Solvent-free synthesis of glycosyl chlorides based on the triphenyl phosphine/hexachloroacetone system

Article abstract of DOI:10.1016/j.tetlet.2017.03.068

Glycosyl chlorides, useful as glycosyl donors in glycoside synthesis and precursors in organic synthesis, can be easily prepared under solvent-free conditions by exposing a sugar hemiacetal to an equimolar mixture of PPh₃ and hexachloroacetone

Full text of DOI:10.1016/j.tetlet.2017.03.068

Accepted Manuscript
Solvent-free synthesis of glycosyl chlorides based on the triphenyl phosphine/
hexachloroacetone system
Serena Traboni, Federica Liccardo, Emiliano Bedini, Maddalena Giordano,
Alfonso Iadonisi
PII:
S0040-4039(17)30371-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.068
TETL 48769
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 February 2017
19 March 2017
22 March 2017
Please cite this article as: Traboni, S., Liccardo, F., Bedini, E., Giordano, M., Iadonisi, A., Solvent-free synthesis
of glycosyl chlorides based on the triphenyl phosphine/hexachloroacetone system, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.03.068
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Solvent-free synthesis of glycosyl chlorides
based on the triphenyl
phosphine/hexachloroacetone system
Leave this area blank for abstract info.
Serena Traboni, Federica Liccardo, Emiliano Bedini, Maddalena Giordano, Alfonso Iadonisi
PO
PO
PO
PO
PO
PO
PPh3 (1.5 eq)
O
O
CCl3COCCl3
(1.5 eq), 70 °C
PO
PO
Cl
OH
11 examples,
30-120 min,
44-95 %
P: Ac, Bn, All, Fmoc,
benzylidene, isopropylidene

1
Tetrahedron Letters
journal homepage: www.els evier.com
Solvent-free synthesis of glycosyl chlorides based on the triphenyl
phosphine/hexachloroacetone system
Serena Traboni,a Federica Liccardo, a,b Emiliano Bedini, a Maddalena Giordano, a and Alfonso Iadonisi a ∗
aDepartment of Chemical Sciences, University of Naples Federico II, Via Cinthia 4, I-80126 Naples (Italy)
bCurrent address: Institute of Protein Biochemistry, National Research Council of Italy, Via P.Castellino 111, I-80131 Naples (Italy)
ARTICLE INFO
ABSTRACT
Article history:
Received
Glycosyl chlorides, useful as glycosyl donors in glycoside synthesis and precursors in organic
synthesis, can be easily prepared under solvent-free conditions by exposing a sugar hemiacetal
to an equimolar mixture of PPh3 and hexachloroacetone at 70 °C. The reaction affords products
in high yields and short times, and is tolerant of a wide range of commonly adopted protecting
groups.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Glycosyl chlorides
Solvent-free reactions
Glycosidation
Chlorination
Carbohydrates
1. Introduction
2. Results and discussion
Glycosyl chlorides are useful glycosyl donors in the synthesis
of O- and C- glycosides,1-8 and can also serve as precursors in
other elaborations of carbohydrates.9 In comparison to
brominated and iodinated counterparts, they are appreciated
because of the higher stability, a feature especially evidenced by
the feasible chromatographical purification of most per-O-
benzylated glycosyl chlorides; in contrast, the corresponding
bromo and iodo donors are commonly too reactive and have to be
directly used just after their generation.10 Known methods for the
synthesis of glycosyl chlorides entail stoichiometric amounts of
sensitive reagents such as CHCl2OMe,11 SOCl2,12 TiCl4,13 oxalyl
Very recently, in the course of a project aimed at investigating
the comparative reactivity of glycosyl halides, we needed a
practical and straightforward approach to armed benzylated
glycosyl chlorides. In pursuing our interest towards practical
approaches to synthetic elaboration of carbohydrates, we
examined the feasibility of a solvent-free anomeric chlorination;
for this purpose procedures of carbinol chlorinations based on
liquid reagents were expected to be more suitable for providing a
minimal mobility to the reaction medium. As a matter of fact, a
preliminary screening demonstrated that the combination of
triphenylphosphine with liquid hexachloroacetone24,25 or
trichloroacetonitrile25 proved compatible with a solvent-free
application. As shown in scheme 1, exposure at 70 °C of tetra-O-
benzyl glucose 1 to just a moderate excess of PPh3 and a liquid
chloride,14
chlorodiphenylphosphate,16
chloroenamine
derivatives,15
PCl5,17
BuLi,16
triphosgene,18
DMF/trichlorotriazine combination,19 and strictly controlled
experimental conditions are thereby required. In addition, in most
of these approaches is lacking a compatibility with both acid- and
base-labile groups.
