Synthesis of 2-thioaldoses via BF3-promoted cycloaddition of β-methoxyvinyl sulfides with 2,3-O-isopropylidene derivatives of aldehydo-aldoses

Article abstract of DOI:10.1055/s-0032-1317860

A highly stereoselective approach to the synthesis of 2-thioaldose derivatives via BF₃-promoted cycloaddition of β-methoxyvinyl sulfides with 2,3-O-isopropylidene derivatives of aldehydo-aldoses is described. Georg Thieme Verlag Stuttgart · New

Full text of DOI:10.1055/s-0032-1317860

LETTER
▌69
lSetyternthesis of 2-Thioaldoses via BF3-Promoted Cycloaddition of β-Methoxyvinyl
Sulfides with 2,3-O-Isopropylidene Derivatives of aldehydo-Aldoses
Synthesis of 2-Thioaldoses
Hideyuki Sugimura,* Kousuke Kusakabe
Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1, Fuchinobe, Chuo-ku, Sagamihara-shi 252-5258, Japan
Fax +81(42)7596227; E-mail: sugimura@chem.aoyama.ac.jp
Received: 26.10.2012; Accepted after revision: 20.11.2012
report the synthesis of 2-thioaldoses using the strategy
Abstract: A highly stereoselective approach to the synthesis of
outlined in Scheme 1. We envisioned that a range of 2-(ar-
2-thioaldose derivatives via BF3-promoted cycloaddition of β-
yl- or alkylthio)aldofuranoses could be readily accessed
via the cycloaddition of β-methoxyvinyl sulfides with 2,3-
O-isopropylidene-aldehydo-aldose derivatives.
methoxyvinyl sulfides with 2,3-O-isopropylidene derivatives of
aldehydo-aldoses is described.
Key words: aldehydes, boron, carbohydrates, cycloaddition, sulfur
β-Methoxyvinyl sulfides 3a–c were prepared as the trans
form by a two-step reaction of bromoacetaldehyde di-
methyl acetal with benzenethiol, 2-naphthalenethiol, and
benzyl mercaptan, according to the literature method12
with minor modifications (Scheme 2).
There are several sulfur-containing sugars found in na-
ture.1 Among them, angucycline class of compounds, BE-
7585A2 and rhodonocardins,3 are the only reported natural
products containing a 2-thioglucose. However, in the field
of synthetic organic chemistry, 2-thioaldoses have been of
much interest for decades and a wide range of synthetic
studies has been reported.4 For instance, some oligomers
of saccharides with sulfur in the glycosidic linkage have
been synthesized as potential glycosidase inhibitors5 or
potentially stable immunogens.6 2-Thioaldose derivatives
have also been used as synthetic equivalents of 2-deoxy-
glycosyl donors in the stereocontrolled synthesis of 2-de-
oxyglycosides.7,8 In this strategy, the sulfur-containing
group controls the glycosylation stereochemistry by act-
ing as a neighboring participation group, and is then re-
moved by reductive desulfurization after the glycoside
formation, stereoselectively furnishing the corresponding
2-deoxyglycosides. In these synthetic studies, 2-thio-
aldoses are usually prepared by an SN2 displacement reac-
tion involving a sulfur-containing nucleophile at C-29 or
by anti-addition of an electrophilic sulfur species to the
double bonds of glycals in the presence of alcohols.10 It is
anticipated that an alternative approach, via carbon elon-
gation reactions, would be useful for obtaining a variety of
2-thioaldose derivatives, but to the best of our knowledge,
such an approach to the synthesis of 2-thioaldoses has not
been reported to date. We previously reported a novel
method for the two-carbon elongation of aldose deriva-
tives based on [2+3]-type cycloaddition reactions of 1-al-
kenyl ethers with 2,3-O-isopropylidene derivatives of
aldehydo-aldoses.11 This synthetic strategy enabled
stereocontrolled installation of two stereogenic centers at
C-2 and C-3 in a single step, and the synthesis of several
2-subsituted or 2,2-disubstituted 2-deoxy-D-gluco-hexose
derivatives was achieved in a highly stereoselective man-
ner. As part of a study to examine the use of these cyclo-
addition products as synthetic intermediates, we now
O
R1
H
O
OMe
O
H
BF3⋅OEt2
R2S
O
+
OMe
R1
O
SR2
O
BF3
O
O
OMe
H
O
SR'
H
H
O
R1
SR2
O
R1
O
MeO
F3B
A
B
Scheme 1 Scheme for synthesis of 2-thioaldose using BF3-promoted
cycloaddition reaction
OMe
OMe
OMe
OMe
RSH, NaH
Br
RS
THF, 0 °C to r.t.
