Enantioselective and protecting group-free synthesis of 1-deoxythionojirimycin, 1-deoxythiomannojirimycin, and 1- deoxythiotalonojirimycin

Article abstract of DOI:10.1021/jo1010125

1-Deoxythioglyconojirimycins were synthesized by using a protecting group-free strategy, starting from readily available carbohydrates, in good overall yield. Use of benzyltriethylammonium tetrathiomolybdate, [BnEt ₃N]₂MoS₄, as a sulfur transfer reagent and borohydride exchange resin (BER) reduction of a lactone enabled the efficient synthesis of the title compounds.

Full text of DOI:10.1021/jo1010125

pubs.acs.org/joc
Enantioselective and Protecting Group-Free
Synthesis of 1-Deoxythionojirimycin,
1
-Deoxythiomannojirimycin, and
-Deoxythiotalonojirimycin
1
Thanikachalam Gunasundari and
Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science,
Bangalore-560012, India
scn@orgchem.iisc.ernet.in
Received May 31, 2010
FIGURE 1. Representative examples of thio-sugars as potent gly-
cosidase inhibitors.
inhibitors. Many of the clinically used and the naturally
occurring glycosidase inhibitors are aza-sugars. Acarbose,
miglitol, deoxynojirimycin, and swainsonine are a few notable
2
examples. On the other hand, thio-sugars isolated from nat-
ural sources also possess promising inhibiting activity against
3
glycosidase. But, only limited examples such as 5-thio-man-
nose 1, salacinol 2, kotalanol 3, and some side chain derivatives
of salacinol are known (Figure 1). To understand the activity of
thio-sugars as glycosidase inhibitors and to elucidate the
structure-activity relationship (SAR), considerable efforts have
been devoted to the synthesis of thio-sugars based on the natural
4
templates. In addition, replacement of nitrogen with sulfur in
aza-sugars to obtain the thio-analogues of aza-sugars also gained
much attention for comparing the bioactivities.
1-Deoxythioglyconojirimycins were synthesized by using a
5
protecting group-free strategy, starting from readily avail-
able carbohydrates, in good overall yield. Use of benzyl-
triethylammonium tetrathiomolybdate, [BnEt N] MoS , as
The vital steps in the synthesis of thio-sugars or thio-sugar
analogues are the introduction of sulfur and protection and
deprotection of functional groups, and these steps always
make the synthesis of thio-sugars or thio-sugar analogues
difficult and more challenging. Traditional methods of in-
3
2
4
a sulfur transfer reagent and borohydride exchange resin
BER) reduction of a lactone enabled the efficient synthesis
of the title compounds.
(
troducing sulfur for the synthesis of thio-sugars include the
6
nucleophilic displacement of the leaving group with Na S or
2
(3) (a) Witczak, Z. J.; Culhane, J. M. Appl. Microbiol. Biotechnol. 2005,
9, 237. (b) Capon, R. J.; MacLeod, J. K. J. Chem. Soc., Chem. Commun.
987, 1200.
(4) For recent references see: (a) Jayakanthan, K.; Mohan, S.; Pinto,
B. M. J. Am. Chem. Soc. 2009, 131, 5621. (b) Mohan, S.; Pinto, B. M.
Carbohydr. Res. 2007, 342, 1551 and references cited therein. (c) Eskandari,
R.; Jayakanthan, K.; Kuntz, D. A.; Rose, D. R.; Pinto, B. M. Bioorg. Med.
Chem. 2010, 18, 2829. (d) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org.
Chem. 2001, 66, 2313. (e) Kumar, N. S.; Pinto, B. M. J. Org. Chem. 2006, 71,
Glycosidases are essential biological enzymes found in all
domains of life that catalyze the hydrolysis of glycosidic
linkage. Hence, their function or dysfunction implicates
different disease states like viral infections such as influenza
and HIV, lysosomal storage disorders, cancer and diabetes,
6
1
1
and mutational diseases (Gaucher and Fabry disease etc.),
and the activity of glycosidase can be controlled by glycosidase
1
262. (f) Kumar, N. S.; Pinto, B. M. Carbohydr. Res. 2006, 341, 1685. (g)
Yuasa, H.; Izumi, M.; Hashimoto, H. Curr. Top. Med. Chem. 2009, 9, 76.
