Convenient synthesis of α- and β-2-deoxyglycosides

Article abstract of DOI:10.1055/s-1998-1689

Readily available O-(2-O-thiobenzoyl-mannopyranosyl)trichloroacetimidate 4a gave with glucosides 7 and 8 as glycosyl acceptors exclusively α-linked disaccharides 9α and 10α. Accordingly, from O-(2-O-thiobenzoyl-glucopyranosyl)trichloroacetimidate 4b exclusively β-linked disaccharides 9β and 10β were obtained. Radical initiated deoxygenation with Bu₃SnH/AIBN directly furnished 2-deoxyglycosides 11α,β and 12α,β.

Full text of DOI:10.1055/s-1998-1689

May 1998
SYNLETT
501
Convenient Synthesis of α- and β-2-Deoxyglycosides
*
Julio C. Castro-Palomino and Richard R. Schmidt
Fakultät Chemie, Universität Konstanz, Fach M 725, D-78457 Konstanz, Germany
FAX +49/7531/88 3135
Received 16 January 1998
Abstract:
Readily
available
O-(2-O-thiobenzoyl-manno-
We propose in this paper a convenient method for 2-deoxyglycoside
synthesis (Scheme 1): the 2-hydroxy group of glucose or mannose is
used for attaching a thiobenzoyl group (Z = Ph); thus – as recently
pyranosyl)trichloroacetimidate 4a gave with glucosides 7 and 8 as
glycosyl acceptors exclusively α-linked disaccharides 9α and 10α.
Accordingly, from O-(2-O-thiobenzoyl-glucopyranosyl)trichloroacet-
imidate 4b exclusively β-linked disaccharides 9β and 10β were
obtained. Radical initiated deoxygenation with Bu SnH/AIBN directly
furnished 2-deoxyglycosides 11α,β and 12α,β.
13
shown
– sterically defined anchimerically assisting groups are
14
generated, which, because of facile five-membered ring formation
exert high diastereocontrol on the glycosylation step; thereafter
immediate radical initiated deoxygenation is available. Neighboring
3
15
group participation by 2-acyloxy groups seems to be less efficient than
that of 2-thioacyloxy groups; additionally, for the deoxygenation firstly
deacylation and then introduction of a thiocarbonyl group is required,
Various types of α- and β-2-deoxyglycosides occur in nature; many of
them exhibit interesting physiological properties. Therefore,
1
12
which also limits the general applicability of this method. A 2-
stereoselective synthesis of α- and β-2-deoxyglycosides has been
2
thiocarbonyloxy group was also used as leaving group for stereospecific
extensively investigated. Yet, starting from 2-deoxysugars, anomeric
16
3
1,2-thio group migrations. The 2-thio sugars obtained are precursors
control turned out to be a problem, therefore, anchimeric assistance
10,16
for α- and β-2-deoxyglycoside synthesis.
with the help of auxiliary groups at C-2 became the methods of
4-12
choice.
In order to demonstrate the usefulness of our concept, D-mannose and D-
glucose were employed for the synthesis of 2-deoxy-α- and -β-D-
glucopyranosides. Two different approaches were studied for the
synthesis of the required glycosyl donors (Scheme 2). (i) Allyl 3,4,6-tri-
Mainly glycals were employed for the introduction of the
anchimerically assisting auxiliary group; yet, for the reaction of glucal
+
-
+
-
with X Y , addition of X to C-2 and Y to C-1 of the CC-double bond
can take place from the α- or the β-site giving α,β-manno- or α,β-
gluco-isomers, thus leading to the required glycosyl donors. The
manno-isomers will then favor α- and the gluco-isomers β-glucoside
formation.
17
O-benzyl-α-D-mannopyranoside (2) was readily obtained from known
18
tri-O-benzylmannose 1. Reaction with N,N-dimethylbenzimidium
15
chloride in the presence of pyridine and then reaction with hydrogen
sulfide afforded 2-O-thiobenzoyl derivative 3 in high yield. Treatment
of 3 with palladium (II) chloride in acetic acid led to selective removal
of the anomeric allyl group, thus exhibiting the compatibility of this
reaction with the presence of a neighboring thiobenzoyl group.
