Deoxythiosugar derivatives with Furano, Pyrano, and septano motifs from L -gulono-1,4-lactone and D-glycero-D-gulo-heptono-1,4-lactone

Article abstract of DOI:10.1002/ejoc.201200906

A short synthesis of thiosugar derivatives mimicking furanose, pyranose, and septanose structures has been achieved starting from L-gulono-1,4-lactone and D-glucoheptono-1,4-lactone. Different strategies used in the synthesis are: (1) a nucleophilic displacement and Michael addition; (2) epoxide ring opening and Michael addition; (3) epoxide ring opening and nucleophilic displacement process; and (4) double nucleophilic displacement. All of these reactions used benzyltriethylammonium tetrathiomolybdate, (BnEt₃N) ₂MoS₄ as the sulfur-transfer reagent. Copyright

Full text of DOI:10.1002/ejoc.201200906

FULL PAPER
DOI: 10.1002/ejoc.201200906
Deoxythiosugar Derivatives with Furano, Pyrano, and Septano Motifs from
L
-Gulono-1,4-lactone and
D
-Glycero- -gulo-heptono-1,4-lactone
D
Thanikachalam Gunasundari[a] and Srinivasan Chandrasekaran*[a]
Keywords: Carbohydrates / Glycomimetics / Sulfur heterocycles / Nucleophilic substitution / Michael addition
A short synthesis of thiosugar derivatives mimicking fur-
anose, pyranose, and septanose structures has been achieved
starting from L-gulono-1,4-lactone and D-glucoheptono-1,4-
lactone. Different strategies used in the synthesis are: (1) a
nucleophilic displacement and Michael addition; (2) epoxide
ring opening and Michael addition; (3) epoxide ring opening
and nucleophilic displacement process; and (4) double nucle-
ophilic displacement. All of these reactions used benzyltri-
ethylammonium tetrathiomolybdate, (BnEt3N)2MoS4 as the
sulfur-transfer reagent.
thioacetals,[6] nucleophilic double displacement using sulfur
nucleophiles,[7] and conjugate addition of sulfur nucleo-
philes to unsaturated esters followed by tandem cycliza-
tion.[8] However, a more general and efficient synthesis of
thiosugars from carbohydrates is required in contemporary
organic synthesis. After our recent success in the enantio-
specific synthesis of 1-deoxy-thio-nojirimycin, 1-deoxy-
thio-mannono-nojirimycin, and 1-deoxy-thio-talono-nojiri-
mycin,[9] we became interested in the development of a ge-
neral approach to the construction of various deoxythio-
sugars mimicking furanoses, pyranoses, and septanoses,
starting from aldonolactones. In this paper, we describe a
short and versatile enantiospecific synthesis of deoxythiosu-
gars with thiofuranose, thiopyranose, and thioseptanose
structures, starting from commercially available aldono-lac-
tones, l-gulono-1,4-lactone (5) and d-glucoheptono-1,4-lac-
tone (22).
Introduction
There is general interest from the glycobiological per-
spective in the synthesis of carbohydrates and their analogs
mainly as enzyme inhibitors.[1] Work in this area is syntheti-
cally challenging which elicits new insights and protocols.
In particular, sulfur-containing analogs of carbohydrates
are interesting from the point of view of their biological
activity as glycomimetics, and are promising pharmaceuti-
cal lead compounds with potential therapeutic applications
as anticancer, antiviral, and anti-AIDS agents.[2] Some rep-
resentative examples, thiosugars and sulfur-containing
sugar mimics, are shown in Figure 1. Research articles de-
scribing the synthesis and biological studies of thiosugars
as inhibitors of glycosidases and glycosyl transferases and
as scaffolds in potent HIV inhibitors are gaining more
prominence.[3]
Results and Discussion
As shown in Figure 2, different strategies were envisioned
for the synthesis of thiofuranoses and thiopyranoses from
dibromo lactone 6, the synthesis of which was planned from
lactone 5.
Figure 1. Thiosugars and sulfur-containing sugar mimics.
Conventional approaches for the synthesis of thiosugars
include ring contraction by episulfonium ion rearrange-
ment,[4] nucleophilic ring opening with sulfur nucleo-
philes,[5,4b] intramolecular cyclization of dithio or mono-
[a] Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
Fax: +91-80-2360-0529/0683
E-mail: scn@orgchem.iisc.ernet.in
Homepage: http://orgchem.iisc.ernet.in/faculty/scn/scn.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200906.
Figure 2. Retrosynthetic analysis for the synthesis of deoxythio-
sugars from l-gulono-1,4-lactone (5).
6986
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6986–6995

Deoxythiosugar Derivatives from Lactones
Initially, the synthesis of dibromolactone 6 was achieved bond with tetrathiomolybdate 11 to give thiolate intermedi-
by the reaction of l-gulono-1,4-lactone (5) with HBr/ ate C.[15] An intramolecular Michael addition of the thio-
AcOH, according to the literature procedure.[10] Next, using late anion to the butenolide in C results in the formation of
6 as the key intermediate, an expeditious synthesis of deoxy- bicyclic lactone 12 in a stereospecific manner.[16]
thiosugar, 3,6-anhydro-2-deoxy-6-thio-l-xylo-hexitol (7)
Next, 7 was obtained by an alternative route. Meth-
was envisaged. Thus, reaction of dibromolactone 6 with anolysis of 10 using MeOH/HCl resulted in a chemoselec-
acetic anhydride gave acetylated product 9[11] in 69% yield. tive de-O-acetylation to yield butenolide 13.[11] Reaction of
Upon debromoacetylation using NaHSO3 and Na2SO3, this 13 with benzyltriethylammonium tetrathiomolybdate (11)
compound yielded butenolide 1011, a precursor for the dis- led to a smooth conversion into lactone 14 in 86% yield.
placement/Michael addition reaction, in 72% yield. Sulfur- The structure and configuration of 14 were unambiguously
containing compound 12 was obtained in excellent yield confirmed by X-ray studies. The synthesis of 7 was achieved
from butenolide 10 on treatment with benzyltriethylammo- upon reduction of 14 with BER (Scheme 3). The formation
nium tetrathiomolybdate (BnEt3N)2MoS4 (11),[12] an ef- of 14 was also achieved via epoxy butenolide 15. In this
ficient sulfur-transfer reagent. Reduction of 12 with approach, butenolide 13 was treated with Ag2O to give the
borohydride exchange resin (BER)[13] gave the required five- required precursor (i.e., 15).[11] As expected, treatment of 15
membered homothiosugar (i.e., 7) in good yield (Scheme 1). with (BnEt3N)2MoS4 (11) resulted in a regioselective ring
opening of the epoxide, followed by an intramolecular
Michael reaction of the resulting thiolate to again give 14
in excellent yield. Compound 14 can be reduced to homo-
thiofuranose derivative 7 on treatment with borohydride ex-
change resin (BER), as shown in Scheme 3.
Scheme 1. Synthesis of homothiofuranose derivative 7. Reaction
conditions: a) HBr/AcOH, 30 °C, 4.5 h, 86%; b) HBr/AcOH, 30 °C,
3.5 h; followed by Ac2O, 0 °C, 1 h, 69%; c) NaHSO3, Na2SO3,
MeOH/H2O (9:1), 3 h, 72%; d) (BnEt3N)2MoS4 (11), CH3CN,
room temp., 1 h, 88%; e) BER, MeOH, 0 °C to r.t., 22 h, 72%.
The mechanism of formation of bicyclic lactone 12 from
Scheme 3. Synthesis of homothiofuranose derivative 7. Reaction
butenolide 10 effected by tetrathiomolybdate 11 is shown in
conditions: a) Methanolic HCl, 48 h, 96%; b) (BnEt3N)2MoS4 (11),
Scheme 2. The reaction of butenolide 10 with tetrathio-
CH3CN, room temp., 1 h, 86%; c) Ag2O, H2O, 0 °C, 4 h, 70%;
molybdate 11 leads to intermediate A by an SN2 displace-
d) (BnEt3N)2MoS4 (11), CH3CN/EtOH, room temp., 1 h, 90%;
ment of the terminal bromide by the sulfide anion of 11.[14]
e) BER, MeOH, 0 °C to r.t., 22 h, 73%.
Intermediate A can then undergo an internal redox pro-
cess[14] with the oxidation of the ligand and concomitant
After successfully achieving the synthesis of 7 by epoxide
reduction of the metal center to give disulfide B. Based on ring opening followed by Michael addition, we wanted to
our earlier work[12] and that of Stiefel,[15] it is anticipated carry out the synthesis of a thio analog 8a of deoxyido-
that disulfide B undergoes reductive cleavage of the S–S nojirimycin by an epoxide-ring-opening/bromide-displace-
ment process (Scheme 4).
Reaction of dibromolactone 6 with potassium fluoride[17]
gave a mixture of three products, including five-membered
ring lactone epoxide 16, six-membered ring lactone epoxide
17, and an unidentified product (Scheme 4). The ratio of
16/17 was found to be ca. 2:3, based on NMR analysis. To
improve the selectivity towards the formation of lactone 17,
dibromo lactone 6 was treated with K2CO3, which resulted
in the formation of six-membered ring lactone epoxide 17
as the major product, along with a minor amount of five-
membered ring lactone epoxide 16 in a ca. 4:1 ratio. The
subsequent reaction of 17 with tetrathiomolybdate 11
yielded bicyclic lactone 18 in good yield. The structure and
configuration of bicyclic lactone 18 were unambiguously
confirmed by single-crystal X-ray analysis (Figure 3). The
formation of bicyclic lactone 18 is expected to occur by ini-
tial ring-opening of the epoxide in 17 with tetrathiomolyb-
Scheme 2. Proposed mechanism for the displacement/Michael
addition reaction of butenolide 10 with tetrathiomolybdate
(BnEt3N)2MoS4 (11).
Eur. J. Org. Chem. 2012, 6986–6995
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6987

T. Gunasundari, S. Chandrasekaran
FULL PAPER
Scheme 5. Synthesis of thio-deoxy-nojirimycin 8b by double dis-
placement process. Reaction conditions: a) 2,2-DMP, pTsOH,
CH2Cl2, room temp., 45 min, 62%; b) (BnEt3N)2MoS4 (11),
CH3CN, room temp., 1 h, 84%; c) Glacial AcOH, overnight, 98%;
d) BER, MeOH, 0 °C Ǟ r.t., 5 h, 86%; e) BER, MeOH, 0 °C to
r.t., 10 h; followed by glacial AcOH, 78%.