(5) (a) Pearson, M. S. M.; Math ꢀe -Allainmat, M.; Fargeas, V.; Lebreton, J.
Eur. J. Org. Chem. 2005, 2159 and references cited therein. (b) Kato, A.;
Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48, 2036. (c) Malle,
B. M.; Lundt, I.; Wrodnigg, T. M. Org. Biomol. Chem. 2008, 6, 1779.
(d) Song, X.; Hollingsworth, R. I. Tetrahedron Lett. 2007, 48, 3115.
(6) (a) Halila, S.; Benazza, M.; Demailly, G. Tetrahedron Lett. 2001, 42,
3307. (b) Benazza, M.; Halila, S.; Viot, C.; Danquigny, A.; Pierru, C.;
Demailly, G. Tetrahedron 2004, 60, 2889. (c) Merrer, Y. L.; Fuzier, M.;
Dosbaa, I.; Foglietti, M. J.; Depezay, J. C. Tetrahedron 1997, 53, 16731 and
references cited therein.
(
1) (a) Gloster, T. M.; Davies, D. J. Org. Biomol. Chem. 2010, 8, 305. (b)
Rempel, B. P.; Withers, S. G. Glycobiology 2008, 18, 570. (c) Lieberman,
R. I.; Wustman, B. A.; Huertas, P.; Powe, A. C.; Pine, C. J.; Khanna, R.;
Schlossmacher, M. G.; Ringe, D.; Petsko, G. A. Nat. Chem. Biol. 2007, 3,
1
01. (d) Brumshtein, B.; Greenblatt, H. M.; Butters, T. D.; Shaaltiel, Y.;
Aviezer, D.; Silman, I.; Futerman, A. H.; Sussman, J. L. J. Biol. Chem. 2007,
82, 29052.
2) For books and reviews see: (a) Iminosugars as Glycosidase Inhibitors:
2
(
Nojirimycin and Beyond; Stutz, A. E., Ed.; Wiley-VCH: Weinheim,
Germany, 1999. (b) Iminosugars: From Synthesis to Therapeutic Applica-
tions; Compain, P., Martin, O. R., Eds.; John Wiley: Chichester, UK, 2007.
(
c) Asano, N. Glycobiology 2003, 13, 93R. (d) Lillelund, V. H.; Jensen, H. H.;
Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515 and references cited therein.
e) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199.
(7) (a) Cubero, I. I.; L oꢀ pez-Espinosa, M. T. P.; Richardson, A. C.; Suarez
Ort ꢀe ga, 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.
(
DOI: 10.1021/jo1010125
r 2010 American Chemical Society
Published on Web 09/03/2010
J. Org. Chem. 2010, 75, 6685–6688 6685

Gunasundari and Chandrasekaran
JOCNote
a
SCHEME 1. Retrosynthesis of Thio-Analogues of 1-Deoxygly-
conojirimycin
SCHEME 2. Synthesis of 1-Deoxythionojirimycin (8)
7
KSAc, NaSH, (NH ) CS, and AcSH, and they have
8
9
10
2
2
been utilized earlier in the synthesis of targeted thio-sugars,
7a
deoxythionojirimycin (8), deoxythiomannojirimycin (13),
6c
10b
and deoxythiotalonojirimycin (17).
