Facile synthesis of 2-0-lodoacetyl protected glycosyl iodides: Useful precursors of 1→2-linked 1,2-trans-glycosides

Article abstract of DOI:10.1021/ol8026472

(Chemical Equation Presented) The preparation and utilization of novel iodide glycosyl donors, 2-0-iodoacetyl-glycopyranosyl iodides, is described. The mechanism for the reaction of iodine with carbohydrate cyclic ketene acetal was investigated through lo

Full text of DOI:10.1021/ol8026472

ORGANIC
LETTERS
2009
Vol. 11, No. 3
609-612
Facile Synthesis of 2-O-Iodoacetyl
Protected Glycosyl Iodides: Useful
Precursors of 1f2-Linked
1,2-trans-Glycosides
Yoon-Joo Ko,*,† Seung-Bo Shim,‡ and Jung-Hyu Shin†
National Center for Inter-UniVersity Research Facilities, Seoul National UniVersity,
Seoul, 151-747, Korea
yjko@snu.ac.kr
Received November 16, 2008
ABSTRACT
The preparation and utilization of novel iodide glycosyl donors, 2-O-iodoacetyl-glycopyranosyl iodides, is described. The mechanism for the
reaction of iodine with carbohydrate cyclic ketene acetal was investigated through low-temperature NMR experiments. 2-O-Iodoacetyl-
glycopyranosyl iodides can serve as effective glycosyl donors giving 2-O-iodoacetyl 1,2-trans-glycosides in high yields and excellent
stereoselectivities. The 2-O-iodoacetyl group was removed selectively with thiourea to afford 2-hydroxy 1,2-trans-glycosides in high yield
without affecting other protecting groups and anomeric configurations.
1f2-O-Linked 1,2-trans-glycosides are key subunits of
many biologically important compounds such as vancomy-
cin,1 the immunosuppressant plakoside A,2 and other useful
agents.3 Synthetic approaches to these glycosides have
focused on two important concepts: regioselective protection
and anomeric center activation. Many challenges have been
overcome to create efficient stereoselective glycosyl donors
as synthetic tools. Established donors include 2-O-protected
glycosyl halides, trichloroacetimidates, thioglycosides, n-
pentenyl glycosides, and glycals.4 Most of these donors,
however, require multistep syntheses that involve selective
protection and deprotection procedures. The development of
a direct and efficient glycosyl donor for the construction of
1f2-O-linked 1,2-trans glycosides is desirable but hitherto
has not been forthcoming.
Glycosyl iodides display a significantly higher reactivity
than the corresponding bromides and chlorides and show a
greater reactivity toward nucleophilic displacement under
neutral conditions.5 Recent studies have shown that glycosyl
iodides offer many advantages in terms of reaction times,
efficiencies, and stereochemical outcomes.6,7 Here, we report
a series of novel iodide glycosyl donors for 1,2-O-glycosi-
dation, namely, 2-O-iodoacetyl-glycopyranosyl iodides
(9∼12).
(4) For recent reviews, see: (a) Nicolaou, K. C.; Mitchell, H. J. Angew.
Chem., Int. Ed. 2001, 40, 1576–1624. (b) Pellissier, H. Tetrahedron 2005,
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† Seoul National University
‡ Samsung Electronics Co., Ltd.
(1) Nicolaou, K. C.; Winssinger, N.; Hyghes, R.; Smethurst, C.; Cho,
S. Y. Angew. Chem., Int. Ed. 2000, 39, 1084–1088.
(2) Nicolaou, K. C.; Li, J.; Zenke, G. HelV. Chim. Acta 2000, 83, 1977–
2006.
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31, 4769–4772. (b) Schmid, U.; Waldemann, H. Tetrahedron Lett. 1996,
37, 3837–3840.
(6) (a) Perrie, J. A.; Harding, J. R.; King, C.; Sinnott, D.; Stachulski,
A. V. Org. Lett. 2003, 5, 4545–4548. (b) Bhat, A. S.; Gervay-Hague, J.
Org. Lett. 2001, 3, 2081–2084. (c) Hadd, M. J.; Gervay, J. Carbohydr.
Res. 1999, 320, 61–69. (d) Gervay, J. Org. Synth.: Theory Appl. 1998, 4,
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1 1999, 54, 5–557. (b) Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998, 63,
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10.1021/ol8026472 CCC: $40.75
Published on Web 12/31/2008
2009 American Chemical Society

