NMR spectral analysis of
compound 21. Complete deprotection of 21 was carried out in
three steps. First, the removal of silyl groups of the ceramide chain
of 21 was realized using TBAF in THF20 to furnish 22 in 86% yield.
Next, the treatment of 22 with NaOMe/MeOH resulted in the
deprotection of benzoyl groups on galactose sugar affording 23 in
quantitative yield. Finally, hydrogenolysis of NAP groups of 23
yielded the desired KRN7000 24 in quantitative yield. The spectro-
scopic data for 24 were in accord with those previously reported in
the literature.21,22
tially with
disaccharide 8 in 88% yield with complete
entry 2). The 1H NMR spectra of compound 8 are indicative of
the -stereochemistry in the glycosylation reaction.
Encouraged by the initial results, we tested for the generality
and efficiency of -selectivity of donor 5 with other acceptors. A
a-
L-fucoside 6 in the presence of TMSOTf to give the
a-selectivity (Table 1,
a
a
series of suitably protected mono- and disaccharide acceptors were
glycosylated with donor 5 and the results are summarized in Table
1 (entries 2–6). It is evident from Table 1 that the donor 5 is a
O
C25H51
O
O
C25H51
C25H51
NH2 OH
C14H29
NH OH
NH OTBS
a
c
NH OTBS
HO
b
HO
TBSO
HO
C14H29
C14H29
OTBS
C14H29
OTBS
OH
OH
17
18
19
20
d
OH
O
OBz
O
HO
OBz
O
BzO
BzO
NAPO
O
O
O
C25H51
C25H51
NH OTBS
C14H29
OTBS
C25H51
f
e
NAPO
NAPO
NH OH
NH OH
NAPO
NAPO
NAPO
O
O
O
C14H29
C14H29
OH
OH
23
22
21
g
OH
O
HO
HO
O
C25H51
NH OH
HO
O
C14H29
OH
24
Scheme 2. Synthesis of
a-galactosyl ceramide 24. (a) hexacosanoic acid (1 equiv), EDC (2 equiv), HOBT (1.1 equiv), DMF, 100 °C, 6 h, 92%; (b) TBSOTf (5 equiv), 2,6-lutidine
(15 equiv), CH2Cl2, 82%; (c) 10% aq TFA, ꢀ10 to 10 °C, 2 h, 88%; (d) 5 (1.2 equiv), TMSOTf (0.3 equiv), anhydrous THF, ꢀ30 °C, 4 h, 68%; (e) TBAF (4 equiv), THF, 3 h, 86%; (f)
NaOMe (1 M), CH3OH, rt, 6 h, 100%. (g) H2, Pd–C (10 %), CH3OH, 8 h, 100%.

4414
S. D. Khaja et al. / Tetrahedron Letters 51 (2010) 4411–4414
13. (a) Kumar, V.; Xue, J.; Locke, R. D.; Matta, K. L. Synlett 2009, 2633–2636; (b) Xia,
3. Conclusions
J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.; Matta, K. L. Tetrahedron
Lett. 2000, 41, 169–173.
In summary, the findings described above indicated that the
14. (a) Xia, C.; Zhang, W.; Zhang, Y.; Woodward, R. L.; Wang, J.; Wang, P. G.
Tetrahedron 2009, 65, 6390–6395; (b) Huang, Y.; Chen, A.; Li, X.; Chen, Z.;
Zhang, W.; Song, Y.; Gurner, D.; Gardiner, D.; Basu, S.; Ho, D. D.; Tsuji, M.
Vaccine 2008, 26, 1807–1816; (c) Morales-Serna, J. A.; Boutureira, O.; Díaz, Y.;
Matheu, M. I.; Castillón, S. Carbohydr. Res. 2007, 342, 1595–1612.
a-linked glycosidic bond can be easily accessed using NAP as a
non-participating group at C-2 position of the galactosyl donor 5.
As indicated by the results from glycosylation reactions, it appears
15. (a) Szabó, Z. B.; Borbás, A.; Bajza, I.; Liptak, A. Tetrahedron: Asymmetry 2005, 16,
83–95; (b) Ishiwata, A.; Ito, Y. Trends Glycosci. Glyc. 2009, 21, 266–289.
