Applications of thiyl radical cyclizations for the synthesis of thiosugars

Article abstract of DOI:10.1021/ol303310u

The use of intramolecular thiyl radical cyclizations for the synthesis of thiosugars has been investigated, and a new free-radical-based methodology for the synthesis of biologically important thiosugars has been developed. The methodology is mild and pro

Full text of DOI:10.1021/ol303310u

ORGANIC
LETTERS
2013
Vol. 15, No. 3
504–507
Applications of Thiyl Radical Cyclizations
for the Synthesis of Thiosugars
Aoife Malone and Eoin M. Scanlan*
School of Chemistry, Trinity College Dublin, Trinity Biomedical Sciences Insitute,
152-160 Pearse Street, Dublin 2, Ireland
eoin.scanlan@tcd.ie
Received December 3, 2012
ABSTRACT
The use of intramolecular thiyl radical cyclizations for the synthesis of thiosugars has been investigated, and a new free-radical-based
methodology for the synthesis of biologically important thiosugars has been developed. The methodology is mild and proceeds via either 6-endo
or 5-exo cyclization to furnish the thiosugar ring. This represents the first examples of thiyl radical cyclization being applied to the synthesis of
thiosugars.
Thiosugars are carbohydrate analogues where one or
more oxygen atoms are substituted with sulfur in both
furanoside and pyranoside structures.1 These compounds
haveattracted significant interestin recent years because of
their biological activity as potent inhibitors of glycosidase
enzymes.2 Glycosidases are essential enzymes involved in
catalyzing the hydrolysis of glycosidic bonds.3 A number
of thiosugar-based therapeutics have been developed,
including treatments for diabetes1b,4 and antiviral5,6 and
anticancer compounds.7 A small number of thiosugars
have been isolated from natural sources; these include
5-thiomannose, salacinol, and kotalonal.8 However, in
order to gain a better understanding of the biological
activity of these compounds and to fully exploit their
therapeutic potential it is necessary to develop synthetic
methodologies to access their core structure.
In recent years, a large number of efficient strategies
have been developed for the synthesis of thiosugars.1a,9
Despite these intensive synthetic studies, the use of intra-
molecular thiyl radical cyclization reactions has not pre-
viously been investigated. Examples of intramolecular
thiyl radical cyclizations onto alkenes for the prepara-
tion of sulfur containing heterocycles are rare,10 but the
(1) (a) Yuasa, H.; Izumi, M.; Hashimoto, H. Curr. Top. Med. Chem.
2009, 9, 76. (b) Witczak, Z. J.; Culhane, J. M. Appl. Microbiol.
Biotechnol. 2005, 69, 237. (c) Capon, R. J.; MacLeod, J. K. J. Chem.
Soc., Chem. Commun. 1987, 1200.
(2) (a) Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342, 1551.
(b) Yuasa, H.; Nakano, Y.; Hashimoto, H. Carbohydr. Lett. 1996, 2, 23.
(c) Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.; Zhong, Z.; Ichikawa,
Y.; Porco, J. A., Jr.; Wong, C.-H. J. Am. Chem. Soc. 1991, 113, 6187.
(3) (a) Asano, N. Glycobiology 2003, 13, 93R. (b) Winchester, B.;
Fleet, G. W. J. Glycobiology 1992, 2, 199.
(9) Recent examples include: (a) Zhang, J.; Niu, Y.; Cao, X.; Ye, X. S.
Tetrahedron 2012, 68, 4242. (b) Gunasundari, T.; Chandrasekaran, S.
J. Org. Chem. 2010, 75, 6685. (c) Eskandari, R.; Jayakanthan, K.;
Kuntz, D. A.; Rose, D. R.; Pinto, B. M. Bioorg. Med. Chem. 2010, 18,
2829. (d) Jayakanthan, K.; Mohan, S.; Pinto, B. M. J. Am. Chem. Soc.
2009, 131, 5621. (e) Mohan, S.; Pinto, B. M. Carbohydr. Res. 2007, 342,
1551. (f) Passacantilli, P.; Centore, C.; Ciliberti, E.; Piancatelli, G.;
Leonelli, F. Eur. J. Org. Chem. 2006, 3097. (g) Benazza, M.; Halila, S.;
Viot, C.; Danquigny, A.; Pierru, C.; Demailly, G. Tetrahedron 2004, 60,
2889. (h) Southern, J. M.; O’Neil, I. A.; Kearns, P. SYNLETT 2008, 14,
2158.
(4) Hellman, B.; Lernmark, A.; Sehlin, J. B.; Taljedal, J. B.; Whistler,
R. L. Biochem. Pharmacol. 1973, 22, 29.
(5) Selwood, D. L.; Carter, K.; Young, R. J.; Jandu, K. S. Bioorg.
Med. Chem. Lett. 1996, 6, 991.
(6) Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.;
Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1996, 61, 822.
(7) (a) Yoshimura, Y.; Endo, M.; Sakata, S. Tetrahedron Lett. 1999,
40, 1937. Kim, J. H.; Kim, S. H.; Hahn, E. W.; Song, C. W. Science 1978,
200, 206.
(10) (a) Aimetti, A. A.; Shoemaker, R. K.; Linc, C. C.; Anseth, K. S.
Chem. Commun. 2010, 46, 4061. (b) Ozaki, S.; Matsui, E.; Saiki, T.;
Yoshinaga, H.; Ohmori, H. Tetrahedron Lett. 1998, 39, 8121. (c) Cabri,
W.; Candiani, I.; Bedeschi, A. Tetrahedron Lett. 1992, 33, 4783. (d)
Crozet, M. P.; Kaafarani, M.; Kassar, W.; Surzur, J. M. Tetrahedron
Lett. 1982, 23, 5039. (e) Nouguier, R.; Surzur, J. M. Tetrahedron 1976,
32, 2001. (f) Crozet, M. P.; Surzur, J. M.; Dupuy, C. Tetrahedron Lett.
1971, 23, 2031. (g) Surzur, J. M.; Crozet, M. P.; Dupuy, C. Tetrahedron
Lett. 1971, 22, 2025.
(8) (a) Capon, R. J.; MacLeod, J. K. J. Chem. Soc., Chem. Commun.
1987, 1200.
r
10.1021/ol303310u
Published on Web 01/18/2013
2013 American Chemical Society

