Iodine promoted glycosylation with glycosyl iodides: α-glycoside synthesis

Article abstract of DOI:10.1081/CAR-200067028

Glycosidation of fully acetylated glucopyranosyl iodide with methanol under the influence of iodine gave α-glucoside selectively. Use of less reactive acceptors led to the formation of α/β-mixtures. Glycosylations with fully benzoylated glucosyl iodide yielded β-glucosides only. In contrast, iodine-promoted glycosylation of serine and threonine with 2-azido-2-deoxy-glycosyl iodides, easily obtained in three steps, proceeded smoothly, resulting in only α-linked products in high yield in most cases. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/CAR-200067028

Journal of Carbohydrate Chemistry, 24:463–474, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200067028
Iodine Promoted
Glycosylation with Glycosyl
Iodides: a-Glycoside
Synthesis
Renate M. van Well
Centre for Carbohydrate Chemistry, School of Chemical Sciences and Pharmacy,
University of East Anglia, Norwich, U.K.
K. P. Ravindranathan Kartha
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Punjab, India
Robert A. Field
Centre for Carbohydrate Chemistry, School of Chemical Sciences and Pharmacy,
University of East Anglia, Norwich, U.K.
Glycosidation of fully acetylated glucopyranosyl iodide with methanol under the
influence of iodine gave a-glucoside selectively. Use of less reactive acceptors led to
the formation of a/b-mixtures. Glycosylations with fully benzoylated glucosyl iodide
yielded b-glucosides only. In contrast, iodine-promoted glycosylation of serine and
threonine with 2-azido-2-deoxy-glycosyl iodides, easily obtained in three steps,
proceeded smoothly, resulting in only a-linked products in high yield in most cases.
Keywords Glycosyl iodine, Iodine, Glycosylated amino acids, a-glycosylation
INTRODUCTION
Since the pioneering work of Koenigs and Knorr[1] on the activation of glycosyl
bromides and chlorides with silver salts, glycosyl halides have become widely
employed in carbohydrate chemistry. Although glycosyl chlorides are more
stable donors, glycosyl bromides are often the donor of choice due to their
Received January 27, 2005; accepted March 14, 2005.
Address correspondence to R. A. Field, School of Chemical Sciences and Pharmacy,
University of East Anglia, Norwich, NR4 7TJ, U.K. E-mail: r.a.field@uea.ac.uk
463

R. M. van Well, K. P. Ravindranathan, and R. A. Field
464
enhanced reactivity.[2] Glycosyl fluorides[3] and iodides have received less
attention because the former are less reactive and the latter have generally
been considered as too unstable to be useful. However, in the past two
decades several laboratories have demonstrated that glycosyl iodides are
easily accessible in a variety of ways and display unique properties in glycosy-
lation reactions.[4] Most reports are on the use of “armed” glycosyl iodides as,
for example, in the work by Gervay, Hague, and coworkers, who constructed
N-, C- and O-glycosides and oligosaccharides either by SN2 displacement or
by an in situ anomerization procedure.[5] More recently, glycosylation reactions
with “disarmed” glycosyl iodides, either in the presence or absence of a
promotor, have been explored.[6]
Our laboratory has a long-standing interest in the use of iodine as a cheap
and easy to handle reagent for the activation of glycosyl donors.[7] From these
studies it has emerged that armed thioglycosides and bromides can be easily
glycosidated by the action of iodine in a straightforward manner.[8] However,
disarmed thioglycosides cannot be activated with iodine alone, and the
results with disarmed bromosugars are variable.[7] As glycosyl iodides are
more reactive, we investigated the potential to activate disarmed glycosyl
iodide donors with iodine. We present here the results of our investigation
and demonstrate the utility of this method in the synthesis of glycosylated
amino acids.
RESULTS
Fully acetylated a-glucopyranosyl iodide (2) was prepared according to the one-
pot procedure recently developed in our laboratory, which employs sequential
per-O-acetylation (Ac2O/I2) and glycosyl iodide formation (I2/hexamethyldisi-
lane).[7] The first attempt to react 2 with a simple acceptor under the influence
of iodine resulted in the formation of the a-methyl glucopyranoside 3 as the
major product (a/b ¼ 7.5/1; see Sch. 1).[9–11] Apparently, neighbouring group
participation of the acyl function on C-2 does not dominate under these
reaction conditions.
