A Rapid and Diastereoselective Synthesis of 2-Deoxy-2-iodo-α-glycosides and its Mechanism for Diastereoselectivity

Article abstract of DOI:10.1055/s-0036-1588440

Reductive deiodination of 2-deoxy-2-iodo-glycoside is an efficient and practical approach for the synthesis of 2-deoxyglycosides, which are moieties of bioactive compounds. However, inseparable diastereoisomers are usually formed in the preparation of 2-deoxy-2-iodo-glycosides via glycosylation of glycals with alcohols using current methods. To overcome this problem, a rapid and diastereoselective transformation of glycals and alcohols into 2-deoxy-2-iodo-α-glycosides enabled by I ₂ /PhI(OAc) ₂ has been developed. 14 glycals, derived from 13 monosaccharides and one disaccharide, diastereoselectively yielded α-glycosides. Only in two cases the diastereoselectivity of the glycosylation was poor. The yields of glycosylation range from 73% to 95%, and the reactions are finished in only five minutes. Investigations for better diastereoselectivity by comparing I ₂ /Ph(OAc) ₂ - with I ₂ /Cu(OAc) ₂ -mediated glycosylations using UV analysis have been conducted.

Full text of DOI:10.1055/s-0036-1588440

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
W. Yuan et al.
Letter
Synlett
A Rapid and Diastereoselective Synthesis of 2-Deoxy-2-iodo-α-
glycosides and its Mechanism for Diastereoselectivity
Wenjiao Yuana,c
Yali Liub
Chunbao Li*a
AcO
ROH (10 euqiv)
I2/PhI(OAc)2
I
O
OAc
O
AcO
AcO
AcO
AcO
CH3CN
OR
13 examples
a Department of Chemistry, School of Science, Tianjin University,
Tianjin 300350, P. R. of China
Rapid: 5 min
Yield: 73–95%
Selective: α-glycosides
lichunbao@tju.edu.cn
b Department of Pharmaceutical Engineering, School of Chemical
Engineering, Hebei University of Technology, Tianjin 300130,
P. R. of China
c Department of Biochemical Engineering, Tianjin Modern
Vocational Technology College, Tianjin 300350, P. R. of China
Received: 28.03.2017
Accepted after revision: 04.05.2017
Published online: 24.05.2017
ertheless, diastereoisomers are inevitably formed with
these methods, which are difficult to separate by column
chromatography.
DOI: 10.1055/s-0036-1588440; Art ID: st-2017-w0212-l
Herein we wish to report a rapid and diastereoselective
transformation of glycals and glycosyl acceptors into 2-de-
Abstract Reductive deiodination of 2-deoxy-2-iodo-glycoside is an ef-
ficient and practical approach for the synthesis of 2-deoxyglycosides,
which are moieties of bioactive compounds. However, inseparable dias-
tereoisomers are usually formed in the preparation of 2-deoxy-2-iodo-
glycosides via glycosylation of glycals with alcohols using current meth-
ods. To overcome this problem, a rapid and diastereoselective transfor-
mation of glycals and alcohols into 2-deoxy-2-iodo-α-glycosides en-
abled by I2/PhI(OAc)2 has been developed. 14 glycals, derived from 13
monosaccharides and one disaccharide, diastereoselectively yielded α-
glycosides. Only in two cases the diastereoselectivity of the glycosyla-
tion was poor. The yields of glycosylation range from 73% to 95%, and
the reactions are finished in only five minutes. Investigations for better
diastereoselectivity by comparing I2/Ph(OAc)2- with I2/Cu(OAc)2-medi-
ated glycosylations using UV analysis have been conducted.
oxy-2-iodo-α-glycosides mediated by I2/PhI(OAc)2.10
A
mechanism is proposed that rationalizes the better α-man-
no selectivity of our method compared to the literature
ones.