Scheme 4. Synthesis of thio-deoxy-ido-nojirimycin 8a by epoxide-
ring-opening/bromide-displacement process. Reaction conditions:
a) KF, acetone, room temp., 7 h, 71% (combined yield of 16 and
17); b) K2CO3, acetone, room temp., 5 h, 64% (combined yield of
16 and 17); c) (BnEt3N)2MoS4 (11), CH3CN/EtOH, room temp.,
4 h, 66%; d) BER, MeOH, 0 °C Ǟ r.t., 20 h, 67%.
date 11, followed by displacement of the primary bromide
by the thiolate nucleophile (Scheme 4).[18] Next, the synthe-
sis of thiosugar 8a, a thio analog of deoxy-ido-nojirimycin,
was achieved in 67% yield from bicyclic lactone 18 by re-
duction with BER (Scheme 4). There are not many papers
published that describe the synthesis of thio-deoxy-ido-noji-
rimycin 8a.
Figure 4. ORTEP diagram of thiosugar carboxylate 21.
us to further expand the scope of this methodology by using
a higher homologue. The next higher homologue chosen for
the study was dibromoheptonolactone 23, and an expedi-
tious synthesis of thio-homo-deoxy-gulo-nojirimycin 27 was
envisaged with 23 as a key intermediate.
The synthesis of dibromoheptonolactone 23 could be
easily achieved from commercially available d-glucohep-
Figure 3. ORTEP diagram of bicyclic lactone 18.
Subsequently, double displacement of dibromide 19a tono-1,4-lactone (22) by reaction with HBr/AcOH.[19] Acet-
with tetrathiomolybdate 11 was adopted as a strategy for ylation of dibromoheptonolactone 23 using acetic anhy-
the synthesis of thio-deoxy-nojirimycin 8b (Scheme 5).
dride gave acetylated lactone 24. A regioselective reductive
Simultaneous protection and lactone ring opening of 6 trans-β-bromo-acetoxy elimination of acetate 24 using
were envisaged for the synthesis of 19a. Reaction of 6 with Na2S2O5 and Na2SO3 provided the required precursor, 5,6-
2,2-dimethoxypropane (2,2-DMP) and pTsOH gave a mix- di-O-acetyl-7-bromo-2,3,7-trideoxy-d-arabino-hept-2-
ture of 19a and 19b in a 3:1 ratio, with the required com- enono-1,4-lactone (25) in 81% yield.[20] The reaction of 25
pound (i.e., 19a) as the major product. The double-displace- with benzyltriethylammonium tetrathiomolybdate (11) in
ment reaction of 19a with 11 smoothly gave acetonide-pro- CH3CN (r.t., 5 h) resulted in thia-Michael addition in an
tected deoxythiosugar carboxylate 20 in 84% yield. Depro- intramolecular fashion to give 1,6-dideoxy-2,3-diacetoxy-5-
tection of the acetonide in 20 with acetic acid gave thiosu- thio-l-homogulono-4,7-lactone (26) as a white crystalline
gar 21 in excellent yield. X-ray analysis of deoxythiosugar solid in 50% yield.
carboxylate 21 unambiguously proved its structure and con-
X-ray diffraction analysis of 26 further confirmed the
figuration (Figure 4). BER reduction of the ester in deoxy- structure and the configuration of this bicyclic lactone (Fig-
thiosugar 21 led to thio-deoxy-nojirimycin 8b in 86% yield ure 5). The reduction of lactone 26 with borohydride ex-
(Scheme 5).
change resin (BER) in methanol gave the six-membered
The successful synthesis of various thiosugar derivatives ring structure, thio-homo-deoxy-gulo-nojirimycin 27, in
12, 14, and 18, ester 20 and deoxythiosugars homothiofur- 57% yield (Scheme 6). To the best of our knowledge, this
anose 7, thio analog 8a of deoxy-ido-nojirimycin, and thio- constitutes the first synthesis of thio-homo-deoxy-gulo-noji-
deoxy-nojirimycin 8b from a single precursor 6 encouraged rimycin 27.
6988
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6986–6995

Deoxythiosugar Derivatives from Lactones
Figure 5. ORTEP diagram of 1,6-dideoxy-2,3-diacetoxy-5-thio-l-
homogulono-4,7-lactone (26).
Scheme 7. Synthesis of 1,6-dideoxy-2,3-diacetoxy-5-thio-l-homo-
gulono-4,7-lactone (26). Reaction conditions: a) MeOH/HCl, 72 h,
room temp., quantitative yield; b) Ag2O, toluene, 80 °C, 1 h, 82%;
c) (BnEt3N)2MoS4 (11), CH3CN/EtOH, room temp., 1 h, 77%;
d) (BnEt3N)2MoS4 (11), CH3CN, room temp., 30 min, 90%;
e) Ac2O, cat. DMAP, pyridine, 0 °C Ǟ r.t., 2 h, 94%; f) LiOH·H2O,
aq. THF, 20 min, 96%.
d-galacto-[(2,3)-(4,5)]-bis-isopropylidene-6-thio-6-methyl
carboxylate (34) in 80% yield. The structure and configura-
tion of thioseptanose derivative 34 were unambiguously
confirmed by X-ray crystallography (Scheme 8).
Scheme 6. Synthesis of thio-homo-deoxy-gulo-nojirimycin 27 by
Michael addition to 25. Reaction conditions: a) HBr/AcOH, 1 h;
b) Ac2O, HClO4, 1 h, 51% yield over two steps; c) Na2S2O5,
Na2SO3, MeOH/H2O (9:1), room temp., 3.5 h, 81%; d) (BnEt3N)2-
MoS4 (11), CH3CN, room temp., 5 h, 50%; e) BER, MeOH, 0 °C
to r.t., 17 h, 57%.
Alternatively, the synthesis of 1,6-dideoxy-2,3-diacetoxy-
5-thio-l-homogulono-4,7-lactone (26) was also achieved by
epoxide ring opening with concomitant intramolecular
thia-Michael addition. Initially, olefin 25 was deacetylated
using MeOH/HCl to give 7-bromo-2,3,7-trideoxy-d-arab-
ino-hept-2-enono-1,4-lactone (28) in quantitative yield.
Then reaction of olefin 28 with Ag2O gave epoxide 29 in
82% yield. The reaction of epoxide 29 with tetrathiomo-
lybdate 11 gave bicyclic lactone 30 in 77% yield. Acetyl-
ation of 30 gave the required sulfur compound 26 in 94%
yield. The reaction of olefin 28 with tetrathiomolybdate 11
also gave compound 30 in 90% yield by a bromide-displace-
ment reaction with concomitant thia-Michael addition.
Upon deacetylation using LiOH, lactone 26 also gave 30 in
96% yield (Scheme 7).
Scheme 8. Acetonation of 2,7-dibromo-2,7-dideoxy-d-glycero-d-
ido-heptono-1,4-lactone (23). Reaction conditions: a) 2,2-DMP,
pTsOH, DCM, 45 min; b) (BnEt3N)2MoS4 (11), CH3CN, r.t.;
c) Glacial AcOH, room temp., 8 h, 96%; d) (BnEt3N)2MoS4 (11),
CH3CN, room temp., 5 h, 80%.
The utility of thiosugar derivatives was then extended to
The successful synthesis of six-membered ring thiosugars the synthesis of azido-thiosugar derivatives. The synthesis
from the five-membered ring lactone, d-glucoheptono-1,4- was started with epoxy butenolide 29 by protecting the hy-
lactone (22),further encouraged us to synthesize a thiosugar droxy group as its benzyl ether. Reaction of epoxide 35 with
derivative with a septanose-mimicking structure.
tetrathiomolybdate 11 yielded sulfur-containing compound
Accordingly, dibromoheptonolactone 23 was suitably 36 in 80% yield. Reaction of compound 36 with mesyl
protected using 2,2-DMP and a catalytic amount of pTsOH chloride/pyridine provided mesylate 37. Mesylate 37 was
in dichloromethane to give a 2:1 mixture of isopropylidene treated with sodium azide at 80 °C, and this produced two
lactone 31 and ester 32. Unfortunately, various attempts to products in a 1:1 ratio. The products were identified as
improve the selectivity in the acetonation reaction were un- azido thiopyranose 38 and thiofuranose 39 derivatives
successful. The reaction of major isomer, lactone 31, with (Scheme 9).
tetrathiomolybdate 11 did not yield the expected product
An explanation for the formation of azido lactones 38
(i.e., 33). Acetonide 31 was then converted back into the and 39 can be offered based on the crystal structure of lac-
starting dibromide (i.e., 23) by simply stirring it in glacial tone 26, since mesylate 37 has the same stereochemistry as
acetic acid. Next, the reaction of dibromide 32 with tetra- compound 26 (Scheme 10).
thiomolybdate 11 provided the expected seven-membered-
Sulfur initially displaces the mesyl group in 37 due to the
ring-containing thioseptanose derivative, 1-deoxy-d-glycero- anti-periplanar arrangement of the sulfur atom and the me-
Eur. J. Org. Chem. 2012, 6986–6995
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6989

T. Gunasundari, S. Chandrasekaran
FULL PAPER
ment processes were used effectively for the synthesis of
thiosugar derivatives 26, 27, 30, and 34 from commercially
available d-glucoheptono-1,4-lactone (22). These com-
pounds serve as excellent precursors for the synthesis of de-
oxythiosugars mimicking furanose, pyranose, and sep-
tanose structures. The synthesis of azido thiopyranose de-
rivative 38 and the ring contracted azido thiofuranose de-
rivative 39 by episulfonium ion rearrangement is interesting,
as thse compounds can serve as precursors for the synthesis
of thiosugar amino acids. The methodology uses short syn-
thetic sequences to synthesise well-known and new thio-
sugars and their derivatives.
Scheme 9. Synthesis of azido sugars 38 and 39. Reaction conditions:
a) Ag2O, BnBr, toluene, 80 °C, 3.5 h, 59%; b) (BnEt3N)2MoS4 (11),
CH3CN/EtOH (1:1), room temp., 5 h, 80%; c) MsCl, pyridine, 0 °C
to room temp. 3 h, 72%; d) NaN3, DMF, 80 °C, 2 h, 51%.
