Efficient O-Functionalization of Carbohydrates with Electrophilic Reagents

Article abstract of DOI:10.1002/anie.201605999

Novel methodology for O-functionalization of carbohydrate derivatives has been established using bench-stable and easily prepared iodonium(III) reagents. Both electron-withdrawing and electron-donating aryl groups were introduced under ambient conditions and without precautions to exclude air or moisture. Furthermore, the approach was extended both to full arylation of cyclodextrin, and to trifluoroethylation of carbohydrate derivatives. This is the first general approach to introduce traditionally non-electrophilic groups into any of the OH groups around the sugar backbone. The methodology will be useful both in synthetic organic chemistry and biochemistry, as important functional groups can be incorporated under simple and robust reaction conditions in a fast and efficient manner.

Full text of DOI:10.1002/anie.201605999

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605999
German Edition: DOI: 10.1002/ange.201605999
Hypervalent Compounds
Efficient O-Functionalization of Carbohydrates with Electrophilic
Reagents
Gergely L. Tolnai, Ulf J. Nilsson, and Berit Olofsson*
Abstract: Novel methodology for O-functionalization of
carbohydrate derivatives has been established using bench-
stable and easily prepared iodonium(III) reagents. Both
electron-withdrawing and electron-donating aryl groups were
introduced under ambient conditions and without precautions
to exclude air or moisture. Furthermore, the approach was
extended both to full arylation of cyclodextrin, and to
trifluoroethylation of carbohydrate derivatives. This is the
first general approach to introduce traditionally non-electro-
philic groups into any of the OH groups around the sugar
backbone. The methodology will be useful both in synthetic
organic chemistry and biochemistry, as important functional
groups can be incorporated under simple and robust reaction
conditions in a fast and efficient manner.
Scheme 1. Approaches to introduce noncarbohydrate functional
groups. LG=leaving group, Pg=protecting group.
E
arly geniuses of organic chemistry chose their interest
wisely. Their topics initiated modern organic chemistry and
are still fascinating for the scientists of the modern time. One
of these great topics is the chemistry of carbohydrates, which
is important in biochemistry, medicinal chemistry, and drug
discovery, as well as in sustainable chemistry as a cheap and
renewable energy source. However, the tremendous variety
of carbohydrate structures complicates the development of
general methodology for their derivatization. The function-
alization of carbohydrates with non-carbohydrate structures
has an essential role in organic and medicinal chemistry.[1]
Such groups are commonly introduced by stepwise prepara-
tion of leaving groups and subsequent nucleophilic substitu-
tion (Scheme 1a), and by either esterification or traditional
Williamson etherfication of carbohydrate hydroxy groups
with reactive primary electrophiles (e.g. allyl, propargyl, and
benzyl halides, or a-halocarbonyl compounds; Scheme 1b).[2]
The first strategy leads to (sometimes undesired) inversion of
carbohydrate carbon stereochemistry, while the last two are
limited in structural scope or require subsequent transforma-
tions to reach structural diversity.[2]
chemical and enzymatic instability of these molecules restricts
their use in many applications. Methods for introduction of
pharmaceutically interesting, non-electrophilic functional
groups to nonglycosidic carbohydrate hydroxy groups would
broaden the chemical space and could improve the biological
activities and pharmacokinetic profiles of the compounds.
Such methods would indeed be valuable tools in the discovery
and development of glycomimetic compounds targeting
medically relevant proteins.[1b,c,4]
While the first synthesis of an O-arylated carbohydrate
(phenyl glycoside) was accomplished in 1879,[5] there are no
general solutions for introduction of conventionally non-
electrophilic groups to the carbohydrate hydroxy groups.
Herein, we report a general methodology to functionalize
carbohydrate hydroxy groups with either aryl or fluoroalkyl
groups using electrophilic hypervalent iodine reagents (Sche-
me 1c). The methodology is transition metal-free, has unsur-
passed efficiency and yields, features mild reaction conditions,
and demonstrates very broad substrate scope.