Preferential formation of the a-glucoside might be explained by the inter-
mediacy of a b-glucosyl iodide (Fig. 1). The b-form, being thermodynamically
less stable[12] and hence more reactive than its a-oriented counterpart, reacts
Scheme 1: Reaction of glucosyl iodide with MeOH under the influence of I2. Reagents and
˚
conditions (i) a) Ac2O, I2; b) I2, HMDS, DCM, 5 hr (91% over two steps); (ii) MeOH, I2, DCM, 4 A MS
(35%).

a-Glycoside Synthesis
465
in an SN2 fashion with methanol to give the a-methyl glucoside. b-Glycosyl
iodide formation was not detectable by NMR. In fact, addition of methanol to
the glycosyl iodide and iodine in deuterated chloroform only gave a small
amount of methyl glycoside after several hours. It appears that the acidic
nature of chloroform impedes the reaction with iodine. The addition of molecu-
lar sieves to the reaction in DCM proved to be essential for the reaction to
proceed smoothly.[13,14]
Extension of this glycosylation method to other acceptors resulted in
reduced a-selectivity. For example, reaction of glucosyl iodide 2 with a long-
chain alcohol acceptor (4) gave an a/b mixture of glycoside 5 with a slight pre-
ference for the formation of the a-configured product (see Table 1). Moreover, in
the glycosylation of the 6-OH of glucoside 6 with 2, the b-linked disaccharide 7
was the only isolable glycoside product. The reduced activity of these acceptors
compared to methanol may allow the formation of an oxocarbenium intermedi-
ate and neighbouring group participation to occur. As benzoyl protecting
groups are more disarming,[16] the fully benzoylated glucosyl iodide 8 was
prepared by reaction between perbenzoylated glucose and HMDS-I2. Surpris-
ingly, glycosylation of methanol or 11-bromoundecanol with 8 under the
same reaction conditions gave only the b-oriented glucosides.
Next, iodine activation was attempted for the glycosidation of 2-azido-2-
deoxyglycosyl iodides, having a nonparticipating neighbouring group on
C-2 that has a more disarming effect than acyl protecting groups.[16b]
2-Azido-2-deoxy-sugars have proven practical building blocks for the synthesis
of glycopeptides and glycoproteins, a class of molecules ubiquitous in nature.[17]
Figure 1: Possible mechanism for iodine activation of glucosyl iodide.15

R. M. van Well, K. P. Ravindranathan, and R. A. Field
466
Table 1: Glycosylations with glucosyl iodide. Reaction conditions: Donor (1 eq.),
˚
acceptor (MeOH, 4: 2eq., 6: 0.8 eq.), I2 (1.5 eq.), 4 A MS, DCM.
Donor
Acceptor
Product
Yield
1
65%, a/b ¼ 1.7/1
1
25%, b only
MeOH
84%, b only
76%, b only
8
6
Their importance in a variety of biologic processes has inspired numerous
synthetic efforts toward a-linked O-serinyl and threoninyl 2-acetamido-2-
deoxy-glycosides.[18] The methods reported thus far for the formation of the
a-glycosidic bond suffer from either low yields or poor a-selectivity, especially
in the case of serine.
Tri-O-acetyl-2-azido-2-deoxy-glycosyl iodide in the galacto (14a) and gluco
(14b) configuration were obtained in three straightforward steps, starting from
the commercially available aminosugars. Thus, introduction of the azide by
diazotransfer[19] and standard acetylation was followed by reaction with
I2-HMDS to introduce the anomeric iodide (see Sch. 2).[7]
Scheme 2: Synthesis of 2-azido-2-deoxy-glycosyl iodides. Reagents and conditions: (i) TfN3,
CuSO4, K2CO3, DCM, H2O, MeOH, 16 hr. (ii) Ac2O, pyridine, 2 hr (12a: 72%, 12b: 75% over two
steps). (iii) I2, HMDS, DCM, 4 hr (13a: 71%, 13b: 78%).