Subsequent addition of trichloroacetonitrile in the presence of DBU as
base furnished trichloroacetimidate 4a in high yield. (ii) For the
Various XY-additions have been investigated. For instance, reaction of
glucal with iodine, silver salts and base gave via the manno-intermediate
4
5
6
mainly α-glucosides. The same result was obtained for NBS, NIS,
7
8
PhSeCl addition in acetonitrile, and related approaches; the NIS-
method introduced by Thiem and coworkers gained wide use.
Phenylsulfenate ester addition gave varying manno/gluco ratios.
6
9
synthesis of the corresponding glucose derivative 4b, readily available
19
2-O-acetyl-tri-O-benzyl glucose
5
was firstly treated with
Phenylsulfenyl chloride addition occurred from the α-site, thus
10,11
thexyldimethylsilyl chloride (TDS-Cl) in the presence of imidazole (Im)
preferentially leading to β-2-deoxyglucosides.
Obviously, in this
in order to gain 1-O-TDS protection. Then, with NaOMe/MeOH at -20
glycal route often neither the XY-addition nor the subsequent glycoside
bond formation are highly stereoselective because anchimeric assistance
necessitates three-membered ring formation.
o
C
clean 2-O-deacetylation was performed; subsequent 2-O-
thiobenzoylation as described above gave 6 in high yield. Desilylation
Scheme 1

502
LETTERS
SYNLETT
Scheme 2
Scheme 3
of 6 was performed with TBAF in THF which on treatment with CCl -
CN/DBU afforded desired 4b in high overall yield.
powerful anchimerically assisting groups without using their potential
in deoxygenations. For instance, treatment of 10α with NaOMe/MeOH
led to quantitative removal of the thiobenzoyl group furnishing 2b-O-
unprotected disaccharide 13α. The structural assignments of newly
3
Glycosylation studies were performed with known 6-O- and 3-O-
20
21
unprotected glucose derivatives 7 and 8 as acceptors. According to
o
synthesized compounds (4a,b, 9α,β, α,β, α) could be based on
10 12
our expectations, 4a gave with 7 at 0 C in the presence of TMSOTf as
catalyst exclusively α-glycoside 9α in high yield (Scheme 3). Under
24
22
NMR data.
the same reaction conditions from 4a and 8 and 4b and 7,8 the α(1-3)-
connected disaccharide 10α, the β(1-6)-connected disaccharide 9β, and
the β(1-3)-connected disaccharide 10β, respectively, were obtained.
Radical initiated deoxygenation of 9α,β and 10α,β with tributyltin
In conclusion, the thiocarbonyloxy group exhibits excellent anchimeric
assistance in glycosylation reactions, thus providing either α- or β-2-
thiocarbonyloxy-glycosides; they can be directly employed in radical
initiated deoxygenation reactions. The use of O-glycosyl
trichloroacetimidates as glycosyl donors is advantageous because the
presence of a 2-oxygen in the sugar moiety provides stability, yet on
mild acid catalysis, powerful glycosyl donors are generated. Therefore,
15
hydride in the presence of azobisisobutyronitrile (AIBN) furnished the
23
desired 2b-deoxy-disaccharides 11α,β and 12α,β, respectively.
Obviously, the 2-O-thiocarbonyl moieties can be also employed as

May 1998
SYNLETT
503
(19) Excoffier, G.; Gagnaire, D.; Utille, J.-P. Carbohydr. Res. 1975, 39, 368-
application of this method to other 2-deoxyglycoside syntheses, for
instance, 2,6- and 2,3-dideoxy- and 2,3,6-trideoxy-glycoside synthesis,
etc., should be successful as well.
373.
(20) Eby, R.; Schuerch, C. Carbohydr. Res. 1974, 34, 79-80; Bernet, B.;
Vasella, A. Helv. Chem. Acta 1979, 62, 1990-2016.
(21) Küster, J.M.; Dyong, I. Liebigs Ann. Chem. 1975, 2179-2189.
Acknowledgement. This work was supported by the Deutsche
Forschungsgemeinschft, the Deutscher Akademischer Austauschdienst,
and the Fonds der Chemischen Industrie. – J.C. C.-P. is grateful for a
DAAD stipend.
