I2-mediated α-selective Ferrier glycosylation approach to synthesis of O-glycosyl amino acids

Article abstract of DOI:10.2478/s11696-013-0482-x

I₂ is an effective promoter for the synthesis of 2,3-unsaturated glycosides via Ferrier glycosylation. This reaction was used in the present work for the synthesis of O-glycosylated Fmoc amino acid building blocks. This metal-free reaction affo

Full text of DOI:10.2478/s11696-013-0482-x

Chemical Papers 68 (4) 525–530 (2014)
DOI: 10.2478/s11696-013-0482-x
ORIGINAL PAPER
I2-mediated α-selective Ferrier glycosylation approach to synthesis
of -glycosyl amino acids
Li Ren, Yang Liu*, Gui-Hua Yu, Jing-Zheng Hao, Mao-Sheng Cheng*
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University,
Shenyang 110016, China
Received 27 March 2013; Revised 9 July 2013; Accepted 18 July 2013
I2 is an effective promoter for the synthesis of 2,3-unsaturated glycosides via Ferrier glycosylation.
This reaction was used in the present work for the synthesis of O-glycosylated Fmoc amino acid
building blocks. This metal-free reaction afforded the desired products with good to excellent yields
with good α-selectivity.
c
ꢀ 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: O-glycosides, Ferrier rearrangement, I2, α-selectivity
Introduction
group of an appropriately protected serine (Ser)
or threonine (Thr), using some standard glycosyl
donors (Tsuda & Nishimura, 1996; Jensen et al.,
1993). Although the α-glycosidic bonds are typically
found in natural O-glycopeptides, the method of con-
structing this type of pattern represents a challenge
to O-glycopeptide synthesis. A general method for
preparing α-glycosyl amino acid building blocks for
the synthesis of O-glycopeptides was reported by
Kunz (1987) In this case, α-glycosyl amino acids
were synthesised by the glycosylation reaction of
per-O-acetylated-2-azido-2-deoxy-hexopyranosyl bro-
mides (prepared in the first step by the azidonitration
reaction of per-O-acetylated glycal using ceric ammo-
nium nitrate) (Lemieux & Ratcliffe, 1979) and N-(9-
fluorenylmethoxycarbonyl)-L-threonine tert-butyl es-
ter (Fmoc-Thr-OtBu) promoted with AgClO4/
Ag2CO3. Subsequently, improved procedures have in-
troduced various glycosyl donors for the preparation
of O-glycopeptides with suitable promoters, such as
trimethylsilyl trifluoromethanesulfonate (TMSOTf),
phenyl sulfoxide/trifluoroacetic anhydride (Ph2SO/
Tf2O), and Ag2CO3. All of these methods, however,
suffer from low yields or long reaction times.
Glycoproteins, which have been reported as play-
ing pivotal roles in processes as diverse as fertilisation,
neuronal development, hormone activities, immune
surveillance and inflammatory responses (Bertozzi &
Kiessling, 2001; Dwek, 1996; Rudd et al., 2001; Talbot
et al., 2003; Varki, 1993), are the key to understand-
ing many complex biological processes. Hence, much
effort has been devoted to developing facile methods
for synthesising glycopeptides.
Currently, there are two major assembly strategies
for synthesising O-glycopeptides: convergent assembly
(Wang et al., 2000; Halkes et al., 2001; Schleyer et al.,
1997) and building block assembly (St. Hilaire et al.,
1998; Mitchell et al., 2001; van Ameijde et al., 2002).
The latter method, which possesses many advantages,
for example, glycosylated amino acid building blocks
can be easily introduced into solid-phase syntheses
through peptide chemistry, has been widely applied
to the preparation of a wide variety of glycopeptides
and even large glycopeptide libraries (Kunz, 1987;
Kihlberg & Elofsson, 1997; Herzner et al., 2000). Ac-
cordingly, the preparation of glycosylated amino acid
building blocks attracts ever-increasing interest.
The O-glycosidic bond in O-linked glycans is usu-
ally formed through glycosylation of the hydroxyl
Glycals, viz. 1,2-unsaturated derivatives of pen-
toses and hexoses, are among the most versatile of
chiral building blocks and have attracted considerable
*Corresponding author, e-mail: ly 99@sina.com; mscheng@syphu.edu.cn

526
L. Ren et al./Chemical Papers 68 (4) 525–530 (2014)
interest in carbohydrate chemistry (Lemieux & Rat-
cliffe, 1979). One of the most investigated and most ex-
ploited synthetic transformations for the initial step in
glycal chemistry is the Ferrier rearrangement (Collins
& Ferrier, 1995), which produces the 2,3-unsaturated
O-glycosides. The 2,3-double bond in the pyran ring of
these molecules can readily be modified by dihydroxy-
lation, hydrogenation, epoxidation and aminohydrox-
ylation to achieve structural complexity and diversity.