a-Glycoside Synthesis
467
The results of the glycosylation reactions with iodine are summarized in
Table 2; all reactions proceeded smoothly in good yield (73–87%). In the case
of serine the glycosylation reactions proceeded in a completely a-selective
fashion. Similarly, glycosylation of N-Fmoc threonine benzyl ester with
azidogalactose donor 14a only gave an a-linked product. However, reaction
with azidoglucose donor 14b yielded an a/b mixture of threoninyl 2-azido-2-
deoxy-glucoside. As observed with the fully acylated glucosyl iodide
donors, reaction with a less reactive acceptor (threonine) resulted in a poorer
a-selectivity. Attempts to enhance the a-selectivity through the use of
solvents known to favor a-glycoside formation (i.e., diethyl ether/DCM or
1,4- dioxane/toluene)[20] were unfortunately hampered by the poor acceptor
Table 2: Glycosylations of serine and threonine. Reaction conditions: Donor (1 eq.),
˚
acceptor (0.98 eq.), I2 (1.5 eq.), 4 A MS, DCM.
Donor
Acceptor
Product
Result
14a
73%, a only
14a
74%, a only
14b
14b
14
17
78%, a only
87%, a/b:2.5/1

R. M. van Well, K. P. Ravindranathan, and R. A. Field
468
solubility. Possibly, remote neighboring group participation of the acetate on
C-4 enhances the high a-selectivity observed for the glycosylations with the
galacto-configured donor.[21]
In conclusion, disarmed glycosyl iodides are readily activated by iodine;
however, the nature of the protecting group at C-2 and the reactivity of the
acceptor influence the stereochemical outcome of the glycosylation reaction.
While glycosylations with acetate protected donors give a-linked products with
reactive acceptors, the benzoylated donors only give b-linked product. Neighbor-
ing group participation clearly dominates in the latter reaction. Good yields and
good a-selectivity were observed in the glycosylation of serine and threonine
with a 2-azido-2-deoxy-galactosyl iodide donor. The less reactive 2-azido-2-
deoxy-glucosyl donor only gave good a-selectivity with serine. It appears that
reduced reactivity of either donor or acceptor favors the formation of an oxycar-
benium intermediate and loss of a-selectivity in this case.
EXPERIMENTAL
General Experimental
All reagents were obtained from commercial sources and used without
purification. Toluene and dicholoromethane were distilled from calcium
˚
hydride and stored over molecular sieves (3 or 4 A). TLC analysis was
conducted on 0.25-mm precoated silica gel plates (Whatman, AL SIL G/UV,
aluminium backing) with detection by fluorescence and/or dipping in
4% H2SO4 in ethanol, followed by heating. Column chromatography was
1
performed on silica gel 60 (Fluka). H and 13C NMR spectra were recorded
on a Varian Unity Plus spectrometer at 400 MHZ and 100.6 MHz, respectively.
Chemical shifts are given in ppm (d) relative to tetramethylsilane as internal
standard. Optical rotations were measured at ambient temperature on a
Perkin Elmer 141 polarimeter using the sodium D-line. [a]D values are given
in units of 1021 deg cm2 g21. Compounds 2,[8] 6,[22] 15,[23] and 17[23] were
prepared as recorded in the literature.
General protocol for glycosidations of glucosyl iodide donors 2 and 8
˚
with I2: Glucosyl iodide (0.33 mmol) was dissolved in DCM (1 mL), 4 A MS
(150 mg) was added, and the reaction mixture was stirred for 0.5 hr, after
which the acceptor (MeOH 2 eq., compound 4 2 eq., compound 6 0.8 eq.) and
I2 (1.5 eq.) were added. After TLC (EtOAc/hexane:2/3:v/v) showed the
complete conversion of 2 the reaction mixture was diluted with EtOAc
(20 mL), filtered, and washed with aq. Na2S2O3 (1 M, 2 ꢀ 10 mL) and
brine (1 ꢀ 10 mL). Purification by column chromatography (hexane to
EtOAc/hexane:2/3:v/v) gave 3 in 35%, 5 in 65%, 7 in 25%, 9 in 84%, and 10
in 76% yield.