Initially, glucal 1a (1 equiv) was treated with cyclohexa-
nol (1 equiv) in the presence of I2 (0.6 equiv) and PhI(OAc)2
(1.2 equiv) in acetonitrile at room temperature. 2-Deoxy-2-
iodo-α-D-mannopyranosyl acetate 3 was produced in 79%
Table 1 Optimization of Glycosylation Reaction Conditionsa
Key words 2-deoxy-2-iodo-glycoside, selective glycosylation, glycal,
alcohol, iodine, iodobenzene diacetate
AcO
I
O
AcO
AcO
cyclohexanol
I2/PhI(OAc)2
AcO
AcO
I
OAc
O
O
AcO
O
AcO
AcO
+
As moieties occurring in many biologically active natu-
ral products,1 drugs,2 and important intermediates3 in or-
ganic synthesis, 2-deoxy sugars4 are well-known. However,
efficient and selective syntheses of 2-deoxy sugar deriva-
tives remains a challenge in carbohydrate chemistry and
natural product synthesis.5 Due to the absence of neighbor-
ing substituents such as OR, diastereoselective preparations
of specific 2-deoxy-glycosides are hardly achieved using a
direct glycosylation reaction.6 Consequently, several indi-
rect methods7 are established to solve this problem. For ex-
ample, reductive deiodination of 2-deoxy-2-iodo-glyco-
sides is a reliable and practical approach to yield 2-deoxy
sugars with an indirect glycosylation strategy.8 2-Deoxy-2-
iodo-glycosides have been synthesized via glycosylation of
glycals with glycosyl acceptor in the presence of iodate re-
agent and oxidant, such as NIS,9a NH4I/H2O2,9b NaI/CAN,9c
I2/CAN,9d I2/Cu(OAc)2,9e NIS/PPh3,9f Me3SI(OAc)2,9g etc. Nev-
CH3CN, r.t.
OAc
1a
2a
3
Entry
Cyclohexanol Solvent
(equiv)
Yield of 2a
Yield of 3
(%)b
(%)b
1
2
3
4
5
6
7
8
1
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
toluene
THF
–
79
77
58
13
–
–
5
33
74
88
80
75
56
8
10
10
10
10
–
–
–
aGlucal (1 mmol), I2 (0.6 mmol), PhI(OAc)2 (1.2 mmol) in CH3CN (4 mL) at
r.t.
bAll yields were isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
W. Yuan et al.
Letter
Synlett
yield (Table 1, entry 1). Increasing the amount of glycosyl
acceptor cyclohexanol from one equivalent to two, five, and
eight equivalents, the mixture of compounds 2a and 3 were
formed in 0% and 77%, 33% and 58%, 74% and 13% yields, re-
spectively (Table 1, entries 2–4). Further increasing the
amount of cyclohexanol to ten equivalents, the reaction
was quickly finished in five minutes and only cyclohexyl 2-
deoxy-2-iodo-α-D-mannopyranoside (2a) was formed in
88% yield. A screen of various solvents, including CH2Cl2,
toluene, and THF, indicated that acetonitrile was the opti-
mal solvent. Hence, the optimized conditions were glucal (1
equiv), excess glycosyl acceptor (10 equiv), PhI(OAc)2 (1.2
equiv), and I2 (0.6 equiv) in acetonitrile at room tempera-
ture for five minutes (Table 1, entry 5).