Due to their potential use as chiral building blocks,
2,3-unsaturated-O-glycosides are suited to be the pre-
cursors of the O-glycosyl amino acids.
Table 1. Characterisation data of newly prepared compounds
◦
Compound
Formula
Mr
[α]aD
/
M.p./◦C
IIa
IIb
IIc
IId
IIe
IIf
C35H35NO10
C35H35NO10
C33H33NO8
C32H31NO8
C32H31NO8
C28H29NO10
C36H37NO10
C41H39NO10
629.65
629.65
571.62
557.59
557.59
539.53
643.24
705.28
+27.4
–94.7
–35.5
+53.9
–63.7
+42.7
+7.5
48–50
57–59
119–124
49–50
40–41.0
38–39.0
48–49
IIg
IIh
+11.4
243–246
a) (c = 1.08, CHCl3, T = 20◦C).
I2 was recently used for the thioglycosidation of
D-glycals with various thiols through Ferrier rear-
rangement by Subba Reddy et al. (2010). This in-
spired us to study its application in glycosylation re-
actions with certain amino acids. As a part of ongo-
ing research into the synthesis of O-glycopeptides, a
glycosylation method was developed using I2 as the
promoter (Fig. 1) to prepare O-glycosylated N-Fmoc
amino acid (Fmoc denotes an amine-protecting group,
9-fluorenylmethoxycarbonyl) building blocks. An ef-
fective approach to accessing 2,3-unsaturated glycosyl
amino acids with good α-selectivity is reported here.
ica gel column using petroleum ether/EtOAc (ϕr
= 5 : 1) as eluent to afford the product. Thus,
starting from 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-
D-arabino-hex-l-enitol (3,4,6-tri-O-acetyl-D-glucal, Ia)
or 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-lyxo-hex-
l-enitol (3,4,6-tri-O-acetyl-D-galactal, Ib) or 3,4-di-O-
acetyl-1,5-anhydro-2,6-dideoxy-D-arabino-hex-l-enitol
(3,4-di-O-acetyl-D-rhamnal, Ic) or 3,4-di-O-acetyl-1,5-
anhydro-2-deoxy-D-threo-pent-1-enitol
acetyl-D-xylal, Id) or 3,4-di-O-acetyl-1,5-anhydro-2-
deoxy-D-erythro-pent-1-enitol (3,4-di-O-acetyl-D-
(3,4-di-O-
Experimental
arabinal, Ie) and N-(9-fluorenylmethoxycarbonyl)-
L-serine benzyl ester (Fmoc-Ser-OBn), correspond-
ing O-(4,6-di-O-acetyl-2,3-dideoxy-α-D-arabino-hex-2-
enopyranosyl)-N-(9-fluorenylmethoxycarbonyl)-L-
serine benzyl ester (IIa) or O-(4,6-di-O-acetyl-2,3-
dideoxy-α-D-lyxo-hex-2-enopyranosyl)-N-(9-fluor-
enylmethoxycarbonyl)-L-serine benzyl ester (IIb) or
O-(4-O-acetyl-2,3,6-trideoxy-α-D-arabino-hex-2-eno-
pyranosyl)-N-(9-fluorenylmethoxycarbonyl)-L-serine
benzyl ester (IIc) or O-(4-O-acetyl-2,3-dideoxy-α-D-
threo-pent-2-enopyranosyl)-N-(9-fluorenylmeth-
oxycarbonyl)-L-serine benzyl ester (IId) or O-(4-O-
acetyl-2,3-dideoxy-α-D-erythro-pent-2-enopyranosyl)-
N-(9-fluorenylmethoxycarbonyl)-L-serine benzyl ester
(IIe), respectively, were obtained. Analogously, start-
ing from glycal Ia and N-(9-fluorenylmethoxycarbon-
yl)-L-serine (Fmoc-Ser-OH) or N-(9-fluorenylmeth-
oxycarbonyl)-L-threonine benzyl ester (Fmoc-Thr-
OBn) or N-(9-fluorenylmethoxycarbonyl)-L-tyrosine
benzyl ester (Fmoc-Tyr-OBn), corresponding O-(4,6-
di-O-acetyl-2,3-dideoxy-α-D-arabino-hex-2-enopyrano-
syl)-N-(9-fluorenylmethoxycarbonyl)-L-serine (IIf ) or
O-(4,6-di-O-acetyl-2,3-dideoxy-α-D-arabino-hex-2-eno-
pyranosyl)-N-(9-fluorenylmethoxycarbonyl)-L-threo-
nine benzyl ester (IIg) or O-(4,6-di-O-acetyl-2,3-
dideoxy-α-D-arabino-hex-2-enopyranosyl)-N-(9-fluor-
enylmethoxycarbonyl)-L-tyrosine benzyl ester (IIh),
respectively, were prepared (see Fig. 1, Table 1).