Introduction of O-linked aglycones in the glycosidic
linkage has great importance in modern science,[3] but the
Fluoroalkylated and aromatic compounds are important
building blocks in modern pharmaceutical and fine-chemical
industries.[6] Because of their low electrophilicity, there is no
general method to introduce such functionalities to carbohy-
drate hydroxy groups, and only a handful of examples
[*] Dr. G. L. Tolnai, Prof. B. Olofsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 10691 Stockholm (Sweden)
E-mail: berit.olofsson@su.se
À
functionalized with such groups at O2 O6 have been
Homepage: http://www.organ.su.se/bo/
reported. Carbohydrate hydroxy groups can be decorated
with highly electron-deficient aryl groups by SNAr reactions
(Scheme 2a).[7] Arylation of secondary alcohols on the sugar
backbone usually requires leaving-group preparation, and
results in epimerization.[8] A phenyl group was introduced in
the O3-position with an organobismuth(V) reagent in low
Prof. U. J. Nilsson
Centre for Analysis and Synthesis, Department of Chemistry
Lund University, 22100 Lund (Sweden)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201605999.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: Screening of the arylation of secondary hydroxy groups.[a]
Entry
1
Base
t
3
Yield [%][a]
1[b]
2
3
tBuOK
KOH
NaOH
NaOH(aq)
20 min 3a
95
96
95
93
3 h
3 h
3 h
[c]
4
5
NaOH
tBuOK
2 h
40 min
3b quant
6[b]
92
7
NaOH
tBuOK
5 h
10 min
3c
3d
89
97
8[b]
Scheme 2. State of the art in carbohydrate O-arylation. EWG=elec-
tron-withdrawing group, DMF=N,N-dimethylformamide, HMDS=hex-
amethyldisilazide, TMS=trimethylsilyl.
9
NaOH
tBuOK
3 h
10 min
99
99
10[b]
yield.[9] Transition metal catalyzed alkyl–aryl C O couplings
À
are usually sensitive to steric hindrance and require high
temperatures.[10] This sensitivity could explain why transition
metals have not been applied in carbohydrate OH function-
alization, with the exception of a nickel/iridium-catalyzed
photoredox arylation of the primary OH of galactose
(Scheme 2b).[11] Ritter and co-workers presented an elegant
[a] Reaction conditions: sugar 1 (0.2 mmol), salt 2a (1.5 equiv) and base
(1.5 equiv), toluene (1 mL), RT. Yield of isolated product. [b] 0.4 mmol
scale. [c] 0.3 mmol NaOH in 100 mL water. Tf=trifluoromethanesulfonyl.
À
OH OH coupling strategy which was also exemplified on
To investigate the scope of the reaction, a set of furanose
and pyranose structures 1 were subsequently converted into
the corresponding nitrophenylated derivatives (Scheme 3).
Protected glucosamine and allose derivatives were both O3-
arylated to provide 3e,f. A series of galactose derivatives were
also subjected to the reaction conditions. The O6-unprotected
carbohydrates, but it did require an expensive carbene
reagent and strictly anhydrous conditions (Scheme 2c).[12]
Recent developments in hypervalent iodine chemistry
have enabled efficient synthesis of highly electrophilic, and
bench-stable iodonium reagents for the transfer of carbon
ligands.[13] While hypervalent iodine reagents have been
utilized as oxidants in carbohydrate chemistry,[14] they have
never been applied as group-transfer agents to derivatize
carbohydrates. Such an approach could have several advan-
tages: 1) direct O-functionalization instead of leaving group/
glycal preparation; 2) retention of stereochemistry; 3) no
need for Lewis acid or transition-metal catalyst; 4) robust,
mild, and user-friendly conditions; and 5) no need for excess
carbohydrate derivatives.