1
2a (84%)
2b (98%)
2c (98%)
a: R = Ph
b: R = 2-naphthyl
c: R = Bn
BuLi
THF, –78 °C
RS
OMe
3a (85%)
3b (56%)
3c (57%)
Scheme 2 Preparation of β-methoxyvinyl sulfides 3a–c
With β-methoxyvinyl sulfides 3a–c in hand, the cycliza-
tion reaction was then investigated using 2,3;4,5-di-O-
isopropylidene-aldehydo-D-arabinose (4). The reaction
was carried out using 1.5 equivalents of 3a–c in the pres-
ence of 1.2 equivalents of BF3·OEt2 at –78 °C in CH2Cl2,
affording the desired furanoside derivatives 5a–c13,14 with
high diastereoselectivities (>95%). The vinyl sulfides em-
ployed in this study underwent cycloaddition to give ad-
SYNLETT 2013, 24, 0069–0072
Advanced online publication: 10.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317860; Art ID: ST-2012-U0919-L
© Georg Thieme Verlag Stuttgart · New York

70
H. Sugimura, K. Kusakabe
LETTER
ducts in good yields and diastereoselectivities, regardless methanol under reflux, followed by treatment with acetic
of the steric and electronic properties of the substituents anhydride in pyridine. The anomeric configuration of the
on the sulfur (Table 1, entries 1–3). The newly formed ste- major isomer was confirmed as α-gluco by the 1H NMR J
reogenic centers, C-1, C-2, and C-3, were proved to have values of the C-2 axial proton (3.2 Hz and 11.5 Hz).
1,2-cis–2,3-trans–3,4-cis relationships, using NMR spec-
troscopy (vide infra).
1. DOWEX 50W(H+)
OAc
O
MeOH, reflux, 50 h
AcO
AcO
Encouraged by the above results, we next embarked on
the synthesis of 2-thioglucose. Starting from 2,3-O-iso-
propylidene derivatives of aldehydo-D-erythrose, the ad-
dition of β-methoxyvinyl sulfides 3 to the carbonyl group,
followed by cyclization, proceeded in a similar stereo-
chemical fashion, affording 2-thio-D-glucofuranoside de-
rivatives stereoselectively. We investigated the reactions
of aldehydes 6a and 6b, derived from D-erythrose, with
vinyl sulfide 3c under the same reaction conditions. As a
result, the desired cycloadducts 7a and 7b15 were again re-
spectively obtained as the sole diastereomers, although
the yield of 7a was somewhat lower, probably due to in-
stability of the silyl-protecting group under the reaction
conditions (Table 2).
OMe
7a
SBn
2. Ac2O, pyridine, r.t., 24 h
96% (α/β = 5:1)
8
Scheme 3 Transformation to methyl 2-thio-D-glucopyranoside 8
Detailed structural and conformational elucidations of the
cycloadducts were achieved by NMR spectroscopic anal-
ysis. As a result of the fixed bicyclic structure of the fu-
ranoside, the coupling constants and NOE effects are very
distinctive. Furanosides 5 and 7 both show relatively large
coupling constants of J1,2 = 5.0–5.5 Hz, indicating cis vic-
inal protons. In addition, furanoside 5 has a typical trans
vicinal coupling constant, J2,3 = 0.0 Hz, indicating that the
dihedral angle between 2-H and the axial 3-H is near 90°,
whereas furanoside 7 has J2,3 = 4.6 Hz, probably as a result
of a larger dihedral angle between 2-H and the equatorial
3-H than that in 5. Moreover, the results of detailed NOE
The furanoside 7a was converted into the corresponding
methyl pyranoside 816 in good yield as an inseparable 5:1
(α/β) mixture (Scheme 3) by treatment with an ion-
exchange resin (DOWEX-50W, H+-form) in absolute
Table 1 Cycloaddition of β-Methoxyvinyl Sulfides 3a–c with Aldehyde 4
O
O
O
O
O
O
H
O
BF3⋅OEt2
CH2Cl2, –78 °C
O
RS
+
OMe
OMe
H
O
3a–c
O
SR
4
5a–c
Entry
Sulfide
Reaction time (h) Product
Yield (%)a
O
O
O
O
O
O
S
H
O
OMe
O
O
O
1
3a
2
5a
98
OMe
O
O
O
SPh
S
H
O
OMe
2
3
3b
3c
3
2
5b
5c
84
84
OMe
SNaph
H
O
OMe
SBn
S
OMe
a Isolated yield.