analogous, intermolecular thiolÀene click (TEC) reaction
is becoming widely used in carbohydrate and peptide
chemistry for the synthesis of glycopeptides and glyco-
proteins.11 The mild initiation conditions and tolerance of
a range of functional groups makes this a very attractive
methodology for ligation reactions.11d The reaction can
be initiated either photochemically or thermally, and
the efficient radical chain process offers excellent yields
and atom economy. By taking advantage of the reversible
nature of the radical cyclization12 and by promoting either
the 5-exo or 6-endo cyclization, it is possible to prepare
both pyranose and furanose thiosugars from the same
starting materials (Figure 1). This offers a unique synthetic
advantage for the radical cyclization strategy over alter-
native synthetic methods.
Scheme 1. Synthesis of Radical Precursor 4 from Arabinose 1
Herein, we report the results of our investigation into the
use of intramolecular thiyl radical cyclizations for the
synthesis of thiosugars. The aim of this investigation was
to prepare open-chain carbohydrate derivatives containing
a free thiol and an alkene and to investigate if these
precursors could undergo intramolecular radical cyclization
reactions to give the desired thiosugar products. Radical
reactions are advantageous for thiosugar synthesis because
of their mild activating conditions and tolerance of a range
of protecting groups. ThiolÀene reactions are compatible
with aqueous conditions which may allow for fully unpro-
tected or partially protected substrates to be used.11d
6-endo product over the 5-exo product to give the more
syntheticallychallenging pyranose compounds. TheWittig
reaction furnished alkene 2 in a good yield of 84%. After
conversion of the secondary alcohol to the corresponding
triflate, the thioester group was introduced at C-4 through
nucleophilic displacement of the triflate using KSAc as a
nucleophile.14 The displacement reaction proceeded in
61% over two steps and resulted in an inversion of the
stereochemistry at the C-4 position of arabinose. Finally,
treatment with freshly prepared sodium methoxide furn-
ished the thiyl radical precursor 4 in excellent yield.
The introduction of the thioester group required an
inversion of stereochemistry at C-4 of the arabinose start-
ing material. We were also interested in developing a
synthetic pathway that would allow for the retention of
configuration at this center. A double-inversion strategy15
was employed to introduce the desired thio group with
retention of configuration at C-4 (Scheme 2).
Scheme 2. Synthesis of Radical Precursor 8 with Retention of
Configuration at C-4
Figure 1. 5-Exo and 6-endo cyclizations can be employed to
furnish furanose and pyranose thiosugars.
In the first instance, we investigated a general synthetic
procedure to access the precursor compounds for the
radical reaction. The precursor 4 was prepared in four
steps starting from commercially available O-benzyl-
protected arabinose 1 (Scheme 1).
A Wittig reaction13 was carried out on D-arabinose 1 to
introduce the terminal alkene suitable for the intramolec-
ular radical cyclization. An unsubstituted terminal alkene
was introduced in the first instance in order to favor the
(11) (a) Dondoni, A.; Marra, A. Chem. Soc. Rev. 2012, 41, 573. (b)
Dondoni, A.; Massi, A.; Nanni, P.; Roda, A. Chem.;Eur. J. 2009, 15,
11444. (c) Floyd, N.; Vijayakrishnan, B.; Koeppe, J. R.; Davis, B. G.
Angew. Chem., Int. Ed. 2009, 48, 7798. (d) Hoyle, C. E.; Bowman, C. N.
Angew. Chem., Int. Ed. 2010, 49, 1540.
(12) (a) Griesbaum, K. Angew. Chem., Int. Ed. 1970, 9, 273. (b) Zard,
S. Z. Radical Reactions in Organic Synthesis; Oxford University Press:
Oxford, 2003.
(14) (a) Cubero, I. I.; Lopez-Espinosa, M. T. P.; Richardson, A. C.;
Suarez Ortega, M. D. Carbohydr. Res. 1993, 242, 109. (b) Chou, W. C.;
Chen, L.; Fang, J. M.; Wong, C. H. J. Am. Chem. Soc. 1994, 116, 6191.
(15) Martin, O. R.; Saavedra, O. M.; Xie, F.; Liu, L.; Picasso, S.;
Vogel, P.; Kizu, H.; Asano, N. Bioorg. Med. Chem. 2001, 9, 1269.
(13) Pearson, W. H.; Hines, J. V. J. Org. Chem. 2000, 65, 5785.
Org. Lett., Vol. 15, No. 3, 2013
505