chlorinating
hexachloroacetone provided the corresponding glycosyl chloride
agent
such
as
trichloroacetonitrile
or
2 in good yields within short times.
Over the last years, our interest was focused on development
of practically simple approaches for regioselective
functionalization of carbohydrates under solvent-free conditions,
and several approaches were disclosed for selective derivatization
of sugar polylols with alkyl/silyl ethers and acetal protecting
groups.20-23 In this paper we wish to report the scope extension of
the solvent-free elaboration of carbohydrates to the synthesis of
glycosyl chlorides.
BnO
BnO
BnO
PPh3 (1.5 eq)
BnO
BnO
BnO
O
O
CCl3COCCl3
or CCl3CN
(1.5 eq), 70 °C
BnO
Cl
BnO OH
2
1
yields > 75%
Scheme 1 Solvent-free anomeric chlorination of sugar hemiacetals
Both agents gave good yields (in the 75-85 % range), and so
we decided to investigate the scope of the method adopting
perchloroacetone because of its much lower cost and its best
———
∗ Corresponding author. Tel.: +39-081674154; fax: +39-081674393; e-mail: iadonisi@unina.it

2
Tetrahedron Letters
9
performance in the chlorination of simple model alcohols
reported in previous studies.25 A slight yield improvement up to
89 % (Table 1, entry 1) was achieved through a procedure based
45
45
Cl
OH
O
O
BnO
BnO
BnO
BnO
2i, > 90 %c
OBn
on
a very short preliminary interaction of PPh3 and
OBn
1i
hexachloroacetone (for one minute) and subsequent addition of
the sugar hemiacetal. On this basis we applied this latter
procedure in all cases where the physical state of the hemiacetal
allowed its addition in a neat form. The scope of the
methodology was assessed on a wide range of sugar hemiacetals
and results are summarized in Table 1.
10
BnO
BnO
O
O
TrocHN
TrocHN
BnO
OH
BnO
2j, > 90 % c
Cl
1j
Table 1. Synthesis of glycosyl chlorides under solvent-free
conditionsa
11
45
OH
Cl
O
O
OBn
PPh3 (1.5 eq)
OBn
O
O
OBn
BnO
1l
PO
PO
OBn
BnO
2l, > 90 % c
CCl3COCCl3
(1.5 eq), 70 °C
OH
Cl
a General conditions: hexachloroacetone (1.5 eq) added to a mixture of
hemiacetal (1 eq) and PPh3 (1.5 eq) at rt (caution: exothermic reaction) , then
heating to 70 °C. For entries 1, 2, 7, 8, 11: hexachloroacetone (1.5 eq) and
PPh3 (1.5 eq) premixed at rt for 1 minute (caution: exothermic reaction), then
addition of hemiacetal (1 eq) and heating to 70 °C. b Isolated yield, except for
entries 9-11. c Yield evaluated by NMR analysis of the crude mixture.