The starting glycals were prepared using known
general method (Franz et al., 2002). All the other
chemicals were commercially available as analytical-
purity reagents from Merck (Germany) and used with-
out further purification. TLC was performed on pre-
coated silica gel HSGF254 plates (0.5 mm, Yantai,
China). Flash column chromatography was performed
on silica gel H (100–140 mesh, Yantai, China). Melting
points (uncorrected) were determined using a Bu¨chi
B-540 melting points apparatus (Bu¨chi, Switzerland).
NMR spectra were recorded using a Bruker Avance
600 MHz spectrometer (Bruker, Germany). Optical
rotations were determined at ambient temperature on
a Perkin–Elmer 241 MC polarimeter with the sodium
D line. ESI-MS spectra were obtained on an Agilent
1100 mass spectrometer (Agilent Technologies, USA).
General procedure for synthesis of glycosyl
amino acids
I2 (0.5–1.0 eq) was added to a stirred mixture of
acetylated glycal (1.0 eq) and N-Fmoc amino acids
(1.0 eq) in dry CH2Cl2 (10 mL) and the reaction mix-
ture was stirred at ambient temperature (unless stated
otherwise) for 0.5–1 h (monitored by TLC). The re-
action proceeding in the mixture was quenched with
Na2S2O3 and the products extracted with CH2Cl2.
The combined organic layers were washed with brine,
dried with anhydrous Na2SO4 and filtered through
Celite in a sintered funnel. Evaporation of the sol-
vent gave a crude oil that was purified on a sil-
Results and discussion
Initial studies were aimed at optimisation of the
reaction conditions for the glycosylation reaction of

L. Ren et al./Chemical Papers 68 (4) 525–530 (2014)
Table 2. Spectral data of newly prepared compounds
Compound Spectral dataa
527
IIa
1H NMR (CDCl3, 600 MHz), δ: 2.02 (s, 3H, COCH3), 2.09 (s, 3H, COCH3), 3.91–4.25 (m, 5H, CH2O, Glcp-H-6a,
Glcp-H-6b, Glcp-H-5), 4.31 (t, 1H, J = 7.2 Hz, J = 6.6 Hz, Fmoc-H-9ꢀ), 4.34–4.44 (m, 2H, Fmoc-H-10ꢀ), 4.51 (d,
1H, J = 8.4 Hz, H-2), 4.63 (brs, 1H, Glcp-H-1), 5.15–5.26 (dd, 2H, PhCH2), 5.28 (t, 1H, J = 9.6 Hz, Glcp-H-4),
5.57 (d, 1H, J = 10.2 Hz, NH), 5.86 (d, 1H, J = 9.6 Hz, Glcp-H-3), 5.90 (d, 1H, J = 9.0 Hz, Glcp-H-2), 7.26–7.41
(m, 7H, Harom), 7.60–7.77 (m, 7H, Harom
)
13C NMR (CDCl3, 150 MHz), δ: 20.9, 21.2, 47.5, 54.7, 63.0, 65.3, 65.8, 67.4, 67.6, 70.0, 95.5, 120.2, 125.3, 127.2,