a-Glycoside Synthesis
469
Methyl 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside (3):[24] 1H NMR
(CDCl3): d 5.48 (t, 1H, H4, J3,4, J4,5 ¼ 10.2 Hz), 5.07 (t, 1H, H3, J2,3
,
J3,4 ¼ 10.2 Hz), 4.96 (d, 1H, H1, J1,2 ¼ 3.7 Hz), 4.92 (dd, 1H, H2, J1,2 ¼ 3.7 Hz,
J2,3 ¼ 10.2 Hz), 4.27 (dd, 1H, H6a, J5,6a ¼ 4.6 Hz, J6a,6b ¼ 12.3 Hz), 4.11 (dd,
1H, H6b, J5,6b ¼ 2.3, J6a,6b ¼ 12.3 Hz), 3.99 (m, 1H, H5), 3.41 (s, 3H,
1
CH3OMe), 2.11, 2.08, 2.03, 2.01 (4 ꢀ CH3Ac). The H NMR spectrum was in
accordance with literature.[24]
11-Bromoundecyl 2,3,4,6-tetra-O-acetyl-a/b-D-glucopyranoside (5):
1H NMR (CDCl3): d 5.22 (t, 1H, H3a, J2,3, J3,4 ¼ 9.6 Hz), 5.13 (t, 0.6H, H3b,
J2,3, J3,4 ¼ 9.6 Hz), 5.00 (m, 3H, H2a/b, H4a/b), 4.91 (d, 1H, H1a,
J1,2 ¼ 3.8 Hz), 4.35 (d, 0.6H, H1b, J1,2 ¼ 7.7 Hz), 4.27 (m, 1.6H, H6aa, H6ba),
4.10 (dd, 0.6H, H6bb, J5,6b ¼ 2.4 Hz, J6a,6b ¼ 12.3 Hz), 4.06 (dd, 1H, H6ab,
J5,6b ¼ 2.6 Hz, J6a,6b ¼ 12.6 Hz), 3.98–3.94, 3.91–3.89 (2 ꢀ m, 1.6 H, CH2O),
3.76–3.65 (m, 1.6 H, H5a/b), 3.57–3.47 (m, 1.6H, CH2O), 3.43–3.39 (m, 3H,
CH2Br), 2.09, 2.08, 2.07, 2.04, 2.03 (6 ꢀ s, 18H, CH3Ac), 1.88–1.83 (m, 3H,
CH2), 1.65–1.62 (m, 3H, CH2), 1.43–1.38 (m, 3H, CH2), 1.29 (bs, 12H, CH2).
13C NMR (CDCl3): d 171.1, 170.7, 170.6, 169.6 (4 ꢀ C55O, Ac), 102.7 (C1b),
98.1 (C1a), 74.3, 73.5, 72.1, 71.8, 70.8, 70.5, 68.9, 68.4, 67.9, 67.5, 62.1, 61.9
(C2, C3, C4, C5, C6, CH2O, a and b), 34.0, 32.8, 29.4, 29.33, 29.29, 29.1, 28.7,
28.1, 26.1, 25.8 (10 ꢀ CH2), 20.9, 20.8, 20.7, 20.6 (4 ꢀ CH3Ac). HRMS: calcd.
for C25H45O10BrN [M þ NH4]þ 598.2224; found 598.2226.
Methyl
2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl-(1 ! 6)-2,3,4-tri-
benzyl-a-D-gluco pyranoside (7):[25] 1H NMR (CDCl3): d 7.37–7.25 (m, 15H,
Harom Bn), 5.18 (t, 1H, H30, J2,3, J3,4 ¼ 9.5 Hz), 5.08 (t, 1H, H40, J3 4
,
0
0
J4 ,5 ¼ 9.5Hz), 5.04 (dd, 1H, H20, J1 ,2 ¼ 8.1 Hz, J2 ,3 ¼ 9.5 Hz), 4.98 (d, 1H, CH2
Bn, Jgem ¼ 10.8), 4.86 (d, 1H, CH2 Bn, Jgem ¼ 10.8), 4.80 (d, 1H, CH2 Bn,
Jgem ¼ 11.0), 4.79 (d, 1H, CH2 Bn, Jgem ¼ 12.2), 4.65 (d, 1H, CH2 Bn, Jgem ¼ 11.0),
4.58 (d, 1H, H1, J1,2 ¼ 3.5 Hz), 4.53 (d, 1H, CH2 Bn, Jgem ¼ 10.8), 4.51 (d, 1H, H10,
0
0
0
0
0
0
J1 ,2 ¼ 8.1Hz), 4.23 (dd, 1H, H6a0, J5 ,6a ¼ 4.8 Hz, J6a ,6b ¼ 12.4 Hz), 4.11 (dd, 1H,
0
0
0
0
0
0
H6b0, J5 ,6b ¼ 2.9 Hz, J6a ,6b ¼ 12.4 Hz), 4.06 (dd, 1H, H6a, J5,6a ¼ 4.8 Hz,
J6a,6b ¼ 12.4 Hz), 3.97 (t, 1H, H3, J2,3, J3,4 ¼ 9.3Hz), 3.71 (m, 1H, H5), 3.65
(m, 2H, H6b, H5’), 3.51 (dd, 1H, H2, J1,2 ¼ 3.5 Hz, J2,3 ¼ 9.3 Hz), 3.43 (t, 1H, H4,
J3,4 ¼ J4,5 ¼ 9.3 Hz), 3.36 (s, 3H, CH3 Ome), 2.05, 2.02, 1.99, 1.95 (4 ꢀ s, CH3 Ac).