16. Ellervik, U.; Magnusson, G. Carbohydr. Res. 1996, 280, 251–260.
17. Zemplén, G.; Pacsu, E. Ber. Dtsch. Chem. Ges. 1929, 62, 1613–1614.
18. Hanashima, S.; Akai, S.; Sato, K.-I. Tetrahedron Lett. 2008, 49, 5111–5114.
19. Cheng, Y.-P.; Chen, H.-T.; Lin, C.-C. Tetrahedron Lett. 2002, 43, 7721–7723.
20. Zhou, X.-T.; Forestier, C.; Goff, R. D.; Li, C.; Teyton, L.; Bendelac, A.; Savage, P. B.
Org. Lett. 2002, 4, 1267–1270.
that increased a-selectivity in the case of donor 5 is due to its lower
reactivity coupled with the remote participation by 4- and 6-ben-
zoyl groups. Moreover, the NAP-protecting group is found to be ver-
satile in terms of introduction and removal. Glycosylation with this
donor was successfully applied for the synthesis of KRN7000.
Acknowledgments
21. Takikawa, H.; Muto, S.; Mori, K. Tetrahedron 1998, 54, 3141–3150.
22. The selected analytical data of key compounds are listed: Compound 5: 1H NMR
(400 MHz, CDCl3): d (ppm) = 8.62 (s, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.98 (d,
J = 6.9 Hz, 2H), 7.85–7.72 (m, 5H), 7.71–7.64 (m, 2H), 7.60–7.52 (m, 3H), 7.50–
7.32 (m, 10H), 6.67 (d, J = 2.9 Hz, 1H), 6.04 (d, J = 1.9 Hz, 1H), 5.04 (d,
J = 11.8 Hz, 1H), 4.96 (dd, J = 12.8 Hz, 17.7 Hz, 2H), 4.83 (d, J = 11.8 Hz, 1H),
4.59 (t, J = 5.9 Hz, 1H), 4.52–4.45 (m, 1H), 4.37 (dd, J = 5.9 Hz, 11.8 Hz, 1H), 4.25
(dt, J = 2.9 Hz, 9.8 Hz, 12.7 Hz, 2H). Compound 8: 1H NMR (400 MHz, CDCl3): d
(ppm) = 7.99–8.12 (m, 6H), 7.88 (d, J = 8.1 Hz, 2H), 7.69 (dd, J = 8.1 Hz, 15.4 Hz,
2H), 7.28–7.62 (m, 20H), 7.14–7.26 (m, 9H), 5.93 (s, 1H), 5.58 (d, J = 3.7 Hz,
10.3 Hz, 1H, H-1), 5.47 (d, J = 2.93 Hz, 1H, H-10), 5.54 (d, J = 2.9 Hz, 1H), 5.31 (d,
J = 3.7 Hz, 1H), 4.87 (dd, J = 4.4 Hz, 7.3 Hz, 1H), 4.74–4.81 (m, 1H), 4.61–4.71
(m, 2H), 4.51–4.60 (m, 2H), 4.42–4.50 (m, 2H), 4.36 (d, J = 11.7 Hz, 1H), 4.30 (d,
J = 11.7 Hz, 1H), 3.98 (dd, J = 6.6 Hz, 13.2 Hz, 1H), 3.87–3.95 (m, 2H), 1.10 (d,
J = 5.9 Hz, 3H). Compound 10: 1H NMR (400 MHz, CDCl3): d (ppm) = 8.04 (d,
J = 8.8 Hz, 2H), 7.93 (d, J = 7.3 Hz, 2H), 7.81–7.66 (m, 6H), 7.61–7.51 (m, 4H),
7.49–7.38 (m, 8H), 7.30 (t, J = 8.1 Hz, 2H), 5.83–5.72 (m, 2H), 5.79 (d, J = 2.9 Hz,
1H), 5.52 (d, J = 2.9 Hz, 1H), 5.28 (d, J = 2.9 Hz, 1H), 5.25–5.21 (m, 1H), 5.20–
5.18 (m, 1H), 5.17–5.12 (m, 1H), 4.95 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 4.4 Hz, 1H),
4.80 (d, J = 10.9 Hz, 1H), 4.47 (dd, J = 4.4 Hz, 10.9 Hz, 1H), 4.38–4.26 (m, 2H),
4.10 (d, J = 6.6 Hz, 2H), 4.03 (dd, J = 3.6 Hz, 8.1 Hz, 2H), 3.97 (d, J = 8.1 Hz, 1H),
3.93–3.83 (m, 3H), 3.57 (t, J = 6.6 Hz, 1H), 2.08 (s, 3H), 1.86 (s, 3H), 1.84 (s, 3H).