We have previously demonstrated metal-free O-arylations
with diaryliodonium salts,[15] and set out to assess the
feasibility of this approach. Carbohydrate derivatives 1 were
treated with 4-nitrophenyl(phenyl)iodonium triflate (2a) to
provide nitroarylated carbohydrates 3 (Table 1). The nitroaryl
group was chosen as it can be used as a protecting group, as
a handle for conjugation to other bioactive structures after
reduction, or serve as a good substrate for enzymes in the
glycosidic position.[16] To our delight, the anomeric OH of
mannofuranose (1a) was smoothly arylated (entry 1). The use
of simple alkali bases proved sufficient (entries 2–3), and even
aqueous sodium hydroxide resulted in 95% yield (entry 4).
The method also allowed the arylation of fructose and glucose
derivatives 1b–d with both NaOH and tBuOK in excellent
yields (entries 5–10). The practical benefit of extremely short
reaction times with tBuOK led us to choose this base for
subsequent experiments.
Scheme 3. Scope of the nitroarylation reaction. Yield of isolated
product given. [a] 3.0 equiv of base and 2a. Bz=benzoyl.
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
galactose gave 3h in good yield within a 30 minute reaction
The use of azido groups has a great impact on carbohy-
time, and the O3-product 3i was obtained in even shorter
time. Noteworthy is that modification of the O3 of galacto-
sides is an important approach towards selective ligands for
galectin proteins.[17]
drate chemistry, even more so since click chemistry has
revolutionized the field of biochemistry.[21] In addition,
azidophenyl groups are important groups in photolabeling
biochemistry. To the best of our knowledge, azido-substituted
diaryliodonium salts have never been applied to azidopheny-
late organic molecules.[22] Importantly, both para- and meta-
azidophenylated glucopyranose derivatives 3w,x could be
obtained under mild reaction conditions (Figure 1). Arylation
of the glycosidic OH of mannose to give 3y,z proved more
difficult than the O3 of glucose, thus highlighting that this
method is complementary to existing methods to introduce
aryl groups to carbohydrates.
The methodology was extended to the synthesis of more
complex products, as exemplified with an arylation using
a phenylalanine-derived iodonium salt to generate the
unprecedented glucose tyrosine glycopeptide-type system
3aa (Scheme 4a). Under unoptimized reaction conditions,
the reaction proceeded in moderate yield with recovered 1b.
Furthermore, a cyclodextrin derivative was sevenfold nitro-
arylated in to give 4 in 57% yield (Scheme 4b).
Furthermore, the typically unreactive axial O4 of a mixed
benzoyl- and benzyl-protected galactoside was also nitro-
arylated to 3j in a very fast reaction, albeit in moderate yield
(Scheme 3). Arylation of the glycosidic OH in anomeric
mixtures of substrates provided the products 3k,l in 1:1
anomeric ratios. Diarylation of a glucose diol was also
conducted, thus resulting in the corresponding diether 3m.
Isosorbide is one of the promising sustainable resources,[18]
and both the more accessible and the hydrogen bonded
hydroxy group of isosorbide were arylated in a fast reaction to
provide 3n. Attempts to selectively monoarylate diols failed,
and might be explained by the poor solubility of the diol
compared to the monoarylated alcohol, thus leading to faster
arylation of the latter. Synthesis of similar compounds in an
SNAr manner required heating at 1508C for 4 hours.[18c]
Topiramate is an effective drug in the treatment of epilepsy
and bipolar disorder.[19] The sugar-component of this drug was
nitroarylated to 3o in the same short reaction time and high
efficacy.
Having established efficient nitroarylation conditions, the
transfer of various other aryl groups was investigated next.[20]
As isopropylidene glucofuranose can be easily deprotected
and isomerized into glucopyranose, this was chosen as
a model substrate (Figure 1). Aryl groups with electron-
withdrawing substituents were easily installed to yield 3p,q,
and even a sterically demanding ortho-methoxycarbonyl aryl
group could be transferred to give 3r at a slightly elevated
temperature. The incorporation of a phenyl ring (3s), aryl
groups with electron-donating alkyl substituents (3t–u), and
the sterically congested mesityl group (3v) were also possible
in good yields.