127,3, 128.6, 128.7, 128.8, 129.0, 129.6, 131.1, 135.5, 141.5, 156.2, 170.1, 170.4, 170.9
ESI-MS, m/z: 652.0 (M + Na)+
IIb
1H NMR (CDCl3, 600 MHz), δ: 2.02 (s, 3H, COCH3), 2.09 (s, 3H, COCH3), 4.01–4.11 (m, 2H, CH2O), 4.16–
4.27 (m, 4H, Fmoc-H-9ꢀ, H-2, Galp-H-6a, Gal-H-6b), 4.38–4.49 (m, 2H, Fmoc-H-10ꢀ), 4.64–4.66 (m, 1H, Galp-
H-5), 4.93 (d, 1H, J = 3 Hz, Galp-H-1), 4.97–4.98 (dd, 1H, J = 1.8 Hz, J = 5.4 Hz, Galp-H-4), 5.18–5.31 (dd, 2H,
PhCH2), 5.78–5.80 (dd, 2H, J = 3.0 Hz, J = 10.2 Hz, Galp-H-2), 5.96 (d, 1H, J = 9.0 Hz, NH), 6.10–6.12 (dd,
1H, J = 5.4 Hz, J = 10.2 Hz, Galp-H-3), 7.31–7.43 (m, 9H, Harom), 7.63 (d, 2H, J = 7.2 Hz, Harom), 7.79 (d, 2H,
J = 7.2 Hz, Harom
)
13C NMR (CDCl3, 150 MHz), δ: 20.6, 20.8, 46.2, 47.0, 53.4, 54.6, 62.5, 62.7, 67.2, 67.3, 69.5, 94.8, 120.0, 125.0,
125.1, 125.3, 127.0, 127.7, 128.1, 128.4, 128.5, 128.6 (2 ×), 128.7, 129.8, 135.3, 141.3, 143.7, 143.8, 155.9, 169.8,
170.2, 170.6
ESI-MS, m/z: 652.0 (M + Na)+
IIc
1H NMR (CDCl3, 600 MHz), δ: 1.11 (d, 1H, J = 6.0 Hz, CH3), 2.11 (s, 3H, COCH3), 3.73–3.75 (m, 2H, CH2O),
4.23–4.26 (m, 2H, Fmoc-H-9ꢀ, Rhap-H-5), 4.36–4.47 (m, 2H, Fmoc-H-10ꢀ), 4.62–4.64 (m, 1H, H-2), 4.93 (brs, 1H,
Rhap-H-4), 5.01–5.03 (dd, 1H, J = 1.8 Hz, J = 9.6 Hz, Rhap-H-3), 5.19–5.26 (2H, PhCH2), 5.65 (d, 1H, J =
9.6 Hz, NH), 5.75–5.77 (m, 1H, Rhap-H-2), 5.84 (brs, 1H, Rhap-H-1), 7.30–7.42 (m, 9H, Harom), 7.61 (d, 2H, J
= 7.2 Hz, Harom), 7.77 (d, 2H, J = 7.8 Hz, Harom
)
13C NMR (CDCl3, 150 MHz), δ: 17.8, 21.1, 47.2, 54.4, 65.1, 67.2, 67.42, 68.1, 70.7, 94.5, 120.0, 125.1, 127.1,
127.7, 128.1, 128.2, 128.4, 128.6, 130.0, 135.2, 141.3, 143.7, 143.9, 170.4
ESI-MS, m/z: 571.0 (M+
)
IId
1H NMR (CDCl3, 600 MHz), δ: 2.08 (s, 3H, COCH3), 3.59 (d, 1H, J = 13.2 Hz, Xylp-H-5a), 3.67–3.75 (m, 2H,
CH2O), 4.21–4.25 (m, 2H, Fmoc-H-9ꢀ, Xylp-H-5b), 4.36–4.47 (m, 2H, Fmoc-H-10ꢀ), 4.59–4.62 (m, 1H, H-2), 4.80
(brs, 1H, Xylp-H-4), 4.94 (d, 1H, J = 2.4 Hz, Xylp-H-1), 5.15–5.28 (dd, 2H, PhCH2), 5.66 (d, 1H, J = 8.4 Hz,
NH), 5.95–5.98 (m, 1H, Xylp-H-2), 6.03–6.05 (m, 1H, Xylp-H-3), 7.29–7.41 (m, 9H, Harom), 7.62 (d, 2H, J =
7.2 Hz, Harom), 7.77 (d, 2H, J = 7.8 Hz, Harom
)
13C NMR (CDCl3, 150MHz), δ: 21.0, 21.1, 46.3, 47.1, 54.3, 54.6, 56.15, 60.3, 61.2, 61.6, 63.0, 63.1, 63.3, 64.6,
67.2, 67.3 (2 ×), 67.4, 67.5, 68.0, 69.3, 93.1, 120.0, 125.1, 125.2, 125.4, 127.1, 127.5, 127.7, 128.19, 128.3, 128.5 (2