2-O-Iodoacetyl protected glycosyl iodides (9∼12) were
readily synthesized from the O-acetyl glycosyl bromide or
chloride via carbohydrate cyclic ketene acetal intermediates
as shown in Table 1. Treatment of the glycosyl halides 1∼4
glycosyl iodides 9∼12 as shown in Table 1. Glucosyl iodide
derivative 9 was synthesized in 87% yield over two steps
from the commercially available glucosyl bromide 1 (entry
1). Similarly, galactosyl iodide 10 and mannosyl iodide 11
were synthesized in 86% and 81% yields from galactosyl
bromide 2 and mannosyl chloride 3, respectively (entries 2
and 3). Maltosyl iodide 12 was synthesized in 62% yield
from maltosyl bromide precursor 49 which was readily
available from the treatment of octa-O-acetyl-R-D-maltoside
with 33% hydrogen bromide in AcOH (entry 4). Therefore,
this synthetic procedure can be used with readily available
monosaccharides and oligosaccharides.
Table 1. Synthesis of 2-O-Iodoacetyl-glycosyl Iodide
The stability of 2-O-iodoacetyl-R-D-glycopyranosyl iodide
derivatives is greatly dependent on the type of sugar. The
order of stability for glycosyl iodides is as follows: glucosyl
iodide 9 > galactosyl iodide 10 ≈ maltosyl iodide 12 >
mannosyl iodide 11. Especially, glucosyl iodide 9 is quite
stable and can be stored for 5 months in the dark at room
temperature or over one year at -18 °C. However, under
concentrated conditions, mannosyl iodide 11 is so unstable
that it has to be used for glycosylation without purification.
Under the experimental conditions in Table 1, only
R-glycosyl iodides were obtained without any trace of their
ꢀ-anomers; this was verified by extensive NMR experiments
and NOE measurements. The anomeric protons H-1 of
compounds 9, 10, 11, and 12 show the chemical shifts of
6.96, 7.03, 6.72, and 6.90 ppm, respectively.10 Upon irradia-
tion of H-2 of the R-glucosyl iodide 9 in a selective 1D NOE
experiment,11 strong interactions were observed with the
anomeric proton H-1 (NOE 3.5%), the 1,3-diaxial proton H-4
(2.4%), and transdiaxial H-3 (1.1%), which suggested an
R-configuration of the anomeric proton as shown in Figure
1. In addition, irradiation of the anomeric proton H-1 resulted
in no detectable NOE signal except those of neighboring H-2.
a Yields are obtained over two steps from I-1
8
with AgClO4 in anhydrous benzene at room temperature
for 1 h yielded the ketene acetals 5∼8 in 60∼90% yields.
Unexpectedly, we found that carbohydrate ketene acetals
5∼8 showed good stability to water during workup. They
could easily be purified by filtration through Celite to remove
AgBr and finally washed with water to remove the residual
AgClO4, ammonium salts, and other water-soluble impurities.
NMR analysis of these products indicated that no additional
purification was necessary.
Figure 1. NOE measurements for ꢀ-glucosyl iodide 9 in toludene-
d8 at 298 K.
A detailed plausible mechanism for the formation of
glycosyl iodides is depicted in Scheme 1. Reaction of
electron-rich ketene acetal12 with iodine would give a
dioxocarbenium ion 13. A nucleophilic ring opening of a
dioxocarbenium ion 13 by an iodide first gives ꢀ-glycosyl
The ketene acetals 5∼8 reacted with iodine in the presence
of 4 Å MS in benzene at ambient temperature to afford the
(7) (a) Schmid, U.; Waldmann, H. Liebigs Ann./Relc. 1997, 2573–2577.
(b) Tanaka, H.; Sakamoto, H.; Sano, A.; Nakamura, S.; Nakajima, M.;
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1999, 314, 7–3150.
(9) Brauns, D. H. J. Am. Chem. Soc. 1929, 51, 1820–1831.
(10) J1,2 values of H-1 at 9, 10, and 12 are 4.3 Hz, which suggests
R-anomer. H-1 of 11 shows a broad single peak.
(11) Stott, K.; Keeler, J.; Shaka, Q. N.; Van, A. J. J. Magn. Reson. 1997,
125, 302–324.
(8) (a) Paulsen, H. Angew. Chem., Int. Ed. 1982, 21, 184–201. (b) Ness,
R. K.; Fletcher, H. G.; Hudson, C. S. J. Am. Chem. Soc. 1951, 73, 296–
300. (c) Hanessian, S.; Banoub, J. Carbohyd. Res. 1975, 44, C14–Cl7.
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610
Org. Lett., Vol. 11, No. 3, 2009