(22) General procedure for the glycosylation reactions: A mixture of 4a or
4b (0.25 mmol) and 7 or 8 (0.225 mmol) and molecular sieves (3 Å, 200
mg) in dry CH2Cl2 (10 mL) was stirred under argon at room temperature
for 20 min; then the mixture was cooled to 0 oC and trimethylsilyl
trifluoromethanesulfonate (0.05 mmol) added. After stirring at room
temperature for 2 h, triethylamine (25 µL) was added, the mixture was
diluted with CH2Cl2 (20 mL), filtered, and concentrated. Silica gel
column chromatography with hexane/ethyl acetate, 2:1 as eluent gave
glycosides 9α,β and 10α,β.
References and Notes
(1) Wright, D.E. Tetrahedron 1979, 35, 1207-1237.
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R.R. in Comprehensive Organic Synthesis, Vol.
6 (Trost, B.M.;
Fleming, I.; Winterfeld, E., Eds.), Pergamon Press, Oxford 1991, pp. 33-
64; Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503-1531; Schmidt,
R.R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21-123;
Bilodeon, M.T.; Danishefsky, S.J. in Modern Methods in Carbohydrate
Synthesis (s. Khan, H., O'Neill, R.A., Eds.) Harwood Academic
Publishers, Amsterdam, 1996, pp. 171-193.
(23) General procedure for the deoxygenation reactions: To a solution of
9α,β or 10α,β (0.42 mmol) in toluene (5 mL) was added
tributylstannane (0.69 mmol) and catalytic amounts of
azoisobutyronitrile under argon. The mixture was heated to 110 oC
under argon for 3 h and then the solvent was evaporated. Column
chromatography on silica gel of the residue with toluene/acetone, 3:1 as
eluent afforded disaccharides 11α,β and 12α,β.
(3) Garegg, P.J.; Köpper, S.; Thiem, J. J. Carbohydr. Chem. 1986, 5, 59-65;
Müller, T.; Schneider, R.; Schmidt, R.R. Tetrahedron Lett. 1994, 35,
4763-4766.
(24) 4a: [α]D +18o ( c 1, CHCl3). 1H NMR (250 MHz, CDCl3): δ 3.70 - 4.30
(m, 4 H, 5-H, 6a-H, 6b-H, 3-H), 4.50-5.00 (m, 7 H, 3 CH2Ph, 4-H), 5.77
(d, 1 H, J1,2 = J2,3 < 1 Hz, 2-H), 6.45 (d, 1 H, J1,2 < 1 Hz, 1-H), 7.20-
(4) Lemieux, R.U.; Levine, S. Can. J. Chem. 1964, 42, 1473-1476;
Lemieux, R.U.; Morgan, A.R. Can. J. Chem. 1965, 43, 2190-2193.
8.10 (m, 20 H, Ar), 8.71 (s, 1 H, NH). 4b: [α]D +22o (c 1, CHCl3). 1
H
NMR (250 MHz, CDCl3): δ 3.75-4.40 (m, 4 H, 5-H, 6a-H, 6b-H, 3-H),
4.50-5.00 (m, 7 H, 2 CH2Ph), 4-H), 5.80 (d, 1 H J1,2 = J2,3 = 9.1 Hz, 2-
H), 6.21 (d, 1 H, J1,2 = 9.1 Hz, 1-H), 7.20-8.10 (m, 20 H, Ar), 8.60 (s, 1
H, NH).
(5) Tatsuta, K.; Fujimoto, K.; Kinoshita, M.; Umezawa, S. Carbohydr. Res.
1977, 54, 85-104.
(6) Thiem, J.; Karl, H.; Schwentner, H. Synthesis 1978, 696-698; Thiem J.;
Karl, H. Tetrahedron Lett. 1978, 4999-5002.
9α: [α]D +26o . 1H NMR (600 MHz, CDCl3): δ 3.34 (s, 3 H, OCH3),
(7) Jaurand, G.; Beau, J.-M.; Sinaÿ, P. J. Chem. Soc., Chem. Commun.
