Improved synthesis of 1,2-trans-acetates and 1,2-trans ethyl 1-thioglycosides derived from 3,4,6-tri-o-acetyl-2-deoxy-2-phthalimido-D-hexopyranosides

Article abstract of DOI:10.1135/cccc20031264

Effective one-pot synthesis of 1,2-trans-acetates 4b, 5b and 6a derived from N-phthaloyl-protected D-glucosamine, D-galactosamine and D-mannosamine, respectively, is presented. Anomerisation of the corresponding 1,2-cis-acetates 4a, 5a and 6b and direct conversion of all of them to 1,2-trans ethyl 1-thioglycosides 7, 8 and 9 are also described and discussed.

Full text of DOI:10.1135/cccc20031264

1264
Veselý, Ledvina, Jindřich, Šaman, Trnka:
IMPROVED SYNTHESIS OF 1,2-tra n s-ACETATES AND 1,2-tra n s ETHYL
1-THIOGLYCOSIDES DERIVED FROM 3,4,6-TRI-O-ACETYL-2-DEOXY-
2-PHTHALIMIDO-D-HEXOPYRANOSIDES
b2
Jan VESELÝa1, Miroslav LEDVINAb1,*, Jindřich JINDŘICHa2, David ŠAMAN and
a3
Tomáš TRNKA
a
Department of Organic Chemistry, Charles University, Albertov 2030, 128 40 Prague 2,
Czech Republic; e-mail: jxvesely@mail.natur.cuni.cz, jindrich@natur.cuni.cz,
trnka@natur.cuni.cz
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: ledvina@uochb.cas.cz,
saman@uochb.cas.cz
1
2
3
b
1
2
Received Decem ber 20, 2002
Accepted May 17, 2003
Effective on e-pot syn th esis of 1,2-trans-acetates 4b, 5b an d 6a derived from N-ph th aloyl-
protected D-glucosam in e, D-galactosam in e an d D-m an n osam in e, respectively, is presen ted.
An om erisation of th e correspon din g 1,2-cis-acetates 4a, 5a an d 6b an d direct con version of
all of th em to 1,2-trans eth yl 1-th ioglycosides 7, 8 an d 9 are also described an d discussed.
Keyw ord s: Carboh ydrates; Am in osugars; Th ioglycosides; Glycosyl don ors; Ph th alim ide;
An om erisation ; Protectin g groups; Glycosides; Glycocon jugates.
2-Am in o-2-deoxyh exopyran osides lin ked with 1,2-trans-glycosidic bon ds
are frequen tly en coun tered con stituen ts of m an y n aturally occurrin g oligo-
sacch arides an d glycocon jugates1–3. Th e β(1→4)-lin ked N-acetylglucos-
am in e m oieties form , e.g., an im portan t structural polysacch aride ch itin 4,
glycan part of peptidoglycan of bacterial cell walls5,6 as well as th e reducin g
en d of glycan residues of N-glycoprotein s3. N-Acetylgalactosam in e residue
β(1→4)-lin ked to 3-O-sialyl-β-D-galactopyran oside subun it con stitutes a
core un it of gan gliosides7–9. Most com m on ly, in troduction of th e
glycosidically lin ked 1,2-trans-2-am in o-2-deoxyh exopyran oside residue was
obtain ed in th e oligosacch aride syn th esis by th e oxazolin e m eth od10–12 or
th e ph th alim ide m eth od in troduced by Lem ieux13. Th e latter is preferred,
because 2-deoxy-2-ph th alim idoh exopyran oses with h alogen , (trich loroacet-
im idoyl)oxy or alkylsulfan yl group at C-1 h ave con sisten tly proved to be
m ore efficien t don ors th an th e oxazolin es3. Th e advan tage of th e latter al-
kyl 1-th ioglycosides is th at th ese can be used directly as glycosyl don or (by
Collect. Czech. Chem. Commun. (Vol. 68) (2003)
doi:10.1135/cccc20031264

Improved Synthesis of 1,2-trans-Acetates and 1,2-trans Ethyl 1-Thioglycosides
1265
activation via sulfon ium ion ) or sim ply con verted to altern ative glycosyl
don ors carryin g on C-1 oth er leavin g groups, such as h alogen or (trich loro-
acetim idoyl)oxy group14,15. Th e preferred m eth od for th e preparation of al-
kyl 1-th ioglycosides in recen t years h as been Lewis acid-catalyzed sub-
stitution of th e an om eric acetate of peracetylated sugars with a desired
alkan eth iol14,15. In gen eral, 1,2-trans-acetates react faster th an th eir 1,2-cis
coun terparts3,15 an d th e described6,16,17 preparation s of N-ph th aloyl-
protected eth yl 1-th ioglycoside derived from D-glucosam in e 7 an d
D-galactosam in e 8, usin g th is approach , require 1,2-trans-acetates (β-ace-
tates) 4b an d 5b as startin g m aterials (Sch em e 1). Th ese β-acetates are avail-
able from correspon din g D-h exosam in e h ydroch lorides in five steps via
N-(4-m eth oxyben zyliden e) derivatives6,17,18. Th e “on e-pot” syn th esis of
peracetylated 2-deoxy-2-ph th alim ido-D-h exopyran oses led to a m ixture of
α- an d β-an om ers19–22. Th e stan dard m eth od of th e con version of α-acetates
to β-acetates proceeded in two steps via glycosyl h alide23. Access to
1,2-trans-acetates of 2-deoxy-2-ph th alim idoh exopyran oses was n ot on ly
crucial for th e preparation of target 1,2-trans eth yl 1-th ioglycosides of
2-deoxy-2-ph th alim idoh exopyran oses, but th ese 1,2-trans-acetates can
also directly serve as glycosyl don ors for th e preparation of 1,2-trans-
O-glycosides in Lewis acid-catalyzed con den sation s with reactive glycosyl
acceptors24.