Synlett 2013, 24, 69–72
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Thioaldoses
71
Table 2 Cycloaddition of β-Methoxyvinyl Sulfide 3c with Aldehydes 6a and 6b
RO
RO
H
O
O
OMe
BF3⋅OEt2
CH2Cl2, –78 °C
BnS
+
OMe
H
O
O
O
O
3c
SBn
7a,b
6a,b
Entry
1
Aldehyde
Reaction time (h) Product
Yield (%)a
t-BuMe2SiO
t-BuMe2SiO
t-BuPh2SiO
H
O
O
OMe
6a
2
2
7a
7b
62
H
O
O
O
O
H
SBn
t-BuPh2SiO
O
O
OMe
2
6b
82
H
O
O
O
O
SBn
a Isolated yield.
studies are in good accordance with this conformational genic centers at C-2 and C-3 were installed in a complete-
analysis, based on a fixed bicyclic structure, as illustrated ly stereocontrolled manner.
in Figure 1.
Supporting Information for this article is available online at
NOE
NOE
H2
H5
H3
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
H1
H5
OMe
R
O
H4
SPh
BnS
O
R
O
O
References and Notes
H2
O
O
J1,2 = 5.5 Hz
J2,3 = 0 Hz
J3,4 = 2.3 Hz
J4,5 = 2.3 Hz
H3
J1,2 = 5.0 Hz
J2,3 = 4.6 Hz
J3,4 = 5.5 Hz
J4,5 = 8.7 Hz
(1) Sasaki, E.; Ogasawara, Y.; Liu, H.-W. J. Am. Chem. Soc.
2010, 132, 7405 ; and references cited therein.
(2) Okabe, T.; Suda, H.; Sato, F.; Okanishi, M. Jpn. Kokai
Tokkyo Koho JP 02-164894, 1990 ; Chem. Abstr. 1991, 114,
22464.
(3) Etoh, H.; Iguchi, M.; Nagasawa, T.; Tani, Y.; Yamada, H.;
Fukami, H. Agric. Biol. Chem. 1987, 51, 1819.
(4) For early studies, see: (a) Hardegger, E.; Schüep, W. Helv.
Chim. Acta 1970, 53, 951. (b) Wirz, P.; Hardegger, E. Helv.
Chim. Acta 1971, 54, 2017.
(5) (a) Johnston, B. D.; Pinto, B. M. Carbohydr. Res. 1998, 310,
17. (b) Andrews, J. S.; Johnston, B. D.; Pinto, B. M.
Carbohydr. Res. 1998, 310, 27.
(6) (a) Knapp, S.; Malolanarasimhan, K. Org. Lett. 1999, 1, 611.
(b) Nitz, M.; Bundle, D. R. J. Org. Chem. 2001, 66, 8411.
(7) (a) Hashimoto, S.-I.; Yanagiya, Y.; Honda, T.; Ikegami, S.
Chem. Lett. 1992, 21, 1511. (b) Roush, W. R.; Sebesta, D.
P.; James, R. A. Tetrahedron 1997, 53, 8837.
(8) For a review, see: Marzabadi, C. H.; Franck, R. W.
Tetrahedron 2000, 56, 8385.
H4
H1
OMe
7
5
Figure 1 Structural comparison of cycloadducts 5 and 7
The exclusive formation of a single diastereomer in all the
reactions can be explained by the open transition-state
model A, as depicted in Scheme 1, which serves to mini-
mize steric interactions between the nucleophile R′S and
the aldehyde substituents and allows an antiperiplanar ar-
rangement of the C=O and C=C. Subsequent ring closure
of the resulting addition intermediate B is postulated to
occur through the attack of the oxygen at C4 on the oxo-
carbenium ion with the sterically favorable arrangement
of the methoxy substituent, forming the cyclization prod-
uct.
(9) (a) Knapp, S.; Naughton, A. B. J.; Jaramillo, C.; Pipik, B.
J. Org. Chem. 1992, 57, 7328. (b) Knapp, S.; Kirk, B. A.
Tetrahedron Lett. 2003, 44, 7601.
(10) Grewal, G.; Kaila, N.; Franck, R. W. J. Org. Chem. 1992, 57,
2084.
(11) Sugimura, H.; Osumi, K.; Koyama, T. Chem. Lett. 1991, 20,
1379.
(12) According to a literature procedure, vinyl sulfides 3a–c were
prepared using BuLi instead of t-BuLi: Maddaluno, J.;
Gaonach, O.; Marcual, A.; Toupet, L.; Giessner-Prettre, C.