3.52 (dd, 1 H, J3,4 = J4,5 = 9.2 Hz, 4a-H), 3.61 (dd, 1 H, J1,2 = 1.2, J2,3
=
1981, 572-573; Perez, M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75-
9,5 Hz, 2a-H), 3.69 (m, 2 H, 6b-H, 6b'-H), 3.77 (m, 3 H, 5a-H, 4b-H, 6a-
H), 3.90 (m, 1 H, 5b-H), 4.04 (dd, 1 H, J2,3 = 9.5, J3,4 = 9.2 Hz, 3a-H),
4.10 (m, 2 H, 3b-H, 6a'-H), 4.64 (d, 1 H, J1,2 = 1.2 Hz, 1a-H), 4.49-5.06
(m, 12 H, 6 CH2-Ph), 5.06 (d, 1 H, J1,2 < 1 Hz, 1b-H), 5.67 (dd, 1 H, J1,2
= J2,3 < 1 Hz, 2b-H), 7.18-8.09 (m, 35 H, 7 Ph).- 9β: [α]D +13o (c 1,
CHCl3). 1H NMR (600 MHz, CDCl3): d 3.35 (s, 3 H, OMe), 3.55 (dd, 1
H, J3,4 = J4,5 = 9.1 Hz, 4a-H), 3.61 (dd, 1 H, J1,2 = 1.2, J2,3 = 9.5 Hz, 2a-
H), 3.67 (m, 2 H, 6b-H, 6'b-H), 3.72 (m, 3 H, 5a-H, 4b-H, 6a-H), 3.88
(m, 1 H, 5b-H), 4.00 (dd, 1 H, J2,3 = 9.5, J3,4 = 9.2 Hz, 3a-H), 4.15 (m, 2
H, 3b-H, 6'a-H), 4.67 (d, 1 H, J1,2 = 1.2 Hz, 1a-H), 4.49-5.06 (m, 12 H, 6
78.
(8) Fogh, A.; Lundt, I.; Pedersen, C.; Rasmussen, P. Acta Chem. Scand. Ser.
B 1977, 31, 765-770; Bock, K.; Lundt, I., Pedersen, C. Carbohydr. Res.
1981, 90, 7-16; 1984, 130, 125-134; Thiem, J.; Gerken, M. J.
Carbohydr. Chem. 1983, 1, 229-249; Thiem, J.; Gerken, M.; Bock, K.
Liebigs Ann. Chem. 1983, 462-470.
(9) Ito, Y.; Ogawa, T. Tetrahedron Lett. 1987, 28, 2723-2726.
(10) Preuss, R.; Schmidt, R.R. Synthesis 1988, 694-697.
(11) For other approaches with 2-phenylthio groups: Nicolaou, K.C.,
Ladduwahetty, T.; Randall, J.L.; Chuchulowski, A. J. Am. Chem. Soc.
1986, 108, 2466-2467; Nicolaou, K.C.; Hummel, C.W.; Bockovich,
N.J.; Wong, C.-H. J. Chem. Soc., Chem. Commun. 1991, 870-874;
Zuurmond, H.M.; van der Klein, P.A.M.; van der Marel, G.A.; van
Boom, J.H. Tetrahedron Lett. 1992, 33, 2063-2066.
