Stereoselective synthesis of 2-C-branched (acetylmethyl) oligosaccharides and glycoconjugates: Lewis acid-catalyzed glycosylation from 1,2-cyclopropaneacetylated sugars

Article abstract of DOI:10.1021/jo1016579

1,2-Cyclopropaneacetylated sugars as glycosyl donors reacted with a series of glycosyl acceptors (monosaccharides, amino acids, and other alcohols) in the presence of Lewis acid to produce oligosaccharides and glycoconjugates containing 2-C-acetylmethylsugars. Galactosyl donor gave good to excellent α-selectivities with TMSOTf as a catalyst, whereas galactosyl donor offered moderate to good β-selectivities when BF₃·Et ₂O was used as a catalyst. However, glucosyl donors produced β-exclusive selectivity under both conditions. The stereoselectivities of glycosylation depend on the reactivity of donor sugars and Lewis acid catalyst, which effectively dictated the glycosylation pathways. The evidence suggests that galactosyl donors (e.g., 7) can undergo S_N1 pathway with a strong Lewis acid (TMSOTf) and S_N2 pathway under BF ₃·Et₂O, whereas the glucosyl donors (e.g., 8 and 10) followed S_N2 pathway. The stereoselectivity was also consequential to the formation of a C2′-acetal intermediate formed via the 2-C-acetylmethyl group and the anomeric carbonium intermediate in glycosylation.

Full text of DOI:10.1021/jo1016579

pubs.acs.org/joc
Stereoselective Synthesis of 2-C-Branched (Acetylmethyl)
Oligosaccharides and Glycoconjugates: Lewis Acid-Catalyzed
Glycosylation from 1,2-Cyclopropaneacetylated Sugars
Qiang Tian,† Liang Dong,‡ Xiaofeng Ma,† Liyan Xu,† Changwei Hu,*,‡ Wei Zou,§ and
Huawu Shao*,†
†Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China, ‡Key Laboratory of
Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China, and §Institute for Biological Sciences, National Research Council of Canada,
100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada, and Graduate School of
Chinese Academy of Sciences, China
shaohw@cib.ac.cn; gchem@scu.edu.cn
Received September 25, 2010
1,2-Cyclopropaneacetylated sugars as glycosyl donors reacted with a series of glycosyl acceptors
(monosaccharides, amino acids, and other alcohols) in the presence of Lewis acid to produce
oligosaccharides and glycoconjugates containing 2-C-acetylmethylsugars. Galactosyl donor gave
good to excellent R-selectivities with TMSOTf as a catalyst, whereas galactosyl donor offered
moderate to good β-selectivities when BF3 Et2O was used as a catalyst. However, glucosyl donors
3
produced β-exclusive selectivity under both conditions. The stereoselectivities of glycosylation
depend on the reactivity of donor sugars and Lewis acid catalyst, which effectively dictated the
glycosylation pathways. The evidence suggests that galactosyl donors (e.g., 7) can undergo SN1
pathway with a strong Lewis acid (TMSOTf) and SN2 pathway under BF3 Et2O, whereas the
3
glucosyl donors (e.g., 8 and 10) followed SN2 pathway. The stereoselectivity was also consequential to
the formation of a C20-acetal intermediate formed via the 2-C-acetylmethyl group and the anomeric
carbonium intermediate in glycosylation.
Introduction
and labeling of single-chain antibodies5,6 for therapeutic and
diagnostic purposes. For example, 2-C-acetylmethylsugar
(2-keto-Gal) is used as a substrate for mutant GalT to detect
O-GlcNAc-glycosylated proteins,7-9 and LacNAc moiety of
glycoproteins and glycolipids.10
Promiscuous use of 2-C-acetylmethylsugars by eukaryotic
enzymes as substrates leads to incorporation of 2-C-
branched sugars into cell surface glycoconjugates as a re-
placement of 2-N-acetamidosugars,1 consequently providing
chemical targets for aminooxy and hydrazide compounds2-4
(7) (a) Khidekel, N.; Ficarro, S. B.; Clark, P. M.; Bryan, M. C.; Swaney,
D. L.; Rexach, J. E.; Sun, Y. E.; Coon, J. J.; Peters, E. C.; Hsieh-Wilson, L. C.
Nat. Chem. Biol. 2007, 3, 339–348. (b) Boeggeman, E.; Ramakrishnan, B.;
Kilgore, C.; Khidekel, N.; Hsieh-Wilson, L. C.; Simpson, J. T.; Qasba, P. K.
Bioconjugate Chem. 2007, 18, 806–814. (c) Khidekel, N.; Ficarro, S. B.;
Peters, E. C.; Hsieh-Wilson, L. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
13132–13137.
(8) Tai, H. C.; Khidekel, N.; Ficarro, S. B.; Peters, E. C.; Hsieh-Wilson,
L. C. J. Am. Chem. Soc. 2004, 126, 10500–10501.
(9) Khidekel, N.; Arndt, S.; Lamarre-Vincent, N.; Lippert, A.; Poulin-
Kerstien, K. G.; Ramakrishnan, B.; Qasba, P. K.; Hsieh-Wilson, L. C. J. Am.
Chem. Soc. 2003, 125, 16162–16163.
(1) Hang, H. C.; Bertozzi, C. R. J. Am. Chem. Soc. 2001, 123, 1242–1243.
(2) Lemieux, G. A.; Yarema, K. J.; Jacobs, C. L.; Bertozzi, C. R. J. Am.
Chem. Soc. 1999, 121, 4278–4279.
(3) Yarema, K. J.; Mahal, L. K.; Bruehl, R. E.; Rodriguez, E. C.;
Bertozzi, C. R. J. Biol. Chem. 1998, 273, 31168–31179.
(4) Lee, J. H.; Baker, T. J.; Mahal, L. K.; Zabner, J.; Bertozzi, C. R.;
Wiemer, D. F.; Welsh, M. J. J. Biol. Chem. 1999, 274, 21878–21884.
(5) Ramakrishnan, B.; Boeggeman, E.; Qasba, P. K. Bioconjugate Chem.
2007, 18, 1912–1918.
(6) Ramakrishnan, B.; Boeggeman, E.; Manzoni, M.; Zhu, Z. Y.;
Loomis, K.; Puri, A.; Dimitrov, D. S.; Qasba, P. K. Bioconjugate Chem.
2009, 20, 1383–1389.
(10) Pasek, M.; Ramakrishnan, B.; Boeggeman, E.; Manzoni, M.;
Waybright, T. J.; Qasba, P. K. Bioconjugate Chem. 2009, 20, 608–618.
DOI: 10.1021/jo1016579
r
Published on Web 01/19/2011
J. Org. Chem. 2011, 76, 1045–1053 1045
2011 American Chemical Society

Tian et al.