Table 2 Selective Synthesis of 2-Deoxy-2-iodo-glycosides Enabled by
I2/PhI(OAc)2a and its Comparisons with the Literature Results
I
O
O
I2/PhI(OAc)2
R'OH/CH3CN
O
OR'
R
R
+
R
I
OR'
α-manno
β−gluco
1a–e
2a–m
Entry Product
Yield (%) dr (α-manno/β-gluco)
This workb
Lit.c
AcO
I
O
AcO
AcO
88
only α
779d
1
O
8:19d
To further demonstrate the synthetic potential of this
method, we conducted this reaction on glycals derived
from D-glucose (Table 2, entries 1–9), D-xylose (Table 2, en-
try 10), D-arabinose (Table 2, entry 11), D-galactose (Table
2, entry 12), and D-maltose (Table 2, entry 13) and glycosyl
acceptor including primary (Table 2, entries 2–4, 6, and 7),
secondary (Table 2, entries 1, 5, 9–13), and tertiary alcohols
(Table 2, entry 8). All the rates of these reactions were rap-
id, only taking five minutes. The yields of these reactions
ranged from good to excellent (73–95%). Only in the two
cases of glycosylation of methanol with glucal and of iso-
propanol with xylal poor diastereoselectivity was observed
(Table 2, entries 2 and 10). For the rest of glycosylations, α-
manno products were synthesized diastereoselectively. The
diastereoselectivity of this method is better than most of
the current methods. In previous reports, the glycosylation
products were almost always mixtures of α-manno and β-
gluco, which are often inseparable 11 In addition, this meth-
od provides α-linked 2-deoxy-2-iodo-glycosides in shorter
reaction times and higher yields.
An experiment was carried out to further investigate
the influence of excess alcohol on glycosylation. A solution
of 0.6 equivalents of I2 and 1.2 equivalents of PhI(OAc)2 in
CH3CN was stirred for five minutes, followed by slow addi-
tion of one equivalent of glucal and ten equivalents of EtOH
to the above resulting solution. It was found that only com-
pound 3 was obtained in 80% yield. Hence, excess alcohols
are required for generation of 2a–m from glycals to en-
hance the competitive edge of alcohol over AcO–.
To understand the much better diastereoselectivity of
our method over those in the literature,7 we conducted a
comparison experiment to indirectly analyze the concen-
trations of unreacted iodine in the reaction solutions via UV
measurements (Figure 1). In the I2/PhI(OAc)2-mediated re-
action, its absorption reduced from 0.972 to nearly 0 in one
minute, while in the I2/Cu(OAc)2-mediated reaction the ab-
sorption reduced from 0.498 to 0.325 in one minute, to
0.232 in ten minutes, and to 0.098 in 60 minutes. This
strongly suggests that PhI(OAc)2is much more efficient than
Cu(OAc)2 in oxidizing I2 to I+. In the I2/PhI(OAc)2-mediated
reaction, the concentration of I2 is very low.
2a
AcO
AcO
I
O
85
4:1
989e
AcO
2
5:19e
OMe
2b
2c
AcO
AcO
I
O
92
only α
959e
AcO
3
4
7:19e
OEt
AcO
AcO
I
O
AcO
88
>24:1
929e
7:19e
O
2d
AcO
AcO
I
O
94
only α
809e
AcO
5
6
9:19e
O
2e
AcO
AcO
I
O
AcO
85
only α
909e
O
7:19e
2f
AcO
AcO
I
O
AcO
80
only α
7
8
–
O
2g
AcO
AcO
I
O
AcO
91
only α
519e
14:19e
O
2h
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
W. Yuan et al.
Letter
Synlett
Table 2 (continued)
Entry Product
Yield (%) dr (α-manno/β-gluco)
This workb Lit.c
AcO
I
O
AcO
AcO
779d
O
82
only α
9
8:19d
2i
I
O
AcO
AcO
82
4:3
10
–
–
O
Figure 1 UV-absorption comparison between I2/PhI(OAc)2-mediated
glycosylation (red) and I2/Cu(OAc)2-mediated glycosylation (black) (for
conditions, see ref.12).
2j
I
O
AcO
OAc
87
only α
O
11
O
AcO
OAc
AcO
AcO
AcO
I
O
I+
2k
AcO
ROH
– H+
ROH
OR
B
OAc
OAc
I
OAc
α-manno
AcO
AcO
O
O
AcO
AcO
I
O
AcO
AcO
I
95
>20:1
12
13
–
–
– I–
I–
A
O
AcO
AcO
A
I
major
O
I
AcO
2l
– I–
AcO
AcO
C
O
I
OAc
AcO
O
OAc
I
AcO
AcO
D
minor
73
>14:1
AcO
O
O
AcO
O
OAc
O
AcO
AcO
ROH
O
I
OR
AcO
AcO
2m
AcO
– H+
I
aGlycal (1 mmol), PhI(OAc)2 (1.2 mmol), I2 (0.6 mmol), and alcohol (10
mmol) in CH3CN (4 mL) at r.t. for 5 min.