OH
R2
OAc
OAc
R2
R2
(i)
O
O
R1
HO
O
R1
AcO
R1
AcO
+
OH
OAc
NH2. HCl
PhtN
PhtN
OAc
1, R1 = OH, R2 = H
2, R1 = H, R2 = OH
4a, R1 = AcO, R2 = H
5a, R1 = H, R2 = AcO
4b, R1 = AcO, R2 = H
5b, R1 = H, R2 = AcO
4b
4a
OH
NH2.HCl
O
(i)
+
HO
HO
OAc
PhtN
OAc
PhtN
OH
O
O
AcO
AcO
AcO
AcO
3
OAc
6a
OAc
6b
(i) conditions A: phthalic anhydride and NaHCO3 (excess) in acetone/water, then Ac2O in
pyridine; conditions B: phthalic anhydride (excess) and NaHCO3 in acetone/water, then Ac2O
in pyridine; conditions C: phthalic anhydride in pyridine/acetone/water, then Ac2O in pyridine;
conditions D: phthalic anhydride in pyridine/acetone/water, then Ac2O and DMAP in pyridine
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1266
Veselý, Ledvina, Jindřich, Šaman, Trnka:
RESULTS AND DISCUSION
It stan ds to reason th at th e effective syn th esis of 1,2-trans-acetates an d
1,2-trans eth yl 1-th ioglycosides of th e 2-deoxy-2-ph th alim idoh exopyran -
oses is still a problem . Th ese facts m otivated us to focus our atten tion on
th e an om erization an d on e-step con version of 1,2-cis-acetates to th e corre-
spon din g 1,2-trans eth yl th ioglycosides an d on e-pot syn th esis of per-
O-acetyl-2-deoxy-2-ph th alim idoh exopyran oses with preferen tial form ation
of 1,2-trans-acetates.
Th e on e-pot syn th esis of peracetylated 2-deoxy-2-ph th alim ido-D-h exo-
pyran oses is based on th e reaction of D-h exosam in e h ydroch loride with
ph th alic an h ydride in th e presen ce of base an d subsequen t cyclization an d
O-acetylation of in term ediary ph th alam ic acid. It can be assum ed th at
1,2-trans- an d 1,2-cis-acetates are obtain ed un der th e used reaction con di-
tion s. Th e ch oice of th e reaction con dition s can also suppress th e un desired
base-catalyzed epim erisation of in term ediary ph th alam ic acid at position
C-2 in th e first step. By m odification of th e on e-pot syn th esis providin g as
m ain product α-acetate 4a, described by Koch etkov et al.19 (Sch em e 1), i.e.,
by th e reaction of D-glucosam in e h ydroch loride (1) with ph th alic an h y-
dride in th e presen ce of sodium h ydrogen carbon ate in a m ixture of water–
aceton e an d subsequen t reaction of crude ph th alam ic acid with acetic an -
h ydride in pyridin e (con dition s A), a m ixture of α- an d β-acetates 4a an d 4b
in th e 1:1 ratio was obtain ed. An attem pt to use th is procedure for on e-pot
syn th esis of α- an d β-acetates derived from D-m an n osam in e (3) was n ot
successful, because it yielded, in addition to th e expected acetates with
manno con figuration , 6a an d 6b, acetates with gluco con figuration , 4a
an d 4b, in sign ifican t am oun ts. Th e form ation of th e products with gluco
con figuration can be explain ed by base-catalyzed epim erisation of th e in -
term ediate ph th alam ic acids A at position C-2, via en am in e B, to th e D-
glucosam in e derivative C (Sch em e 2). Fortun ately, th is side reaction could
be avoided by usin g an excess of ph th alic an h ydride relative to sodium
h ydrogen carbon ate in th e first step (con dition s B), or by usin g pyridin e as a
softer base th an sodium h ydrogen carbon ate (con dition s C). Th e reaction of
D-m an n osam in e h ydroch loride (3) un der con dition s B yielded a m ixture of
α- an d β-acetates 6a an d 6b in th e 1:1 ratio. D-Man n osam in e h ydroch loride
(3) un der con dition s C, i.e., by th e reaction with ph th alic an h ydride in a
m ixture of pyridin e–water–aceton e, an d subsequen t reaction of crude
ph th alam ic acid with acetic an h ydride in pyridin e afforded a m ixture of α-
an d β-acetates 6a an d 6b in th e 5:2 ratio. D-Glucosam in e h ydroch loride (1)
gave a m ixture of α- an d β-acetates 4a an d 4b in th e 3:4 ratio un der con di-
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Improved Synthesis of 1,2-trans-Acetates and 1,2-trans Ethyl 1-Thioglycosides
1267
tion s C. Th e preferen tial form ation of 1,2-trans-acetates un der con dition s C
can be attributed to acetylation of th e an om eric h ydroxy group followed by
th e cyclisation of 2-carboxyben zam ido group, sin ce th e 1,2-cis side of th e
pyran ose rin g gets sh ielded as soon as th e ph th alim ido group is form ed.