JOCArticle
To explore their potential applications in glycobiology
and medicine, we decided to synthesize oligosaccharides and
glycoconjugates containing 2-C-acetylmethyl-2-deoxysugar
(2-ketosugar) with diverse structures. Currently, a few syn-
thetic methods are available for simple 2-C-branched sugars
and 2-C-acetylmethyl monosaccharides, typically, through
selective ring-opening of 1,2-cyclopropanated sugar via sol-
volysis in the presence of a stoichiometric amount of mercury
salt, strong acid, and halonium ions, or by a radical reaction
from 2-iodosugars and glycals, and Baylis-Hillman reaction
from R,β-unsaturated δ-lactones.11 Although much progress
has been made for 2-C-branched monosaccharide synthe-
sis,11,12 stereoselective integration of 2-C-branched sugars
into oligosaccharides and glycoconjugates remains a signifi-
cant challenge. Recently, Linker et al. demonstrated the
direct syntheses of 2-C-malonyl disaccharides via CAN-
mediated radical addition to D-glucal.13 However, this pro-
tocol suffers from low yield and reactive complexity. Reissig
et al.14 and Pagenkopf et al.15 respectively described NIS/
TfOH-promoted glycosylations using thioglycoside donors
for preparing 2-C-branched oligosaccharides. In addition,
1,2-cyclopropanated carbohydrate donors are employed in
the preparation of 2-C-branched glycosides,16 ring expand-
ing septanosides,17 and Lewis acid-assisted pyran ring
expansion to oxepanes.16b,18 But only Zeise’s dimer ([Pt-
(C2H4)Cl2]2)19 and NIS/TMSOTf20 are effective in promot-
ing the stereoselective glycosylation of 1,2-cyclopropanated
sugar donors with sugar alcohols. Obviously, more effective
synthetic methods to 2-C-branched oligosaccharides and
glycoconjugaes are needed. Recently, we have developed a
stereoselective glycosylation method using 1,2-cyclopropa-
SCHEME 1. Synthesis of 1,2-Cyclopropaneacetylated Sugars
7, 8, and 10
2-C-acetylmethylated oligosaccharides, glycosylamino acids,
and glycosyl cholesterol.
Results and Discussion
Synthesis of 1,2-Cyclopropaneacetylated Sugars (7, 8, and
10). Previously prepared allyl C-taloside 121 and allyl
C-mannoside 222 were 2-O-tosylated (TsCl/Py) to give corre-
sponding 3 and 4 (see Scheme 1), which was followed by
olefin oxidation (Hg(OAc)2/Jones reagent) to afford 1-C-
talosyl acetone 5 and 1-C-mannosyl acetone 6, respectively,
with 1,2-trans configuration. However, treatment of 5 with
K2CO3 in MeOH failed to produce ring-closing product 7,
instead resulting in complicated products, likely from com-
petitive β-elimination and further elimination of 20-O-Ts
prior to nucleophilic ring-closing in protonic solvent,23
whereas, under the same conditions, 1,2-cyclopropaneace-
tylated 8 was easily obtained from 6.24
neacetylated sugars as glycosyl donors and BF3 OEt2 or
3
TMSOTf as catalyst. The glyosylation with various glycosyl
acceptors led to concurrent ring-opening and formation of
(11) (a) Scott, R. W.; Heathcock, C. H. Carbohydr. Res. 1996, 291, 205–
208. (b) Kim, C.; Hoang, R.; Theodorakis, E. A. Org. Lett. 1999, 1, 1295–
1297. (c) Hoberg, J. O.; Claffey, D. J. Tetrahedron Lett. 1996, 37, 2533–2536.
(d) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem. 1997, 62, 7694–
7703. (e) Gammon, D. W.; Kinfe, H. H. J. Carbohydr. Chem. 2007, 26, 141–
157. (f) Ramana, C. V.; Nagarajan, M. Carbohydr. Lett. 1998, 3, 117–120. (g)
Sridhar, P. R.; Ashalu, K. C.; Chandrasekaran, S. Org. Lett. 2004, 6, 1777–
1779. (h) Yin, J.; Spindler, J.; Linker, T. Chem. Commun. 2007, 2712–2713. (i)
Krishna, P. R.; Reddya, P. S.; Narsingama, M.; Sateeshb, B.; Sastry, G. N.
Synlett 2006, 595–599.
Fortunately, by replacing methanol with aprotic dimethyl
sulfoxide as a solvent, the ring-closing reaction of 5 procee-
ded smoothly to provide desired 7 as the main product.21 Fur-
thermore, ZnCl2/Ac2O/AcOH-mediated selective debenzy-
lation-acetolysis of 6 gave 60-O-Ac-mannosyl acetone 9, and
subsequent intramolecular ring-closure under basic condi-
tions (K2CO3/DMF) afforded cyclopropane 10. Extensive
NMR and other analytical methods confirmed that com-
pounds 7, 8, and 10 were pure diastereoisomers, supported
(12) Du, Y. G.; Chen, Q.; Liu, J. In Glycoscience; Fraser-Reid, B.,
Tatsuta, K., Thiem, J., Eds.; Springer-Verlag: Berlin, Germany, 2008;
pp 305-342.
(13) Elamparuthi, E.; Kim, B. G.; Yin, J.; Maurer, M.; Linker, T.
Tetrahedron 2008, 64, 11925–11937.
(14) Pfrengle, F.; Lentz, D.; Reissig, H. U. Angew. Chem., Int. Ed. 2009,
48, 3165–3169.
(15) Yu, M.; Pagenkopf, B. L. Tetrahedron 2003, 59, 2765–2771.
(16) For reviews, see: (a) Cousins, G. S.; Hoberg, J. O. Chem. Soc. Rev.
2000, 29, 165–174. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–
347.
(17) (a) Hewitt, R. J.; Harvey, J. E. J. Org. Chem. 2010, 75, 955–958. (b)
Ganesh, N. V.; Raghothama, S.; Sonti, R.; Jayaraman, N. J. Org. Chem.
2010, 75, 215–218. (c) Ganesh, N. V.; Jayaraman, N. J. Org. Chem. 2009, 74,
739–746. (d) Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle,
P.; Hoberg, J. O. J. Org. Chem. 2009, 74, 7627–7632. (e) Ganesh, N. V.;
Jayaraman, N. J. Org. Chem. 2007, 72, 5500–5504.
(18) (a) Hoberg, J. O.; Bozell, J. J. Tetrahedron Lett. 1995, 36, 6831–6834.
(b) Hoberg, J. O. J. Org. Chem. 1997, 62, 6615–6618. (c) Batchelor, R.;
Hoberg, J. O. Tetrahedron Lett. 2003, 44, 9043–9045.
(21) Tian, Q.; Xu, L. Y.; Ma, X. F.; Zou, W.; Shao, H. W. Org. Lett. 2010,
12, 540–543.
(22) Zou, W.; Wang, Z. R.; Lacroix, E.; Wu, S. H.; Jennings, H. J.
Carbohydr. Res. 2001, 334, 223–231.
(23) (a) Shao, H. W.; Wang, Z. R.; Lacroix, E.; Wu, S. H.; Jennings, H. J.;
Zou, W. J. Am. Chem. Soc. 2002, 124, 2130–2131. (b) Wang, Z.; Shao, H. W.;
Lacroix, E.; Wu, S. H.; Jennings, H. J.; Zou, W. J. Org. Chem. 2003, 68, 8097–
8105.
(24) (a) Shao, H. W.; Ekthawatchai, S.; Wu, S. H.; Zou, W. Org. Lett.
2004, 6, 3497–3499. (b) Shao, H. W.; Ekthawatchai, S.; Chen, C. S.; Wu,
S. H.; Zou, W. J. Org. Chem. 2005, 70, 4726–4734.
(19) (a) Beyer, J.; Madsen, R. J. Am. Chem. Soc. 1998, 120, 12137–12138.
(b) Beyer, J.; Skaanderup, P. R.; Madsen, R. J. Am. Chem. Soc. 2000, 122,
9575–9583.
(20) Sridhar,P.R.;Kumar, P. V.;Seshadri,K.;Satyavathi,R.Chem.-Eur. J.
2009, 15, 7526–7529.
1046 J. Org. Chem. Vol. 76, No. 4, 2011

Tian et al.