Compound 14: 1H NMR (400 MHz, CDCl3): d (ppm) = 8.13–8.00 (m, 6H), 7.88 (d,
J = 8.1 Hz, 2H), 7.70 (t, J = 8.8 Hz, 2H), 7.60–7.51 (m, 4H), 7.50–7.27 (m, 16H),
7.26–7.15 (m, 4H), 6.73 (d, J = 8.1 Hz, 1H), 5.94 (d, J = 1.4 Hz, 1H), 5.83–5.72 (m,
1H), 5.60 (dd, J = 3.7 Hz, 10.3 Hz, 1H), 5.55 (d, J = 2.9 Hz, 1H), 5.47 (d, J = 2.9 Hz,
1H), 5.29 (d, J = 3.6 Hz, 1H), 5.27–5.09 (m, 2H), 4.92–4.86 (dd, J = 4.4 Hz, 8.1 Hz,
1H), 4.78 (d, J = 11.7 Hz, 1H), 4.67 (dd, J = 2.9 Hz, 10.3 Hz, 1H), 4.62–4.55 (m,
1H), 4.49–4.42 (m, 2H), 4.32 (dd, J = 12.4 Hz, 24.8 Hz, 2H), 4.15–4.08 (m, 1H),
3.97 (dd, J = 5.8 Hz, 13.2 Hz, 2H), 3.92 (dd, J = 2.2 Hz, 7.3 Hz, 2H), 1.12 (d,
J = 6.6 Hz, 3H). Compound 21: 1H NMR d (ppm) = 8.04–7.98 (m, 4H), 7.68–7.83
(m, 7H), 7.65 (d, J = 7.96, 1H), 7.62 (d, J = 7.96, 1H), 7.52–7.58 (m, 2H), 7.33–
7.51 (m, 9H), 5.98 (d, J = 2.7 Hz, 1H), 5.92 (d, J = 7.92 Hz, 1H), 5.04 (d,
J = 11.5 Hz, 1H), 5.00 (d, J = 3.1 Hz, 1H), 4.96 (d, J = 11.9 Hz, 1H), 4.87 (d,
J = 11.9 Hz, 1H), 4.76 (d, J = 11.5 Hz, 1H), 4.47 (dd, J = 5.8 Hz, 11.1 Hz, 1H), 4.39
(t, J = 6.6 Hz, 1H), 4.29 (dd, J = 7.1 Hz, 11.1 Hz, 1H), 4.20–4.26 (m, 1H), 4.17 (dd,
J = 3.1 Hz, 9.7 Hz, 1H), 4.10–4.15 (m, 1H), 4.05 (dd, J = 3.5 Hz, 10.2 Hz, 1H),
3.91–3.95 (m, 1H), 3.76 (t, J = 8.8 Hz, 1H), 3.67 (m, 1H), 1.91–1.96 (m, 2H),
1.44–1.51 (m, 6H), 1.18–1.33 (m, 66H), 0.88–0.90 (m, 6H), 0.91 (s, 9H), 0.87 (s,
9H), 0.07 (s, 3H), 0.04 (s, 6H), 0.03 (s, 3H); 13C NMR (400 MHz, CDCl3): d
(ppm) = 173.1, 135.6, 135.6, 133.3, 133.2, 133.1, 133.1, 133.0, 132.9, 129.9,
129.8, 129.7, 129.7, 128.4, 128.3, 128.2, 127.2, 127.7, 127.6, 127.0, 126.4, 126.1,
126.0, 125.9, 125.9, 125.8, 125.7, 99.8, 76.6, 76.0, 75.6, 75.1, 73.8, 72.0, 68.6,
68.4, 67.4, 62.5, 51.6, 36.8, 33.6, 31.9, 29.9, 29.7, 29.68, 29.64, 29.60, 29.5,
29.43, 29.38, 29.33, 26.1, 26.0, 25.6, 22.6, 18.5, 18.3, 18.1, 14.1, -3.7, -3.9, -4.6, -
4.8. Compound 22: 1H NMR d (ppm) = 8.04–7.95 (t, J = 8.7 Hz, 4H), 7.85–7.72
(m, 5H), 7.62–7.72 (m, 3H), 7.52–7.60 (m, 2H), 7.35–7.51 (m, 10H), 6.22 (d,
J = 8.8 Hz, 1H), 5.95 (d, J = 2.9 Hz, 1H), 5.04 (m, 3H), 4.87 (d, J = 11.7 Hz, 1H),
4.77 (d, J = 10.9 Hz, 1H), 4.43–4.49 (m, 1H), 4.42–4.35 (m, 3H), 4.12–4.17 (m,
1H), 4.04 (dd, J = 3.7 Hz, 9.5 Hz, 1H), 3.98 (dd, J = 3.7 Hz, 10.3 Hz, 1H), 3.89 (dd,
J = 2.9 Hz, 10.2 Hz, 1H), 3.45–3.56 (m, 2H), 2.27 (bs, H) 2.08 (t, J = 8.1 Hz, 2H),
1.53–1.62 (m, 6H), 1.06–1.37 (m, 66H), 0.88 (t, J = 7.3 Hz, 6H); 13C NMR d