Our long-standing interest in the use of benzyltriethylammo-
nium tetrathiomolybdate, [BnEt N] MoS (5), as a sulfur transfer
3
2
4
11
reagent and our recent success in the synthesis of conformation-
ally locked thio-levomannosan 4 as mannosidase inhibitor
a
12
Reaction conditions: (a) HBr/AcOH, 30 °C, 4.5 h, 86%; (b) NaBH
4
,
þ
MeOH, Amberlite 120 H , 20%; (c) [BnEt
MoS
3
N]
, DMSO, rt, 30 min, 56%;
2
MoS
4
, CH
3
CN:EtOH
prompted us to develop an efficient synthesis of various thio-
sugars utilizing the same. Additionally, benzyltriethylammonium
tetrathiomolybdate (5) wasshowntobeamildreagentandmore
(
1:1), rt, 30 min, 38%; (d) [BnEt
3
N]
2
4
(e) BER, MeOH, 0 °C-rt, 18 h, 62%.
11
specific toward certain kinds of functional groups. Herein,
we disclose the protecting group-free synthesis of thio-analogues
of deoxyglyconojirimycins using tetrathiomolybdate 5.
We envisioned that the synthesis of thio-analogues of 1-deoxy-
glyconojirimycins 6 can be readily achieved starting from
commercially available carbohydrates, one of the functionally
richest building blocks (Scheme 1). Thus, conversion of carbo-
hydrate into suitably positioned dibromide 7 followed by reac-
tion with benzyltriethylammonium tetrathiomolybdate (5) was
expected to yield the 1-deoxythioglyconojirimycins.
a
SCHEME 3. Synthesis of 1-Deoxythiomannojirimycin (13)
Initially, synthesis of 1-deoxythionojirimycin (8) was visua-
lized from commercially available L-gulonic acid-γ-lactone (9).
Thus, bromination of 9 with HBr in acetic acid yielded 2,6-
dibromo-2,6-dideoxy-D-idono-1,4-lactone (10) in excellent
1
3
yield. Dibromolactone 10 on reduction with sodium borohy-
þ
a
Reaction conditions: (a) (i) Br /BaCO , 2 h, (ii) HBr/AcOH, 4 h, rt,
2
3
dride in the presence of Amberlite 120 H resin gave the
1
4
27% in two steps; (b) [BnEt
MeOH, 0 °C-rt, 4 h, 74%.
3 2 4
N] MoS , DMSO, rt, 30 min, 59%; (c) BER,
required dibromide 11, the precursor for the synthesis of
1
5
1
-deoxythionojirimycin (8), in 20% yield. Subsequently, the
reaction of 11 with tetrathiomolybdate 5 in acetonitrile/ethanol
1:1) mixture provided the expected 1-deoxythionojirimycin (8)
1-deoxy-5-thio-D-glucopyrano-3,6-lactone (12) in good yield
1
6
(
(56%). The structure and stereochemistry of 12 was un-
ambiguously confirmed by X-ray analysis (see the Support-
ing Information). Reduction of bicyclic thialactone 12 with
borohydride exchange resin (BER) in methanol furnished
the 1-deoxythionojirimcin (8) in good yield with excellent
purity.
15
in 38% yield. Although the synthesis of 8wasachievedinthree
steps starting from readily available 9, the overall yield was low
1
7
(
Scheme 2). To improve the overall yield, the synthetic strategy
was modified slightly and we decided to use the dibromolactone
0 as the precursor for the sulfur transfer reaction.
1
To our delight, 2,6-dibromo-2,6-dideoxy-D-idono-1,4-lac-
tone (10) on reaction with benzyltriethylammonium tetra-
thiomolybdate (5) smoothly furnished the axially enriched
Similarly, synthesis of 1-deoxythiomannose (1-deoxythio-
mannojirimycin) (13) was started from D-mannose (14).
D-Mannose (14) was converted to mannono-1,4-lactone, fol-
lowed by reaction with HBr/acetic acid to yield the 2,6-dibromo-
18
2
,6-dideoxy-D-glucono-1,4-lactone (15). Reaction of dibromo
lactone 15 with benzyltriethylammonium tetrathiomolybdate (5)
DMSO, rt, 30 min) afforded the 1-deoxy-5-thio-D-mannopy-
(
8) Robert, C. C.; Benazza, M.; Fr ꢀe chou, C.; Demailly, G. Carbohydr.
Res. 1997, 303, 359.
(9) Ermert, P.; Vasella, A. Helv. Chim. Acta 1993, 76, 2687.