×), 128.6, 128.7 (2 ×), 128.9, 129.2, 130.1, 130.6, 135.2, 141.3, 143.7, 143.9, 156.0, 170.0, 170.6
ESI-MS, m/z: 557.0 (M+
)
IIe
1H NMR (CDCl3, 600 MHz), δ: 2.09 (s, 3H, COCH3), 3.79 (d, 1H, J = 13.2 Hz, Arap-H-5a), 3.97–4.06 (m, 3H,
CH2O, Arap-H-5b), 4.23–4.26 (m, 1H, Fmoc-H-9ꢀ), 4.35–4.46 (m, 2H, Fmoc-H-10ꢀ), 4.57–4.60 (m, 1H, H-2), 4.79
(d, 1H, J = 2.4 Hz, Arap-H-1), 4.88–4.89 (m, 1H, Arap-H-4), 5.15–5.28 (dd, 2H, PhCH2), 5.74–5.76 (m, 1H,
Arap-H-2), 5.84 (d, 1H, J = 9.0 Hz, NH), 6.02–6.05 (m, 1H, Arap-H-3), 7.30–7.42 (m, 9H, Harom), 7.60 (d, 2H,
J = 7.2 Hz, Harom), 7.77 (d, 2H, J = 7.2 Hz, Harom
)
13C NMR (CDCl3, 150 MHz), δ: 21.0, 21.1, 46.6, 47.1 (2×), 53.4, 54.4, 54.6, 60.0, 61.5, 61.7, 63.0, 63.1, 64.5,
64.8, 66.0, 67.2, 67.3, 67.4, 67.6, 68.1, 68.4, 69.3, 70.0, 89.1, 90.5, 93.8, 94.3, 119.8, 120.0, 124.8, 125.1 (2 ×),
125.2, 126.8, 127.1, 127.5, 127.7, 128.1, 128.2, 128.4 (2 ×), 128.5, 128.6, 128.9, 129.6, 130.0, 130.6, 135.3, 141.3,
143.7, 143.9, 156.0, 170.0
ESI-MS, m/z: 557.0 (M+
)
IIf
1H NMR (CDCl3, 600 MHz), δ: 2.02 (s, 3H, COCH3), 2.09 (s, 3H, COCH3), 3.91–4.25 (m, 5H, CH2O, Glcp-H-
6a, Glcp-H-6b, Glcp-H-5), 4.31 (t, 1H, J = 7.2 Hz, J = 6.6 Hz, Fmoc-H-9ꢀ), 4.34–4.44 (m, 2H, Fmoc-H-10ꢀ), 4.51
(d, 1H, J = 8.4 Hz, H-2), 4.64 (brs, 1H, Glcp-H-1), 5.28 (t, 1H, J = 9.6 Hz, Glcp-H-4), 5.57 (d, 1H, J = 10.2 Hz,
NH), 5.86 (d, 1H, J = 9.6 Hz, Glcp-H-3), 5.90 (d, 1H, J = 9.0 Hz, Glcp-H-2), 7.26–7.41 (m, 4H, Harom), 7.60–7.77
(m, 4H, Harom
)
13C NMR (CDCl3, 150 MHz), δ: 20.9, 21.2, 47.5, 54.6, 63.0, 65.3, 65.8, 67.6, 70.0, 95.5, 120.2, 125.2, 127.7, 129.0,
129.6, 131.0, 140.9, 156.3, 170.2, 170.8, 175.2
ESI-MS, m/z: 562.6 (M + Na)+
IIg
1H NMR (CDCl3, 600 MHz), δ: 1.34 (d, 3H, J = 6.0 Hz, CH3), 2.07 (s, 3H, COCH3), 2.08 (s, 3H, COCH3), 4.02–
4.06 (m, 1H, OCH(CH3)), 4.05 (d, 2H, J = 4.2 Hz, Glcp-H-6a, Glcp-H-6b), 4.23 (m, 1H, Glcp-H-5), 4.25 (t, 1H, J
= 7.2 Hz, Fmoc-H-9ꢀ), 4.38–4.46 (m, 3H, Fmoc-H-10ꢀ, H-2), 4.72 (brs, 1H, Glcp-H-1), 5.12–5.27 (m, 4H, PhCH2,
Glcp-H-4, NH), 5.49 (d, 1H, J = 10.2 Hz, Glcp-H-3), 5.76 (d, 1H, J = 10.2 Hz, Glcp-H-2), 7.26–7.61 (m, 9H,
Harom), 7.63 (d, 2H, J = 6.6 Hz, Harom), 7.77 (d, 2H, J = 7.8 Hz, Harom
)
13C NMR (CDCl3, 150 MHz), δ: 20.9, 21.2, 47.5, 54.7, 63.0, 65.3, 65.8, 67.4, 67.6, 70.0, 95.5, 120.2, 125.3, 127.2,