Experimental Section
General Remarks: Melting points were recorded with a Büchi B540
1
melting point apparatus. H and 13C NMR spectra were recorded
at 400, 300 and 100, 75 MHz, respectively, with a Bruker spectrom-
eter. Chemical shifts are reported in parts per million downfield
from the internal reference, tetramethylsilane. Coupling constants
are reported wherever necessary in Hertz (Hz). Column chromatog-
raphy was performed on silica gel (230–400 mesh). Mass spectra
were recorded with a Q-TOF electrospray instrument. Microanaly-
ses were recorded with a Thermo Finnigan FLASH EA 1112
CHNS analyzer. Optical rotations were recorded with a polarime-
ter, model P1020 (A077860638). X-ray data was recorded with a
Bruker SMART APEX CCD single crystal diffractometer.
2,6-Dibromo-2,6-dideoxy-L
-idono-1,4-lactone (6):[10] A solution of
l-gulono-1,4-lactone (5; 10 g, 0.056 mol) in HBr (33% in glacial
acetic acid; 56.2 mL) was stirred for 4.5 h at 30 °C. After comple-
tion of reaction, methanol (150 mL) was added slowly, and the mix-
ture was left overnight at room temperature. The reaction mixture
was then concentrated to a quarter of its volume. The concentrate
was then diluted with water (200 mL), and then extracted with di-
ethyl ether (4ϫ100 mL). The organic phase was dried with MgSO4
and concentrated in vacuo to yield 2,6-dibromo-2,6-dideoxy-l-
idono-1,4-lactone (6; 14.8 g, 86%) as a pale yellow syrup. The
crude product was sufficiently pure for further transformation. IR
Scheme 10. Plausible mechanism for the formation of azido thio-
sugar lactones 38 and 39 via episulfonium ion 40.
syl group, to give episulfonium ion 40. Episulfonium ion 40
can then be attacked by the azide anion in two possible
ways. The azide anion can attack intermediate 40 by follow-
ing path a to give the azido sugar 38, or by following path
b to give azido sugar 39. Since the two azides (i.e., 38 and
39) are formed in a 1:1 ratio, as observed from their NMR
spectrum and by isolation, it is assumed that the attack of
the azide anion by path a or path b is equally facile
(Scheme 10).
(neat): ν = 3443, 1779, 1428, 1221, 1183, 1100, 1059, 1014 cm–1. 1H
˜
NMR (400 MHz, [D6]acetone): δ = 3.56 (d, J = 6.4 Hz, 2 H), 4.31
(td, J = 9.5, 5.5 Hz, 1 H), 4.63 (d, J = 5.0 Hz, 1 H), 4.83–4.75 (m,
4 H) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 34.1, 44.8, 68.9,
75.5, 82.0, 171.4 ppm. HRMS: calcd. for C6H879Br2O4Na
[M + Na]+ 324.8687; found 324.8684.
3,5-Di-O-acetyl-2,6-dibromo-2,6-dideoxy-L
-idono-1,4-lactone (9):[11]
l-Gulono-1,4-lactone (5; 10 g, 0.056 mol), was added, with stirring,
to HBr (33% in glacial acetic acid; 56.6 mL, 0.6 mol), and stirred
at 30 °C for 3.5 h. Then the reaction mixture was cooled to 0 °C,
Conclusions
In conclusion, the synthesis of deoxythiosugars contain-
ing five- or six-membered rings was achieved from commer-
cially available l-gulono-1,4-lactone (5). Strategies used for and acetic anhydride (21.8 mL) was added dropwise. After stirring
for an additional 1 h, the mixture was slowly poured into vigor-
ously stirred ice-water (250 mL). The resulting precipitate was fil-
tered and then washed with water (5ϫ20 mL), propan-2-ol
(5ϫ5 mL), and diisopropyl ether (3ϫ5 mL). The residue was pure
the introduction of sulfur using benzyltriethylammonium
tetrathiomolybdate (11) include: (1) a nucleophilic displace-
ment and Michael addition; (2) epoxide ring opening fol-
lowed by Michael addition; (3) epoxide ring opening and
nucleophilic displacement process; and (4) double nucleo-
philic displacement. The short and efficient synthesis of
thiosugars, such as thio-deoxy-ido-nojirimycin 8a and thio-
deoxy-nojirimycin 8b, from a single precursor was achieved.
Similarly, bromide-displacement/Michael addition, epox-
acetate 9 (15.0 g, 69%). IR (neat): ν = 1782, 1780, 1750, 1222, 1111,
˜
1040, 826 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.16 (s, 6 H,
-OCOCH3), 3.41 (dd, J = 11, 4.9 Hz, 1 H, -CH2Br), 3.42 (dd, J =
11, 6.0 Hz, 1 H, -CH2Br), 4.46 [d, J = 5.4 Hz, 1 H, -CH(Br)-], 5.23–
5.25 [m, 1 H, -CHOCO- and -CH(OCOCH3)-], 5.56 [t, J = 5.6 Hz,
1 H, -CH(OCOCH3)-] ppm. 13C NMR (100 MHz, CDCl3): δ =
ide-ring-opening/Michael-addition, and double-displace- 20.4 (-OCOCH3), 20.9 (-OCOCH3), 27.9 (-CH2Br), 39.0 [-CH(Br)-
6990
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6986–6995

Deoxythiosugar Derivatives from Lactones
], 69.0 (-CHOCO-), 75.8 [-CH(OCOCH3)-], 77.9 [-CH(OCOCH3)-
], 168.6 [-OC(O)-], 169.0 [-OC(O)-], 169.6 [-OC(O)-] ppm.
3.54–3.61 (m, 1 H, -SCH-), 3.62–3.69 (m, 2 H, -CH2CH2OH), 4.00
[t, J = 3.3 Hz, 1 H, -CH(OH)-], 4.26 [t, J = 2.0 Hz, 1 H, -CH(OH)-]
ppm. 13C NMR (100 MHz, CD3OD): δ = 34.2 (-CH2CH2OH), 36.7
(-SCH2-), 47.8 (-SCH-), 62.2 (-CH2OH), 79.4 [-CH(OH)-], 80.1
[-CH(OH)-] ppm. HRMS: calcd. for C6H12O3SNa [M + Na]+
187.0405; found 187.0415.
5-O-Acetyl-6-bromo-2,3,6-trideoxy-L-threo-hex-2-enono-1,4-
lactone (10):[11] NaHSO3 (2.68 g, 0.026 mol) was added to com-
pound 9 (10 g, 0.025 mol) in methanol/water (9:1, 93 mL), and then
Na2SO4 (6.5 g, 0.052 mol) was added to the mixture portionwise.
The reaction mixture was stirred for 3 h, and then it was quenched
with HCl (1 m; 78 mL), and extracted with dichloromethane
(75 mL). The combined extracts were then washed with water
(100 mL), dried (MgSO4), and concentrated in vacuo to give com-
pound 10 (4.62 g, 72%) as an oil. The product was pure, and was
6-Bromo-2,3,6-trideoxy-L-threo-hex-2-enono-1,4-lactone
(13):[11]
Butenolide 10 (4.13 g, 0.17 mol) was stirred with HCl (1 m in meth-
anol; 110 mL, 0.11 mol) at 5 °C for 2 d. The reaction mixture was
then concentrated in vacuo at 30 °C to give bromoalcohol 13
(3.28 g, 96%) as a gummy solid that was pure, and that was used
used as such in further reactions. IR (neat): ν = 1783, 1750, 1374,
in further reactions. IR (neat): ν = 3422, 1749, 1172, 1111, 1042,
˜
˜
1
1222, 1161, 1040, 826 cm–1. H NMR (400 MHz, CDCl3): δ = 2.1 849, 821, 616 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.48 (dd,
(s, 3 H, -OCOCH3), 3.57 (dd, J = 10.6, 6.6 Hz, 1 H, -CH2Br), 3.68
(dd, J = 10.7, 6.8 Hz, 1 H, -CH2Br), 5.33 (ddd, J = 6.7, 4.2, 2.5 Hz,
1 H, -CHOCO-), 5.59 [t, J = 2.2 Hz, 1 H, -CH(OCOCH3)-], 6.21
(dd, J = 5.7, 2.0 Hz, 1 H, -CH=CHCOO-), 7.46 (dd, J = 5.7,
J = 10.3, 6.2 Hz, 1 H, -CH2Br), 3.58 (dd, J = 10.4, 6.6 Hz, 1 H,
-CH2Br), 4.07–4.12 [m, 1 H, -CH(OH)-], 5.38 (s, 1 H, -CHOCO-),
6.19 (d, J = 5.6 Hz, 1 H, -CH=CHCOO-), 7.52 (d, J = 5.7 Hz, 1
H, -CH=CHCOO-) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.7
1.6 Hz, 1 H, -CH=CHCOO-) ppm. 13C NMR (100 MHz, CDCl3): (-CH2Br), 70.7 [-CH(OH)-], 83.5 (-CHOCO-), 122.7 (-CH=
δ = 20.3 (-OCOCH3), 28.8 (-CH2Br), 70.3 (-CHOCO-), 81.2 CHCOO-), 153.9 (-CH=CHCOO-), 173.2 [-OC(O)-] ppm.
[-CH(OCOCH3)-], 122.8 (-CH=CHCOO-), 152.1 (-CH=CHCOO-),
Synthesis of Compound 14 from 13: (BnEt3N)2MoS4, (11; 3.55 g,
169.6 [-OC(O)-], 171.9 [-OC(O)-] ppm.
5.8 mmol) was added to a solution of bromohydrin 13 (0.549 g,
Synthesis of Compound 12: (BnEt3N)2MoS4[12] (3.75 g, 6 mmol) was
added to a solution of bromobutenolide 10 (0.7 g, 3 mmol) in ace-
tonitrile (25 mL), and the reaction mixture was stirred for 1 h. The
mixture was then concentrated in vacuo, and the residue was re-
peatedly extracted with THF (5ϫ5 mL). The organic phase was
then concentrated to give the crude product, which, upon column
chromatography on silica gel (elution with hexanes/ethyl acetate,
2:3), gave a white solid. This was recrystallized from CHCl3 to give
bicyclic lactone 12 (0.5 g, 88%) as colorless blocks; m.p. 113–
2.65 mmol) in acetonitrile (20 mL), (Bnand the reaction mixture
was stirred for 1 h. The mixture was then concentrated in vacuo,
and the residue was repeatedly extracted with THF (5ϫ5 mL). The
organic phase was concentrated to give the crude product, which,
upon column chromatography on silica gel (eluting with hexanes/
ethyl acetate, 1:1) gave a white solid. This solid was recrystallized
from a mixture of hexanes and ethyl acetate to give sulfur com-
pound 14 (0.365 g, 86%) as colorless crystals; m.p. 104–105 °C.