The 1H NMR spectrum was in accordance with literature.[25]
0
0
0
0
2,3,4,6-Tetra-O-benzoyl-a-D-glucopyranosyliodide (8): Perbenzoylated
glucose (1 g, 1.43 mmol) was dissolved in DCM; I2 (0.22 g, 0.86 mmol) and
HMDS (0.18 mL, 0.86 mmol) were added; and the reaction mixture was
stirred for 6 hr. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (hexane to EtOAc/
hexane:2/3:v/v) to yield 8 in 95% (1.05 g). 1H NMR, 1H-COSY (CDCl3):
d 8.13–7.88 (4 ꢀ d, 8H, CHarom Bz), 7.59–7.23 (m, 13H, H1, CHarom Bz),

R. M. van Well, K. P. Ravindranathan, and R. A. Field
470
6.24 (t, 1H, H3, J2,3, J3,4 ¼ 9.9 Hz), 5.92 (t, 1H, H4, J3,4, J4,5 ¼ 9.9 Hz), 4.80 (dd,
1H, H2, J1,2 ¼ 4.4 Hz, J2,3 ¼ 9.9 Hz), 4.69 (br.d, 1H H6a), 4.58 (m, 2H, H5, H6b).
13C NMR (CDCl3): d 171.8, 165.5, 165.1, 165.0 (4 ꢀ C55O, Bz), 133.7, 133.6,
133.3, 133.2, 130.1, 130.0, 129.84, 129.78, 129.7, 129.6, 128.5, 128.4, 128.3,
128.2 (CHarom, Bz), 75.3 (C1), 72.9, 72.2, 70.9, 67.6, 61.8 (C2, C3, C4, C5,
C6). [a]D ¼ þ138 (c 1 in CHCl3); this value is in accordance with literature.[25]
Methyl 2,3,4,6 -tetra-O-benzoyl-b-D-glucopyranoside (9):[27] 1H NMR
(CDCl3): d 8.11–7.82 (m, 8H, CHarom Bz), 7.57–7.32 (m, 12H, CHarom Bz),
5.93 (t, 1H, H4, J3,4, J4,5 ¼ 9.7 Hz), 5.70 (t, 1H, H3, J2,3, J3,4 ¼ 9.7 Hz), 5.54
(dd, 1H, H2, J1,2 ¼ 7.9 Hz, J2,3 ¼ 9.7 Hz), 4.78 (d, 1H, H1, J1,2 ¼ 7.9 Hz), 4.66
(dd, 1H, H6a, J5,6a ¼ 3.3 Hz, J6a,6b ¼ 12.3 Hz), 4.52 (dd, 1H, H6b,
J5,6b ¼ 5.1 Hz, J6a,6b ¼ 12.3 Hz), 4.18 (m, 1H, H5), 3.56 (s, 3H, CH3 OMe). The
1H NMR spectrum was in accordance with literature.[26]
11-Bromoundecyl 2,3,4,6-tetra-O-benzoyl-b-D-glucopyranoside (10):
1
1H NMR, H-COSY (CDCl3): d 8.03, 8.01, 7.99, 7.95 (4 ꢀ d, 8H, Harom Bz),
7.91–7.82 (m, 12 H, Harom Bz), 5.91 (t, 1H, H3, J2,3, J3,4 ¼ 9.7 Hz), 5.68 (t, 1H,
H4, J3,4, J4,5 ¼ 9.7 Hz), 5.53 (dd, 1H, H2, J1,2 ¼ 7.9 Hz, J2,3 ¼ 9.7 Hz), 4.84
(d, 1H, H1, J1,2 ¼ 7.9 Hz), 4.64 (dd, 1H, H6a, J5,6a ¼ 3.3 Hz, J6a,6b ¼ 12.3 Hz),
4.51 (dd, 1H, H6b, J5,6b ¼ 5.1 Hz, J6a,6b ¼ 12.2 Hz), 4.15 (m, 1H, H5), 4.11
(m, 1H, CH2O), 3.53 (m, 1H, CH2O), 3.40 (m, 2H, CH2Br), 1.82 (m, 2H), 1.54