JOCArticle
TABLE 2. Glycosylation of 1,2-Cyclopropaneacetylated Sugar
Donor 7
SCHEME 2. Hydrolysis of 1,2-Cyclopropaneacetylated Sugar 7
TABLE 1. Lewis Acid-Catalyzed Glycosylation of Glycosyl Donor 7
and Acceptor 12a
entry
catalyst
condition
yieldc (%)
R/βd
1b
2
3
4
5
6
7
8
BF3 Et2O
BF3 Et2O
AlCl3
BiCl3
ZnCl2
InCl3
PdCl2
AgOTf
TMSOTf
TMSOTf
-78-0 °C, 3 h
-20 °C-rt, 2 h
-20 °C-rt, 2 h
-20 °C-rt, 2 h
-20 °C-rt, 2 h
-20 °C-rt, 16 h
-20 °C-rt, 16 h
-20 °C-rt, 16 h
-20 °C-rt, 2 h
0 °C-rt, 1.5 h
58
84
76
80
1:4
1:5
1:3
1:4
1:2
3
3
73
trace
trace
0
87
86
9
10
2:1
7:1
aReactions were performed with 1.1 equiv of acceptor in CH2Cl2
(0.1 M). b10 mol % catalyst was employed. cIsolated yield. dValues were
determined by 1H NMR.
by the NOEs between H10, H3, and H5, and the coupling
constants (JH1,H1 e 2.1 Hz).23,25
0
The stability of 1,2-cyclopropaneacetylated sugars ap-
pears to depend on the type of sugar. Galactose derivative
7 rapidly hydrolyzed in CDCl3 to hemiacetal 11 as a 2:1
mixture of R- and β-isomers, whereas glucose derivatives 8
and 10 can be stored in CDCl3 at -4 °C (Scheme 2).
Lewis Acid-Catalyzed Ring-Opening of 1,2-Cyclopropa-
neacetylated Sugars. The instability of 1,2-cyclopropaneace-
tylated sugar 7 in CDCl3 demonstrated its high reactivity and
suggested that this type of compound may be used as a novel
glycosyl donor. Consequently, we attempted Lewis acid-
catalyzed glycosylation of 7 with sugar alcohol 12. Reaction
aReactions were carried out with 20 mol % BF3 OEt2 at -20 °C to rt.
3
bReactions were carried out with 20 mol % TMSOTf at 0 °C to rt.
of 7 with 12, under 10 mol % of BF3 OEt2 in dichloromet-
3
cReactions were carried out with 40 mol % TMSOTf at rt. dIsolated
yield. eValues were determined by 1H NMR.
hane at -78 °C followed by gradual warming to 0 °C,
gave the desired disaccharide 13 in 58% yield with R/β =
1:4 (Table 1, entry 1). Increasing the amount of BF3 OEt2 to
3
which led to modest R-selectivity (Table 1, entry 9). The
diastereoselectivity was improved to R/β=7:1 with similar
yield when the reaction was performed at 0 °C to rt (Table 1,
entry 10). It is also noteworthy that no anomeric epimeriza-
tion was observed in this Lewis acid-catalyzed glycosylation
as monitored by TLC. These results suggest that the glyco-
sylation likely proceeded in different pathways under the
20 mol % and reaction at -20 °C to rt improved the yield to
84% with slightly higher β-selectivity (Table 1, entry 2).
AlCl3, BiCl3, and ZnCl2 were found to be less effective for
O-glycosylation than BF3 OEt2 (Table 1, entries 3-5). InCl3
3
and PdCl2 only resulted in a trace amount of desired
products, and the reaction did not occur in the presence of
AgOTf (Table 1, entries 6-8).
conditions of BF3 OEt2 and TMSOTf.
Interestingly, a switch in diastereoselectivity was observed
when TMSOTf was used under otherwise similar conditions,
3
To investigate the scope of the reaction, a range of glycosyl
acceptors were reacted with 1,2-cyclopropaneacetylated
sugar 7. As shown in Table 2, glycosylations of monosacchar-
ides 14-16,serine17, and threonine 18 as well as cholesterol and
adamantanol gave disaccharides and glycoconjugates 21-27 in
71-89% yields. To our delight, in all cases TMSOTf-catalyzed
couplings showed good R-anomeric selectivity. In contrast,
(25) Proton-proton coupling constants in a cyclopropane system: J=
0-6 Hz for a trans stereochemistry and J=8-10 Hz for a cis stereochemistry.
See: (a) Kawabata, N.; Nakagawa, T.; Nakao, T.; Yamashita, S. J. Org.
Chem. 1977, 42, 3031–3035. (b) Wiberg, K. B.; Barth, D. E.; Schertler, P. H.
J. Org. Chem. 1973, 38, 378–381. (c) Williamson, K. L.; Lanford, C. A.;
Nicholso., C. R. J. Am. Chem. Soc. 1964, 86, 762–765.
J. Org. Chem. Vol. 76, No. 4, 2011 1047

Tian et al.
JOCArticle
TABLE 3. Acid-Catalyzed Glycosylation of Glycosyl Donor 8 and
Acceptor 12a
TABLE 4. Glycosylation of 1,2-Cyclopropaneacetylated Sugar Donor
8 and 10a
entry
catalystc
condition
time (h)
yieldd (%)
1
2
3
4
5
TMSOTf
BF3 Et2O
AgOTf
Hg(OAc)2
AcOH
TFA
p-TsOH
Amberlyst 15
D-CSA
-20 °C-rt
-20 °C-rt
-20 °C-rt
-20 °C-rt
-20 °C-rt
-20 °C-rt
0 °C-rt
1
1
5
5
2
2
1.5
1.5
1
80
89
0
0
0
3
6
0
7
75
73
69
61
8b
9
0 °C-rt
-20 °C-rt
-20 °C-rt
10
TfOH
1
aReactions were performed with 1.25 equiv of donor and 1.0 equiv of
acceptor in CH2Cl2. b20 wt % catalyst was employed. 20 mol % for
c
donor. dIsolated yield.
BF3 OEt2-catalyzed glycosylations led to anomeric selectivity
3
and β-linked conjugates were isolated as major products.
Furthermore, no ring expansion product was detected in this
Lewis acid-promoted glycosylation that is often associated with
unsubstituted and ester-substituted sugar cyclopropanes. We
believe that both the 20-acetyl substitution and Lewis acid
catalysts are contributing factors to the chemoselectivity and
diastereoselectivity of glycosylation.
Next we examined the glycosylation using 1,2-cyclopro-
paneacetylated glucosyl donor 8. Surprisingly, the reaction
of 8 with 12 gave, exclusively, β-anomeric conjugate 28 under
both BF3 OEt2 and TMSOTf conditions in 89% and 80%
3
yields, respectively (Table 3, entries 2 and 1). Other Lewis
acids such as AgOTf and Hg(OAc)2 did not catalyze the
coupling reaction, neither did AcOH and trifluoroacetic acid
as catalysts (Table 3, entries 3-6). Further study indicated
that several sulfonic acids, for example p-TsOH, Amberlyst
15, D-CSA, and TfOH, could promote the ring-opening and
glycosylation of cyclopropane 8, to produce β-anomer 28 but
with lower yields (Table 3, entries 7-10). The above results
showed that glucosyl donor 8 favors β-anomeric glycosyla-
tion regardless of the acid catalysts used.
The BF3 OEt2-catalyzed glycosylation with donor 8 was
3
further applied to an array of sugar alcohols including
primary and secondary alcohols as well as a thiol to obtain
corresponding β-anomeric products in 72-93% yields
(Table 4, entries 1-4). As the first step toward O-glycopro-
tein with 2-C-acetylmethyl glucose as a replacement of 2-N-
acetamidoglucosamine, we performed the reaction of 8 with
serine and threonine derivatives 17 and 18. As expected,
glycoamino acids, 35 and 36, were obtained in 79% and 76%
yields, respectively (Table 4, entries 5 and 6). Similarly, reaction
of 8 with cholesterol produced 37 steroselectively (Table 4,
entry 7). In addition, the coupling of 6-O-Ac cyclopropane
10 with acceptor 12 also proceeded smoothly under those
conditions, producing disaccharide 38 in 81% yield (Table 4,
entry 8). Overall, the glycosylation method provided highly
stereoselective β-anomeric products in good to excellent yields.