Scheme 4. Advanced arylation of carbohydrates. Boc=tert-butoxycar-
bonyl.
Fluorine-containing functional groups have high impact in
pharmaceutical and crop science. While trifluoromethylation
is straightforward, the introduction of a trifluoroethyl moiety
to hydroxy groups is not established despite their potential
use in medicinal carbohydrate chemistry.[23] The low electro-
philicity of trifluoroethyl iodide and related pseudohaloge-
nides prevents O-functionalization with these reactants under
mild reaction conditions.[24] Inspired by our earlier findings,
we envisioned the use of trifluoroethyl(mesityl)iodonium
triflate (5), which is another class of hypervalent iodine
reagent,[25] for carbohydrate O-functionalization (Scheme 5).
To our delight, 5 was successfully used to trifluoroethylate
a small series of mono-unprotected sugar derivatives. The
reactions took place with complete chemoselectivity, that is,
without formation of any arylated byproducts, to give
fluorinated carbohydrates 6 under mild and practical reaction
conditions.
Figure 1. Scope with respect to the aryl groups. Reaction conditions:
sugar 1 (1 equiv), salt 2 (2 equiv), and tBuOK (2 equiv) in toluene
(4 mL) at RT for 2–4 h. Yield of isolated product given. [a] At 508C.
[b] 56% with TMP salt; see the Supporting Information.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
[1] a) M. Dalziel, M. Crispin, C. N. Scanlan, N. Zitzmann, R. A.
Dwek, Science 2014, 343, 1235681; b) J. E. Hudak, C. R.
Bertozzi, Chem. Biol. 2014, 21, 16 – 37; c) B. Ernst, J. L. Magnani,
Nat. Rev. Drug Discovery 2009, 8, 661 – 677; d) R. J. Pieters,
ChemBioChem 2006, 7, 721 – 728.
[2] a) M. Jacobsson, J. Malmberg, U. Ellervik, Carbohydr. Res. 2006,
341, 1266 – 1281; b) K. J. Jensen, J. Chem. Soc. Perkin Trans.
1 2002, 2219 – 2233; For recent examples, see c) J. P. Issa, C. S.
Bennett, J. Am. Chem. Soc. 2014, 136, 5740 – 5744 and referer-
ences therein.
Scheme 5. Fluoroalkylation of carbohydrates. Mes=mesityl.
[3] a) H. M. Burke, T. Gunnlaugsson, E. M. Scanlan, Chem.
Commun. 2015, 51, 10576 – 10588; b) E. Pershagen, K. E.
Borbas, Angew. Chem. Int. Ed. 2015, 54, 1787 – 1790; Angew.
Chem. 2015, 127, 1807 – 1810; c) M. E. Dirks-Hofmeister, T.
Verhaeghe, K. De Winter, T. Desmet, Angew. Chem. Int. Ed.
2015, 54, 9289 – 9292; Angew. Chem. 2015, 127, 9421 – 9424; d) Y.
Ichikawa, M. Kamiya, F. Obata, M. Miura, T. Terai, T. Komatsu,
T. Ueno, K. Hanaoka, T. Nagano, Y. Urano, Angew. Chem. Int.
Ed. 2014, 53, 6772 – 6775; Angew. Chem. 2014, 126, 6890 – 6893.
[4] A. Fernꢃndez-Tejada, F. J. CaÇada, J. Jimꢄnez-Barbero, Chem.
Eur. J. 2015, 21, 10616 – 10628.
[5] A. Michael, J. Am. Chem. Soc. 1879, 1, 305 – 312.
[6] All top-selling small-molecule drugs contain aromatic or fluo-
rinated groups. See: N. A. McGrath, M. Brichacek, J. T. Njar-
darson, J. Chem. Educ. 2010, 87, 1348 – 1349.
[7] a) A. S. Henderson, S. Medina, J. F. Bower, M. C. Galan, Org.
Lett. 2015, 17, 4846 – 4849; b) U. Huchel, C. Schmidt, R. R.