(10) (a) Hashimoto, H.; Kawanishi, M.; Yuasa, H. Carbohydr. Res. 1996,
(
rano-3,6-lactone (16) in 59% yield (Scheme 3). Subsequent
reduction of bicyclic thialactone 16 with BER furnished the
2
82, 207. (b) Cubero, I. I.; L oꢀ pez-Espinosa, M. T. P.; Asenjo, R. A.;
Fern ꢀa ndez, A. R. Carbohydr. Lett. 1999, 3, 323.
11) (a) Prabhu, K. R.; Devan, N.; Chandrasekaran, S. Synlett 2002, 11,
762. (b) Sureshkumar, D.; Koutha, S. M.; Chandrasekaran, S. J. Am. Chem.
(
1-deoxythiomannose (13) in good yield.
1
Next, the synthesis of 1-deoxythiotalonojirimycin (17) was
accomplished starting from D-ribose 18. Accordingly, one
Soc. 2005, 127, 12760. (c) Sureshkumar, D.; Gunasundari, T.; Ganesh, V.;
Chandrasekaran, S. J. Org. Chem. 2007, 72, 2106.
(
12) (a) Sivapriya, K.; Chandrasekaran, S. Carbohydr. Res. 2006, 341,
204. (b) Sivapriya, K.; Hariharaputran, S.; Suhas, V. L.; Chandra, N.;
Chandrasekaran, S. Bioorg. Med. Chem. 2007, 15, 5659.
13) (a) Vekemans, J. A. J. M.; Dapperens, C. W. M.; Claessen, R.;
2
2
(16) The reaction of dibromolactone 10 with Na S (DMSO, 30 min) gave
a mixture of products from which bicyclic thialactone 12 could be isolated in
11% yield.
(17) (a) Bandgar, B. P.; Modhave, R. K.; Wadgaonkar, P. P.; Sande,
A. R. J. Chem. Soc., Perkin Trans. 1 1996, 1993. (b) Gibson, H. W.; Bailey,
F. C. J. Chem. Soc., Chem. Commun. 1977, 815a.
(
Koten, A. M. J.; Godefroi, E. F. J. Org. Chem. 1990, 55, 5336. (b) Bock, K.;
Lundt, I.; Pedersen, C.; Refn, S. Acta Chem. Scand. 1986, B40, 740.
(
(
14) Lundt, I.; Madsen, R. Synthesis 1993, 720.
15) The low yield of products 8 and 11 is attributed to difficulties in
isolation from the reaction medium.
(18) Lundt, I.; Pedersen, C. Synthesis 1991, 669.
6
686 J. Org. Chem. Vol. 75, No. 19, 2010

Gunasundari and Chandrasekaran
JOCNote
a
SCHEME 4. Synthesis of 1-Deoxythiotalonojirimycin (17)
SCHEME 5. Proposed Mechanism for the Double Displacement
3 2 4
of Dibromolactone 10 with [BnEt N] MoS (5)
a
Reaction conditions: (a) (i) Reference 19, (ii) HBr/AcOH, 2 h, rt, 49%;
N] MoS
, DMSO, rt, 30 min, 63%; (c) BER, MeOH, 0 °C-rt,
h, 58%.
(
4
b) [BnEt
3
2
4
carbon extension of D-ribose using NaCN under Kiliani-
Fischer synthesis conditions produced altronolactone,
1
9
which on subsequent bromination with HBr in acetic acid
afforded the 2,6-dibromo-2,6-dideoxy-D-allono-1,4-lactone (19).