Mechanistic Studies and Neighboring Group Participation.
The relative energy difference between glucosyl 8and galactosyl
aReactions were carried out with 20 mol % BF3 OEt2 at -20 °C to rt.
3
bGlycosyl donor 10 was used. cIsolated yield.
7 was 22.2 kJ/mol calculated under optimal B3LYP/6-31G**,
which suggests that the cyclopropane ring of 8 is more stable
than that of 7. The isolation of a significant amount of ketal 39
(42% yield) and serine conjugates 24 (27% yield, R/β=1:3.5)
from the reaction of 7 and L-serine derivative 17 in the
BF3 OEt2-catalyzed glycosylation (Scheme 3) suggests that
3
the reaction may proceed through an enol ether intermediate 42.
On the basis of the above results, we propose three possible
reaction pathways as illustrated in Scheme 4. BF3 OEt2-
3
catalyzed β-selective glycosylation of 7 (pathway a) was
consistent with an SN1 mechanism involving an anomeric
1048 J. Org. Chem. Vol. 76, No. 4, 2011

Tian et al.
JOCArticle
SCHEME 3. The Coupling of 1,2-Cyclopropaneacetylated
Sugar 7 and L-Serine Derivative 17
SCHEME 5. The Synthesis of Thioglycosyl Donors 45 and 46
SCHEME 6. The Glycosylations of Thiogalactosyl Donor 45 or
46 with 17
SCHEME 4. Proposed Potential Mechanism for the BF3 OEt2-
or TMSOTf-Catalyzed Ring-Opening of 1,2-Cyclopropaneace-
tylated Sugars 7, 8, and 10
3
group participation27 thus to afford R-glycoside 41, as
favored by anomeric effect. On the other hand, the glycosy-
lation reactions of cyclopropane 8 and 10 are believed to
proceed through an SN2-type pathway (pathway c) involving
electrophilic cyclopropane acetyl activation by BF3 OEt2
3
followed by C1-C10 bond cleavage and nucleophilic attack
from the β face to the anomeric center, similar to the
glycosylation of 1,2-anhydrosugars.28 Notably, this method
does not cause Lewis acid-promoted removal of the 3-OR
group, as occurred in ring enlargement by C1-C2 cleavage of
unsubstituted and ester-substituted sugar cyclopropanes.18
The neighboring participation by the 2-C-acetylmethyl
group could be verified by using 2-acetylmethylthioglyco-
sides (45 and 46) as glycosyl donors, which were prepared
carbonium or oxocarbenium intermediate and a neighboring
group participation, and Lewis acid-induced nucleophilic
addition from β face to cyclopropane and enol intermediate
42. For the TMSOTf-catalyzed R-selective glycosylation of 7
(pathway b), a tight coordination of the carbonyl oxygen
atom with TMSOTf followed by C1-C10 bond breakage
may produce an oxocarbenium triflate and the formation of
2-C-trimethylsilyl enolether4426 thateliminated neighboring
from BF3 OEt2-catalyzed nucleophilic ring-opening of 7
3
(26) Glycosyl triflates or the corresponding oxocarbenium triflates were
used as glycosyl donors. See: (a) Leroux, J.; Perlin, A. S. Carbohydr. Res.
1978, 67, 163–178. (b) Lacombe, J. M.; Pavia, A. A. J. Org. Chem. 1983, 48,
2557–2563. (c) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348.
(27) We hypothesized that trimethylsilyl enol ether 42 could form tem-
porarily due to the fast coordination between the oxygen atom of acetyl and
the trimethylsilyl cation, and decompose after nucleophilic attack because of
the free proton. During this process, the trimethylsilyl enol ether 42 can
hardly contribute to the stabilization of the oxocarbenium triflate.
with ethyl thiol and from 6 and ethyl thiol by a tandem
SN2-SN2 reaction, respectively (Scheme 5). Interestingly,
(28) (a) Li, Y; Tang, P. P.; Chen, Y. X.; Yu, B. J. Org. Chem. 2008, 73,
4323–4325. (b) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1380–1419. (c) Halcomb, R. L.; Danishefsky, S. J. J. Am.
Chem. Soc. 1989, 111, 6661–6666.
J. Org. Chem. Vol. 76, No. 4, 2011 1049

Tian et al.
JOCArticle
SCHEME 7. The Neighboring Group Participation from C2 Acetylmethyl Group with BF3 OEt2 or TMSOTf As Catalyst
3
glycosylations of thioglycosyl donors 45 and 46 with 17 using
1.5 equiv of NIS and 0.2 equiv of TMSOTf as the catalyst
system in dichloromethane at -20 °C followed by gradual
warming to room temperature produced ketal products 39 in
73% yield with major/minor=5:2, and 47 in 86% yield with
major/minor=4:1, respectively (Scheme 6). When a catalytic
SCHEME 8. The Glycosylation of 2-Acetylmethyl-Thioglyco-
syl Donor 46 with 17 Catalyzed by NIS/TMSOTf
amount of BF3 OEt2 was added to the reaction system at
3
0 °C the intermediates 39 and 47 were transformed into
corresponding glycosides, 24 and 35, in good yield
(Scheme 6). Obviously, the ketal conjugates indicated that
the neighboring group participation from C2 acetylmethyl
35 in 69% yield together with a small amount of hydrolyzed
product (Scheme 8).
Conclusions
indeed occured and the subsequent BF3 OEt2-promoted
3
intramolecular rearrangement gave rise to 1,2-trans products
(Scheme 7). However, the rearrangement of 39 to 24 was not
as highly β-selective as that of 47 to 35, where the 4-O-benzyl
group of Gal may induce R-addition to some degree. Thus,
the neighboring participation by the 2-C-acetyl group and
the steric effect by the 4-O-benzyl group of Gal are opposing
factors to anomeric stereoselectivity. Three possible path-
ways, as shown in Scheme 7, all involve neighboring parti-
cipation by the 2-C-acetylmethyl group.
We have developed a TMSOTf- and BF3 OEt2-catalyzed
3
glycosylation reaction using 1,2-cyclopropaneacetylated
sugars as a new type of glycosyl donor. The glycosylation
is efficient and provides a method for stereoselective synth-
esis of 2-C-acetylmethyl-2-deoxy-glycosides, oligosacchar-
ides, glycosylamino acids, and other 2-C-acetylmethylglyco-
sides. The glycosylation of glucosyl donors 8 and 10 is totally
stereoselective in favor of β-anomer products and in good to
excellent yield, whereas the stereoselectivity in couplings of
galactosyl donor 7 with acceptors depends on the catalysts
Because the proposed mechanism involves an acid-cata-
lyzed intramolecular rearrangement to form glycosides,
removal of acid such as TfOH produced in the NIS- and
(BF3 OEt2 and TMSOTf). In addition, 2-C-acetylmethyl-2-
3
deoxy-thioglycosides are also effective glycosyl donors and
provide neighboring group participation in glycosylation.
˚
TMSOTf-catalyzed coupling reactions by addition of 4 A
molecular sieve should effectively stall the glycosylation
reaction. To test this hypothesis, 2-acetylmethyl-thioglycosyl
donor 46 was reacted with 17 under otherwise similar con-
ditions (NIS/TMSOTf) without MS 4 A. The reaction pro-
ceeded smoothly, as expected, to give the desired conjugate
Experimental Section
General Procedure for BF3 OEt2-Catalyzed β-Selective Gly-
cosylation Reactions of 1,2-Cyclopropaneacetylated Sugar
7. Procedure A (for compounds 13, 21-27). A suspension of
3
˚
1050 J. Org. Chem. Vol. 76, No. 4, 2011

Tian et al.