Schmidt, Eur. J. Org. Chem. 1998, 1998, 1353 – 1360; c) U.
Huchel, C. Schmidt, R. R. Schmidt, Tetrahedron Lett. 1995, 36,
9457 – 9460; d) S. K. Sharma, G. Corrales, S. Penadꢄs, Tetrahe-
dron Lett. 1995, 36, 5627 – 5630.
In conclusion, novel methodology to O-functionalize
carbohydrate derivatives was developed using bench-stable
and easily prepared iodonium(III) reagents. To the best of our
knowledge, this is the first general approach to introduce
traditionally non-electrophilic (aryl and trifluoroethyl)
groups onto a variety of different carbohydrate hydroxy
groups, thus attaining products which have previously been
unobtainable or required long synthetic sequences. The
strategy was applied to introduce both electron-withdrawing
and electron-donating aryl groups under ambient conditions
and without precautions to avoid air and moisture. Further-
more, the reaction could be extended both to full arylation of
cyclodextrin, and to trifluoroethylation of carbohydrate
derivatives.
We anticipate that this methodology will receive great
interest in both organic chemistry and biochemistry, as
important functional groups can be implemented under
simple and robust reaction conditions. Application of the
methodology towards synthesis and evaluation of novel
bioactive compounds are underway in our laboratories.
[8] N. Das Adhikary, P. Chattopadhyay, Eur. J. Org. Chem. 2011,
7346 – 7354.
[9] D. H. R. Barton, J.-P. Finet, W. B. Motherwell, C. Pichon, J.
Chem. Soc. Perkin Trans. 1 1987, 251 – 259.
[10] a) K. E. Torraca, X. Huang, C. A. Parrish, S. L. Buchwald, J. Am.
Chem. Soc. 2001, 123, 10770 – 10771; b) S. Bhadra, W. I. Dzik,
L. J. Goossen, J. Am. Chem. Soc. 2012, 134, 9938 – 9941; c) G. L.
Experimental Section
The carbohydrate derivative 1 (0.04–0.4 mmol) was stirred in a 20 mL
screw-cap vial in toluene (no dry solvent needed; 0.4–4 mL) for
3 minutes. A mixture of 4-nitrophenyl(phenyl) iodonium triflate (2a;
1.5 equiv/OH) and potassium tert-butoxide (1.5 equiv/OH) was
added, without taking precautions to exclude air, over a period of
2–3 minutes, while the mixture turned yellow. The reaction was stirred
for 5–60 min, followed by TLC. Upon completion, the mixture was
transferred to a round-bottom flask with EtOAc (3 ꢀ 10 mL) and
Celite was added. The volatiles were removed under reduced
pressure, and the residue was subjected to column chromatography
to provide the product 3.
˝
Tolnai, B. Petho, P. Krꢃll, Z. Novꢃk, Adv. Synth. Catal. 2014, 356,
125 – 129; d) S. Bhadra, W. I. Dzik, L. J. Gooßen, Angew. Chem.
Int. Ed. 2013, 52, 2959 – 2962; Angew. Chem. 2013, 125, 3031 –
3035.
[11] J. A. Terrett, J. D. Cuthbertson, V. W. Shurtleff, D. W. C. Mac-
Millan, Nature 2015, 524, 330 – 334.
[12] X. Shen, C. N. Neumann, C. Kleinlein, N. W. Goldberg, T. Ritter,
Angew. Chem. Int. Ed. 2015, 54, 5662 – 5665; Angew. Chem.
2015, 127, 5754 – 5757. Ligand price at Sigma – Aldrich, 360 E/
mmol, April 2016.
[13] a) A. Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116, 3328 –
3435; b) K. Aradi, B. L. Tꢅth, G. L. Tolnai, Z. Novꢃk, Synlett
2016, 27, 1456 – 1485; c) B. Olofsson, Top. Curr. Chem. 2015, 373,
135 – 166; d) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed.
2009, 48, 9052 – 9070; Angew. Chem. 2009, 121, 9214 – 9234.