P: protecting group
Entry Substrate
Time
(min)
Product, yieldb
1
45
BnO
BnO
BnO
BnO
BnO
BnO
The protocol was initially examined on per-O-benzylated and
per-O-acetylated hexoses and good yields were invariably
obtained in short times (45-60 minutes) with different sugar
precursors (entries 1, 2, 4 and 5). The methodology was then
assessed on more elaborated hexose hemiacetals carrying other
functional groups such as 1c26 (allylated at O-3) (entry 3), 1f
(with an azido group) (entry 6), and 1g (with a benzylidene, a
Fmoc carbonate and a Troc carbamate in the same structure)27
(entry 7) with satisfying isolated yields being obtained. An
excellent result was also recorded with the di-isopropylidene
mannofuranose 1h (entry 8). Interestingly, glycosyl chlorides
were generally obtained with an excellent α-selectivity, and
detectable lower amounts of β-anomers were observed only when
starting from manno-precursors, both in the pyranose (entries 3,
5) and furanose (entry 8) form (spectra in the supplementary
material).
O
O
BnO
BnO
OH
OH
Cl
1a
2a, 89 %
2
3
4
5
45
60
60
45
BnO
OBn
O
BnO
OBn
O
BnO
BnO Cl
2b, 92 %
BnO
BnO
1b
BnO
BnO
OBn
O
OBn
O
BnO
AllO
BnO
AllO
OH
Cl
1c
2c, 81 %
AcO
AcO
AcO
AcO
AcO
AcO
O
O
All the glycosyl chlorides thus far described generally
displayed a satisfying stability to silica gel chromatography, as
evidenced by the good to excellent yields recorded after isolation
(except for 2g which exhibited some instability). In all cases this
purification approach allowed easy separation from
triphenyloxide and chloroacetone side-products. When the
methodology was applied to L-rhamno 1i,28 D-fucosamine 1j,29
and commercially available L-fuco 1l 6-deoxysugar hemiacetals
(entries 9-11), an effective chlorination process was still
observed, as evidenced by NMR analysis of the reaction
mixture; unfortunately in these cases chromatograpical
purification caused extensive degradation of the generated
chlorides to the detriment of the isolated yield. Aiming at
avoiding a chromatograpical approach for purification of these
especially labile compounds, we attempted the selective
precipitation of triphenyloxide with several solvents, but glycosyl
chlorides underwent partial decomposition even under these
conditions.
AcO
AcO
Cl
OH
OH
2d, 85 %
1d
AcO
AcO
AcO
AcO
OAc
O
OAc
O
AcO
AcO
Cl
1e
2e, 92 %
BnO
6
60
BnO
BnO
1f
OBn
O
OBn
O
BnO
N3
N3 Cl
OH
2f, 76 %
7
8
45
45
Ph
O
FmocO
Ph
O
O
O
O
O
FmocO
TrocHN
2g, 44 %
TrocHN
OH
Cl
1g
In order to ascertain the feasible applicability of these labile
glycosyl chlorides in a crude form, an attempt was then made to
exploit them in the synthesis of O-glycosides. In a test reaction,
commercial L-fucose hemiacetal 1l was converted into the
corresponding chloride 2l, and then 2-chloro-4-nitro phenol and
DIPEA were added to the mixture. The reaction occurred
smoothly at 60°C, affording aryl-O-fucoside 3l with high β-
selectivity (Scheme 2).
O
O
O
O
O
O
OH
Cl
O
O
O
O
1h
2h, 95 % (α:β >
10)

3
easy to handle reagents, does not require application of an inert
Cl
O
1) Cl3CCOCCl3 and
PPh3 (1.5 eq both),
45 min, 70 °C
OH
NO2
atmosphere, and is experimentally very simple. In addition, the
conditions were found compatible with a large set of protecting
groups of common application in organic synthesis. In one
example was also shown the potential of glycosyl chlorides thus
prepared in one-pot synthesis of glycosides.
O
OBn
OBn
O
OBn
OBn
BnO
1l
BnO
3l, 75%
2) DIPEA (6 eq),
2-chloro-4-nitro
phenol (5 eq),
60 °C, 1h
Acknowledgments
Scheme 2: One-pot solvent-free chlorination/O-glycosylation of 2,3,4-tri-O-
benzylated L-fucose hemiacetal
Financial
support
from
Ministero
dell’Istruzione,
dell’Univeristà e della Ricerca (MIUR) (Progetto PON_00117:
“Antigeni ed adiuvanti per vaccini ed immunoterapie”) and
Regione Campania (“Progetto di Ricerca POR-BIP BioIndustrial
In conclusion, we have developed a very simple approach for
the solvent-free chlorination of sugar hemiacetals.30 Unlike most
reported approaches, the proposed method is based on cheap and
Processes”)
are
acknowledged.