E
D'
β-gluco
bIsolated yields: dr determined by 1H NMR analysis.
cYield and anomer ratios reported by references.
I
OH
I+
AcO
OAc
O
O
AcO
O
2k
OAc
OAc
OAc
F
According to these facts, the following mechanism is
proposed (Scheme 1). Oxidation of I2 by PhI(OAc)2 leads to
I+, parts of them may be in the form of AcOI. This iodonium
ion is in association with the β-OAc of C-313 and forms β-
oriented three-membered iodonium. Nucleophilic attack
by sugar acceptor at C-1 yields α-manno product B. Howev-
er, if I– is in high concentration, as in the case of glycosyla-
tion mediated by Cu(OAc)2, it will compete with sugar ac-
ceptor to open the three-membered ring, forming diiodide
C, which via neighboring-group participation forms minor
intermediate D. D′ is attacked by sugar acceptor to afford β-
gluco product E, diastereoisomer of B.
Scheme 1 Possible ways to α-manno and β-gluco isomers in glycosyla-
tion
glucal, the α-side of diacetyl arabinal has no hindered
groups. All these factors favor the α-oriented iodonium F,
which leads to 2k. The same argument is applicable to the
poor selectivity in the formation of 2j, because the β-side
hindrance of diacetyl xylal is larger than diacetyl arabinal
and smaller than triacetyl glucal.
In summary, we have developed a rapid and diastereo-
selective method for synthesis of 2-deoxy-2-iodo-α-glyco-
sides from glycals and glycosyl acceptors. A highly selective
access to α-manno isomer in glycosylation under our reac-
tion conditions has been realized. On the basis of control
experiment, we propose a reaction mechanism and discuss
In the case of 2k (Table 2, entry 11), the two neighbor-
ing AcO groups at C-3 and C-4 are both on the same side,
which makes the α-side hindered and probably weakens
the association between I+ and AcO– at C-3. In contrary to
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
W. Yuan et al.
Letter
Synlett
the influence of PhI(OAc)2 and Cu(OAc)2 on the diastereose-
lectivity glycosylations. And the better performance of this
procedure is attributed to the PhI(OAc)2 efficiency in oxi-
dizing I2 into I+.
(8) (a) Tatsuta, K.; Fujimoto, K.; Kinoshita, M.; Umezawa, S. A. Car-
bohydr. Res. 1977, 54, 8. (b) Thiem, J.; Karl, H. Tetrahedron Lett.
1978, 19, 4999. (c) Kessler, H.; Kottenhahn, M.; Kling, A.; Kolar,
C. Angew. Chem., Int. Ed. Engl. 1987, 26, 888. (d) Friesen, R. W.;
Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6656. (e) Wang, H.;
Tao, J.; Cai, X.; Chen, W.; Zhao, Y.; Xu, Y.; Yao, W.; Zeng, J.; Wan,
Q. Chem. Eur. J. 2014, 20, 17319.
Supporting Information
(9) (a) Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696.
(b) Gammon, D. W.; Kinfe, H. H.; De Vos, D. E.; Jacobs, P. A.; Sels,
B. F. Tetrahedron Lett. 2004, 45, 9533. (c) Roush, W. R.; Narayan,
S.; Bennett, C. E.; Briner, K. Org. Lett. 1999, 1, 895. (d) Saeeng, R.;
Sirion, U.; Sirichan, Y.; Trakulsujaritchok, T.; Sahakitpichan, P. S.
Heterocycles 2010, 81, 2569. (e) Sirion, U.; Purintawarrakun, S.;
Sahakitpicchan, P.; Saeeng, R. Carbohydr. Res. 2010, 345, 2401.
(f) Kimura, T.; Takahashi, D.; Toshima, K. J. Org. Chem. 2015, 80,
9552. (g) Reddy, T. R.; Rao, D. S.; Babachary, K.; Kashyap, S. Eur. J.