(ppm) = 172.9, 171.9, 133.6, 133.5, 130.2, 130.0, 128.8, 128.7, 128.4, 128.3,
128.2, 128.0, 127.9, 127.6, 126.9, 126.5, 126.4, 126.3, 126.2, 126.1, 99.2, 77.7,
77.3, 76.7, 76.1, 74.9, 74.6, 73.5, 72.2, 69.9, 68.4, 67.8, 63.3, 49.7, 37.0, 33.7,
32.2, 30.0, 29.8, 29.7, 29.7, 29.6, 26.5, 26.0, 22.9, 14.4. Compound 23: 1H NMR d
(ppm) = 7.72–7.87 (m, 8H), 7.53–7.43 (m, 6H), 6.46 (d, J = 8.1 Hz, 1H), 4.99 (d,
J = 3.7 Hz, 1H), 4.98 (d, J = 3.6 Hz, 1H), 4.90 (s, 2H), 4.86 (d, J = 11.7 Hz, 1H), 4.27
(d, J = 3.6 Hz, 1H), 4.11 (s, 1H), 3.91–4.00 (m, 3H), 3.81–3.91 (m, 3H), 3.70–3.78
(m, 2H), 3.48 (s, 2H), 2.08 (t, J = 7.3 Hz), 1.47–1.66 (m, 6H), 1.37–1.46 (m, H),
1.05–1.38 (m, 66H), 0.89 (t, J = 6.6 Hz, 6H); 13C NMR d (ppm) = 173.3, 134.94,
134.91, 133.0, 132.9, 128.23, 128.20, 127.8, 127.7, 127.55, 127.52, 126.7, 126.5,
126.1, 126.0, 125.99, 125.93, 125.6, 125.5, 98.4, 77.6, 76.1, 75.4, 74.0, 73.0,
72.4, 70.0, 68.9, 68.4, 62.7, 49.8, 36.8, 33.6, 32.0, 29.8, 29.7, 29.5, 29.4, 29.3,
25.9, 25.84, 22.80, 14.3.
We acknowledge grant support from DOD (W81XWH-06-1-
0013) and support, in part, by the NCI Cancer Center Support Grant
to the Roswell Park Cancer Institute (5R21CA121294-02) and core
P30 CA 016056.
References and notes
1. (a) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A. Science 2001,
291, 2370–2376; (b) Gagneau, P.; Varki, A. Glycobiology 1999, 9, 747–755; (c)
Dwek, R. A. Chem. Rev. 1996, 96, 683–720; (d) Varki, A. Glycobiology 1993, 3, 97–
130; (e) Hart, G. W. Curr. Opin. Cell Biol. 1992, 4, 1017–1023; (f) Paulson, J. C.
Trends Biochem. Sci. 1989, 14, 272–276; (g) Rademacher, T. W.; Parekh, R. B.;
Dwek, R. A. Annu. Rev. Biochem. 1988, 5, 785–838.
2. (a) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934; (b)
Demchenko, A. V. Handbook of Chemical Glycosylation; Wiley-VCH: Weinheim,
2008; (c) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007; (d) Bongat, A. F.
G.; Demchenko, A. V. Carbohydr. Res. 2007, 342, 374–406; (e) Toshima, K.
Carbohydr. Res. 2006, 341, 1282–1297; (f) Demchenko, A. V. Synlett 2003, 1225–
1240; (g) Jensen, K. J. J. Chem. Soc., Perkin Trans. 1 2002, 2219–2233; (h)
Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357–2364; (i) Koeller, K. M.;
Wong, C. H. Chem. Rev. 2000, 100, 4465–4493; (j) Jung, K. –H.; Müller, M.;
Schmidt, R. R. Chem. Rev. 2000, 100, 4423–4442; (k) Boons, G.-J. Contemp. Org.