18. Cicchillo, R. M.; Norris, P. Carbohydr. Res. 2000, 328, 431-434.
19. Chang, C.-W.; Chang S.-S.; Chao, C.-S.; Mong, K.-K. T.
Tetrahedron Lett. 2019, 50, 4536-4540.
References and notes
20. Giordano, M.; Iadonisi, A. Tetrahedron Lett. 2013, 54, 1550-1552.
−222.
21. Giordano, M.; Iadonisi, A. J. Org. Chem. 2014, 79, 213
1. (a) Matwiejuk, M.; Thiem, J. Eur. J. Org. Chem. 2011, 5860–
5878; (b) Boettcher, S.; Matwiejuk, M.; Thiem, J. Beilstein J.
Org. Chem. 2012, 8, 413–420; (c) Bottcher, S.; Thiem, J. RSC
Adv. 2014, 4, 10856-10861.
22. Traboni, S.; Bedini, E.; Giordano, M.; Iadonisi, A. Adv. Synt.
Catal .2015, 357, 3562-3572.
23. Traboni, S.; Bedini, E.; Iadonisi, A. Beilstein J. Org. Chem. 2016,
12, 2748-2756.
2. Richardson, M. B.; Torigo, S.; Yamasaki, S.; Williams, S. J.
Chem. Commun. 2015, 51, 15027-15030.
24. Magid, R. M.; Fruchey, S.; Johnson, W. L.; Allen, T. G. J. Org.
Chem. 1979, 44, 359-361.
3. Matsuo, I.; Wada, M.; Manabe, S.; Yamaguchi, Y.; Otake, K.;
Kato, K.; Ito, Y. J. Am. Chem. Soc., 2003, 125 , 3402–3403.
4. Ohrui, H.; Fox, J. J. Tetrahedron Lett. 1973, 14, 1951–1954.
5. Park, Y.; Harper, K. C.; Kuhl, N.; Kwan, E. E.; Liu, R. Y.;
Jacobsen, E. N. Science 2017, 355, 162-166.
25. Pluempanupat, W.; Chantarasriwong, O.; Taboonpong, P.; Jangb,
D. O.; Chavasiria, W. Tetrahedron Lett. 2007, 48, 223-226.
26. Valerio, S.; Pastore, A.; Adinolfi, M.; Iadonisi, A. J. Org. Chem.
2008, 73, 4496-4503.
6. Sun, L.; Wu, X.; Xiong, D.-C.; Ye, X.-S. Angew. Chem. Int. Ed.
2016, 55, 8041–8044.
27. Obtained from the corresponding allyl glycoside: Lewicky, J.D.;
Vlanova, M.; Jiang, Z.-H. Carbohydr. Res. 2011, 346, 1705-1713.
28. Obtained from the corresponding 1-O-acetylated precursor: (a)
Cirillo, L.; Bedini, E.; Parrilli, M. Eur. J. Org. Chem. 2008, 34,
5704-5714; (b) Cirillo, L.; Di Nola, A.; Bedini, E.; Parrilli,
M. Carbohydr. Res. 2009, 344, 2406-2411.
−5739
7. Feng, S.; Li, C. J. Agric. Food Chem. 2015, 63, 5732
.
8. Animati, F.; Berettoni, M.; Bigioni, M.; Binaschi, M.; Felicetti, P.;
Gontrani, L.; Incani, O.; Madami, A.; Monteagudo, E.; Olivieri,
L.; Resta, S.; Rossi, C.; Cipollone, A. Chem. Med. Chem. 2008, 3,
266-279.