J. Org. Chem. 1996, 61, 5290.
In conclusion, we have successfully developed a facile
method for the synthesis of 2-thioaldose derivatives using
a BF3-promoted cyclization reaction between β-me-
thoxyvinyl sulfides and 2,3-isopropylidene derivatives of
aldehydo-aldoses. The reaction proceeded in a highly ste-
reoselective manner to afford the corresponding methyl
furanoside derivatives with 1,2-cis–2,3-trans–3,4-cis re-
lationships. The applicability of this approach was dem-
onstrated by the preparation of methyl 2-
thioglucopyranoside, in which the newly formed stereo-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 69–72

72
H. Sugimura, K. Kusakabe
LETTER
(13) General Procedure for the Cyclization: To a solution of
aldehyde (1.0 mmol) and β-methoxyvinyl sulfide (1.5
mmol) in anhyd CH2Cl2 (10 mL) under argon atmosphere
was added BF3·OEt2 (1.2 mmol) dropwise at –78 °C. After
being stirred for 2–3 h at –78 °C, the reaction mixture was
quenched with Et3N (0.5 mL). The resulting mixture was
poured into sat. aq NaHCO3. After the phase separation, the
aqueous layer was extracted twice with CH2Cl2. The organic
layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified
by silica gel column chromatography (hexane–EtOAc,
19:1 → 9:1) to afford the corresponding cycloadduct.
(14) Methyl 3,5;6,7-Di-O-isopropylidene-2-deoxy-2-
phenylthio-β-D-glycero-D-ido-heptofuranoside (5a): 1H
NMR (500 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.37 (s, 3 H),
1.39 (s, 3 H), 1.42 (s, 3 H), 3,49 (s, 3 H), 3.88 (dd, J = 2.3,
7.8 Hz, 1 H), 3.94 (d, J = 5.5 Hz, 1 H), 3.97 (d, J = 5.0 Hz, 1
H), 4.07 (dd, J = 6.0, 8.7 Hz, 1 H), 4.22 (t, J = 2.3 Hz, 1 H),
4.27 (d, J = 2.3 Hz, 1 H), 4.31–4.36 (m, 1 H), 5.43 (d, J = 5.5
Hz, 1 H), 7.16–7.36 (m, 5 H). 13C NMR (125 MHz, CDCl3):
δ = 19.5, 25.3, 26.9, 29.2, 55.4, 56.3, 66.7, 69.5, 69.7, 74.6,
77.1, 98.4, 103.5, 109.1, 125.9, 128.5, 129.0, 136.1.
Methyl 3,5;6,7-Di-O-isopropylidene-2-deoxy-2-(2-
naphthylthio)-β-D-glycero-D-ido-heptofuranoside (5b):
1H NMR (500 MHz, CDCl3): δ = 1.33 (s, 3 H), 1.37 (s, 3 H),
1.42 (2 × s, 6 H), 3.51 (s, 3 H), 3.89 (d, J = 7.3 Hz, 1 H), 3.96
(dd, J = 5.0, 8.7 Hz, 1 H), 4.07–4.10 (m, 2 H), 4.24 (s, 1 H),
4.33–4.37 (m, 2 H), 5.47 (d, J = 5.5 Hz, 1 H), 7.41–7.49 (m,
3 H), 7.71–7.84 (m, 4 H). 13C NMR (125 MHz, CDCl3): δ =
19.6, 25.3, 26.9, 29.3, 55.4, 56.3, 66.7, 69.6, 69.7, 74.6, 77.1,
98.4, 103.5, 109.1, 125.6, 125.9, 126.6, 126.7, 127.0, 127.7,
128.4, 131.5, 133.8, 133.9.
Hz, 1 H), 4.28 (dd, J = 5.0, 6.0, 7.3 Hz, 1 H), 5.21 (d, J = 5.5
Hz, 1 H), 7.22–7.33 (m, 5 H). 13C NMR (125 MHz, CDCl3):
δ = 19.6, 25.3, 26.9, 29.2, 37.1, 54.5, 56.1, 66.7, 69.4, 69.6,
74.6, 77.2, 98.1, 103.7, 109.0, 127.1, 128.5, 129.1, 137.9.