Double displacement of dibromide in 19 with benzyltriethylam-
monium tetrathiomolybdate 5 in DMSO smoothly furnished the
bicyclic thialactone 20 in 63% yield. BER reduction of
tetrathiomolybdate ([BnEt N] MoS (5), 1.411 g, 2.3 mmol) in
3
2
4
DMSO (15 mL) over a period of 15 min. After the reaction mixture
was stirred for 30 min, DMSO was removed under reduced pressure
and the residue was repeatedly extracted with THF (5 ꢀ 10 mL) and
filtered over a Celite pad. The solvent was concentrated to give the
crude product, which was subjected to column chromatography on
silica gel (elution with hexanes:ethyl acetate 1:1) furnishing a white
solid. It was then recrystallized from acetone to afford colorless
crystals of the bicyclic thialactone 12 (0.104 g, 56%). Mp 156-157 °C;
1
-deoxy-5-thio-D-talopyrano-3,6-lactone (20) in methanol
yielded the required 1-deoxythiotalonojirimycin 17 in good
yield (Scheme 4).
In our opinion the reaction of dibromo lactone 10 with
benzyltriethylammonium tetrathiomolybdate 5 leads to the
intermediate A via S 2 displacement of the more reactive
[
R] þ13.0 (c 1.0, MeOH); IR (neat) 3422, 1430, 1288, 1170, 1116,
D
-1
1
1
1
1
054 cm ; H NMR (400 MHz, CD COCD ) δ 2.68 (d, J =
3 3
N
5 Hz, 1H), 3.20 (dd, J = 14.5, 3.3 Hz, 1H), 3.41 (d, J = 5.5 Hz,
H), 4.36 (br s, 1H), 4.55 (t, J = 5.4 Hz, 1H), 4.60 (br s, 1H), 5.43
2
0
bromide with sulfide anion. Intermediate A can then
2
1a,b
1
3
undergo an internal redox process
of the ligand and concomitant reduction of the metal center
with the oxidation
(
d, J= 5.3 Hz, 1H), 5.63 (d, J= 4.5 Hz, 1H); C NMR (100 MHz,
CD COCD ) δ 31.5, 44.6, 66.7, 69.0, 74.5, 171.8; HRMS for
3
3
1
1
to give the disulfide B. On the basis of our own earlier work
and that of Stiefel, B can undergo reductive cleavage of
the disulfide bond with tetrathiomolybdate 5 to give thiolate
C H O S þ Na calcd 199.0041, found 199.0043. Anal. Calcd: C,
6
8 4
21c,d
41.01; H, 5.08; S, 17.98. Found: C, 40.90; H, 4.58; S, 18.2. Crystal
structure data CCDC 774511; C6 H8 O4 S1; mol wt = 176.18,
crystal dimensions 0.26 ꢀ 0.21 ꢀ 0.18, T= 293(2) K, orthorhombic,
2
1c,d
intermediate C.
Finally an intramolecular displacement
˚
˚
space group P 21 21 21, a = 5.7460(18) A, b = 11.149(4) A, c =
of primary bromide with sulfide anion in C results in the
formation of bicyclic thialactone 12 in a stereospecific man-
ner (Scheme 5).
3
˚
1
1
1.329(4) A,R=β=γ=90.00°,Z=4,V=725.8(4) cm ,Fcalcd
=
,
3
-1
˚
.61 g/cm , Mo KR radiation (λ° = 0.71073 A), μ = 4.06 mm
2
θ = 2.60-28.0°; of 3594 reflections collected, 1623 were inde-
In conclusion, efficient synthesis of 1-deoxythioglycono-
jirimycins is accomplished in good overall yield employing a
protecting group-free strategy. Effective utilization of ben-
zyltriethylammonium tetrathiomolybdate, [BnEt N] MoS
pendent (R(int) = 0.0337); refinement method full matrix least-
squares on F , 102 refined parameters, absorption correction
(SADABS, Bruker, 1996 software, Tmin 0.9019 and Tmax
2
3
2
4
0.9306), GooF = 1.221, R = 0.0620, wR = 0.1907 (σ >2σ(I )),
1
2
(
5), as sulfur transfer reagent and borohydride exchange
absolute structure parameter 0.00(2), residual electron density
˚
-
3
0
.553/-0.739 eA . The structure was solved and refined with the
resin (BER) as reducing reagent are notable features of the
methodology.
programs WinGXv1.64.05, Sir92, and SHELXL-97.