[α]D = +64.0 (c = 1.0, MeOH). IR (neat): ν = 3447, 1748, 1178,
˜
114 °C. [α]D = +132.0 (c = 1.0, CHCl ). IR (neat): ν = 1789, 1750,
1154, 1040, 1001, 692 cm–1. 1H NMR (400 MHz, [D6]acetone): δ =
˜
3
1376, 1250, 1168, 1136, 1047, 980 cm–1. 1H NMR (400 MHz, 2.57 (d, J = 17.8 Hz, 1 H, -CH2COO-), 2.88 (d, J = 11.7 Hz, 1 H,
CDCl3): δ = 2.12 (s, 3 H, -OCOCH3); 2.78 (d, J = 18.1 Hz, 1 H,
-CH2COO-), 3.11 (dd, J = 17.8, 6.9 Hz, 1 H, -SCH2-), 3.22 (dd, J
-CH2COO-), 3.01 (dd, J = 18.7, 7.3 Hz, 2 H, -CH2COO- and = 11.7, 3.7 Hz, 1 H, -SCH2-), 4.24 (d, J = 5.9 Hz, 1 H, -SCH-),
-SCH2-), 3.40 (dd, J = 12.7, 3.9 Hz, 1 H, -SCH2-), 4.21 (t, J =
6.4 Hz, 1 H, -SCH-), 4.96 (d, J = 4.8 Hz, 1 H, -CHOCO-), 5.63 [s,
1 H, -CH(OCOCH3)-] ppm. 13C NMR (100 MHz, CDCl3): δ =
20.9 (-OCOCH3), 36.1 (-CH2COO-), 37.8 (-SCH2-), 44.7 (-SCH-),
4.59 [d, J = 4.2 Hz, 1 H, -CH(OH)-], 4.70 (s, 1 H, -OH), 4.91 (d,
J = 4.8 Hz, 1 H, -CHOCO-) ppm. 13C NMR (100 MHz, [D6]ace-
tone): δ = 38.5 (-CH2COO-), 39.4 (-SCH2-), 45.8 (-SCH-), 77.3
[-CH(OH)-], 90.2 (-CHOCO-), 175.4 [-OC(O)-] ppm. HRMS:
78.4 (-CHOCO-), 87.1 [-CH(OCOCH3)-], 169.6 [-OC(O)-], 174.1 calcd. for C6H8O3SNa [M + Na]+ 183.0092; found 183.0091.
[-OC(O)-] ppm. HRMS: calcd. for C8H10O4SNa [M + Na]+
225.0198; found 225.0193.
C6H8O3S (160.02): calcd. C 45.06, H 5.11, S 20.00; found C 44.99,
H 5.03, S 20.02.
Preparation of Borohydride Exchange Resin (BER):[13] A solution
of sodium borohydride (0.5 m, 100 mL) in water was stirred with
Amberlite IRA-400 Cl– resin (10.0 g) for 1 h. The borohydride-
bound ion exchange resin was washed thoroughly with distilled
water and dried in vacuo at 60° C for 5 h.
Crystal Structure Data: C6H10O4S; Mr = 178.20; crystal dimen-
sions: 0.25ϫ0.23ϫ0.16 mm; T = 291(2) K; orthorhombic; space
group P212121; a = 5.2242(5), b = 7.5040(7), c = 20.4727(19) Å;
α = β = γ = 90.00°; Z = 4, V = 802.58(13) cm3; ρcalcd. = 1.475 gcm–3;
Mo-Kα radiation (λ = 0.71073 Å); μ = 3.7.00 mm–1; 2θ = 2.9–23.0°;
of 8316 reflections collected, 1123 were independent [R(int) =
0.0413]; refinement method full-matrix least-squares on F2, 109 re-
fined parameters, absorption correction SADABS software, Bruker,
BER Reduction of Compound 12 to Homothiofuranose Derivative 7:
BER (4.0 g, 0.012 mol) was added to a stirred solution of lactone
12 (0.3 g, 1.48 mmol) in dry methanol (18 mL) at 0 °C, and the
solution was stirred for 22 h. The reaction mixture was filtered,
methanol (10 mL) was added to the resin, and the methanol/resin
mixture was sonicated (ultrasonic cleaning bath, 20 kHz) for 5 min
at room temperature. The reaction mixture was then neutralized
with glacial acetic acid. The mixture was filtered, and the filtrate
was concentrated in vacuo to give the crude product. This residue
was then subjected to column chromatography on silica gel (eluting
1996; Tmin = 0.8376 and Tmax = 0.9642; GooF = 1.063, R1
=
0.0413, wR2 = 0.0244 [σϾ2σ(I)]; absolute structure parameter:
–0.09(9); residual electron density: 0.169/–0.106 eÅ–3.
5,6-Anhydro-2,3-dideoxy-L-threo-hex-2-enono-1,4-lactone
(15):
Ag2O (0.56 g, 2.4 mmol) was added to a solution of compound 13
(0.5 g, 2.4 mmol) in water (2 mL) at 0 °C, and the mixture was
stirred for 4 h at the same temperature. After completion of the
reaction, HBr was added to precipitate AgBr. The mixture was fil-
tered, and the precipitate was washed with CH2Cl2 (2ϫ5 mL). The
collected washings and filtrate were mixed together and extracted
again with CH2Cl2 (3ϫ5 mL). The combined organic extracts were
dried with MgSO4 and concentrated in vacuo below 30 °C to give
with methanol/chloroform, 1.5:8.5) to give homothiosugar
7
(0.175 g, 72%) as a gummy solid. [α]D = +48.0 (c = 1.0, MeOH).
IR (neat): ν = 3404, 3394, 3384, 1671, 1523, 1252, 1102, 1022, 1070,
˜
850 cm–1. 1H NMR (400 MHz, CD3OD): δ = 1.77–1.83 (m, 1 H,
-CH2CH2OH), 2.03–2.08 (m, 1 H, -CH2CH2OH), 2.66 (d, J =
11.3 Hz, 1 H, -SCH2-), 3.20 (dd, J = 11.3, 4.4 Hz, 1 H, -SCH2-),
15 (0.213 g, 70%) as a low-melting white solid. IR (neat): ν = 1780,
˜
Eur. J. Org. Chem. 2012, 6986–6995
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6991

T. Gunasundari, S. Chandrasekaran
FULL PAPER
1349, 1192, 1156, 1065, 1042, 893, 866 cm–1. H NMR (400 MHz,
CDCl3): δ = 2.77 (dd, J = 4.6, 2.1 Hz, 1 H, -CH2O-), 2.84 (dd, J
= 4.7, 2.5 Hz, 1 H, -CH2O-), 3.13 [d, J = 2.6 Hz, 1 H, -C(H)O-],
5.03 (t, J = 1.9 Hz, 1 H, -CHOCO-), 6.18 (dd, J = 5.6, 1.4 Hz, 1
H), 5.10 (d, J = 3.4 Hz, 1 H, -CHOCO-) ppm. 13C NMR
(100 MHz, [D6]acetone): δ = 23.2 (-SCH2-), 40.6 (-SCH-), 73.9
[-CH(OH)-], 77.7 [-CH(OH)-], 78.0 (-CHOCO-), 169.3 [-OC(O)-]
ppm. HRMS: calcd. for C6H8O4SNa [M + Na]+ 199.0041; found
1
H, -CH=CHCOO-), 7.45 (d, J = 5.6 Hz, 1 H, -CH=CHCOO-) 199.0039. C6H8O4S (176.01): calcd. C 40.9, H 4.58, S 18.2; found
ppm. 13C NMR (100 MHz, CDCl3): δ = 43.8 (-CH2O-), 50.6 C 40.8, H 4.6, S 18.2.
[-C(H)O-], 81.8 (-CHOCO-), 123.1 (-CH=CHCOO-), 152.0
Crystal Structure Data: C6H8O4S; Mr = 176.18; crystal dimensions:
(-CH=CHCOO-), 172.3 [-OC(O)-] ppm.
0.27ϫ0.21ϫ0.18 mm; T = 273(2) K; monoclinic, space group:
Synthesis of 14 from 15: (BnEt3N)2MoS4 (11; 0.629 g, 2.7 mmol)
was added to a stirred suspension of epoxy butenolide 15 (0.156 g,
1.2 mmol) in a mixture of acetonitrile (4 mL) and ethanol (4 mL),
and the reaction mixture was stirred for 1 h. The mixture was then
concentrated in vacuo, and the residue was repeatedly extracted
with THF (5ϫ5 mL). The combined extracts were concentrated to
give the crude product, which, upon column chromatography on
silica gel (eluting with hexanes/ethyl acetate, 1:1) gave a white solid.
This solid was recrystallized from a mixture of hexanes and ethyl
acetate to give bicyclic lactone 14 (0.178 g, 90%) as colorless crys-
tals.
P2(1); a = 6.4978(8), b = 10.5423(13), c = 10.6323(13) Å; α = γ =
90.00, β = 91.712(2)°; Z = 4, V = 728.01(15) cm3; ρcalcd.
=
1.607 gcm–3; Mo-Kα radiation (λ = 0.71073 Å); μ = 4.0 mm–1; 2θ
= 1.9–26.0°; of 3481 reflections collected, 2781 were independent
[R(int) = 0.0133]; refinement method full-matrix least-squares on
F2, 263 refined parameters; absorption correction SADABS soft-
ware, Bruker, 1996; Tmin 0.9057 and Tmax 0.9235, GooF = 1.036, R1
= 0.0133, wR2 = 0.0227 [σϾ2σ(I)]; absolute structure parameter:
–0.01(5); residual electron density: 0.194/–0.229 eÅ–3.