(15) Methyl 6-O-tert-Butyldimethylsilyl-3,5-O-
isopropylidene-2-deoxy-2-benzylthio-α-D-
glucofuranoside (7a): 1H NMR (500 MHz, CDCl3): δ =
0.08 (s, 6 H), 0.91 (s, 9 H), 1.35 (s, 3 H), 1.38 (s, 3 H), 3.20
(t, J = 4.6 Hz, 1 H), 3.31 (s, 3 H), 3.61 (ddd, J = 2.8, 6.0, 9.2
Hz, 1 H), 3.73 (dd, J = 6.0, 11.0 Hz, 1 H), 3.80–3.85 (m, 3
H), 4.09 (dd, J = 5.5, 8.7 Hz, 1 H), 4.36 (dd, J = 5.0, 5.5 Hz,
1 H), 4.80 (d, J = 5.0 Hz, 1 H), 7.23–7.38 (m, 5 H). 13C NMR
(125 MHz, CDCl3): δ = –5.3, –5.2, 18.4, 24.0, 25.2, 25.8,
36.1, 52.4, 55.2, 63.6, 71.6, 75.5, 78.8, 100.5, 103.5, 127.0,
128.4, 129.1, 138.3.
Methyl 6-O-tert-Butyldiphenylsilyl-3,5-O-
isopropylidene-2-deoxy-2-benzylthio-α-D-
glucofuranoside (7b): 1H NMR (500 MHz, CDCl3): δ =
1.04 (s, 9 H), 1.35 (s, 3 H), 1.38 (s, 3 H), 3.19 (t, J = 4.6, 1
H), 3.27 (s, 3 H), 3.69 (ddd, J = 2.8, 6.0, 9.2 Hz, 1 H), 3.76–
3.84 (m, 3 H), 3.86 (dd, J = 2.8, 11.0 Hz, 1 H), 4.13 (dd, J =
5.5, 8.7 Hz, 1 H), 4.35 (dd, J = 5.0, 5.5 Hz, 1 H), 4.77 (d, J =
5.0 Hz, 1 H), 7.22–7.42 (m, 11 H), 7.69–7.71 (m, 4 H). 13
C
NMR (125 MHz, CDCl3): δ = 19.3, 24.1, 25.2, 26.7, 36.1,
52.4, 55.2, 64.4, 71.6, 75.6, 78.8, 100.4, 103.5, 127.0, 127.5,
127.5, 128.4, 129.1, 129.5, 133.6, 133.7, 135.6, 135.7,
138.3.
(16) Methyl 3,4,6-Tri-O-acetyl-2-deoxy-2-benzylthio-α,β-D-
glucopyranoside (8): 1H NMR (500 MHz, CDCl3; assigned
to the α-anomer): δ = 2.03 (s, 3 H), 2.07 (s, 3 H), 2.08 (s, 3
H), 2.80 (dd, J = 3.2, 11.5 Hz, 1 H), 3.35 (s, 3 H), 3.75 (d, J
= 13.3 Hz, 1 H), 3.81 (dd, J = 13.3 Hz, 1 H), 3.98 (ddd, J =
2.3, 4.6, 10.1 Hz, 1 H), 4.04 (dd, J = 2.3, 12.4 Hz, 1 H), 4.28
(dd, J = 4.6, 12.4 Hz, 1 H), 4.64 (d, J = 3.2 Hz, 1 H), 4.96
(dd, J = 9.2, 10.1 Hz, 1 H), 5.44 (dd, J = 9.2, 11.5 Hz, 1 H),
7.23–7.33 (m, 5 H). 13C NMR (125 MHz, CDCl3): δ = 20.6,
20.6, 20.7, 20.8, 36.3, 36.8, 48.3, 49.1, 55.5, 57.5, 62.1, 62.1,
67.4, 69.4, 69.7, 71.4, 71.5, 72.3, 100.7, 106.0, 127.1, 127.3,
128.4, 128.6, 128.9, 129.1, 137.8, 169.8, 170.0, 170.6.
Methyl 3,5;6,7-Di-O-isopropylidene-2-deoxy-2-
benzylthio-β-D-glycero-D-ido-heptofuranoside (5c): 1H
NMR (500 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.34 (s, 3 H),
1.35 (s, 3 H), 1.40 (s, 3 H), 3.35 (d, J = 5.5 Hz, 1 H), 3.41 (s,
3 H), 3.76 (d, J = 13.0 Hz, 1 H), 3.78 (d, J = 13.0 Hz, 1 H),
3.85(dd, J = 2.3, 7.3 Hz, 1 H), 3.93 (dd, J = 5.0, 8.7 Hz, 1 H),
4.03–4.05 (m, 1 H), 4.06 (t, J = 2.3 Hz, 1 H), 4.11 (d, J = 2.3
Synlett 2013, 24, 69–72
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