JOCArticle
glycosyl donor 7 (47.3 mg, 0.10 mmol) and acceptor alcohol
˚
(0.11 mmol, 1.1 equiv) containing activated 4 A molecular sieves
7.1 Hz, 1H), 3.65 (dd, J=8.7, 8.3 Hz, 1H), 3.62 (dd, J=10.4, 2.2
Hz, 1H), 3.59 (dd, J=10.6, 5.9 Hz, 1H), 3.55 (dd, J=9.1, 5.5 Hz,
1H), 2.98-2.94 (m, 1H), 2.72 (dd, J=17.2, 5.2 Hz, 1H), 2.48 (dd,
J=17.2, 8.3 Hz, 1H), 2.08 (s, 3H), 1.51 (s, 3H), 1.41 (s, 3H), 1.32
(s, 3H), 1.31 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 207.6,
138.8, 138.1, 138.0, 128.4, 128.2, 128.0, 127.9, 127.7, 127.7,
127.6, 127.5, 109.3, 108.5, 98.7, 96.4, 78.2, 74.4, 73.5, 71.7,
71.4, 71.3, 71.1, 70.7, 70.5, 69.6, 69.0, 65.6, 65.6, 41.6, 36.6,
30.1, 26.1, 26.0, 24.9, 24.5; ESI-HRMS m/z calcd for
C42H52O11Na [M þ Na]þ 755.3402, found 755.3382.
(75 mg) in dry CH2Cl2 (1.0 mL) was stirred at room temperature
for 30 min under argon. After cooling to -20 °C, the solution of
BF3 OEt2 (2.5 μL, 0.02 mmol) in dry CH2Cl2 (0.25 mL) was
3
added dropwise. The reaction mixture was then warmed slowly
to room temperature, stirred for 1-2 h, and then quenched by
the addition of Et3N. The suspension was diluted with CH2Cl2
(5.0 mL) and filtered through Celite. The filtrate was concen-
trated in vacuo and purified by silica gel flash column chroma-
tography (petroleum ether/ethyl acetate) to give the correspond-
ing coupled products.
Cholesteryl 3,4,6-Tri-O-benzyl-2-C-acetylmethyl-2-deoxy-r-
D-galactopyranoside (26r). Following procedure C, 26r was
1,2:3,4-Di-O-isopropylidene-6-O-(30,40,60-tri-O-benzyl-20-C-
acetylmethyl-20-deoxy-β-D-galactopyranosyl)-r-D-galactopyr-
anoside (13β). Following procedure A, 13β was obtained as a
obtained as a colorless syrup; yield 83%, R/β = 15:1. [R]20
D
þ41.5 (c 0.2, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.36-7.23
(m, 15H), 5.25 (d, J=4.6 Hz, 1H), 5.05 (d, J=3.3 Hz, 1H), 4.86
(d, J=11.6 Hz, 1H), 4.69 (d, J=11.3 Hz, 1H), 4.55 (d, J=11.6
Hz, 1H), 4.51 (d, J=11.6 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 4.42
(d, J=11.1 Hz, 1H), 4.01 (dd, J=6.6, 6.6 Hz, 1H), 3.96 (br s, 1H),
3.64 (dd, J=8.9, 7.6 Hz, 1H), 3.60-3.55 (m, 2H), 3.40-3.34 (m,
1H), 2.92-2.86 (m, 1H), 2.75 (dd, J=17.1, 5.2 Hz, 1H), 2.41 (dd,
J=17.0, 8.9 Hz, 1H), 2.30-2.21 (m, 2H), 2.08 (s, 3H), 2.01-0.89
(m, 32H), 0.87 (d, J=2.5 Hz, 3H), 0.86 (d, J=2.5 Hz, 3H), 0.67
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 208.0, 140.8, 138.8,
138.1, 138.0, 128.4, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6,
127.5, 121.7, 97.3, 78.6, 74.4, 73.5, 72.0, 71.4, 69.6, 69.5, 56.8,
56.2, 50.1, 42.3, 42.1, 40.1, 39.8, 39.5, 37.0, 36.9, 36.7, 36.2, 35.8,
31.9, 30.0, 28.2, 28.0, 27.9, 24.3, 23.8, 22.8, 22.6, 21.0, 19.4, 18.7,
11.9; ESI-HRMS m/z calcd for C57H78O6K [M þ K]þ 897.5430,
found 897.5413.
colorless syrup; yield 84%, R/β = 1:5. [R]20 -28.5 (c 0.2,
D
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.35-7.22 (m, 15H),
5.48 (d, J=5.0 Hz, 1H), 4.84 (d, J=11.7 Hz, 1H), 4.62 (d, J=11.6
Hz, 1H), 4.56 (d, J=11.3 Hz, 1H), 4.55 (dd, J=7.4, 2.2 Hz, 1H),
4.48 (d, J=11.9 Hz, 1H), 4.45 (d, J=11.7 Hz, 1H), 4.39 (d, J=8.2
Hz, 1H), 4.36 (d, J=11.3 Hz, 1H), 4.26 (dd, J=4.7, 2.1 Hz, 1H),
4.14 (dd, J=8.0, 1.6 Hz, 1H), 3.99 (dd, J=11.3, 3.1 Hz, 1H),
3.94-3.90 (m, 2H), 3.67 (dd, J=8.6, 8.0 Hz, 1H), 3.61-3.54 (m,
3H), 3.46 (dd, J=10.8, 1.6 Hz, 1H), 2.65-2.60 (m, 2H), 2.54 (dd,
J=17.6, 7.8 Hz, 1H), 2.09 (s, 3H), 1.50 (s, 3H), 1.41 (s, 3H), 1.31
(s, 3H), 1.29 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 208.6,
138.7, 138.0, 137.7, 128.4, 128.1, 127.9, 127.9, 127.8, 127.8,
127.5, 109.3, 108.6, 103.7, 96.3, 81.0, 74.3, 73.5, 73.5, 71.6,
71.4, 70.8, 70.7, 70.4, 69.2, 68.9, 67.9, 41.7, 40.1, 29.7, 26.0,
25.9, 25.0, 24.3; ESI-HRMS m/z calcd for C42H52O11Na [M þ
Na]þ 755.3402, found 755.3379.
General Procedure for BF3 OEt2-Catalyzed β-Selective Gly-
3
cosylation Reactions of 1,2-Cyclopropaneacetylated Sugar 8 and
10 (for compounds 28, 31-38). The mixture of donor 8 (59.0 mg,
0.125 mmol) or 10 (53.0 mg, 0.125 mmol), acceptor (0.1 mmol),
General Procedure for TMSOTf-Catalyzed r-Selective Gly-
cosylation Reactions of 1,2-Cyclopropaneacetylated Sugar
7. Procedure B (for compounds 13, 21-25). A suspension of
glycosyl donor 7 (47.3 mg, 0.10 mmol) and acceptor alcohol
˚
and freshly dried powdered MS 4 A (75 mg) in CH2Cl2 (1.0 mL)
was stirred under Ar atmosphere at room temperature for
˚
(0.11 mmol, 1.1 equiv) containing activated 4 A molecular sieves
30 min and then cooled to -20 °C. BF3 OEt2 (3.1 μL, 0.025
3
(75 mg) in dry CH2Cl2 (1.0 mL) was stirred at room temperature
for 30 min under argon. After cooling to 0 °C, TMSOTf (3.6 μL,
0.02 mmol) was added. The reaction mixture was then warmed
to room temperature, stirred for 1-2 h, and then quenched by
the addition of Et3N. The suspension was diluted with CH2Cl2
(5.0 mL) and filtered through Celite. The filtrate was concen-
trated in vacuo and purified by silica gel flash column chroma-
tography (petroleum ether/ethyl acetate) to give the correspond-
ing coupled products.
mmol) was added. The reaction mixture was warmed slowly to
room temperature, stirred for 1-2 h, and then quenched by the
addition of Et3N. The suspension was diluted with CH2Cl2
(5.0 mL) and filtered through Celite. The filtrate was concen-
trated in vacuo and purified by silica gel flash column chroma-
tography (petroleum ether/ethyl acetate) to give the corre-
sponding coupled products.