Org. Chem. 2016, 291.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588440.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) (a) Scott, J. Bioactive Carbohydrates in Chemistry, Biochemistry
and Biology; Ellis Horwood Publishers: Chichester, 1983.
(b) Thiem, J.; Klaffke, W. Top. Curr. Chem. 1990, 154, 285.
(c) Butler, M. S. Nat. Prod. Rep. 2005, 22, 162.
(10) General Procedures for Preparation of 2-Deoxy-2-iodo-α-
glycosides
(2) (a) Acton, E. M.; Fujiwara, A. N.; Henry, D. W. J. Med. Chem. 1974,
17, 659. (b) Chabala, J. C.; Mrozik, H.; Tolman, R. L.; Eskola, P.;
Lusi, A.; Peterson, L. H.; Woods, M. F.; Fisher, M. H.; Campbell,
W. C. J. Med. Chem. 1980, 23, 1134. (c) Matsumoto, T.;
Yamaguchi, H.; Tanabe, M.; Yasui, Y.; Suzuki, K. Tetrahedron Lett.
2000, 41, 8393. (d) Debono, M.; Merkel, K. E.; Molloy, R. M.;
Barnhart, M.; Presti, E.; Hunt, A. H.; Hamill, R. L. J. Antibiot. 1984,
37, 85.
(3) (a) Roush, W. R.; Narayan, S. Org. Lett. 1999, 1, 899. (b) Roush,
W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(c) Costantino, V.; Imperatore, C.; Fattorusso, E.; Mangoni, A.
Tetrahedron Lett. 2000, 41, 9177. (d) Suzuki, K.; Sulikowski, G.
A.; Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112,
8895. (e) Pokorny, B.; Kosma, P. Org. Lett. 2015, 17, 110.
(4) For preparation of 2-deoxy sugar from glycal, see: (a) Ciment, D.
M.; Ferrier, R. J. J. Chem. Soc. C 1966, 441. (b) Lehmann, J.;
Schröter, E. Carbohydr. Res. 1972, 23, 359. (c) EI Khadem, H. S.;
Swartz, D. L.; Nelson, J. K.; Berry, L. Carbohydr. Res. 1977, 58,
230. (d) Hadfield, A. F.; Sartorelli, A. C. Carbohydr. Res. 1982, 101,
197. (e) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org.
Chem. 1990, 55, 5812. (f) Sabesan, S.; Neira, S. J. Org. Chem.
1991, 56, 5468. (g) Toshima, K.; Nagai, H.; Ushishi, Y.;
Matsumura, S. Synlett 1998, 1007. (h) Rani, S.; Agarwal, A.;
Vankar, Y. D. Tetrahedron Lett. 2003, 44, 5001.
To a solution of glycal (1 mmol), alcohol (10 mmol), and
PhI(OAc)2 (1.2 mmol) in CH3CN (4 mL) was added I2 (0.6 mmol),
the mixture was stirred at r.t. for 5 min. After addition of EtOAc
(50 mL) to the reaction mixture, the organic phase was washed
with sat. Na2S2O3, water and brine, dried over anhydrous
Na2SO4, and concentrated. The residue was further purified by
column chromatography to afford final product.
Cyclohexyl 3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-α-D-mannopy-
ranoside (2a)
438.5 mg, yield 88%, colorless syrup. 1H NMR (400 MHz, CDCl3):
δ = 5.37 (t, J = 9.7 Hz, 1 H), 5.32 (s, 1 H), 4.69 (dd, J = 9.4, 4.3 Hz,
1 H), 4.51 (dd, J = 4.2, 0.9 Hz, 1 H), 4.26–4.16 (m, 2 H), 4.16–4.09
(m, 1 H), 3.60 (ddd, J = 13.1, 9.1, 3.8 Hz, 1 H), 2.12 (s, 3 H), 2.10
(s, 3 H), 2.07 (s, 3 H), 1.92–1.84 (m, 2 H), 1.78–1.72 (m, 2 H),
1.59–1.50 (m, 1 H), 1.48–1.37 (m, 1 H), 1.36–1.20 (m, 4 H). 13C
NMR (101 MHz, CDCl3): δ = 170.69, 169.87, 169.56, 99.59,
76.92, 69.20, 69.15, 67.86, 62.38, 33.19, 31.59, 30.70, 25.45,
24.10, 23.84, 20.98, 20.73, 20.68.