CH2Ph), 5.10 (d, 1 H, J1,2 = 9.1 Hz, 1b-H), 5.69 (dd, 1 H, J1,2 = J2,3
=
9.1 Hz, 2b-H), 7.18-8.09 (m, 35 H, Ph).
o
c 1, CHCl ). 1H NMR (600 MHz, CDCl ): δ 3.37 (s, 3
10α: [α]D +18 (
3
3
H, OMe), 3.59 (m, 2 H, 6a-H, 6'a-H), 3.73 (m, 1 H, 6b-H), 3.84 (m, 1 H,
6'b-H), 3.93 (m, 1 H, 5a-H), 3.99 (dd, 1 H, J1,2 = 1.3, J2,3 = 8.8 Hz, 2a-
H), 4.03 (m, 1 H, 4b-H), 4.19 (m, 1 H, 3b-H), 4.25 (m, 3 H, 3a-H, 4b-H,
5b-H), 4.44-4.96 (m, 12 H, 6 CH2Ph), 4.76 (d. J1,2 = 1.3 Hz, 1a-H), 5.27
(d, 1 H, J1,2 < 1 Hz, 1b-H), 5.51 (dd, 1 H, J1,2 = J2,3 < 1 Hz, 2b-H), 7.18-
8.09 (m, 35 H, Ph). 9β: [α]D +10o (c 1, CHCl3). 1H NMR (600 MHz,
CDCl3): δ = 3.40 (s, 3 H, OMe), 3.61 (m, 2 H, 6a-H, 6'a-H), 3.70 (m, 1
(12) Trumtel, M.; Tavecchia, P.; Veyrières, A; Sinaÿ, P. Carbohydr. Res.
1989, 191, 29-52.
(13) Castro-Palomino, J.C.; Tsvetkov, Y.E.; Schneider, R.; Schmidt, R.R.
Tetrahedron Lett. 1997, 38, 6837-6840; Castro-Palomino, J.C.;
Schmidt, R.R., manuscript in preparation; Castro-Palomino, J.C.
Dissertation, Univ. Konstanz, 1998.
H, 6b-H), 3.81 (m, 1 H, 6'b-H), 3.90 (m, 1 H, 5a-H), 4.01 (dd, 1 H, J1,2
=
1.3, J2,3 = 8.8 Hz, 2a-H), 4.03 (m, 1 H, 4b-H), 4.19 (m, 1 H, 3b-H), 4.25
(m, 3 H, 3a-H, 4b-H, 5b-H), 4.44-4.96 (m, 12 H, 6 CH2Ph), 4.73 (d, J1,2
(14)
A thiocarbonyloxy moiety was claimed to support 2-deoxy-β-
= 1.4 Hz, 1a-H), 5.22 (d, 1 H, J1,2 = 9.1 Hz, 1b-H), 5.53 (dd, 1 H, J1,2
2,3 = 9.1 Hz, 2b-H), 7.18-8.09 (m, 35 H, Ph).
Compounds 11α,5 11β,12 and 12β12 have been previously synthesized
and the 1H NMR data are in accordance with the reported values. – 12α:
[α]D +16o (c 1, CHCl3) 1H NMR (600 MHz, CDCl3): δ = 1.69 (ddd, 1
H, J1,2 < 1, J2ax,2eq = 11.2, J2ax,3 = 11.4 Hz, 2bax-H), 2.06 (ddd, 1 H,
=
ribonucleoside formation via a six-membered intermediate; yet, still
both anomers were obtained: Mukaiyama, T.; Hirano, N.; Nishida, M.;
Uchiro, H. Chem. Lett. 1996, 99-100.
J
(15) Barton, H.R.D.; McCombie, W.S.; J. Chem. Soc., Perkin Trans 1 1975,
1574-1585.
(16) Zuurmond, H.M.; van der Klein, P.A.M.; van der Marel, G.A.; van
J
1,2 < 1, J2eq,2ax = 11.2, J2eq,3 = 1.6 Hz, 2beq-H), 3.31 (s, 3 H, OCH3),
3.56 (m, 3 H, 6a-H, 6a'-H, 6b-H), 3.66 (m, 2 H, 6b'-H, 4b-H), 3.88 (m, 2
H, 2a-H, 5a-H), 3.98 (m, 3 H, 3b-H, 5b-H, 4a-H), 4.12 (dd, 1 H, J3,2
3,4 = 3a-H), 4.33-4.85 (m, 12 H, 6 CH2Ph), 4.68 (d, 1 H, J1,2 = 1.8 Hz,
1a-H), 5.10 (d, 1 H, J1,2 < 1 Hz, 1b-H), 7.12-7.31 (m, 30 H, 6 Ph).
Boom, J.H. Tetrahedron Lett. 1992, 33, 2063-2066.
(17) Ponpipom, M.M. Carbohydr. Res. 1977, 59, 311-317.
=
(18) Ogawa, T.; Sugimoto, M.; Kitajima, T.; Sadozai, K.K.; Nukada, T.
J
Tetrahedron Lett. 1986, 27, 5739-5742.