An oth er sign ifican t en h an cem en t of stereoselectivity in th e form ation of
1,2-trans-acetates was ach ieved by perform in g th e secon d step in th e pres-
en ce of 4-(dim eth ylam in o)pyridin e (DMAP) (con dition s D). D-Glucosam in e
h ydroch loride (1), D-galactosam in e h ydroch loride (2) or D-m an n osam in e
h ydroch loride (3) un der con dition s C, i.e., wh en reacted with ph th alic an -
h ydride in a m ixture of pyridin e–water–aceton e, an d subsequen t reaction
of crude ph th alam ic acid with acetic an h ydride in pyridin e in th e presen ce
of DMAP, afforded 1,2-trans-acetates 4b, 5b or 6a, respectively, in good
yields (4b 66%, 5b 64%, 6a 60%).
OH
O
OH
O
HO
HO
HN
HO
OH
O
OH
O
NH
OH
OH
OH
O
NH
O
O
OH
OH
OH
O
HO
HO
OH
B
C
A
3
4a + 4b
SCHEME 2
We foun d th at th e an om erization of 1,2-cis-acetates an d th eir direct con -
version to th e correspon din g 1,2-trans eth yl 1-th ioglycosides can be accom -
plish ed by usin g stron ger Lewis acid th an FeCl3 or TiCl4, wh ich were
com m on ly used for th e con version of 1,2-trans-acetates to 1,2-trans eth yl
1-th ioglycosides6,16,17 (Sch em e 3). Th e treatm en t of α-acetate of glucosam in e
derivative 4a with trim eth ylsilyl trifluorom eth an esulfon ate (TMSOTf) in
acetic an h ydride led to a m ixture of α- an d β-an om ers 4a an d 4b in th e 7:2
ratio. By TMSOTf-prom oted reaction of eth an eth iol with α-acetate 4a as
well as with th e m en tion ed above m ixture of an om ers 4a an d 4b, eth yl
1-th io-β-glucoside 7 was obtain ed in 80% yield. α-Acetates derived from
D-galactosam in e 5a, wh ich was obtain ed followin g th e procedure in ref.22,
gave un der iden tical con dition s th e correspon din g eth yl 1-th io-β-galacto-
side 8 in h igh yield (77%). Th e sam e reaction with th e above m en tion ed
α/β-an om eric m ixture of m an n osam in e derivatives 6a an d 6b afforded
eth yl 1-th io-α-m an n oside 9 in 70% yield.
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1268
Veselý, Ledvina, Jindřich, Šaman, Trnka:
(i)
4a
4b
2OAc
R
(ii)
O
R1
AcO
4a or 5a
SEt
PhtN
7, R1 = AcO, R2 = H
8, R1 = H, R2 =AcO
OAc
PhtN
(ii)
6a or 6b
O
AcO
AcO
SEt
9
(i) TMSOTf in Ac2O; (ii) EtSH and TMSOTf in CH2Cl2
SCHEME 3
Th e described on e-pot syn th esis of 1,2-trans-acetates derived from
2-deoxy-2-ph th alim idoh exopyran oses an d th e con version of both 1,2-cis-
acetates an d 1,2-trans-acetates to th e correspon din g 1,2-trans eth yl 1-th io-
glycosides substan tially sim plifies m eth ods for syn th esis of glycosyl don ors
suited for th e form ation of 1,2-trans-glycosidic bon ds derived from bio-
logically im portan t 2-am in o-2-deoxyh exoses, such as, D-glucosam in e,
D-galactosam in e an d D-m an n osam in e, used up to n ow. Th e title 1,2-trans-
acetates an d 1,2-trans eth yl 1-th ioglycosides of 2-deoxy-2-ph th alim ido-
h exopyran oses derived from th e above m en tion ed am in osacch arides are
glycosyl don ors, wh ich can also serve as startin g m aterials for th e prepara-
tion of oth er glycosyl don ors tailor-m ade for special application s.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. Specific rotation s
were m easured on a Perkin –Elm er 141 polarim eter at 22 °C an d are given in 10–1 deg cm 2 g–1
.