[14] a) A. Kirschning, Eur. J. Org. Chem. 1998, 1998, 2267 – 2274;
b) T. Kajimoto, K. Morimoto, R. Ogawa, T. Dohi, Y. Kita, Eur. J.
Org. Chem. 2015, 2015, 2138 – 2142; c) E. Kunst, F. Gallier, G.
Dujardin, A. Kirschning, Org. Biomol. Chem. 2008, 6, 893 – 898;
d) A. Kirschning, J. Org. Chem. 1995, 60, 1228 – 1232.
Acknowledgments
We are grateful to Dr. Johan Olsson and Prof. Thisbe
Lindhorst for initial discussions. Olle Engkvist Byggmꢁstare
foundation is acknowledged for project funding and GLTꢂs
postdoctoral scholarship.
Keywords: arylation · carbohydrates · electrophilic addition ·
fluorine · hypervalent compounds
[15] a) R. Ghosh, E. Stridfeldt, B. Olofsson, Chem. Eur. J. 2014, 20,
8888 – 8892; b) R. Ghosh, E. Lindstedt, N. Jalalian, B. Olofsson,
ChemistryOpen 2014, 3, 54 – 57; c) E. Lindstedt, R. Ghosh, B.
Olofsson, Org Lett. 2013, 15, 6070 – 6073; d) N. Jalalian, T. B.
Petersen, B. Olofsson, Chem. Eur. J. 2012, 18, 14140 – 14149; for
other O-arylations of alcohols with diaryliodonium salts, see
e) S. K. Sundalam, D. R. Stuart, J. Org. Chem. 2015, 80, 6456 –
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
6466; f) J. J. Lubinkowski, J. W. Knapczyk, J. L. Calderon, L. R.
2008, 73, 4602 – 4607; c) M. Zhu, N. Jalalian, B. Olofsson, Synlett
Petit, W. E. McEwen, J. Org. Chem. 1975, 40, 3010 – 3015.
[16] a) W. Zhu, Y. Wang, K. Li, J. Gao, C.-H. Huang, C.-C. Chen, T.-P.
Ko, Y. Zhang, R.-T. Guo, E. Oldfield, J. Med. Chem. 2015, 58,
1215 – 1227; b) A. Mꢆller, H. Kobarg, V. Chandrasekaran, J.
Gronow, F. D. Sçnnichsen, T. K. Lindhorst, Chem. Eur. J. 2015,
21, 13723 – 13731; c) O. Ramstrçm, S. Lohmann, T. Bunyapai-
boonsri, J.-M. Lehn, Chem. Eur. J. 2004, 10, 1711 – 1715.
[17] a) I. Cumpstey, E. Salomonsson, A. Sundin, H. Leffler, U. J.
Nilsson, Chem. Eur. J. 2008, 14, 4233 – 4245; b) I. Cumpstey, A.
Sundin, H. Leffler, U. J. Nilsson, Angew. Chem. Int. Ed. 2005, 44,
5110 – 5112; Angew. Chem. 2005, 117, 5240 – 5242; c) P. Sçrme, P.
Arnoux, B. Kahl-Knutsson, H. Leffler, J. M. Rini, U. J. Nilsson, J.
Am. Chem. Soc. 2005, 127, 1737 – 1743; d) V. K. Rajput, H.
Leffler, U. J. Nilsson, B. Mukhopadhyay, Bioorg. Med. Chem.
Lett. 2014, 24, 3516 – 3520.
[18] a) J. A. Galbis, M. d. G. Garcꢇa-Martꢇn, M. V. de Paz, E. Galbis,
Chem. Rev. 2016, 116, 1600 – 1636; b) F. Fenouillot, A. Rousseau,
G. Colomines, R. Saint-Loup, J. P. Pascault, Prog. Polym. Sci.
2010, 35, 578 – 622; c) R. Medimagh, S. Mghirbi, A. Saadaoui, A.
Fildier, M. Desloir-Bonjour, G. Raffin, H. R. Kricheldorf, S.