Synth. 1996, 3, 173–200; (l) Boons, G. J. Tetrahedron 1996, 52, 1095–1121; (m)
Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123; (n)
Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531; (o) Schmidt, R. R.
Angew. Chem., Int. Ed. Engl. 1986, 25, 212–235; (p) Paulsen, H. Angew. Chem., Int.
Ed. Engl. 1982, 21, 155–173.
3. (a) Oligosaccharides in Chemistry and Biology: A Comprehensive Handbook; Ernst,
B., Hart, G., Sinaÿ, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. I, (b) Davis, B. J.
Chem. Soc., Perkin Trans. 1 2000, 2137–2160; (c) Schmidt, R. R.; Jung, K.-H.
Carbohydr. Eur. 1999, 27, 12–21; (d) Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, Basel, Hong Kong, 1997; (e)
Modern Methods in Carbohydrate Chemistry; Khan, S. H., O’Neill, R. A., Eds.;
Harwood Academic: Amsterdam, 1996.
4. (a) Yang, G.; Kong, F. Synlett 2000, 1423–1426; (b) Figueroa-Perez, S.; Verez-
Bencomo, V. Tetrahedron Lett. 1998, 39, 9143–9146; (c) Nicolaou, K. C.;
Winssinger, N.; Pastor, J.; DeRoose, F. J. Am. Chem. Soc. 1997, 119, 449–450;
(d) Ogawa, T. Chem. Soc. Rev. 1994, 23, 397–407; (e) Sinaÿ, P. Pure Appl. Chem.
1991, 63, 519–528; (f) Schmidt, R. R. Pure Appl. Chem. 1989, 61, 1257–1270; (g)
Kovac, P.; Taylor, R. B.; Glaudemans, C. P. J. J. Org. Chem. 1985, 50, 5323–5333;
(h) Paulsen, H. Chem. Soc. Rev. 1984, 13, 15–45.
5. Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. Engl. 1991, 30, 180–
183.
6. Zeng, Y.; Ning, J.; Kong, F. Tetrahedron Lett. 2002, 43, 3729–3733.
7. Chen, L.; Kong, F. Tetrahedron Lett. 2003, 44, 3691–3695.
8. (a) Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681–1690; (b) Crich, D.; Vinogradova,
O. J. Org. Chem. 2006, 71, 8473–8480; (c) Kim, J.-H.; Yang, H.; Boons, G.-J. Angew.
Chem., Int. Ed. 2005, 44, 947–949.
9. (a) Fan, G.-T.; Pan, Y.-s.; Lu, K.-C.; Cheng, Y.-P.; Lin, W.-C.; Lin, S.; Lin, C.-H.;
Wong, C.-H.; Fang, J.-M.; Lin, C.-C. Tetrahedron 2005, 61, 1855–1862; (b)
Plettenburg, O.; Bodmer-Narkevitch, V.; Wong, C.-H. J. Org. Chem. 2002, 67,
4559–4564; (c) Figueroa-Pérez, S.; Schmidt, R. R. Carbohydr. Res. 2000, 328, 95–
102.
10. Zhu, X.; Kawatkar, S.; Rao, Y.; Boons, G.-J. J. Am. Chem. Soc. 2006, 128, 11948–
11957.
11. (a) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2008, 130, 17244–
17245; (b) Halcomb, R. L.; Chappell, M. D. J. Carbohydr. Chem. 2002, 7–9, 723–
768.
12. (a) Baek, J. Y.; Lee, B.-Y.; Jo, M. G.; Kim, K. S. J. Am. Chem. Soc. 2009, 131, 17705–
17713; (b) Kim, K. S.; Fulse, D. B.; Baek, J. Y.; Lee, B.-Y.; Jeon, H. B. J. Am. Chem.
Soc. 2008, 130, 8537–8547; (c) Crich, D.; Wu, B.; Jayalath, P. J. Org. Chem. 2007,
72, 6806–6815; (d) Crich, D.; Jayalath, P. Org. Lett. 2005, 7, 2277–2280; (e)
Crich, D.; Jayalath, P.; Hutton, T. K. J. Org. Chem. 2006, 71, 3064–3070.