i-Propyl 3,4-Di-O-acetyl-2-deoxy-2-iodo-α-D-arabinopyra-
noside (2k)
337.2 mg, yield 87%, white solid. 1H NMR (400 MHz, CDCl3): δ =
5.53 (s, 1 H), 5.19–5.04 (m, 1 H), 4.87 (d, J = 7.5 Hz, 1 H), 4.16
(dd, J = 7.5, 3.2 Hz, 1 H), 4.02–3.90 (m, 2 H), 3.81 (dd, J = 11.3, 9.4
Hz, 1 H), 2.20 (s, 3 H), 2.03 (s, 3 H), 1.24 (dd, J = 8.1, 6.3 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 169.68, 169.54, 99.64, 72.41,
70.23, 66.67, 61.76, 27.59, 23.29, 21.65, 20.80, 20.71. HRMS: m/z
calcd for C12H20O6IH [M + H+]: 387.0299; found: 387.0302.
(11) (a) Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153. (b) Ferrier, R. J.;
Zubkov, O. A. Org. React. 2003, 62, 569.
(5) (a) Langenhan, J. M.; Griffith, B. R.; Thorson, J. S. J. Nat. Prod.
2005, 68, 1696. (b) Křen, V.; řezanka, T. FEMS Microbiol. Rev.
2008, 32, 858.
(6) (a) Sherry, B. D.; Loy, R. N.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 4510. (b) Tanaka, H.; Yoshizawa, A.; Chijiwa, S.; Ueda, J.;
Takagi, M.; Shinya, K.; Takahashi, T. Chem. Asian J. 2009, 4, 1114.
(c) Issa, J. P.; Llod, D.; Steliotes, E.; Bennett, C. S. Org. Lett. 2013,
15, 4170. (d) Kaneko, M.; Herzon, S. B. Org. Lett. 2014, 16, 2776.
(e) Balmon, E. I.; Benito-Alifonso, D.; Coe, D. M.; Alder, R. M.;
Mcgarrigle, E. M.; Galan, M. C. Angew. Chem. Int. Ed. 2014, 126,
8329. (f) Adhikari, S.; Baryal, K. N.; Zhu, D.; Li, X.; Zhu, J. ACS
Catal. 2013, 3, 57. (g) Zhu, D.; Baryal, K. N.; Adhikari, S.; Zhu, J.
J. Am. Chem. Soc. 2014, 136, 3172. (h) Baryal, K. N.; Zhu, J. Synlett
2014, 25, 308.
(12) I2/PhI(OAc)2-Mediated Glycosylation
Glycal (1 mmol), alcohol (10 mmol), I2 (0.6 mmol), and
PhI(OAc)2 (1.2 mmol) in CH3CN (4 mL).
I2/Cu(OAc)2-Mediated Glycosylation
Glycal (0.4 mmol), alcohol (0.6 mmol), I2 (0.6 mmol), molecular
sieves 4 Å (0.108 g) and Cu(OAc)2 (0.6 mmol) in CH2Cl2 (4 mL).
These reaction solutions (diluted at 30 times by CHCl3) are mea-
sured by UV at 530 nm.
(7) (a) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8353.
(b) Hou, D.; Lowary, T. L. Carbohydr. Res. 2009, 344, 1911.
(c) Carmona, A. T.; Moreno-Vargas, A. J.; Robina, I. Curr. Org.
Synth. 2008, 5, 33.
(13) Shimizu, M.; Morita, O.; Itoh, S.; Fujisawa, T. Tetrahedron Lett.
1992, 33, 7003.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D