127.3, 127.9, 128.6, 128.7, 128.8, 129.0, 129.6, 131.1, 135.5, 141.5, 156.2, 170.1, 170.4, 170.9
ESI-MS, m/z: 644.2 (M + H)+, 666.2 (M + Na)+

528
L. Ren et al./Chemical Papers 68 (4) 525–530 (2014)
Table 2. (continued)
Compound Spectral dataa
IIh
1H NMR (CDCl3, 600MHz), δ: 2.00 (s, 3H, COCH3), 2.06 (s, 3H, COCH3), 3.61 (m, 2H, H-3), 4.06 (m, 2H,
Glcp-H-6a, Glcp-H-6b), 4.20 (m, 1H, Glcp-H-5), 4.27–4.37 (m, 2H, Fmoc-H-9ꢀ, Fmoc-H-10ꢀa), 4.43 (dd, 1H, J =
7.2 Hz, J = 10.8 Hz, Fmoc-H-10ꢀb), 4.68 (d, 1H, J = 7.8 Hz, H-2), 5.11–5.24 (m, 3H, PhCH2, Glcp-H-4), 5.40 (d,
1H, J = 9.6 Hz, NH), 5.62 (brs, 1H, Glcp-H-1), 5.96–6.04 (m, 2H, Glcp-H-3, Glcp-H-2), 6.93 (dd, 2H, J = 8.4 Hz,
Tyr-Harom), 7.29–7.41 (m, 11H, Harom), 7.56 (d, 2H, J = 6.0 Hz, Harom), 7.77 (d, 2H, J = 7.8 Hz, Harom
)
13C NMR (CDCl3, 150MHz), δ: 20.7, 21.0, 29.7, 37.2, 47.2, 54.8, 55.0, 61.9, 62.6, 63.6, 65.0, 67.0, 67.8, 69.2, 70.5,
76.8, 77.0, 77.2, 93.1, 117.1, 120.01, 125.1, 126.5, 127.1, 127.7, 128.5, 128.6, 128.7, 130.2, 130.43, 133.0, 140.9,
147.6, 149.7, 170.5, 170.9, 172.0
ESI-MS, m/z: 706.2 (M + H)+, 729.2 (M + Na)+
a) When reporting assignments of 1H NMR signals, data for protons of Fmoc amino acids moiety are identified by a prime;
abbreviations used refer to saccharide moiety: Glcp – glucopyranose, Galp – galactopyranose, Rhap – rhamnopyranose, Xylp –
xylopyranose, Arap – arabinopyranose; brs means broad singlet; Harom means aromatic protons.
Fig. 1. Synthesis of O-glycosylated amino acid based on glycals. Reaction conditions: i) I2, CH2Cl2, ambient temperature, 0.5–1 h.
For the designation of individual compounds Ia–Ie and IIa–IIh, see Experimental.
3,4,6-tri-O-acetyl-D-glucal (Ia) with Fmoc-Ser-OBn as
a model. Firstly, various amounts of I2 were used and
the progress of the reaction was monitored by TLC. It
was noted that the glycosylation proceeded smoothly
with 50 mole % of I2 in CH2Cl2 at ambient temper-
ature with short reaction times, affording the corre-
sponding alkyl 2,3-unsaturated glycosides with good
to high yields. Based on the value of the coupling
constant of the anomeric H atom (J1,2 = 0 Hz) and
chemical shift of the anomeric C atom (δ 95.48) ob-
tained from the NMR spectra, it is evident that the
α-anomers are produced exclusively (Table 2).