The first inversion reaction was carried out with
p-nitrobenzoic acid under Mitsunobu conditions followed
by hydrolysis of the resulting ester 5 under basic conditions
tofurnish 6.15 Treatment withtriflic anhydride followed by
nucleophilic displacement with KSAc furnished 7 in 60%
over two steps.14 The free thiol 8 was prepared on treat-
ment of 7 with freshly prepared sodium methoxide in
quantitative yield.
Table 1. Optimization of Thiyl Radical Cyclization Reaction
With both the radical precursors 4 and 8 in hand, we set
out to investigate the radical-mediated ring-closing reac-
tions. The intramolecular radical reaction starting from 4
is outlined in Table 1. Three potential cyclized products
could result on initiation of the thiyl radical 9. The two
furanose products 11 and 12 resulting from the kinetically
favored 5-exo radical cyclization and the pyranose product
14 resulting from the slower 6-endo cyclization.16 The
distribution of products formed depends on a number of
factors including the relative stability of the alkyl radical
formed after cyclization and the rate of thiyl hydrogen
atom abstraction. The kinetics of the intermolecular
thiolÀene polymerization reaction have been investigated
by a number of groups.17,18 The most important factor
governing the overall kinetics of the thiolÀene polymer-
ization reaction is the ratio of the propagation rate to the
chain transfer rate. For the intramolecular process, we
assume that the chain-transfer step is rate limiting and that
the overall process is first order with respect to thiol
concentration. We anticipated that the 6-endo product
would dominate due to the relative stability of the second-
ary alkyl radical that is formed upon 6-endo cyclization.
We also anticipated that the formation of the dimerized
species15couldbereducedthroughtheuseofhighdilution
conditions. The radical mediated reaction starting from
precursor thiol 4 was investigated under a number of
conditions. Optimization of the radical reaction is outlined
in Table 1.
entry
1
initiatora
conditionsb
yieldc (%)
DPAP (10%),
MAP (10%)
ACVA (10%),
MAP (10%)
ACVA (20%),
MAP (20%)
ACVA (10%),
MAP (10%)
DPAP (10%),
MAP (10%)
DPAP (10%),
MAP (10%)
DPAP (10%),
MAP (10%)
hν
14 (64), 11 (8), 12 (6), 15 (10)
2
3
4
5
6
7
hν
hν
14 (42), 11 (À), 12 (À), 15 (À)
14 (45), 11 (À), 12 (À), 15 (À)
14 (18), 11 (À), 12 (À), 15 (À)
14 (62), 11, 12 (11d), 15 (6)
14 (68), 11, 12 (10d), 15 (4)
14 (73), 11, 12 (9d), 15 (À)
Δ
hνe
hνf
hνe,f
a DPAP (2,2-dimethoxy-2-phenyl-acetophenone), MAP (4-Methoxy-
acetophenone), ACVA (4,4-Azobis(4-cyanovaleric acid). b All reactions
were carried out in DMF as solvent with UV irradiation at rt for 1 h.
c Isolated yields. d Combined yield of 5-exo products. e Reaction mixture
diluted Â5. f Reaction mixture degassed with a stream of argon for
10 min.
Photolysis of thiol 4 in the presence of a radical initia-
tor 2,2-dimethoxy-2-phenylacetophenone (DPAP) and a
photosensitizor 4-methoxyacetophenone (MAP) at room
temperature for 60 min furnished the 6-endo product 14
as the major product in 64% yield (entry 1). The 5-exo
products 11 and 12 were also isolated albeit in low yields
of 8% and 6%, respectively. This is the expected product
distribution for a system involving a terminal alkene where
the carbon centered radical formed on 5-exo cyclization is
not stabilized. The disulfide product 15 was also isolated in
10% yield; this product probably originated from dimer-
ization of thiyl radical 9. Attempts to use an alternative
radical initiator 4,4-Azobis(4-cyanovaleric acid) (ACVA)
failed to give the desired 6-endo product in good yields
(entries 2 and 3). Thermal initiation of the 4,4-azobis(4-
cyanovaleric acid) (ACVA) donor resulted in a diminished
Scheme 3. Thiyl Radical Cyclization Starting from Thiol 8
(16) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Thomas, R. C; Kruse, L. E.; Siberman, L. J. J. Org.
Chem. 1977, 42, 3846.
(17) Cramer, N. B.; Reddy, S. K.; O’Brien, A. K.; Bowman, C. N.
Macromolecules 2003, 36, 7964.
yield of 14. Increasing the dilution of the system 5-fold did
not significantly increase the yield of the 6-endo product,
but the yields of the 5-exo products were reduced (entry 5).
Degassing the system thoroughly with a stream of argon
for 10 min, in order to avoid side reactions with dissolved
(18) Northrop, B. H.; Coffey, R. N. J. Am. Chem. Soc. 2012, 134,
13804.
506
Org. Lett., Vol. 15, No. 3, 2013