1,2:3,4-Di-O-isopropylidene-6-O-(30,40,60-tri-O-benzyl-20-C-
acetylmethyl-20-deoxy-β-D-gluco- pyranosyl)-r-D-galactopyra-
noside (28). 28 was obtained as white solid; yield 89%. Mp
110-111 °C; [R]20D -30.8 (c 1.0, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 7.35-7.25 (m, 15H), 5.48 (d, J=4.9 Hz, 1H, H-1), 4.86
(d, J=11.0 Hz, 1H), 4.77 (d, J=11.0 Hz, 1H), 4.64 (d, J=12.2
Hz, 1H), 4.58-4.54 (m, 4H), 4.40 (d, J=8.6 Hz, 1H, H-10), 4.27
(dd, J=4.9, 2.5 Hz, 1H), 4.16 (dd, J=8.0, 1.7 Hz, 1H), 4.03 (dd,
J=11.0, 3.1 Hz, 1H), 3.94-3.91 (m, 1H), 3.76-3.72 (m, 2H),
3.65 (dd, J=9.3, 9.1 Hz, 1H), 3.60 (dd, J=11.2, 7.8 Hz, 1H), 3.53
(dd, J=10.8, 9.0 Hz, 1H), 3.48-3.44 (m, 1H), 2.59 (dd, J=16.4,
5.5 Hz, 1H), 2.49 (dd, J=16.4, 5.5 Hz, 1H), 2.25-2.20 (m, 1H),
2.06 (s, 3H, COCH3), 1.50 (s, 3H), 1.42 (s, 3H), 1.30 (s, 3H), 1.30
(s, 3H); 13C NMR (CDCl3, 150 MHz) δ 207.6, 138.3, 138.2,
138.1, 128.4, 128.3, 127.8, 127.7, 127.7, 127.6, 127.5, 109.3,
108.5, 103.4, 96.3, 82.5, 79.8, 75.1, 74.6, 74.6, 73.5, 71.4, 70.5,
70.4, 69.4, 68.9, 67.8, 44.5, 41.4, 29.8, 26.0, 25.9, 25.0, 24.3; ESI-
HRMS m/z calcd for C42H52O11Na [M þ Na]þ 755.3402, found
755.3368.
Procedure C (for compounds 26 and 27). A suspension of
glycosyl donor 7 (47.3 mg, 0.10 mmol) and acceptor alcohol
˚
(0.11 mmol, 1.1 equiv) containing activated 4 A molecular sieves
(75 mg) in dry CH2Cl2 (1.0 mL) was stirred at room temperature
for 30 min under argon. Then TMSOTf (7.2 μL, 0.04 mmol) was
added to the above mixture at room temperature, and the
stirring was continued for 1-2 h. The reaction was quenched
by the addition of Et3N. The suspension was diluted with
CH2Cl2 (5.0 mL) and filtered through Celite. The filtrate was
concentrated in vacuo and purified by silica gel flash column
chromatography (petroleum ether/ethyl acetate) to give the co-
rresponding coupled products.
1,2:3,4-Di-O-isopropylidene-6-O-(30,40,60-tri-O-benzyl-20-C-
acetylmethyl-20-deoxy-r-D-galactopyranosyl)-r-D-galactopyr-
anoside (13r). Following procedure B, 13r was obtained as a
colorless syrup; yield 86%, R/β = 7:1. [R]20 þ33.0 (c 0.4,
D
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.35-7.20 (m, 15H),
5.51 (d, J=5.1 Hz, 1H), 4.93 (d, J=3.5 Hz, 1H), 4.85 (d, J=11.6
Hz, 1H), 4.67 (d, J=11.4 Hz, 1H), 4.58 (dd, J=7.9, 2.3 Hz, 1H),
4.55 (d, J=11.6 Hz, 1H), 4.50 (d, J=11.4 Hz, 1H), 4.44 (d, J=
11.6 Hz, 1H), 4.40 (d, J=11.5 Hz, 1H), 4.30 (dd, J=5.2, 2.4 Hz,
1H), 4.16 (dd, J=7.9, 1.6 Hz, 1H), 3.97 (br s, 1H), 3.95 (dd, J=
7.1, 6.3 Hz, 1H), 3.91 (dd, J=7.1, 5.9 Hz, 1H), 3.73 (dd, J=10.7,
Ethyl 3,4,6-Tri-O-benzyl-2-C-acetylmethyl-2-deoxy-1-thio-β-
D-galactopyranoside (45). Following procedure A, 45 was ob-
tained as colorless syrup; yield 92%. [R]20D þ6.0 (c 0.2, CHCl3);
1H NMR (600 MHz, CDCl3) δ 7.34-7.22 (m, 15H), 4.85 (d, J=
11.6 Hz, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.59 (d, J=10.4 Hz, 1H),
4.56 (d, J = 11.6 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.44
J. Org. Chem. Vol. 76, No. 4, 2011 1051

Tian et al.
JOCArticle
(d, J=11.8 Hz, 1H), 4.35 (d, J=11.3 Hz, 1H), 3.95 (d, J=2.3 Hz,
1H), 3.67-3.60 (m, 4H), 2.79 (dd, J = 17.0, 4.1 Hz, 1H),
2.72-2.58 (m, 3H), 2.55 (dd, J = 17.1, 5.9 Hz, 1H), 2.04 (s,
3H), 1.23 (t, J=7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
207.7, 138.9, 138.0, 137.7, 128.4, 128.4, 128.1, 127.9, 127.9,
127.8, 127.8, 127.8, 127.4, 84.7, 81.5, 74.2, 73.5, 71.3, 71.0,
69.1, 42.2, 38.8, 30.4, 24.3, 14.9; ESI-HRMS m/z calcd for
C32H38O5SNa [M þ Na]þ 557.2332, found 557.2315.
170.5, 155.3, 139.0, 138.5, 136.3, 128.3, 128.1, 127.9, 127.8, 127.7,
127.6, 127.5, 127.2, 106.3, 102.6, 79.8, 78.8, 73.9, 72.2, 71.5, 71.3,
68.7, 66.2, 62.1, 54.4, 40.4, 39.6, 27.7, 23.0; ESI-HRMS m/z calcd
for C45H53NO10Na [M þ Na]þ 790.3562, found 790.3542.