Table 3. Screening of conditions for promoter-mediated Fer-
rier reaction of 3,4,6-tri-O-acetyl-D-glucal (Ia) with
Fmoc-Ser-OBn
Product IIa
Entry
Promoter
Yield/%
α/β anomer ratio
1
2
3
4
5
6
I2
NIS
88
32
nd
nd
nd
0
> 9 : 1
nd
nd
nd
nd
BF3 · Et2O
TFA
SnCl4
FeCl3
–
Subsequently, various Lewis and Brønsted acids
used as promoters were investigated; the details are
summarised in Table 3. The glycosylation prod-
ucts were complex and difficult to purify when the
BF3 · Et2O complex, trifluoroacetic acid (TFA) or
SnCl4 were used as the promoter (entries 3, 4, 5, Ta-
ble 3). It was presumed that the strong acidity of these
promoters caused decomposition of the substrates at
ambient temperature, hence, an attempt was made to
perform the reaction at –40◦C. However, the reaction
still did not proceed and the protected amino acid was
not fully consumed. When FeCl3 was used, no product
was detected (entry 6). It is worth noting that when N-
iodosuccinimide (NIS) was used as the promoter, the
starting amino acid continued to be present even after
two days; extending the reaction time yielded a com-
plex product mixture (entry 2). Along with the desired
product IIa isolated with a low yield (32 %), a trace
nd – not determined due to complex mixture of reaction prod-
ucts.
amount of O-(3,4,6-tri-O-acetyl-2-deoxy-2-iodo-α-D-
mannopyranosyl)-N-(9-fluorenylmethoxycarbonyl)-L-
serine benzyl ester was also observed (Hoffmann et al.,
1997). These results indicate that I2 was superior to
other catalysts in terms of yield and stereoselectivity.
Under the optimised conditions, the scope of
this method for the synthesis of 2,3-unsaturated-O-
glycosides using various glycals and protected amino
acids was explored (Table 4). It was found that per-
O-acetylated galactal (Ib) and rhamnal (Ic) gave good
yields and anomer selectivities (entries 1, 2), whereas
per-O-acetylated xylal (Id) and arabinal (Ie) afforded
only moderate yields but with good anomer selectiv-

L. Ren et al./Chemical Papers 68 (4) 525–530 (2014)
Table 4. Scope of I2-mediated Ferrier reaction of per-O-acetylated glycals
Reactants
529
Product
Yield/%
Entry
Amino acid
Glycal
II
α/β anomer ratio
1
2
3
4
5
6
7
8
9
Fmoc-Ser-OBn
Fmoc-Ser-OBn
Fmoc-Ser-OBn
Fmoc-Ser-OBn
Fmoc-Ser-OH
Fmoc-Thr-OBn
Fmoc-Thr-OH
Fmoc-Tyr-OBn
Fmoc-Tyr-OH
Ib
Ic
Id
Ie
Ia
Ia
Ia
Ia
Ia
IIb
IIc
IId
IIe
IIf
IIg
–
83
89
56
54
20
86
trace
33
> 9 : 1
> 9 : 1
> 9 : 1
> 9 : 1
> 9 : 1
> 9 : 1
–
IIh
–
> 9 : 1
–
trace
ities (entries 3, 4). Also, the glycosylation of Fmoc-
Thr-OBn and Fmoc-Tyr-OBn was proved to be effec-
tive (entries 6, 8). Glycosylation of Fmoc amino acids
without prior protection of the carboxyl groups using
similar conditions was also attempted but only low
yields or a trace amount of products were obtained
(entries 5, 7, 9). In addition, the type of hydroxyl
group exerted a significant influence on the glycosy-
lation reaction. The activity of the phenol hydroxyl
was very poor and only low or trace amounts of the
product were detected (entries 8, 9).
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Conclusions
An efficient method for the synthesis of glycosy-
lated Fmoc amino acid building blocks from glycals
was developed. The I2-mediated Ferrier reaction us-
ing Fmoc amino acids having protected or unpro-
tected carboxyl groups was shown to serve as a pow-
erful glycosylation method in the formation of O-
glycosylated amino acid with high yield and high α-
stereoselectivity. To the best of our knowledge, this
is the first example of the glycosylation of Fmoc
amino acids with appropriate O-protected glycals; it
can have extensive applications in the synthesis of
O-glycopeptides/proteins. Further studies on this re-
action in the production of other glycosylated Fmoc
amino acids, as well as in the solid support synthesis
of glycopeptides, are in progress.
Acknowledgements. The authors wish to express their
thanks for the financial support received from the National Nat-
ural Science Foundation of China (nos. 21142010, 81273358)
and National Science and Technology Major Projects for “Ma-
jor New Drugs Innovation and Development” (no. 2009ZX09
102-018).
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