(m, 2H), 1.43–1.14 (m, 14H). 13C NMR (CDCl3): d 165.9, 165.6, 165.0, 164.9
(4 ꢀ C55O, Bz), 133.2, 133.0, 132.9, 129.6, 129.5, 129.4, 129.2, 128.6, 128.2,
182.1, 128.0 (CHarom), 101.1 (C1), 72.7, 71.9, 71.7, 70.1, 69.6, 63.0 (C2, C3, C4,
C6, CH2O), 33.9, 32.6, 32.5, 29.3, 29.24, 29.19, 29.15, 28.5, 27.9, 25.9 (10 ꢀ CH2).
HRMS: calcd. for C45H53O10BrN [M þ NH4]þ 846.2853; found 846.2861.
[a]D ¼ þ8 (c 1 in CHCl3).
3,4,6-Tri-O-acetyl-2-azido-2-deoxy-a-D-galactopyranosyl iodide (14a):[28]
1,3,4,6-Tetra-O-acetyl-2-azido-2-deoxy-galactose, prepared according to the
method of Alper et al.,[19] (0.70 g, 3.5 mmol) was dissolved in DCM (3.5 mL);
I2 (0.52 g, 2.07 mmol) and HMDS (0.42 mL, 2.07 mmol) were added; and the
reaction mixture was stirred at rt. After 4 hr TLC analysis (EtOAc/
hexane:2/3, v/v) revealed complete conversion of the starting material into
the galactosyl iodide and the solvent was removed under reduced pressure.
Flash column chromatography (hexane to EtOAc/hexane:2/3:v/v) yielded
1
71% of 14a (0.89 g). H NMR (CDCl3): d 6.85 (d, 1H, H1, J1,2 ¼ 4.1 Hz), 5.49
(d, 1H, H4, J3,4 ¼ 3.1), 5.21 (dd, 1H, H3, J2,3 ¼ 10.6 Hz, J3,4 ¼ 3.1 Hz), 4.24
(m, 2H, H5, H6a), 4.14 (m, 1H, H6b), 3.43 (dd, 1H, H2, J1,2 ¼ 4.1 Hz,
J2,3 ¼ 10.6 Hz), 2.18, 2.08 (3 ꢀ s, 9H, 3 ꢀ CH3 Ac). The 1H NMR spectrum
was in accordance with literature.[28]
3,4,6-Tri-O-acetyl-2-azido-2-deoxy-a-D-glucopyranosyl iodide (14b): Com-
pound 14b was prepared from 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-glucose

a-Glycoside Synthesis
471
13b, synthesized according to the method of Alper et al.,[19] as described for 14a
1
1
in a 78% yield. H NMR, H-COSY (CDCl3): d 6.78 (d, 1H, H1, J1,2 ¼ 4.2 Hz),
5.37 (t, 1H, H3, J2,3, J3,4 ¼ 9.8 Hz), 5.16 (t, 1H, H4, J3,4, J4,5 ¼ 9.8 Hz), 4.36
(dd, 1H, H6a, J5,6a ¼ 4.2 Hz, J6a,6b ¼ 12.8 Hz), 4.13–4.06 (m, 2H, H5, H6b),
3.31 (dd, 1H, H2, J1,2 ¼ 4.2 Hz, J2,3 ¼ 9.8 Hz), 2.10, 2.09, 2.06 (3 ꢀ s, 3 ꢀ 3H,
3 ꢀ CH3 Ac). 13C NMR (CDCl3): d 170.4, 169.7, 169.6 (3 ꢀ C55O), 75.1, 73.6,
72.5, 66.9, 62.0, 60.8 (C1, C2, C3, C4, C5, C6), 20.6, 20.56, 20.52 (3 ꢀ CH3).