Elem en tal an alyses were perform ed usin g a Perkin –Elm er 2400 II in strum en t. NMR spectra
were recorded on a Varian UNITY-500 spectrom eter in th e FT m ode at 499.8 MHz (1H) an d
at 125.6 MHz (13C) in CDCl3, usin g (CH3)4Si as in tern al stan dard for th e 1H NMR spectra
an d CDCl3 (δ 77.0) sign al as stan dard for th e 13C NMR spectra. For un am biguous assign -
m en t of sign als in 13C NMR spectra, 1H- an d 13C-h eterocorrelated 2D NMR spectra were
m easured by HMQC tech n ique usin g th e stan dard pulse sequen ce delivered by th e producer
of th e spectrom eter. Th e followin g typical param eters were used: spectral width in both f1
an d f2 dim en sion s 5000 an d 17 000 Hz, respectively, n um ber of scan s 16, n um ber of in cre-
m en ts in f1 dim en sion 256, recycle delay 1 s, acquisition tim e 0.2 s, 90° pulse for 1H was
12.5 µs, data m atrix for processin g 2048 × 2048 datapoin ts. For processin g, sh ifted sin ebell
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Improved Synthesis of 1,2-trans-Acetates and 1,2-trans Ethyl 1-Thioglycosides
1269
weigh tin g fun ction was used. Ch em ical sh ifts are given in ppm (δ-scale), couplin g con stan ts
(J) in Hz. Positive-ion FAB m ass spectra were m easured on a BEqG geom etry m ass spectrom e-
ter ZAB-EQ (VG An alytical, Man ch ester, U.K.) usin g an M-Scan FAB gun (Xe, en ergy 8 keV)
at an acceleratin g voltage of 8 kV. Sam ples were dissolved in ch loroform or m eth an ol, an d a
m ixture of glycerol an d th ioglycerol or dim eth yl sulfoxide was used as m atrix. Th in -layer
ch rom atograph y (TLC) was perform ed on DC-Alufolien Kieselgel 60 F254 (Merck, Darm stadt,
Germ an y) or Silufol UV254 (Kavalier, Votice, Czech Republic) silica gel sh eets. Preparative
ch rom atograph y was perform ed on a silica gel colum n , particle size 40–60 µm (Fluka,
Neu-Ulm , Switzerlan d). An alytical RP HPLC was perform ed usin g a Waters in strum en t (PDA
detector, software Milen n ium 32; Milford (MA), U.S.A.) equipped with a Nova-Pak C18 col-
um n (150 × 3.9 m m ), particle size 4 µm . Preparative RP HPLC was perform ed on a colum n
(250 × 25 m m ) filled with LiCh rosorb RP-18, particle size 5 µm (Merck, Darm stadt, Ger-
m an y). Solven ts were evaporated on a rotary vacuum evaporator at 40 °C. An alytical sam -
ples were dried at 6.5 Pa an d 25 °C for 8 h .
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-ph th alim ido-D-h exopyran oses
Method A: D-Glucosam in e h ydroch loride (1) or D-m an n osam in e h ydroch loride (3) (2.15 g,
10 m m ol), ph th alic an h ydride (2.96 g, 20 m m ol) an d sodium h ydrogen carbon ate (4.20 g,
50 m m ol) were stirred in a m ixture of aceton e–water (1:1, 100 m l) at 50 °C for 3 h . Progress
of th e reaction was m on itored by TLC in propan -1-ol–eth yl acetate–water–25% aqueous
am m on ia (6:3:1:1). Th e solven ts were evaporated in vacuo an d to th e residue pyridin e (60 m l)
an d acetic an h ydride (14.1 m l, 150 m m ol) were added. Th e m ixture was th en h eated un der
stirrin g at 50 °C for an oth er 16 h . Progress of th e reaction was m on itored by TLC in toluen e–
eth yl acetate (1:1). Th e reaction m ixture was con cen trated in vacuo to a quarter of its volum e
an d th en diluted with toluen e (30 m l). Th e solution was extracted with 1 M HCl (2 × 25 m l),
saturated aqueous sodium h ydrogen carbon ate (2 × 25 m l) an d water (2 × 25 m l). Th e orga-
n ic ph ase was dried over an h ydrous m agn esium sulfate an d solven ts were evaporated in vacuo.