Thio-deoxy-ido-nojirimycin 8a from Bicyclic Lactone 18: A solution
of lactone 18 (0.3 g, 0.017 mol) in dry methanol (20 mL) was stirred
at 0 °C with borohydride exchange resin (3.4 g, 0.010 mol) for 20 h.
The reaction mixture was filtered, and methanol (10 mL) was
added to the resin and was sonicated (ultrasonic cleaning bath,
20 kHz) for 5 min at room temperature. The sonicated reaction
mixture was then neutralized using glacial acetic acid. The reaction
mixture was filtered and concentrated in vacuo to give a crude
product. This residue was subjected to column chromatography on
silica gel (eluting with methanol/chloroform, 1.5:8.5) to give thio-
Synthesis of Epoxide from Compound 6
Using KF: KF[17] (6.859 g, 0.118 mol) was added to 2,6-dibromo-
2,6-dideoxy-l-gulonolactone (6; 6.9 g, 0.023 mol) in acetone
(140 mL), and the mixture was stirred for 7 h at room temperature.
The mixture was then filtered, and the organic layer was concen-
trated in vacuo to give a crude compound. Upon column
chromatography on silica gel (eluting with hexanes/ethyl acetate,
1:1), this residue gave 6-bromo-2,3-monoepoxygulono-γ-lactone
(five-membered ring lactone, i.e., 16) along with the required 6-
bromo-2,3-monoepoxygulono-δ-lactone (six-membered ring lac-
tone, i.e., 17) in a 2:3 ratio (3.594 g, 71%), as well an unidentified
product. Compounds 16 and 17 were inseparable by column
deoxy-ido-nojirimycin 8a (0.206 g, 67%) as a gummy solid. [α]D
=
–35.0 (c = 1.0, MeOH). IR (neat): ν = 3448, 3444, 3410, 1699,
˜
1
1526, 1253, 1169, 1033 cm–1. H NMR (400 MHz, D2O): δ = 2.45
(dd, J = 13.8, 4.4 Hz, 1 H, -SCH2-), 2.58 (t, J = 13.7 Hz, 1 H,
-SCH2-), 2.89–2.84 (m, 1 H, -SCH-), 3.23 (dd, J = 18.3, 9.1 Hz, 1
H, -CH2OH), 3.58–3.53 (m, 1 H, -CH2OH), 3.62 [t, J = 10.4 Hz, 1
H, -CH(OH)-], 3.82–3.80 [m, 1 H, -CH(OH)-], 3.87 [dd, J = 11.6,
4.0 Hz, 1 H, -CH(OH)-] ppm. 13C NMR (100 MHz, D2O): δ = 27.3
(-SCH2-), 45.9 (-SCH-), 57.1 (-CH2OH), 72.9 [-CH(OH)-], 73.6
[-CH(OH)-], 73.7 [-CH(OH)-] ppm. HRMS: calcd. for
C6H12O4SNa [M + Na]+ 203.0354; found 203.0356.
chromatography. IR (neat): ν = 3407, 1780, 1769, 1173, 1104, 1060,
˜
1009, 910 cm–1. HRMS: calcd. for C6H779Br2O4Na [M + Na]+
244.9476; found 246.9478.
Using K2CO3: K2CO3 (23.7 g, 0.171 mol) was added to 2,6-di-
bromo-2,6-dideoxy-l-gulonolactone (6; 7.8 g, 0.026 mol) in acetone
(160 mL), and the mixture was stirred for 5 h at room temperature.
The mixture was then filtered, and the organic layer was concen-
trated in vacuo to give a crude compound. Upon column
chromatography on silica gel (eluting with hexanes/ethyl acetate,
1:1), this residue gave the required 6-bromo-2,3-mono-
epoxygulono-δ-lactone (six-membered ring lactone) 17 along with
6-bromo-2,3-monoepoxygulono-γ-lactone (five-membered ring lac-
tone) 16 in a 4:1 ratio (3.663 g, 64%). Epoxides 17 and 16 were
inseparable by column chromatography.
Acetonation of 2,6-Dibromo-2,6-dideoxy-L-idono-1,4-lactone (6): A
solution of 2,6-dibromo-2,6-dideoxy-d-idono-1,4-lactone (6; 2.2 g,
6.58 mmol) in CH2Cl2 (8 mL) was stirred with 2,2-DMP (10.3 g,
0.0987 mol) and pTsOH (1.25 g, 6.58 mmol) at room temperature
for 45 min. The reaction mixture was then stirred with solid K2CO3
(to quench pTsOH) for a few minutes. The mixture was then filtered
through a Celite pad, and concentrated. The residue was purified
by column chromatography on silica gel (eluting with hexanes/ethyl
acetate, 8.5:1.5) to give the required compound (i.e., 19a) as the
major product, along with 19b in a 3:1 ratio (19a: 1.26 g, 47%; 19b:
0.43 g, 15%).
Synthesis of the Bicyclic Lactone 18 from 6-Bromo-2,3-anhydrogu-
lono-δ-lactone (six-membered ring lactone) 17: (BnEt3N)2MoS4, (11;
4.2 g, 6.91 mmol) was added to a solution of 6-bromo-2,3-mono-
epoxygulono-δ-lactone 17 (0.7 g, 3 mmol) in a mixture of acetoni-
trile (10 mL) and ethanol (10 mL), and the reaction mixture was
stirred for 4 h. The mixture was then concentrated in vacuo, and
the residue was repeatedly extracted with THF (5ϫ5 mL). The
combined extracts were concentrated to give a crude product,
which, upon column chromatography on silica gel (eluting with
hexanes/ethyl acetate, 1:1) gave a white solid. This was recrys-
tallized from a mixture of hexanes and ethyl acetate to give bicyclic
sulfur compound 18 (0.365 g, 66%) as colorless crystals; m.p. 178–
Compound 19a: IR (neat): ν = 3504, 1741, 1438, 1374, 1240, 1223,
˜
1157, 1074, 880 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.45 [s,
3 H, -C(CH3)2-], 1.47 [s, 3 H, -C(CH3)2-], 2.70 (d, J = 8.0 Hz, 1
H, -OH), 3.48 (d, J = 6.7 Hz, 2 H, -CH2Br), 3.82 (s, 3 H, -CO-
OCH3), 3.89–3.91 [m, 1 H, -CH(Br)-], 4.34 [dd, J = 6.9, 2.1 Hz, 1
H, -CH(O)-], 4.44 [d, J = 6.2 Hz, 1 H, -CH(O)-], 4.48 [d, J =
6.5 Hz, 1 H, -CH(O)-] ppm. 13C NMR (100 MHz, CDCl3): δ =
27.1 [-C(CH3)2-], 27.2 [-C(CH3)2-], 34.0 (-CH2Br), 45.8 [-CH(Br)-],
53.3 (-OCH3), 69.9 [-C(H)O-], 77.3 [-C(H)O-], 78.5 [-C(H)O-],
111.0 [-OC(CH3)2O-], 167.9 [-OC(O)-] ppm. HRMS: calcd. for
C10H16Br2O5Na [M + Na]+ 396.9262; found 396.9262.
179 °C. [α]D = –44.0 (c = 1.0, MeOH). IR (neat): ν = 3350, 3339,
˜
1734, 1527, 1156, 1038, 672 cm–1. 1H NMR (400 MHz, [D6]ace-
tone): δ = 2.99 (dd, J = 11.7, 3.8 Hz, 1 H, -SCH2-), 3.22 (m, J =
20.7, 11.7 Hz, 2 H, -SCH2- and -SCH-), 3.96 (br. s, 1 H), 4.15 (d,
J = 2.1 Hz, 1 H), 4.87 (t, J = 4.1 Hz, 1 H), 5.03 (d, J = 4.5 Hz, 1
Compound 19b: IR (neat): ν = 1790, 1386, 1201, 1178, 1096, 1032,
˜
945, 870 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.41 [s, 3 H,
6992
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6986–6995

Deoxythiosugar Derivatives from Lactones
-C(CH3)2-], 1.50 [s, 3 H, -C(CH3)2-], 3.47 (dd, J = 10.1, 6.0 Hz, 1 8.0 Hz, 1 H), 3.95 (dd, J = 12.0, 4.0 Hz, 1 H) ppm. 13C NMR
H, -CH2Br), 3.58 (dd, J = 10.1, 8.2 Hz, 1 H, -CH2Br), 4.13 [s, 1
(100 MHz, CD3OD): δ = 31.8, 48.2, 61.4, 73.3, 74.4, 79.3 ppm.
H, -CH(O)-], 4.30 [dt, J = 7.0, 1.8 Hz, 1 H, -CH(Br)-], 4.61 [d, J HRMS: calcd. for C6H12O4SNa [M + Na]+ 203.0354; found
= 2.3 Hz, 1 H, -CH(O)-], 4.76 [d, J = 2.0 Hz, 1 H, -CH(O)-] ppm. 203.0354.
13C NMR (100 MHz, CDCl3):
δ = 19.3 [-C(CH3)2-], 28.5
5,6-Di-O-acetyl-7-bromo-2,3,7-trideoxy-D-arabino-hept-2-enono-
[-C(CH3)2-], 29.1 (-CH2Br), 40.3 [-CH(Br)-], 68.5 [-C(H)O-], 70.9
[-C(H)O-], 73.1 [-C(H)O-], 99.6 [-OC(CH3)2O-], 170.8 [-OC(O)-]
ppm. HRMS: calcd. for C9H12Br2O4Na [M + Na]+ 364.9000;
found 364.8999.
1,4-lactone (25): Na2S2O5 (2.57 g, 0.013 mol) was added to a solu-
tion of 3,5,6-tri-O-acetyl-2,7-dibromo-2,7-dideoxy-d-glycero-d-ido-
heptono-1,4-lactone (24; 12.20 g, 0.027 mol) in MeOH (54 mL) and
H2O (7 mL). Na2SO3 (7.02 g, 0.056 mol) was then added in por-
tions, and stirring was continued for 3.5 h at room temperature.
The reaction mixture was quenched with HCl (1 n, 87 mL), and
the product was extracted with CH2Cl2 (4ϫ50 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated to
give a pale yellow solid. The solid was subjected to a short column
chromatography to give 5,6-di-O-acetyl-7-bromo-2,3,7-trideoxy-d-
arabino-hept-2-enono-1,4-lactone (25; 81%) as a cream-colored so-
Synthesis of Deoxythiosugar Carboxylate 20 from Dibromo Ester
19a: A solution of dibromo ester 19a (1.0 g, 2.66 mmol) in acetoni-
trile (20 mL) was stirred with (BnEt3N)2MoS4 (11; 3.56 g,
5.86 mmol) for 1 h. The mixture was then concentrated in vacuo,
and the residue was repeatedly extracted with THF (5ϫ5 mL). The
combined extracts were concentrated to give the crude product.