HRMS: calcd. for C12H20O7N4I [M þ NH4]þ 459.0371; found 459.0372.
[a]D ¼ þ155 (c 1 in CHCl3).
General procedure for the glycosylation of Ser and Thr: Compound 14a
or b (0.120 g, 0.27 mmol) and Fmoc-Ser-Bn or Fmoc-Thr-Bn (0.26 mmol) were
˚
dissolved in DCM (1 mL); 4 A MS (150 mg) was added; and the reaction
mixture was stirred for 0.5 hr. After the addition of I2 (0.10 g, 0.41 mmol) the
reaction was followed by TLC (EtOAc/hexane:2/3:v/v). The reaction mixture
was diluted with EtOAc (20 mL), filtered, and washed with aq. Na2S2O3 (1 M,
2 ꢀ 10 mL) and brine (1 ꢀ 10 mL). Purification by column chromatography
(hexane to EtOAc/hexane:2/3:v/v) gave 16 in 73%, 18 in 74%, 19 in 78%,
and 20 in 87% yield.
N-Fmoc-O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-a-b-D-galactopyranosyl)-
L-serine benzyl ester (16):[29] 1H NMR (CDCl3): d 7.79–7.76, 7.64–7.62, 7.43–
7.32 (3 ꢀ m, 13H, Harom Fmoc, Bn), 5.96 (d, 1H, NH-Ser, JNH, Ha ¼ 8.1 Hz), 5.39
(d, 1H, H4, J3,4 ¼ 2.6 Hz), 5.25 (m, 3H, H3, CH2 Bn), 4.88 (d, 1H, H1,
J1,2 ¼ 3.5 Hz), 4.62 (m, 1H, Ha-Ser), 4.41 (d, 2H, CH2 Fmoc, J ¼ 7.1 Hz), 4.25
(t, 1H, Hb-Ser, J ¼ 7.0 Hz), 4.16 (dd, 1H, H6a, J5,6a ¼ 2.9 Hz, J6a,6b ¼ 10.6 Hz),
4.09–4.00 (m, 4H, 1 ꢀ Hb-Ser, H5, H6b, CH Fmoc), 3.59 (dd, 1H, H2,
1
J1,2 ¼ 3.5 Hz, J2,3 ¼ 10.9 Hz), 2.16, 2.08, 1.98 (3 ꢀ s, 9H, 3 ꢀ CH3 Ac). The H
NMR spectrum was in accordance with literature.[29]
N-Fmoc-O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-a-b-D-galactopyranosyl)-
L-threonine benzyl ester (18):[29] 1H NMR (CDCl3): d 7.79–7.76, 7.64–7.62,
7.43–7.29 (3 ꢀ m, 13H, Harom Fmoc, Bn), 5.69 (d, 1H, NH-Thr, JNH, Ha
¼
9.3 Hz), 5.44 (d, 1H, H4, J3,4 ¼ 2.9 Hz), 5.31–5.20 (m, 3H, H3, CH2 Bn), 4.91
(d, 1H, H1, J1,2 ¼ 3.7 Hz), 4.50–4.21 (m, 6H, Ha-Thr, Hb-Thr, H5, 2 ꢀ H6, CH
Fmoc,) 4.08 (d, 2H, CH2 Fmoc, J ¼ 6.4 Hz), 3.59 (dd, 1H, H2, J1,2 ¼ 3.7 Hz,
J2,3 ¼ 10.9 Hz), 2.16, 2.08, 2.05 (3 ꢀ s, 9H, 3 ꢀ CH3 Ac). The 1H NMR
spectrum was in accordance with literature.[29]
N-Fmoc-O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-a-b-D-glucopyranosyl)-L-