For 1: Th e residue was ch rom atograph ed on silica gel colum n (45 g) in toluen e–eth yl ace-
tate (6:1) to afford 4a, yield 1.96 g (41%) an d 4b, yield 1.95 g (41%). Both an om ers were
crystallized from eth an ol to give 4a, yield 1.72 g (36%) an d 4b, yield 1.62 g (34%).
For 3: Th e residue was separated by HPLC on silica gel C18 colum n in solven t system
water–m eth an ol (lin ear gradien t 50→100%) to give 4b, yield 2.00 g (42%), 4a, yield 0.24 g
(5%) an d a m ixture of 6a an d 6b, yield 0.72 g (15%), as wh ite solids.
Method B: D-Man n osam in e h ydroch loride (3) (2.15 g, 10 m m ol), ph th alic an h ydride
(2.22 g, 15 m m ol) an d sodium h ydrogen carbon ate (1.01 g, 12 m m ol) were stirred in a m ix-
ture of aceton e–water (1:1, 100 m l) at 50 °C for 2 h . Th e oth er portion s of ph th alic an h y-
dride (1.10 g, 7.4 m m ol) an d sodium h ydrogen carbon ate (0.22 g, 1.5 m m ol) were th en
added an d stirrin g was con tin ued at sam e tem perature for an oth er 2 h . Progress of th e reac-
tion was m on itored as described above in m eth od A. Th e solven ts were evaporated in vacuo,
an d pyridin e (40 m l) an d acetic an h ydride (18.5 m l, 200 m m ol) were th en added to th e resi-
due. Th e m ixture was th en stirred an d h eated to 70 °C for 2 h . Progress of th e reaction was
m on itored an d th e reaction m ixture was worked up as described above in m eth od A. Th e
ch rom atograph y of th e residue on a silica gel colum n (45 g) in toluen e–eth yl acetate (6:1)
afforded a m ixture of 6a an d 6b (1:1), yield 2.95 g (62%), as a wh ite solid. Th e ratio of
an om ers was determ in ed by 1H NMR spectra.
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

1270
Veselý, Ledvina, Jindřich, Šaman, Trnka:
Method C: D-Glucosam in e h ydroch loride (1) or D-m an n osam in e h ydroch loride (3) (2.15 g,
10 m m ol), ph th alic an h ydride (1.63 g, 11 m m ol) an d pyridin e (2.0 m l, 25 m m ol) were
stirred in a m ixture of aceton e–water (1:1, 15 m l) at 50 °C for 3 h . Progress of th e reaction
was m on itored as described above in m eth od A. Th e solven ts were evaporated in vacuo an d
pyridin e (40 m l) an d acetic an h ydride (14.1 m l, 150 m m ol) were th en added to th e residue.
Th e m ixture was th en h eated un der stirrin g to 50 °C for 5 h . Progress of th e reaction was
m on itored as described above in m eth od A. Solven ts were evaporated in vacuo an d th e resi-
due was taken in toluen e (30 m l) an d 1 M HCl (25 m l). Th e organ ic ph ase was separated, ex-
tracted with 1 M HCl (25 m l), saturated aqueous sodium h ydrogen carbon ate (2 × 25 m l) an d
water (2 × 25 m l), dried over an h ydrous m agn esium sulfate an d th e solven t was evaporated
in vacuo.
For 1: Th e residue gave a m ixture of α- an d β-an om ers 4a an d 4b (3:4), yield 3.63 g
(76%). Th e ratio of an om ers was determ in ed by 1H NMR spectra. Crystallization of th e
α/β-an om er m ixture from eth an ol afforded β-an om er 4b, yield 1.38 g (29%).
For 3: Th e ch rom atograph y of th e residue on a silica gel colum n (120 g) in toluen e–eth yl
acetate (8:1) afforded 3.20 g (67%) of an α/β-an om er m ixture of com poun ds 6a an d 6b (5:2).
Th e ratio of an om ers was determ in ed by 1H NMR spectra.
Method D: D-Glucosam in e h ydroch loride (1), D-galactosam in e h ydroch loride (2) or
D-m an n osam in e h ydroch loride (3) (2.15 g, 10 m m ol), ph th alic an h ydride (1.63 g, 11 m m ol)
an d pyridin e (2.0 m l, 25 m m ol) were stirred in a m ixture of aceton e–water (1:1, 15 m l) at
55 °C for 4 h . Progress of th e reaction was m on itored as described above in m eth od A. Th e
solven ts were evaporated in vacuo an d th e residue was co-distilled with toluen e (2 × 10 m l).