This residue was purified by column chromatography on silica gel
(eluting with hexanes/ethyl acetate, 3:2) to give deoxythiosugar
lid; m.p. 151.5–153.5 °C. [α]D = +84.0 (c = 1, MeOH). IR (neat): ν
˜
= 1759, 1745, 1426, 1372, 1216, 1192, 1020, 833 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 2.04 (s, 3 H, -OCOCH3), 2.16 (s, 3 H, -
OCOCH3), 3.53 (dd, J = 4.5, 12.0 Hz, 1 H, -CH2Br), 3.86 (dd, J =
4.0, 16.0 Hz, 1 H, -CH2Br), 5.31–5.37 [m, 2 H, -C(H)OCO- and -
CH(OCOCH3)-], 5.43 [dd, J = 7.8, 1.5 Hz, 1 H, -CH(OCOCH3)-],
6.15 (dd, J = 5.7, 2.1 Hz, 1 H, -CH=CHCOO-), 7.41 (dd, J = 5.7,
1.8 Hz, 1 H, -CH=CHCOO-) ppm. 13C NMR (75 MHz, CDCl3):
δ = 20.4 (-OCOCH3), 20.7 (-OCOCH3), 31.1 (-CH2Br), 69.2
[-C(H)O-], 70.1 [-C(H)O-], 80.6 [-C(H)O-], 122.6 (-CH=
CHCOO-), 152.39 (-CH=CHCOO-), 169.3 [-OC(O)-], 169.5
[-OC(O)-], 171.8 [-OC(O)-] ppm.
carboxylate 20 (0.554 g, 84%) as a gummy solid. IR (neat): ν =
˜
1
3531, 1736, 1438, 1375, 1232, 1200, 1059, 982, 870 cm–1. H NMR
(400 MHz, CDCl3): δ = 1.40 [s, 3 H, -C(CH3)2-], 1.42 [s, 3 H,
-C(CH3)2-], 2.70 (dd, J = 18.0, 13.2 Hz, 1 H, -SCH2-), 2.81 (dd, J
= 18.0, 6.4 Hz, 1 H, -SCH2-), 2.93 (s, 1 H, -OH), 3.21 [t, J =
12.4 Hz, 1 H, -CH(OH)-], 3.67 (d, J = 13.6 Hz, 1 H, -SCH-), 3.76
(s, 3 H, -OCH3-), 3.94 [dd, J = 13.6, 12.0 Hz, 1 H, -C(H)O-], 4.04–
4.07 [m, 1 H, -C(H)O-] ppm. 13C NMR (100 MHz, CDCl3): δ =
26.6 [-C(CH3)2-], 26.8 [-C(CH3)2-], 33.8 (-SCH2-), 47.0 (-SCH-),
52.9 (-OCH3), 71.2 [-C(H)O-], 77.3 [-C(H)O-], 82.3 [-C(H)O-],
109.8 [-OC(CH3)2O-], 168.6 [-OC(O)-] ppm. HRMS: calcd. for
C10H16O5SNa [M + Na]+ 271.0616; found 271.0615.
2,3-Di-O-acetyl-1,5-anhydro-6-deoxy-5-thio-L-gulo-heptono-4,7-lac-
tone (26): (BnEt3N)2MoS4, (11; 9.73 g, 0.016 mol) was added to a
solution of 5,6-di-O-acetyl-7-bromo-2,3,7-trideoxy-d-arabino-hept-
2-enono-1,4-lactone (25; 2.332 g, 7.262 mmol) in CH3CN (30 mL),
and the mixture was stirred for 5 h at room temperature. The mix-
ture was then concentrated in vacuo, and the residue was repeatedly
extracted with THF (5ϫ5 mL). The combined extracts were con-
centrated to give a crude product, which upon column chromatog-
raphy on silica gel (eluting with hexanes/ethyl acetate, 1:1) gave a
white solid. This solid was recrystallized from a mixture of hexanes
and ethyl acetate to give 1,6-dideoxy-2,3-diacetoxy-5-thio-l-gu-
lono-4,7-lactone (26; 1.33 g, 67%) as colorless crystals; m.p. 124–
Synthesis of Deoxythiosugar 21 from 20: Compound 20 (0.250 g,
1.0 mmol) was stirred with glacial acetic acid (8 mL) overnight. The
mixture was then concentrated to give a crude product, which,
upon column chromatography on silica gel (eluting with hexanes/
ethyl acetate, 2:3) gave a white solid. This solid was recrystallized
from hot CHCl3 to give deoxythiosugar carboxylate 21 (0.205 g,
98%) as colorless crystals. [α]D = +11.0 (c = 1.0, MeOH). IR (neat):
1
ν = 3474, 1736, 1450, 1376, 1261, 1214, 1163, 1059, 878 cm–1. H
˜
NMR (400 MHz, CD3OD): δ = 2.64–2.67 (m, 2 H, -SCH2-), 3.12
[t, J = 9.0 Hz, 1 H, -CH(OH)-], 3.47 (d, J = 10.2 Hz, 1 H,
-SCH-), 3.63 [dt, J = 9.2, 6.1 Hz, 1 H, -CH(OH)-], 3.73 (s, 3 H,
-COOCH3), 3.75 [dd, J = 15.4, 9.7 Hz, 1 H, -CH(OH)-] ppm.
HRMS: calcd. for C7H12O5SNa [M + Na]+ 231.0303; found
231.0301.
126 °C. IR (neat): ν = 1792, 1746, 1373, 12320, 1040 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 2.07 (s, 3 H, -COCH3), 2.15 (s, 3
H, -COCH3), 2.42 (dd, J = 3.0, 17.5 Hz, 1 H, -CH2COO-), 2.66
(dd, J = 3.9, 13.6 Hz, 1 H, -CH2COO-), 2.85 (dd, J = 6.7, 17.5 Hz,
1 H, -SCH2-), 3.06 (dd, J = 8.6, 13.6 Hz, 1 H, -SCH2-), 3.84 (q, J
= 3.4 Hz, 1 H, -SCH-), 4.66 (t, J = 4.9 Hz, 1 H, -CHOCO-), 5.33–
5.39 [m, 2 H, -CH(OCOCH3)-] ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.7 (-OCOCH3), 20.9 (-OCOCH3), 25.4 (-CH2COO-),
35.3 (-SCH2-), 35.9 (-SCH-), 67.7 [-C(H)O-], 68.1 [-C(H)O-], 78.4
[-C(H)O-], 169.4 [-OC(O)-], 169.6 [-OC(O)-], 173.2 [-OC(O)-] ppm.
HRMS: calcd. for C11H14O6SNa [M + Na]+ 297.0409; found
297.0404.
Crystal Structure Data: C7H12O5S; Mr = 208.23; Crystal dimen-
sions 0.50ϫ0.16ϫ0.12 mm; T = 296(2) K; orthorhombic; space
group P212121; a = 5.1274(2), b = 10.1735(4), c = 17.4541(9) Å;
α = β = γ = 90.00°; Z = 4, V = 910.47(7) cm3; ρcalcd. = 1.512 gcm–3;
Mo-Kα radiation (λ = 0.71073 Å); μ = 3.4 mm–1; 2θ = 2.3–25.0°; of
1760 reflections collected, 1527 were independent [R(int) = 0.0324];
refinement method full-matrix least-squares on F2, 123 refined pa-
rameters; absorption correction SADABS software, Bruker, 1996;
Tmin = 0.8470 and Tmax = 0.9599; GooF = 1.144, R1 = 0.0250,
wR2 = 0.0323 [σϾ2σ(I)]; absolute structure parameter: 0.06(10);
residual electron density: 0.184/–0.161 eÅ–3.
Thio-homo-deoxy-gulo-nojirimycin 27: Gummy solid. 1H NMR
(400 MHz, CD3OD):
δ = 1.67 (sept, J = 6.2 Hz, 1 H,
-CH2CH2OH), 1.80 (sept, J = 6.7 Hz, 1 H, -CH2CH2OH), 2.28 (d,
J = 12.6 Hz, 1 H, -SCH2-), 2.92 (t, J = 12.3 Hz, 1 H, -SCH2-), 3.35
(t, J = 7.4 Hz, 1 H, -SCH-), 3.59–3.69 (m, 2 H, -CH2OH), 3.79 [s,
1 H, -CH(OH)-], 3.87 [s, 1 H, -CH(OH)-], 4.03 [d, J = 10.6 Hz, 1
H, -CH(OH)-] ppm. 13C NMR (100 MHz, CD3OD): δ = 27.4
(-CH2CH2OH), 33.0 (-SCH2-), 37.1 (-SCH-), 59.1 (-CH2OH), 67.1
[-C(H)O-], 71.9 [-C(H)O-], 72.7 [-C(H)O-] ppm.