Following the successful preparation of thiosugar 14 we
next investigated the C-4 epimeric thiol 8 using the opti-
mized reaction conditions. The desired 6-endo product was
isolated in 72% yield, and the 5-exo products were isolated in
a combined yield of 12% (Scheme 3). The two pyranose
thiosugars 14 and 19 were deprotected under Birch condi-
tions and finally reacetylated for characterization (Scheme 4).
The furanose thioglycosides were not deprotected. However
the C-linked thiofuranose compounds 11, 12, 17, and 18 may
be interesting glycosidase inhibitors. Attempts to promote
the 5-exo cyclization reaction are ongoing.
Scheme 4. Deprotection/Acetylation Protocol for Thiosugars
14 and 19
In conclusion, the first thiyl radical cyclization route to
thiosugars has been developed. The methodology is robust
and regioselective, allowing rapid access to thiopyranose
derivatives with high yields under carefully controlled
conditions. The investigation of the scope and potential
of this process in addition to the development of routes to
the corresponding thiofuranose derivatives are underway.
oxygen, increased the yield of the 6-endo product and
reduced the amount of disulfide product formed (entry 6).
Finally, a combination of dilution and degassing was
employed to give the desired 6-endo product in an overall
isolated yield of 73% together with 9% of the combined
5-exo products. This yield is comparable to nonradical
based thiosugar syntheses and demonstrates the synthetic
application of thiyl radicals for the preparation of thiosu-
gars. Compound 14 is an example of a 1,2-dideoxy thiosu-
gar. Similar compounds have previously been prepared
starting from glycals.9f
Acknowledgment. We thank Science Foundation Ireland
(09/RFP/CHS2256) for funding.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
507