10, and 12 is explained by the following path A depicted in
Scheme 1. However, attack on an unstable but more reactive
oxocarbenium 15 equilibrated from 13 by an iodide ion (path
B) should occur rarely since the peak indicating R-glycosyl
iodides 9 did not appear until complete consumption of the
ketene acetal 5 as shown in the 1H NMR spectra (Figure 2).
The formation of 2-O-iodoacetyl-R-mannosyl iodides 11
would be from a direct R-attack of iodine to produce the
ꢀ-ketene acetal.
Scheme 1
.
Proposed Mechanism for Formation of Glucosyl
Iodides 9
To evaluate its properties as a glycosyl donor, 2-O-
iodoacetyl glucosyl iodide 9 was coupled with a variety of
glycosyl acceptors in the presence of AgOTf.8 In all of the
cases examined, only 1,2-trans-ꢀ-glycoside products were
obtained in good yields, as summarized in Table 2. Glyco-
iodide 14, which rearranges13 to the more stable R-glucosyl
iodide 9 (path A). Alternatively, dioxocarbenium ion 13 can
be equilibrated to the reactive but low-abundance oxocar-
benium ion 15, which is then attacked by an iodide anion
and forms directly R-glycosyl iodide 9 without going through
the ꢀ-anomer (path B). To investigate the mechanistic
process, especially to detect ꢀ-glycosyl iodides, NMR
experiments were performed at various temperatures.
Carbohydrate ketene acetal 5 from glucosyl bromide 1 was
treated with 2 equiv of iodine in CD2Cl2 at 0 °C (Figure 2).
After 5 min, the carbohydrate ketene acetal peaks at δ 3.43
and 3.36 ppm disappeared, and two new product peaks for
H-1 of the glucosyl iodide 9 started to appear at δ 5.78 and
6.96 ppm (product ratio 14:1). The anomeric proton of the
major ꢀ-product appeared as a doublet at δ 5.78 ppm (J )
9.4 Hz), while that of the minor R-product appeared at δ
6.96 ppm (J ) 4.1 Hz). Upon warming to room temperature,
the intensity of the proton at δ 5.78 was reduced, while the
intensity of the proton at δ 6.96 was increased. After 30 min,
most of the ꢀ-glucosyl iodide 14 rearranged to the R-glucosyl
iodide 9.
Table 2. Gycosylation and Deprotection
On the basis of these NMR experiments, the mechanism
for the formation of 2-O-iodoacetyl-R-glycosyl iodides 9,
a Isolated yields of P1 prepared from 9. b Isolated yields of P2 prepared
from P1. c 3 equiv of 9 was used. d 2.4 equiv of AgOTf was used.
sylation of an unhindered aliphatic acceptor, benzyl alcohol
16, was complete in 2 h at -10 °C to afford the 1,2-trans-
ꢀ-glycoside 22 in 93% yield (Table 2, entry 1). Phenol
derivatives 17 and 18 (entries 2 and 3) and the primary 6-OH
of partially protected sugar 19 (entry 4) were also glycosy-
lated after reaction for 3 h at -10 to 0 °C and gave rise to
Figure 2. Reaction monitoring on the formation of glucosyl iodide
9 by 1H NMR (600 MHz) analysis. Times indicated are cumulated
ones from the injection of I2 to 5 in CD2Cl2.
Org. Lett., Vol. 11, No. 3, 2009
611

the 1,2-trans-ꢀ-glycoside products in acceptable yield. The
hindered phenol 1714 was glycosylated with 3 equiv of
glucosyl iodide 9 in 96% yield (entry 2). Glycosylation of
the highly hindered secondary 4-OH of 20 was complete after
18 h at an elevated temperature of 10 °C (entry 5). Glyco-
sylation of cholesterol 21 was carried out at 0 °C due to the
limited solubility of cholesterol at low temperature (entry
6). It is noteworthy that 2-O-iodoacetyl glucosyl iodide 9
can be used in glycosylation with a variety of glycosyl
acceptors, it giving 1,2-trans-ꢀ-glycosides in good yields.
Reactions using 10, 11, and 12 also showed complete
stereoselection yielding only 1,2-trans-ꢀ-glycosides with
excellent yields in glycosylation.
Selective removal of the iodoacetyl group at C-2 in 2-O-
iodoacetyl-glycosides (22∼27) using thiourea15 proceeded
successfully without affecting other protecting groups and
anomeric configurations, affording good yields of the ex-
pected products (73%∼98%, Table 2). While little is known
about the properties of the iodoacetyl group in carbohydrate
chemistry, we have successfully demonstrated its advantages
as a protecting group. In this regard, it can be easily removed
under mild conditions after glycosylation.
In conclusion, a facile method for the preparation of 2-O-
iodoacetyl-protected glycosyl iodides from glycosyl bromides
or chlorides via carbohydrate cyclic ketene acetals has been
established. Glycosyl iodides protected with the 2-O-io-
doacetyl group serve as efficient and stereoseletive glycosyl
donors for the preparation of the 1f2-linked 1,2-trans-
glycosides. Glycosylation of various acceptors with 2-O-
iodoacetyl protected glycosyl iodides and subsequent selec-
tiveremovalofthe2-O-iodoacetylgroupgivesthecorresponding
2-hydroxy 1,2-trans-glycosides in high yield and with
excellent stereoselectivity. Therefore, the glycosylation pro-
tocol outlined herein provides a useful method for the
synthesis of oligosaccharides and glycoconjuates containing
1f2-O-linked 1,2-trans-glycosides.
Acknowledgment. Support of this work by the National
Center for Inter-University Research Facilities in Seoul
National University is greatly appreciated.
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R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem.-Eur. J. 1999, 5,
2648–2667. (b) Thompson, C.; Ge, M.; Kahne, D. J. Am. Chem. Soc. 1999,
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F.; Rodriguez, R. M. Angew. Chem., Int. Ed. 1998, 37, 1871–1874. (d)
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3475.
Supporting Information Available: Experimental details
and spectral data (1H and 13C NMR, and HRMS) of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Kova´cˇ, P.; Glaudemans, C. P. J. Carbohyd. Res. 1985, 140, 313–
318.
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