To th e residue, pyridin e (20 m l), acetic an h ydride (10.5 m l, 112 m m ol) an d 4-(dim eth yl-
am in o)pyridin e (50 m g, 0.4 m m ol) were added an d th e m ixture was th en h eated un der
stirrin g at 55 °C for an oth er 5 h . Progress of th e reaction was m on itored as described in
m eth od A. Excess of acetic an h ydride was decom posed by addition of m eth an ol as follows.
To th e stirred reaction m ixture, m eth an ol (10 m l) was added at 0 °C an d after warm in g to
th e room tem perature, stirrin g was con tin ued for 1 h . Th e solven ts were th en evaporated in
vacuo an d th e residue was taken in toluen e (30 m l) an d 1 M HCl (10 m l). Th e organ ic ph ase
was separated, extracted with saturated aqueous sodium h ydrogen carbon ate (10 m l) an d wa-
ter (10 m l), dried over an h ydrous m agn esium sulfate an d evaporated in vacuo.
For 1: Th e residue was crystallized from eth an ol to afford β-an om er 4b , yield 3.15 g
(66%).
For 2: Th e residue was crystallized from isopropan ol to afford β-an om er 5b, yield 3.05 g
(64%).
For 3: Th e residue was crystallized from eth an ol to give α-an om er 6a, yield 2.87 g (60%).
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-ph th alim ido-α-D-glucopyran ose (4a)
M.p. 128 °C (eth an ol), [α]D +114 (c 1.7, ch loroform ); ref.19: m .p. 128–131°C (eth an ol), [α]D
+112 (c 0.9, ch loroform ); ref.25: m .p. 131°C (m eth an ol), [α]D +98 (c 0.5, ch loroform ).
1H NMR: 7.87–7.83 m , 2 H (H-arom ., Ph t); 7.78–7.73 m , 2 H (H-arom ., Ph t); 6.57 dd, 1 H,
J = 9.2, 11.6 (H-3); 6.29 d, 1 H, J = 3.4 (H-1); 5.17 dd, 1 H, J = 9.2, 10.2 (H-4); 4.73 dd, 1 H,
J = 3.4, 11.6 (H-2); 4.37 dd, 1 H, J = 3.9, 12.3 (H-6a); 4.32 ddd, 1 H, J = 2.0, 3.9, 10.2 (H-5);
4.14 dd, 1 H, J = 2.0, 12.3 (H-6b); 2.13 s, 3 H (OCOCH3); 2.09 s, 3 H (OCOCH3); 2.07 s, 3 H
(OCOCH3); 1.88 s, 3 H (OCOCH3). 13C NMR: 170.6 (OCOCH3), 169.7 (OCOCH3), 169.4
(OCOCH3), 169.2 (OCOCH3), 167.4 (2 C), 134.4 (2 C), 131.2 (2 C), 123.7 (2 C) (C-arom .,
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Improved Synthesis of 1,2-trans-Acetates and 1,2-trans Ethyl 1-Thioglycosides
1271
Ph t), 90.5 (C-1), 70.2 (C-5), 69.5 (C-4), 67.1 (C-3), 61.6 (C-6), 52.9 (C-2), 20.9 (OCOCH3),
20.6 (2 × OCOCH3), 20.7 (OCOCH3). For C22H23NO11 calculated: relative m olecular m ass
477.4, m on oisotopic m ass 477.1. FAB MS, m/z: 478 [M + H]+, 500 [M + Na]+. For C22H23NO11
(477.4) calculated: 55.35% C, 4.86% H, 2.93% N; foun d: 55.43% C, 4.96% H, 2.95% N.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-ph th alim ido-β-D-glucopyran ose (4b)
M.p. 78 °C (eth an ol), [α]D +59 (c 0.6, ch loroform ); ref.6: m .p. 79–81 °C (eth an ol), [α]D +62
(c 0.6, ch loroform ). 1H NMR spectrum agrees with th at of th e auth en tic sam ple prepared by
th e procedure described in ref.6 For C22H23NO11 calculated: relative m olecular m ass 477.4,
m on oisotopic m ass 477.1. FAB MS, m/z: 478 [M + H]+, 500 [M + Na]+. For C22H23NO11
(477.4) calculated: 55.35% C, 4.86% H, 2.93% N; foun d: 55.64% C, 4.97% H, 2.92% N.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-ph th alim ido-β-D-galactopyran ose (5b)
M.p. 130 °C (propan -2-ol), [α]D +34 (c 0.18, ch loroform ); ref.22: m .p. 127–131 °C (eth an ol),
[α]D +35 (c 1.3, ch loroform ). 1H NMR spectrum agrees with th at of th e auth en tic sam ple de-
scribed in ref.22 For C22H23NO11 calculated: relative m olecular m ass 477.4, m on oisotopic
m ass 477.1. FAB MS, m/z: 478 [M + H]+, 500 [M + Na]+. For C22H23NO11 (477.4) calculated:
55.35% C, 4.86% H, 2.93% N; foun d: 55.19% C, 4.98% H, 2.89% N.