serine benzyl ester (19):[30] 1H NMR (CDCl3): d 7.78–7.76, 7.64–7.62, 7.43–
7.30 (3 ꢀ m, 13H, CHarom Fmoc, Bn), 5.95 (d, 1H, NH-Ser, JNH,Ha ¼ 8.2 Hz),
5.41 (t, 1H, H3a, J2,3 ¼ J3,4 ¼ 10.3 Hz), 5.27 and 5.22 (2 ꢀ d, 2 ꢀ 1H, CH2 Bn,
Jgem ¼ 12.1 Hz), 4.99 (t 1H, H4, J3,4 ¼ J4,5 ¼ 10.3 Hz), 4.84 (d, 1H, H1,
J1,2 ¼ 3.5 Hz), 4.63 (m, 1H, Ha-Ser), 4.42 (d, 2H, CH2 Fmoc, J ¼ 7.0 Hz),

R. M. van Well, K. P. Ravindranathan, and R. A. Field
472
4.25–4.00 (m, 5H, 2 ꢀ Hb-Ser, CH Fmoc, 2 ꢀ H6), 3.95 (m, 1H, H5), 3.25 (dd, 1H,
H2, J1,2 ¼ 3.5 Hz, J2,3 ¼ 10.3 Hz), 2.11, 2.05, 2.04 (3 ꢀ s, 9H, 3 ꢀ CH3 Ac). The 1H
NMR spectrum was in accordance with literature.[30]
N-Fmoc-O-(3,4,6-Tri-O-acetyl-2-azido-2-deoxy-a–b-D-glucopyranosyl)-L-
threonine benzyl ester (20): 1H NMR (CDCl3): d 7.78–7.75, 7.64–7.59, 7.41–
7.29 (3 ꢀ m, 13H, CHarom Fmoc, Bn), 5.72 (d, 1H, NH-Thr, JNH,Ha ¼ 9.8 Hz),
5.64 (d, 0.4 H, NH-b, JNH,Ha ¼ 9.5 Hz), 5.42 (t, 1H, H3a, J2,3 ¼ J3,4 ¼ 9.8 Hz),
5.29–5.13 (m, 3H, CH2 Bn a/b), 4.99 (t 1H, H4a, J3,4, J4,5 ¼ 9.8 Hz), 4.90
(m, 1H, H3b, H4b), 4.84 (d, 1H, H1a, J1,2 ¼ 3.7 Hz), 4.60–4.32, 4.27–4.18,
4.08–3.99 (3 ꢀ m, 13H, 2 ꢀ Ha-thr, 2 ꢀ Hb-thr, 2 ꢀ CH Fmoc, 2 ꢀ CH2 Fmoc,
H5a, 2 ꢀ H6a, 2 ꢀ H6b), 3.37 (m, 0.8 H, H2b, H5b), 3.27 (dd, 1H, H2a,
J1,2 ¼ 3.7 Hz, J2,3 ¼ 10.6 Hz), 2.11, 2.09, 2.07, 2.06, 2.02, 2.00 (6 ꢀ s, 14H,
6 ꢀ CH3 Ac), 1.35–1.32 (m, 5H, 2 ꢀ CHg-Thr). 13C NMR (CDCl3): d 170.5,
169.6 (3 ꢀ C55O Ac, C55O Thr), 156.8 (C55O Fmoc), 143.8, 141.2 (Cq-arom
Fmoc), 128.65, 128.59, 128.51, 128.4, 127.7, 127.6, 127.1, 125.3, 119.9 (CHarom
Bn, FMoc), 103.3 (C1b), 98.7 (C1a), 74.8, 71.7, 70.3, 68.5, 67.9, 67.7, 67.6, 67.4,
63.2, 61.8, 61.1, 58.7 (C2, C3, C4, C5, C6, CH2 Fmoc, CH2 Bn, Ca-Thr, Cb-Thr),
47.0 (CH Fmoc), 20.7, 20.63, 20.57 (3 ꢀ CH3 Ac), 18.6 (CHg-Thr). HRMS: calcd.
for C37H39O12 [M þ H]þ 731.2564; found 731.2577.
ACKNOWLEDGMENT
This work was supported by an EU Marie Curie Intra-European Fellowship
(to R. v W) and by the Weston Foundation. We thank the UK EPSRC Mass
Spectrometry Service Centre, Swansea, for invaluable support.
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