Typical Procedure for the Synthesis of 1-Deoxythionojirimycin
(
8) from 1-Deoxy-5-thio-D-glucopyrano-3,6-lactone (12). To a
Experimental Section
stirred solution of bicyclic thialactone 12 (0.100 g, 0.587 mmol)
in dry methanol (6 mL) at 0 °C was added borohydride exchange
resin (0.782 g, 2.34 mmol) and the solution was stirred for 18 h.
The reaction mixture was filtered and methanol (10 mL) was
added to the resin and the mixture was sonicated (ultrasonic
cleaning bath, 20 kHz) for 5 min at room temperature. To the
sonicated resin glacial acetic acid was added to neutralize then
the solution was filtered. The solution was then concentrated in
vacuo to afford the crude product which was subjected to
column chromatography on silica gel eluting with methanol/
Typical Procedure for the Synthesis of 1-Deoxy-5-thio-D-glucopyr-
ano-3,6-lactone (12) from 2,6-Dibromo-2,6-dideoxy-D-idono-1,4-lactone
(10). A solution of dibromolactone 10 (0.320 g, 1.05 mmol) in
DMSO (2 mL) was added to a solution of benzyltriethylammonium
(
(
19) Pratt, J. W.; Richtmyer, N. K. J. Am. Chem. Soc. 1955, 77, 1906.
20) Driguez, H.; Macauliffe, J. C.; Stick, R. V.; Tilbrook, D. M. G.;
Williams, S. J. Aust. J. Chem. 1996, 49, 343.
21) (a) Kruhlak, N. L.; Wang, M.; Boorman, P. M.; Parvez, M. Inorg.
(
Chem. 2001, 40, 3141. (b) Boorman, P. M.; Wang, M.; Parvez, M. J. Chem.
Soc., Chem. Commun. 1995, 999. (c) Pan, W. H.; Harmer, M. A.; Halbert,
T. R.; Stiefel, E. I. J. Am. Chem. Soc. 1984, 106, 459. (d) Coyle, C. L.; Harmer,
M. A.; George, G. N.; Daage, M.; Stiefel, E. I. Inorg. Chem. 1990, 29, 14 and
references cited therein.
chloroform 1.5:8.5 to furnish 1-deoxythionojirimycin (8) as a
gummy solid (0.063 g, 62%). [R]
6c
D
þ78.6 (c 1.0, MeOH) [lit.
[
R]
D
-
þ50.0 (c 1.39, H
2
O)]; IR (neat) 3368, 2925, 1430, 1103, 1043
1 1
cm ; H NMR (400 MHz, CD OD) δ 4.27 (quint, J = 2.0 Hz,
3
J. Org. Chem. Vol. 75, No. 19, 2010 6687

Gunasundari and Chandrasekaran
JOCNote
1
1
2
H), 4.01 (t, J = 3.2 Hz, 1H), 3.71-3.62 (m, 2H), 3.61-3.53 (m,
H), 3.31 (quint, J = 1.6 Hz, 1H), 3.19 (dd, J = 11.3, 4.4 Hz, 1H),
.67 (dd, J = 11.3, 1.2 Hz, 1H), 2.11-2.00 (m, 1H), 1.86-1.75
for the CCD X-ray facility. We also thank Ms. Brinda Selvaraj
and Mr. Amol Dikundwar for help in solving the molecular
structures.
13
(
m, 1H); C NMR (100 MHz, CD OD) δ 34.2, 36.7, 47.8, 62.2,
3
7
1
9.4, 80.0; HRMS for C
81.0526.
6
H
12
O
4
S þ 1 calcd 181.0535, found
Supporting Information Available: Experimental proce-
dures and spectroscopic data for the compounds and copies
of H NMR, C NMR spectra, and CIF tables. This material
is available free of charge via the Internet at http://pubs.
acs.org.
1
13
Acknowledgment. We thank IISc, Bangalore for the award
of a Senior Research Fellowship to T.G. and DST, New Delhi
6
688 J. Org. Chem. Vol. 75, No. 19, 2010