29. Obtained from the corresponding thioethyl glycoside: Comegna,
D.; Bedini, E.; Parrilli, M. Tetrahedron 2008, 64, 3381-3391.
30. General procedure: hexachloroacetone (1.5 eq) and PPh3 (1.5 eq)
were premixed at rt for 1 minute (CAUTION: exothermic
reaction). To the resulting mixture, hemiacetal (1 eq) was added
and the reaction flask was placed in an oil bath at 70 °C (see Table
1 for details) with continuous stirring. On completion of the
reaction, the mixture was cooled to rt, adsorbed on a plug of silica
gel, and loaded on the top of the silica gel column. Elution with
hexane/ethyl acetate mixtures afforded glycosyl chlorides in the
yields indicated in Table 1. When the hemiacetal was difficult to
be added in a neat form, the hemiacetal, hexachloroacetone (1.5
eq) and PPh3 (1.5 eq) were mixed altogether at the start of the
reaction and then an analogous procedure was followed.
9. (a) Gomez, A. M.; Casillas, M.; Valverde, S.; Lopez, J. C. Chem.
Commun. 1996, 2357-2358; (b) (a) Gomez, A. M.; Pedregosa, A.;
Casillas, M.; Uriel, C.; Lopez, J. C. Eur J. Org. Chem. 2009,
3579-3588.
10. For some recent examples: Verkhnyatskaya, S. A.; Krylov, V. B.;
Nifantiev, N. E. Eur. J. Org. Chem. 2017, 710-718; (b) Giordano,
M.; Iadonisi, A.; Pastore, A. Eur. J. Org. Chem. 2013, 3137--3147;
(c) Csavas, M.; Majer, G.; Herczeg, M.; Remenyik, J.; Lazar, L.;
Mandi, A.; Borbas, A.; Antus, S. Carbohydr. Res. 2011, 346,
1527-1533; (d) Pastore, A.; Valerio, S.; Adinolfi, M.; Iadonisi, A.
Chem. Eur. J. 2011, 17, 5881 – 5889.
11. (a) Bednarczyk, D.; Walczewska, A.; Grzywacz, D.; Sikorski, A.;
Liberek, B.; Myszka, H. Carbohydr. Res. 2013, 367, 10–17; (b)
Ziegler, T.; Seidl, U. J. Carbohydr. Chem. 1991, 10, 813-831.
12. (a) Singhamahapatra, A.; Sahoo, L.; Paul, K. J. V.; Varghese, B.;
Loganathan, D. Tetrahedron Lett. 2013, 54, 6121–6124; (b) Watt,
G. M.; Boons, G. J. Carbohydr. Res. 2004, 338, 181-193.
13. Bonomi, P.; Attieh, M. D.; Gonzato, C.; Haupt, K. Chem. Eur. J.
2016, 22,10150 –10154.
Supplementary Material
Copy of 1H and 13C NMR spectra of isolated products.
14. (a) Iversen, T.; Bundle, D. R. Carbohydr. Res. 1982, 103, 29–40;
(b) Sugiyama, S.; Diakur, J. M. Org. Lett. 2000, 2, 2713-2715; (c)
Encinas, L.; Chiara, J. L. J. Comb. Chem. 2008, 10, 361--363.
15. Ernst, B.; Winkler, T. Tetrahedron Lett. 1989, 30, 3081-3084.
16. Hung, S. C.; Wong, C.-H. Tetrahedron Lett. 1997, 37, 4903-
4906.rnst, B.; Winkler, T. Tetrahedron Lett. 1989,
17. Ibatullin, F. M.; Selivanov, S. I. Tetrahedron Lett. 2002, 43, 9577-
9580.
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Nella seconda esperienza si è analizzato il P-pentacetil-glucosio in CDC13.
AcO,, O A cOAc
-
-
-
The hexachloroacetone/PPh3 system allows solvent-free chlorination of hemiacetals
Glycosyl chlorides can be prepared in high-yields and short times
Broad compatibility with acid- and base labile protecting groups