Chatti, Compt. Rend. Chim. 2013, 16, 1127 – 1139.
[19] a) D. Arnone, Ann. Gen. Psychiatry 2005, 4, 1 – 14; b) B. E.
Maryanoff, M. J. Costanzo, S. O. Nortey, M. N. Greco, R. P.
Shank, J. J. Schupsky, M. P. Ortegon, J. L. Vaught, J. Med. Chem.
1998, 41, 1315 – 1343; c) B. E. Maryanoff, S. O. Nortey, J. F.
Gardocki, R. P. Shank, S. P. Dodgson, J. Med. Chem. 1987, 30,
880 – 887.
2008, 592 – 596.
[21] V. K. Tiwari, B. B. Mishra, K. B. Mishra, N. Mishra, A. S. Singh,
X. Chen, Chem. Rev. 2016, 116, 3086 – 3240.
[22] J.-H. Chun, V. W. Pike, Eur. J. Org. Chem. 2012, 2012, 4541 –
4547.
[23] a) J. B. Han, J. H. Hao, C. P. Zhang, H. L. Qin, Curr. Org. Chem.
2015, 19, 1554 – 1565; b) K. Le Mai Hoang, X.-W. Liu, Nat.
Commun. 2014, 5, 5051; c) R. F. G. Frçhlich, E. Schrank, K.
Zangger, Carbohydr. Res. 2012, 361, 100 – 104; d) D. Vuluga, J.
Legros, B. Crousse, D. Bonnet-Delpon, Eur. J. Org. Chem. 2009,
2009, 3513 – 3518; e) D. Gueyrard, P. Rollin, T. T. T. Nga, M.
Ourꢄvitch, J.-P. Bꢄguꢄ, D. Bonnet-Delpon, Carbohydr. Res. 1999,
318, 171 – 179.
[24] a) Q. Yang, J. T. Njardarson, Tetrahedron Lett. 2013, 54, 7080 –
7082; b) N. Bodor, M.-J. Huang, C. Szꢃntay, Jr., C. Szꢃntay,
Tetrahedron 1992, 48, 5823 – 5830.
[25] a) B. L. Tꢅth, S. Kovꢃcs, G. Sꢃlyi, Z. Novꢃk, Angew. Chem. Int.
Ed. 2016, 55, 1988 – 1992; Angew. Chem. 2016, 128, 2028 – 2032;
b) G. L. Tolnai, A. Szꢄkely, Z. Makꢅ, T. Gꢃti, J. Daru, T. Bihari,
A. Stirling, Z. Novꢃk, Chem. Commun. 2015, 51, 4488 – 4491.
Similar reagents have been used as promotors in glycosylation
reactions, but have not been utilized as group-transfer reagents.
See: c) A.-H. A. Chu, A. Minciunescu, C. S. Bennett, Org. Lett.
2015, 17, 6262 – 6265; d) A.-H. A. Chu, A. Minciunescu, V.
Montanari, K. Kumar, C. S. Bennett, Org. Lett. 2014, 16, 1780 –
1782.
[20] Diaryliodonium salts were synthesized according to: a) M.
Bielawski, M. Zhu, B. Olofsson, Adv. Synth. Catal. 2007, 349,
2610 – 2618; b) M. Bielawski, D. Aili, B. Olofsson, J. Org. Chem.
Received: June 20, 2016
Revised: July 12, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Hypervalent Compounds
Salty sweet! A novel method for O-
functionalization of carbohydrate deriva-
tives has been established using bench-
stable, easily prepared iodonium(III)
reagents. Both electron-withdrawing and
electron-donating aryl groups were intro-
duced under ambient conditions and
without precautions to exclude air or
moisture. The reaction has been extended
to trifluoroethylations and to full arylation
of cyclodextrin.
G. L. Tolnai, U. J. Nilsson,
B. Olofsson*
&&&& — &&&&
Efficient O-Functionalization of
Carbohydrates with Electrophilic
Reagents
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!