47 was obtained as a syrup (66.0 mg, 86%, major/minor=
1
4:1). 47 (major) as a syrup: [R]20 þ17.5 (c 0.4, acetone); H
D
NMR (600 MHz, acetone-d6) δ 7.41-7.24 (m, 20H), 5.98 (d, J=
8.5 Hz, 1H), 5.34 (d, J=5.7 Hz, 1H), 5.18 (d, J=12.1 Hz, 1H),
5.15 (d, J=12.6 Hz, 1H), 4.71 (d, J=11.8 Hz, 1H), 4.70 (d, J=
11.5 Hz, 1H), 4.63 (d, J=11.9 Hz, 1H), 4.56 (d, J=11.8 Hz, 1H),
4.54 (d, J=11.2 Hz, 1H), 4.52 (d, J=12.2 Hz, 1H), 4.41-4.37 (m,
1H), 3.98 (dd, J=9.7, 3.8 Hz, 1H), 3.78-3.73 (m, 1H), 3.70-3.62
(m, 5H), 2.63-2.59 (m, 1H), 2.06-2.02 (m, 1H), 1.97 (dd, J=
13.2, 7.9 Hz, 1H), 1.40 (s, 9H), 1.39 (s, 3H); 13C NMR (150 MHz,
acetone-d6) δ 170.6, 155.4, 138.9, 138.8, 138.5, 136.1, 128.4,
128.2, 128.2, 128.0, 127.9, 127.6, 127.5, 127.5, 127.3, 78.6, 77.9,
76.7, 72.8, 72.4, 71.8, 71.3, 70.0, 66.4, 61.5, 54.3, 41.1, 39.9, 27.7,
21.8; ESI-HRMS m/z calcd for C45H53NO10Na [M þ Na]þ
790.3562, found 790.3542. 47 (minor) as a syrup: [R]20D þ41.0 (c
0.2, acetone); 1H NMR (600 MHz, acetone-d6) δ 7.37-7.24 (m,
20H), 6.37 (d, J=7.8 Hz, 1H), 5.56 (d, J=5.6 Hz, 1H), 5.32 (d,
J=12.8 Hz, 1H), 5.08 (d, J=12.6 Hz, 1H), 4.79 (d, J=11.6 Hz,
2H), 4.67 (d, J=11.6 Hz, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.58 (d,
J=12.6 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.43-4.38 (m, 1H),
4.12-4.06 (m, 2H), 3.97 (dd, J=9.4, 3.4 Hz, 1H), 3.85 (dd, J=
7.2, 1.0 Hz, 1H), 3.76 (dd, J=10.6, 3.6 Hz, 1H), 3.72-3.66 (m,
2H), 2.36-2.30 (m, 1H), 2.15 (dd, J = 13.2, 1.6 Hz, 1H),
2.09-2.05 (m, 1H), 1.36 (s, 3H), 1.34 (s, 9H); 13C NMR (150
MHz, acetone-d6) δ 170.3, 155.4, 139.4, 139.0, 138.7, 136.4,
128.3, 128.2, 128.1, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4,
127.3, 127.2, 81.5, 78.6, 78.0, 73.9, 73.5, 73.4, 73.0, 69.9, 66.1,
62.5, 54.3, 44.2, 41.1, 27.7, 22.4; ESI-HRMS m/z calcd for
C45H53NO10Na [M þ Na]þ 790.3562, found 790.3542.
Ethyl 3,4,6-Tri-O-benzyl-2-C-acetylmethyl-2-deoxy-1-thio-β-
D-glucopyranoside (46). To a solution of 6 (129 mg, 0.2 mmol)
and ethyl thiol (45 μL, 0.6 mmol) in MeOH (10 mL) was added
K2CO3 (276 mg, 2.0 mmol). The suspension was stirred at 70 °C
for 2 h. The mixture was filtrated, and the filtrate was concen-
trated in vacuo and purified by silica gel flash column chroma-
tography (petroleum ether/ethyl acetate, 10:1, v/v) to afford the
title compound 46 (107 mg, 87%) as a syrup. 46: [R]20D þ4.0 (c
0.3, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.36-7.16 (m,
15H), 4.90 (d, J=11.5 Hz, 1H), 4.77 (d, J=10.9 Hz, 1H), 4.62 (d,
J=12.4 Hz, 1H), 4.60 (d, J=12.2 Hz, 1H), 4.56 (d, J=12.2 Hz,
1H), 4.55 (d, J=10.6 Hz, 2H), 3.77-3.71 (m, 2H), 3.67 (dd, J=
10.1, 9.0 Hz, 1H), 3.62 (dd, J=9.6, 8.8 Hz, 1H), 3.53-3.49 (m,
1H), 2.73-2.66 (m, 2H), 2.63 (dd, J=12.6, 7.4 Hz, 1H), 2.52 (dd,
J=17.3, 5.2 Hz, 1H), 2.26-2.20 (m, 1H), 2.01 (s, 3H), 1.25 (t, J=
7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 207.0, 138.3, 138.3,
138.1, 128.4, 128.4, 128.3, 127.8, 127.8, 127.7, 127.7, 127.5, 84.3,
83.3, 80.0, 79.4, 74.7, 74.7, 73.4, 69.2, 43.6, 42.2, 30.3, 24.4, 15.0;
ESI-HRMS m/z calcd for C32H38O5SNa [M þ Na]þ 557.2332,
found 557.2317.
NIS/TMSOTf-Catalyzed Glycosylations of Thioglycosyl Do-
nor 45 or 46 with L-Serine 17. Protocol A (for compounds 39 and
47). A mixture of the glycosyl donor (64.2 mg, 0.12 mmol), the
˚
acceptor (29.5 mg, 0.10 mmol), and powdered 4 A molecular
sieves (75 mg) in CH2Cl2 (1.0 mL) was stirred at room tempera-
ture for 30 min under argon and then cooled to -20 °C. NIS
(33.7 mg, 0.15 mmol) and TMSOTf (3.6 μL, 0.02 mmol) were
successively added. The reaction mixture was warmed slowly to
room temperature, stirred for 1 h, and then quenched by the
addition of Et3N. The suspension was diluted with CH2Cl2
(5 mL) and filtered through a pad of Celite, and the filtrate
was washed successively with 10% Na2S2O3 (2 mL) and brine
(10 mL). The organic layer was dried with anhydrous Na2SO4
and concentrated in vacuo to give a residue, which was purified
by flash column chromatography (petroleum ether/ethyl acet-
ate, 6:1, v/v).
Protocol B (for compounds 24 and 35). A mixture of the
glycosyl donor (64.2 mg, 0.12 mmol), the acceptor (29.5 mg,
˚
0.10 mmol), and powdered 4 A molecular sieves (75 mg) in
CH2Cl2 (1.0 mL) was stirred at room temperature for 30 min
under argon and then cooled to -20 °C. NIS (33.7 mg, 0.15
mmol) and TMSOTf (3.6 μL, 0.02 mmol) were successively
added. The reaction mixture was warmed slowly to room
temperature, stirred for 1 h, and then cooled to 0 °C. BF3 OEt2
3
(2.5 μL, 0.02 mmol) was added. The mixture was stirred for
30 min and then quenched by the addition of Et3N. Usual
workup and flash column chromatography (petroleum ether/
ethyl acetate, 5:1, v/v) afforded 24 (51.5 mg, 67%, R/β=1:3).