Thio-deoxy-nojirimycin 8b: Compounds 20 and 21 were reduced by
a procedure similar to the synthesis of thio-deoxy-ido-nojirimycin
8a, to give thio-deoxy-nojirimycin 8b; yield (0.142 g, 78%). [α]D
=
+22.0 (c = 1.0, MeOH), lit.[4b] [α]D = +50.0 (c = 1.39, H2O). IR
1
(neat): ν = 3358, 3349, 1581, 1403, 1120, 1017, 770, 671 cm–1. H
˜
NMR (400 MHz, CD3OD): δ = 2.55–2.66 (m, 2 H, -SCH2-), 2.79–
2.84 (m, 1 H, -SCH-), 3.11 (t, J = 8.0 Hz, 1 H), 3.45 (t, J = 12.0 Hz,
1 H), 3.58 (ddd, J = 8.0, 4.0, 4.0 Hz, 1 H), 3.72 (dd, J = 12.0,
1-Deoxy-5-thio-L-gulono-4,7-lactone (30): Gummy solid; [α]D =
–116.0 (c = 1, MeOH). IR (neat): ν = 3409, 1779, 1652, 1417, 1385,
˜
Eur. J. Org. Chem. 2012, 6986–6995
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6993

T. Gunasundari, S. Chandrasekaran
FULL PAPER
1116, 1023, 990, 749 cm–1. H NMR (300 MHz, [D6]acetone): δ =
2.28 (dt, J = 3.9, 13.1 Hz, 2 H, -CH2COO-), 2.90–3.05 (m, 2 H,
-SCH2-), 3.83 (sept, J = 1.9 Hz, 1 H, -SCH-), 3.94 [td, J = 3.9,
1
upon column chromatography on silica gel (eluting with hexanes/
ethyl acetate, 3:2) gave thioseptanose derivative 34 (0.628 g, 80%)
as a pale yellow solid; m.p. 140–142 °C. IR (neat): ν = 2988, 1743,
˜
9.9 Hz, 1 H, -CH(OH)-], 4.02 [d, J = 2.1 Hz, 1 H, -CH(OH)-], 4.68 1381, 1260, 1232, 1215, 1161, 1048, 876 cm–1. 1H NMR (400 MHz,
(d, J = 4.5 Hz, 1 H, -CHOCO-) ppm. 13C NMR (75 MHz,
CDCl3): δ = 1.38 [s, 3 H, -C(CH3)2-], 1.44 [s, 3 H, -C(CH3)2-], 1.46
[D6]acetone): δ = 27.2 (-CH2COO-), 35.6 (-SCH2-), 37.7 (-SCH-), [s, 3 H, -C(CH3)2-], 1.52 [s, 3 H, -C(CH3)2-] 2.81–2.87 (m, 2 H,
68.4 [-C(H)O-], 68.9 [-C(H)O-], 83.8 [-C(H)O-], 177.3 [-OC(O)-] -SCH2-), 3.55 (d, J = 7.3 Hz, 1 H, -SCH-), 3.66 [t, J = 3.4 Hz, 1
ppm. HRMS: calcd. for C7H10O4SNa [M + Na]+ 213.0198; found
213.0192.
H, -C(H)O-], 3.79 (s, 3 H, -COOCH3), 3.96 [t, J = 8.8 Hz, 1 H,
-C(H)O-], 4.15 [dd, J = 9.2, 18.6 Hz, 1 H, -C(H)O-], 4.37 [dd, J =
7.1, 15.6 Hz, 1 H, -C(H)O-], 4.44–4.52 [m, 1 H, -C(H)O-] ppm. 13
C
Synthesis of Epoxy Butenolide 29: Silver oxide (2.07 g, 8.932 mmol)
was added to a solution of lactone 28 (0.8 g, 3.375 mmol) in tolu-
ene (15 mL), and the mixture was heated at 80 °C under an atmo-
sphere of N2. The mixture was then filtered and concentrated to
give a syrupy liquid. This residue was subjected to column
chromatography on silica gel (eluting with EtOAc/hexanes, 1:1) to
NMR (100 MHz, CDCl3): δ = 24.4 [-C(CH3)2-], 26.7 [-C(CH3)2-],
27.0 [-C(CH3)2-], 27.3 [-C(CH3)2-], 30.6 (-SCH2-), 49.7 (-SCH-),
52.9 (-COOCH3), 76.7 [-C(H)O-], 78.4 [-C(H)O-], 78.6 [-C(H)O-],
79.6 [-C(H)O-], 109.9 [-OC(CH3)2O-], 110.3 [-OC(CH3)2O-], 169.3
[-OC(O)-] ppm. HRMS: calcd. for C14H22O6SNa [M + Na]+
341.1035; found 341.1019.
give epoxide 29 (0.299 g, 56%) as a gummy compound. [α]D
=
+78.0 (c = 1, MeOH). IR (neat): ν = 3451, 1752, 1638, 1172, 1042,
Thiosugar 36: Gummy solid. [α]D = –69.0 (c = 1, CHCl3). IR (neat):
˜
CDCl3): δ = 2.31–2.49 (m, 1 H), 2.79 (dd, J = 17.1, 6.3 Hz, 1 H),
˜
828 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.81 (dd, J = 2.4,
4.8 Hz, 1 H, -CH2O-), 2.89 (dd, J = 4.2, 4.8 Hz, 1 H, -CH2O-),
ν = 3422, 1778, 1095, 1068, 752, 699 cm–1. 1H NMR (300 MHz,
3.18 [m, 1 H, -C(H)O-], 3.71 [m, 2 H, -C(H)O-], 5.24 (tt, J = 1.5, 2.99 (dd, J = 13.2, 9.3 Hz, 1 H), 3.81 (t, J = 4.5 Hz, 1 H), 3.89 (t,
2.1 Hz, 1 H, -CHOCO-), 6.22 (dd, J = 2.1, 5.7 Hz, 1 H, J = 3.5 Hz, 1 H), 4.11–4.15 (m, 1 H), 4.66–4.77 (m, 1 H), 7.26–
-CH=CHCOO-), 7.56 (dd, J = 2.1, 6.0 Hz, 1 H, -CH=CHCOO-) 7.41 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.8, 35.1,
ppm. 13C NMR (75 MHz, CDCl3): δ = 45.5 (-CH2O-), 51.1 36.4, 66.8, 73.7, 76.2, 80.0, 127.9, 128.3, 128.7, 137.3, 174.2 ppm.
[-C(H)O-], 71.1 [-C(H)O-], 84.1 [-C(H)O-], 122.6 (-CH=CHCOO-),
Synthesis of Sugar Mesylate 37: Gummy solid. [α]D = –45.0 (c = 1,
CHCl3). H NMR (300 MHz, CDCl3): δ = 2.33 (d, J = 18.3 Hz, 1
H, -CH2COO-), 2.65 (dd, J = 13.2, 3.6 Hz, 1 H, -CH2COO-), 2.82
153.3 (-CH=CHCOO-), 173.1 [-OC(O)-] ppm. HRMS: calcd. for
1
C7H8O4Na [M + Na]+ 179.0320; found 179.0320.
Acetonide Protection of Dibromoheptonolactone 23: A solution of
dibromoheptonolactone 23 (16.957 g, 0.05 mol) in CH2Cl2
(100 mL) was stirred with 2,2-DMP (6.346 g, 0.061 mol) and
pTsOH (1.932 g, 0.01 mol) at room temperature for 45 min. The
mixture was then stirred with solid K2CO3 (to quench the pTsOH)
for a few minutes, and then it was filtered through a Celite pad and
concentrated. The residue was purified by column chromatography
on silica gel (eluting with hexanes/ethyl acetate, 8.5:1.5) to give di-
bromide 31 (8.69 g, 46%) and 32 (4.34 g, 23%), formed in a 2:1
ratio.
(dd, J = 17.7, 6.3 Hz, 1 H, -SCH2-), 3.00 (s, 3 H, -SO2CH3), 3.04
(dd, J = 17.7, 9.3 Hz, 1 H, -SCH2-), 3.94 (t, J = 5.1 Hz, 1 H,
-SCH-), 4.10 [m, 1 H, -C(H)O-] 4.64–4.68 (m, 2 H, -OCH2Ph), 4.83
[t, J = 4.2 Hz, 1 H, -C(H)O-], 5.09 [dd, J = 5.1, 2.1 Hz, 1 H,
-C(H)O-], 7.27–7.37 (m, 5 H, -C6H5) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.2, 35.1, 36.3, 38.5, 74.0, 74.1, 80.4, 128.1, 128.3,
128.6, 136.9, 173.5 ppm.
Azidation of Sugar Mesylate 37: A solution of sugar mesylate 37
(0.411 g, 1.15 mmol) in DMF (15 mL) was treated with NaN3
(0.447 g, 6.88 mmol) at 80 °C, and stirred for 2 h. After completion
of the reaction, the solvent was evaporated under vacuum, and the
residue was partitioned between water (10 mL) and EtOAc
(3ϫ5 mL). The combined organic extracts were concentrated,
Isopropylidene Lactone 31: IR (neat): ν = 873, 1046, 1121, 1184,
˜
1385, 1789, 2995, 3484 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.39 [s, 3 H, -C(CH3)2-], 1.49 [s, 3 H, -C(CH3)2-], 2.81 (d, J =
5.4 Hz, 1 H, -OH), 3.68 (s, 2 H, -CH2Br), 4.11 [d, J = 9.9 Hz, 3 dried (Na2SO4), and purified by column chromatography on silica
H, -CH(Br)- and -C(H)O-], 4.56 [d, J = 2.1 Hz, 1 H, -C(H)O-], gel to give azido lactones 38 and 39 in a 1:1 ratio (38: 0.089 g, 26%;
4.82 (s, 1 H, -CHOCO-) ppm. 13C NMR (75 MHz, CDCl3): δ =
19.3 [-C(CH3)2-], 28.8 [-C(CH3)2-], 37.8 (-CH2Br), 40.6 [-CH(Br)-],
68.3 [-C(H)O-], 69.2 [-C(H)O-], 70.9 [-C(H)O-], 73.4 [-C(H)O-],
99.3 [-OC(CH3)2O-], 171.3 [-OC(O)-] ppm.
39: 0.089 g, 26%) as gummy solids.
Azide 38: [α]D = –88.0 (c = 1, MeOH). IR (neat): ν = 2106, 1785,
˜
1255, 1161, 1096, 1003, 751, 699 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 2.42–2.54 (m, 2 H, -CH2COO-), 2.64–2.73 (m, 2 H,
-SCH2-), 3.34 (dd, J = 9, 7.2 Hz, 1 H, -SCH-), 3.57–3.70 [m, 2 H,
-CH(N3)- and -C(H)O-], 4.68 [t, J = 7.2 Hz, 1 H, -C(H)O-], 4.75
(d, J = 8.1 Hz, 1 H, -OCH2Ph), 4.86 (d, J = 8.1 Hz, 1 H,
-OCH2Ph), 7.19–7.36 (m, 5 H, -C6H5) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.9 (-CH2COO-), 33.6 (-SCH2-), 37.2 (-SCH-), 61.8
Isopropylidene Ester 32: IR (neat): ν = 877, 1061, 1161, 1215, 1382,
˜
1
1744, 2988 cm–1. H NMR (300 MHz, CDCl3): δ = 1.385 [s, 3 H,
-C(CH3)2-], 1.424 [s, 3 H, -C(CH3)2-], 1.459 [s, 3 H, -C(CH3)2-],
1.518 [s, 3 H, -C(CH3)2-], 3.63 (d, J = 6.3 Hz, 2 H, -CH2Br), 3.82
(s, 3 H, -COOCH3), 4.27 [dd, J = 7.2, 12.6 Hz, 2 H, -CH(Br)- and
-C(H)O-], 4.42–4.49 [m, 2 H, -C(H)O-], 4.55 [dd, J = 6.6, 13.5 Hz, [-CH(N3)-], 75.0 [-C(H)O-], 80.5 [-C(H)O-], 82.8 [-C(H)O-], 128.2
1 H, -C(H)O-] ppm. 13C NMR (75 MHz, CDCl3): δ = 25.2
[-C(CH3)2-], 26.6 [-C(CH3)2-], 26.9 [-C(CH3)2-], 27.1 [-C(CH3)2-],
(-C6H5), 128.4 (-C6H5), 128.5 (-C6H5), 136.9 (-C6H5), 173.5
[-OC(O)-] ppm. HRMS: calcd. for C14H15N3O3SNa [M + Na]+
30.4 (-CH2Br), 45.4 [-CH(Br)-], 53.2 (-COOCH3), 75.1 [-C(H)O-], 328.0732; found 328.0724.