1,3,4,6-tetra-O-acetyl-2-deoxy-2-ph th alim ido-α-D-m an n opyran ose (6a)
M.p. 136 °C (eth an ol), [α]D –8 (c 0.3, ch loroform ). 1H NMR: 7.92–7.75 m , 4 H (H-arom .,
Ph t); 6.59 d, 1 H, J = 3.9 (H-1); 5.55 dd, 1 H, J = 6.8, 8.2 (H-4); 5.50 dd, 1 H, J = 5.3, 6.8
(H-3); 4.89 dd, 1 H, J = 3.9, 5.3 (H-2); 4.45 dd, 1 H, J = 6.0, 12.2 (H-6a); 4.31 dd, 1 H, J = 3.3,
12.2 (H-6b); 4.23 ddd, 1 H, J = 3.3, 6.0, 8.2 (H-5); 2.15 s, 3 H (OCOCH3); 2.13 s, 3 H
(OCOCH3); 2.10 s, 3 H (OCOCH3); 1.96 s, 3 H (OCOCH3). 13C NMR: 170.8 (OCOCH3), 169.9
(OCOCH3), 169.5 (OCOCH3), 168.5 (OCOCH3), 167.6 (2 C), 134.5 (2 C), 131.3 (2 C), 123.8
(2 C) (C-arom ., Ph t), 90.4 (C-1), 71.1 (C-5), 69.0 (C-3), 67.8 (C-4), 62.5 (C-6), 50.5 (C-2),
21.0 (OCOCH3), 20.8 (2 × OCOCH3), 20.7 (OCOCH3). For C22H23NO11 calculated: relative
m olecular m ass 477.4, m on oisotopic m ass 477.1. ESI MS, m/z: 500.1 [M + Na]+. For
C
22H23NO11 (477.4) calculated: 55.35% C, 4.86% H, 2.93% N; foun d: 57.30% C, 5.16% H,
2.67% N.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-ph th alim ido-β-D-m an n opyran ose (6b)
1H NMR an d 13C NMR spectra of β-an om er 6b were extracted from NMR spectra of th e
α/β-an om er m ixture of com poun ds 6a an d 6b obtain ed un der con dition s B. 1H NMR:
7.92–7.75 m , 4 H (H-arom ., Ph t); 6.06 t, 1 H, J = 9.5, 9.5 (H-4); 5.99 d, 1 H, J = 2.8 (H-1);
5.37 dd, 1 H, J = 6.8, 9.4 (H-3); 5.06 dd, 1 H, J = 2.8, 6.8 (H-2); 4.48 dd, 1 H, J = 6.0, 12.2
(H-6a); 4.27 dd, 1 H, J = 2.3, 12.2 (H-6b); 3.93 ddd, 1 H, J = 2.3, 6.0, 9.7 (H-5); 2.16 s, 3 H
(OCOCH3); 2.07 s, 3 H (OCOCH3); 1.97 s, 3 H (OCOCH3); 1.91 s, 3 H (OCOCH3). 13C NMR:
170.7 (OCOCH3), 169.7 (OCOCH3), 169.5 (OCOCH3), 168.4 (OCOCH3), 168.0 (2 C), 134.3
(2 C), 131.2 (2 C), 123.6 (2 C) (C-arom ., Ph t), 90.3 (C-1), 73.9 (C-5), 69.8 (C-3), 66.7 (C-4),
62.5 (C-6), 49.9 (C-2), 20.7 (2 × OCOCH3), 20.5 (OCOCH3), 20.4 (OCOCH3).
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Veselý, Ledvina, Jindřich, Šaman, Trnka:
An om erization of Com poun d 4a
To a stirred solution of α-an om er 4a (70 m g, 0.15 m m ol) in acetic an h ydride (2 m l),
trim eth ylsilyl trifluorom eth an esulfon ate (5 µl, 0.025 m m ol) was added an d stirrin g was con -
tin ued at 35 °C for 1 h . Progress of th e reaction was m on itored by TLC in toluen e–eth yl ace-
tate (1:1). Th e m ixture was poured in to a stirred m ixture of toluen e–saturated aqueous
sodium h ydrogen carbon ate (1:1, 8 m l) cooled in an ice bath . After 1 h stirrin g, th e organ ic
layer was separated, extracted with water (2 × 3 m l) an d poured on a colum n of silica gel
(3 g). Th e product was desorbed with a m ixture of toluen e–eth yl acetate (1:1). Th e eluen t
was evaporated in vacuo to obtain a m ixture of α- an d β-an om ers 4a an d 4b (2:7). Th e ratio
of an om ers was determ in ed by 1H NMR spectra.