24β, colorless syrup: [R]20D -0.6 (c 0.5, CHCl3); 1H NMR (600
MHz, CDCl3) δ 7.36-7.15 (m, 20H), 5.56 (d, J=8.6 Hz, 1H),
5.21 (d, J=13.0 Hz, 1H), 5.10 (d, J=12.7 Hz, 1H), 4.87 (d, J=
11.3 Hz, 1H), 4.66 (d, J=11.5 Hz, 1H), 4.59 (d, J=11.6 Hz, 1H),
4.48 (d, J=12.2 Hz, 1H), 4.47-4.42 (m, 1H), 4.45 (d, J=11.9 Hz,
1H), 4.36 (d, J=11.6 Hz, 1H), 4.29-4.24 (m, 2H), 3.93 (br s,
1H), 3.68 (dd, J=8.7, 7.9 Hz, 1H), 3.63 (d, J=10.2 Hz, 1H), 3.58
(dd, J=9.1, 5.4 Hz, 1H), 3.53 (dd, J=6.2, 5.9 Hz, 1H), 3.35 (d,
J=10.8 Hz, 1H), 2.62 (dd, J=15.2, 4.1 Hz, 1H), 2.59-2.53 (m,
1H), 2.31 (dd, J=15.2, 7.1 Hz, 1H), 1.99 (s, 3H), 1.44 (s, 9H); 13C
NMR (150 MHz, CDCl3) δ 209.9, 170.0, 155.7, 138.6, 137.9,
137.5, 135.6, 128.5, 128.5, 128.5, 128.3, 128.2, 128.1, 128.0,
127.9, 127.9, 127.8, 127.7, 103.5, 80.3, 79.8, 74.7, 73.7, 73.6,
71.6, 70.9, 69.5, 68.7, 67.0, 54.0, 42.2, 40.3, 29.2, 28.3; ESI-
HRMS m/z calcd for C45H53NO10Na [M þ Na]þ 790.3562,
39 was obtained as a syrup (56.1 mg, 73%, major/minor=
1
5:2). H NMR (600 MHz, acetone-d6) major, δ 7.44-7.24 (m,
20H), 5.93 (d, J=8.9 Hz, 1H), 5.22 (d, J=4.1 Hz, 1H), 5.12
(ABq, J=12.9 Hz, 2H), 4.91 (d, J=11.5 Hz, 1H), 4.82 (d, J=11.9
Hz, 1H), 4.64 (d, J=11.4 Hz, 1H), 4.57 (d, J=11.8 Hz, 1H), 4.54
(d, J=12.1 Hz, 1H), 4.51 (d, J=12.1 Hz, 1H), 4.37-4.34 (m,
1H), 4.14-4.12 (m, 1H), 4.01-3.97 (m, 1H), 3.69 (dd, J=9.3, 7.3
Hz, 1H), 3.64 (dd, J=9.5, 3.5 Hz, 1H), 3.56 (dd, J=9.3, 5.8 Hz,
1H), 3.44 (dd, J = 10.3, 2.3 Hz, 1H), 2.38-2.33 (m, 1H),
2.08-2.03 (m, 1H), 1.89 (dd, J = 13.8, 1.6 Hz, 1H), 1.40 (s,
9H), 1.21 (s, 3H); 13C NMR (150 MHz, acetone-d6) δ 170.5,
155.3, 139.3, 138.7, 138.5, 136.1, 128.4, 128.3, 128.2, 128.2,
128.1, 127.7, 127.4, 127.3, 104.1, 101.1, 78.6, 73.9, 72.9, 72.0,
70.7, 70.3, 69.1, 66.5, 61.7, 54.3, 40.6, 38.9, 27.6, 23.3; ESI-
HRMS m/z calcd for C45H53NO10Na [M þ Na]þ 790.3562,
found 790.3542. 1H NMR (600 MHz, acetone-d6) minor, δ
7.44-7.24 (m, 20H), 6.16 (d, J=8.2 Hz, 1H), 5.46 (d, J=4.9
Hz, 1H), 5.27 (d, J=12.6 Hz, 1H), 5.14 (d, J=12.6 Hz, 1H), 4.88
(d, J=11.5 Hz, 1H), 4.77 (d, J=11.4 Hz, 1H), 4.61 (d, J=11.5
Hz, 1H), 4.57-4.49 (m, 3H), 4.43-4.39 (m, 1H), 4.17-4.12 (m,
2H), 4.04 (d, J=10.1, 2.3 Hz, 1H), 3.91 (d, J=3.7 Hz, 2H), 3.74
(dd, J=9.1, 7.7 Hz, 1H), 3.64-3.60 (m, 1H), 2.50-2.46 (m, 1H),
2.17 (dd, J=13.4, 1.9 Hz, 1H), 2.11 (dd, J=13.6, 8.0 Hz, 1H),
1.40 (s, 9H), 1.37 (s, 3H); 13C NMR (150 MHz, acetone-d6) δ
found 790.3547. 24r, colorless syrup: [R]20 þ55.0 (c 0.3,
D
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.36-7.21 (m, 20H),
5.47 (d, J=8.6 Hz, 1H), 5.13 (ABq, J=12.9 Hz, 2H), 4.89 (d, J=
2.0 Hz, 1H), 4.82 (d, J=11.3 Hz, 1H), 4.66 (d, J=11.3 Hz, 1H),
4.52 (d, J=11.3 Hz, 1H), 4.51 (d, J=11.8 Hz, 1H), 4.49-4.45
(m, 1H), 4.43 (d, J=11.7 Hz, 1H), 4.38 (d, J=11.4 Hz, 1H), 3.93
(br s, 1H), 3.85-3.80 (m, 3H), 3.61 (dd, J=8.5, 7.9 Hz, 1H), 3.55
(dd, J=9.1, 5.8 Hz, 1H), 3.46 (d, J=10.8 Hz, 1H), 2.88-2.82
1052 J. Org. Chem. Vol. 76, No. 4, 2011

Tian et al.
JOCArticle
(m, 1H), 2.67 (dd, J=17.5, 4.6 Hz, 1H), 2.19 (dd, J=17.5, 9.3 Hz,
1H), 2.03 (s, 3H), 1.45 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
207.6, 170.5, 155.5, 138.6, 138.0, 137.8, 135.3, 128.6, 128.5,
128.4, 128.4, 128.2, 128.0, 127.9, 127.8, 127.8, 127.7, 127.6,
100.1, 80.1, 78.1, 74.4, 73.6, 71.4, 69.9, 69.0, 67.2, 54.2, 41.5,
36.5, 30.0, 28.3; ESI-HRMS m/z calcd for C45H53NO10Na [M þ
Na]þ 790.3562, found 790.3560.
Protocol C (for compound 35). To a solution of the glycosyl
donor 46 (64.2 mg, 0.12 mmol) and the acceptor 17 (29.5 mg,
0.10 mmol) in dry CH2Cl2 (1.0 mL) was added NIS (33.7 mg,
0.15 mmol) and TMSOTf (3.6 μL, 0.02 mmol) successively
at -20 °C. The reaction mixture was warmed slowly to room
temperature, stirred for 1 h, and then quenched by the addition
of Et3N. Usual workup and flash column chromatography
(petroleum ether/ethyl acetate, 5:1, v/v) afforded 35 (53.0 mg,
69%, β only).
35 (62.2 mg, 81%, β only), colorless syrup: [R]20D þ10.1 (c 1.0,
1
CHCl3); H NMR (600 MHz, CDCl3) δ 7.32-7.18 (m, 15H),
5.53 (d, J=8.4 Hz, 1H), 5.20 (d, J=12.4 Hz, 1H), 5.13 (d, J=12.3
Hz, 1H), 4.87 (d, J=11.2 Hz, 1H), 4.77 (d, J=10.9 Hz, 1H), 4.61
(d, J=10.8 Hz, 1H), 4.59 (d, J=12.3 Hz, 1H), 4.53 (d, J=11.2
Hz, 1H), 4.51 (d, J=11.9 Hz, 1H), 4.47-4.46 (m, 1H), 4.32-4.30
(m, 2H), 3.75-3.65 (m, 4H), 3.45-3.38 (m, 2H), 2.53 (dd, J=
15.7, 4.5 Hz, 1H), 2.30 (dd, J=15.4, 7.2 Hz, 1H), 2.13-2.05
(m, 1H), 1.96 (s, 3H), 1.44 (s, 9H); 13C NMR (150 MHz, CDCl3)
δ 208.8, 170.0, 155.7, 138.1, 138.0, 135.5, 128.5, 128.4, 128.3,
128.2, 128.0, 127.9, 127.8, 127.6, 102.9, 81.9, 79.8, 79.6, 75.2,
74.9, 74.7, 73.5, 69.4, 68.7, 67.0, 54.1, 44.9, 42.1, 29.2, 28.3; ESI-
HRMS m/z calcd for C45H53NO10Na [M þ Na]þ 790.3562,
found 790.3543.
Acknowledgment. We are grateful for the financial sup-
port from the Chinese Academy of Sciences (Hundreds of
Talents Program) and the National Science Foundation of
China (20972151).
Supporting Information Available: Experimental proce-
dures and characterization data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 4, 2011 1053