76.8 [-C(H)O-],109.5 [-OC(CH3)2O-], 110.8 [-OC(CH3)2O-], 167.8
Azide 39: IR (neat): ν = 2102, 1788, 1455, 1360, 1165, 1136, 1066,
˜
[-OC(O)-] ppm.
1038, 985, 738, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.64
(d, J = 18.3 Hz, 1 H, -CH2COO-), 2.87 (dd, J = 17.7, 7.2 Hz, 1
H, -CH2COO-), 3.43–3.61 (m, 2 H, -CH2N3), 3.70–3.76 (m, 1 H,
-SCH-), 4.13–4.20 (m, 1 H, -SCH-), 4.33 [br. s, 1 H, -C(H)O-], 4.60
(s, 2 H, -OCH2Ph), 4.85–4.88 [m, 1 H, -C(H)O-], 7.20–7.31 (m, 5
H, -C6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.2, 34.9, 36.3,
38.5, 72.0, 73.1, 79.5, 127.9, 128.3, 128.6, 136.9, 173.1 ppm.
Methyl 1-Thiepane-2-carboxylate Derivative 34: A solution of di-
bromo ester 32 (1.0 g, 2.24 mmol) in acetonitrile (25 mL) was
stirred with (BnEt3N)2MoS4, (11; 3.0 g, 4.93 mmol) for 5 h at room
temperature. The mixture was then concentrated in vacuo, and the
residue was repeatedly extracted with THF (5ϫ5 mL). The com-
bined extracts were concentrated to give a crude product, which,
6994
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6986–6995

Deoxythiosugar Derivatives from Lactones
HRMS: calcd. for C14H15N3O3SNa [M + Na]+ 328.0732; found
328.0722.
[4]
a) N. A. Hughes, C. J. Wood, J. Chem. Soc. Perkin Trans. 1
1986, 695; b) Y. L. Merrer, M. Fuzier, I. Dosbaa, M.-J. Fogli-
etti, J.-C. Depezay, Tetrahedron 1997, 53, 16731.
a) H.-J. Altenbach, G. F. Merhof, Tetrahedron: Asymmetry
1996, 7, 3087.
a) C. Birk, J. Voss, J. Wirsching, Carbohydr. Res. 1998, 304, 239;
b) H. Ait-sir, N. E. Fahmi, G. Goethals, G. Ronco, B. Tber, P.
Villa, D. F. Ewing, G. Mackenzie, J. Chem. Soc. Perkin Trans.
1 1996, 1665.
The structures were solved and refined with the programs
WinGXv1.64.05, Sir92, and SHELXL-97. CCDC-802218 (for
14), -802219 (for 21), and -802220 (for 18) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[5]
[6]
[7]
S. Halila, M. Benazza, G. Demailly, Tetrahedron Lett. 2001, 42,
Supporting Information (see footnote on the first page of this arti-
cle): Common synthetic procedures adopted. NMR spectra of the
compounds synthesized.
3307.
[8]
J. Reidner, I. Robina, J. G. Fernandez-Bolanos, S. Gomez-Bu-
jedo, J. Fuentes, Tetrahedron: Asymmetry 1999, 10, 3391.
T. Gunasundari, S. Chandrasekaran, J. Org. Chem. 2010, 75,
6685.
a) J. A. J. M. Vekemans, C. W. M. Dapperens, R. Claessen,
A. M. J. Koten, E. F. Godefroi, J. Org. Chem. 1990, 55, 5336;
b) K. Bock, I. Lundt, C. Pedersen, S. Refn, Acta Chem. Scand.
Ser. B 1986, 40, 740.
J. A. J. M. Vekemans, G. A. M. Franken, C. W. M. Dapperens,
E. F. Godefroi, G. J. F. Chittenden, J. Org. Chem. 1988, 53, 627.
a) K. R. Prabhu, N. Devan, S. Chandrasekaran, Synlett 2002,
11, 1762; b) D. Sureshkumar, S. M. Koutha, S. Chandraseka-
ran, J. Am. Chem. Soc. 2005, 127, 12760; c) D. Sureshkumar,
T. Gunasundari, V. Ganesh, S. Chandrasekaran, J. Org. Chem.
2007, 72, 2106.
[9]
Acknowledgments
[10]
We thank IISc, Bangalore for the award of senior research fellow-
ship to T. G., and the Department of Science and Technology
(DST), New Delhi for the CCD X-ray facility. We thank Ms.
Brinda Selvaraj and Mr. Amol Dikundwar for help in solving crys-
tal structures. We also thank AstraZeneca, Bangalore for providing
financial support.
[11]
[12]
[1] a) S. G. Withers, B. P. Rempel, Glycobiology 2008, 18, 570, and
references cited therein; b) E. B. Melo, A. S. Gomes, I. Carv-
alho, Tetrahedron 2006, 62, 10277.
[2] a) B. Ganem, Acc. Chem. Res. 1996, 29, 340; b) G. B. Karlsson,
T. D. Butters, R. A. Dwek, F. M. Platt, J. Biol. Chem. 1993,
268, 570; c) I. Robina, P. Vogel, Z. J. Witczak, Curr. Org. Chem.
2001, 5, 1177.
[13] a) H. W. Gibson, F. C. Bailey, J. Chem. Soc., Chem. Commun.
1977, 815; b) B. P. Bandgar, R. K. Modhave, P. P. Wadgaonkar,
A. R. Sande, J. Chem. Soc. Perkin Trans. 1 1996, 1993; c) For
a review, see: D. H. Drewry, D. M. Coe, S. Poon, Med. Res.
Rev. 1999, 19, 97, and references cited therein.
[14] a) N. L. Kruhlak, M. Wang, P. M. Boorman, M. Parvez, R.
McDonald, Inorg. Chem. 2001, 40, 3141; b) P. M. Boorman,
M. Wang, M. Parvez, J. Chem. Soc., Chem. Commun. 1995,
999.
[15] a) W.-H. Pan, M. A. Harmer, T. R. Halbert, E. I. Stiefel, J. Am.
Chem. Soc. 1984, 106, 459; b) C. L. Coyle, M. A. Harmer,
G. N. Gorge, M. Daage, E. I. Stiefel, Inorg. Chem. 1990, 29,
14, and references cited therein.
[3] a) D. L. Selwood, K. Carter, R. J. Young, K. S. Jandu, Bioorg.
Med. Chem. Lett. 1996, 6, 991, and references cited therein; b)
Y. Yoshimura, K. Kitano, H. Sato, M. Watanabe, S. Miura, S.
Sakata, T. Sasaki, A. Matsuda, J. Org. Chem. 1996, 61, 822,
and references cited therein; c) Z. J. Witczak, J. M. Culhane,
Appl. Microbiol. Biotechnol. 2005, 69, 237; H. Yuasa, M. Izumi,
H. Hashimoto, Curr. Top. Med. Chem. 2009, 9, 76; d) W. Xie,
G. Tanabe, K. Matsuoka, M. F. A. Amer, T. Minematsu, X.
Wu, M. Yoshikawa, O. Muraoka, Bioorg. Med. Chem. 2011,
19, 2252; e) W. Xie, G. Tanabe, J. Akaki, T. Morikawa, K.
Ninomiya, T. Minematsu, M. Yoshikawa, X. Wu, O. Muraoka,
Bioorg. Med. Chem. 2011, 19, 2015; f) G. S. Jacob, Curr. Opin.
Struct. Biol. 1995, 5, 605; g) C. U. Kim, L. R. McGee, S. H.
Krawczyk, E. Harwood, Y. Harada, S. Swaminathan, N. Bi-
schofberger, M. S. Chen, J. M. Cherrington, S. F. Xiong, L.
Griffin, K. C. Cundy, A. Lee, B. Yu, S. Gulnik, J. W. Erickson,
J. Med. Chem. 1996, 39, 3431, and references cited therein; h)
H. Choo, X. Chen, V. Yadav, J. Wang, R. F. Schinazi, C. K.
Chu, J. Med. Chem. 2006, 49, 1635, and references cited
therein; i) K. Haraguchi, H. Shimada, H. Tanaka, T. Hama-
saki, M. Baba, E. A. Gullen, G. E. Dutschman, Y.-C. Cheng,
J. Med. Chem. 2008, 51, 1885.
[16] a) P. Ramusridhar, K. R. Prabhu, S. Chandrasekaran, Eur. J.
Org. Chem. 2004, 4809.
[17] I. Lundt, C. Pedersen, Synthesis 1992, 669, and references cited
therein.
[18] a) J. Junnemann, I. Lundt, J. Thiem, Acta Chem. Scand. 1994,
48, 265; b) It has been demonstrated that in similar systems
having primary bromide and epoxy lactone functional groups
in the same molecule, the nucleophile reacts preferentially at
the epoxide carbon.
[19] K. Bock, I. Lundt, C. Pedersen, R. Sonnischen, Carbohydr.
Res. 1988, 174, 331.
[20] A. M. Horneman, I. Lundt, Tetrahedron 1997, 53, 6879.
Received: July 9, 2012
Published Online: November 6, 2012
Eur. J. Org. Chem. 2012, 6986–6995
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6995