Preparation of Eth yl 3,4,6-Tri-O-acetyl-2-deoxy-2-ph th alim ido-1-th io-
1,2-trans-D-h exopyran osides
Glucosam in e derivative 4a (4.77 g, 10 m m ol), α/β-an om er m ixture of galactosam in e deriva-
tive 5a an d 5b (4.77 g, 10 m m ol), obtain ed by th e procedure in ref.22, or α/β-an om er m ix-
ture of m an n osam in e derivatives 6a an d 6b (1:1), obtain ed by m eth od B (4.77 g, 10 m m ol),
was dried with crush ed m olecular sieves 4A (0.5 g) in an apparatus equipped with a septum
at room tem perature an d 20 Pa for 5 h . Th e apparatus was flush ed with argon twice an d
th en dry dich lorom eth an e (120 m l) was added th rough th e septum . After dissolution of th e
startin g m aterial, eth an eth iol (13.1 m l, 17.3 m m ol) an d trim eth ylsilyl trifluorom eth an e-
sulfon ate (1.9 m l, 10.7 m m ol) were added th rough th e septum un der stirrin g an d stirrin g
was th en con tin ued at room tem perature for 1 h . Progress of th e reaction was m on itored by
TLC in toluen e–eth yl acetate (1:1). Th e m ixture was filtered over a sh ort colum n of Celite
an d th e colum n was wash ed with ch loroform (270 m l). Th e filtrate was wash ed with satu-
rated aqueous sodium h ydrogen carbon ate (3 × 100 m l), water (3 × 100 m l), dried over an h y-
drous m agn esium sulfate an d evaporated in vacuo. Th e residue was ch rom atograph ed on a
silica gel colum n (200 g) in toluen e–eth yl acetate (6:1).
For 4a: Th e reaction afforded 7, yield 3.84 g (80%), as a syrupy residue, wh ich was crystal-
lized from toluen e to give 7, yield 3.21 g (67%).
For 5a an d 5b: Th e reaction gave 8, yield 3.69 g (77%).
For 6a an d 6b: Th e reaction afforded 9, yield 3.34 g (70%), as a syrupy residue, wh ich was
crystallized from toluen e, yield 2.86 g (67%).
Eth yl 2,4,6-Tri-O-acetyl-2-deoxy-2-ph th alim ido-1-th io-β-D-glucopyran oside (7)
M.p. 117–118 °C (toluen e), [α]D +42 (c 0.7, ch loroform ); ref.6 m .p. 115–118 °C, [α]D +46 (c 0.8,
dich lorom eth an e). 1H NMR spectrum agrees with th at of th e auth en tic sam ple prepared by
th e procedure described in ref.6 For C22H25NO9S calculated: relative m olecular m ass 479.5,
m on oisotopic m ass 479.1. FAB MS, m/z: 480 [M + H]+, 502 [M + Na]+. For C22H25NO9S
(479.5) calculated: 55.11% C, 5.26% H, 2.92% N, 6.69% S; foun d: 55.24% C, 5.34% H,
2.98% N, 6.57% S.
Eth yl 2,4,6-Tri-O-acetyl-2-deoxy-2-ph th alim ido-1-th io-β-D-galactopyran oside (8)
Syrup, [α]D +17 (c 0.3, ch loroform ); ref.17 [α]D +18 (c 1.0, ch loroform ). 1H NMR spectrum
agrees with th at of th e auth en tic sam ple described in ref.17 For C22H25NO9S calculated: rela-
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Improved Synthesis of 1,2-trans-Acetates and 1,2-trans Ethyl 1-Thioglycosides
1273
tive m olecular m ass 479.5, m on oisotopic m ass 479.1. FAB MS, m/z: 480 [M + H]+, 502 [M +
Na]+. For C22H25NO9S (479.5) calculated: 55.11% C, 5.26% H, 2.92% N, 6.69% S; foun d:
55.24% C, 5.34% H, 2.98% N, 6.57% S.
Eth yl 2,4,6-Tri-O-acetyl-2-deoxy-2-ph th alim ido-1-th io-α-D-m an n opyran oside (9)
M.p. 129 °C (toluen e), [α]D +24 (c 1.5, ch loroform ). 1H NMR: 7.86–7.73 m , 4 H (H-arom .,
Ph t); 5.96 d, 1 H, J = 7.0 (H-1); 5.39 dd, 1 H, J = 4.3, 5.2 (H-3); 4.28 dd, 1 H, J = 5.2, 6.4
(H-4); 4.79 dd, 1 H, J = 4.3, 7.0 (H-2); 4.56 dd, 1 H, J = 7.0, 12.0 (H-6a); 4.37 dt, 1 H, J = 3.7,
6.6, 6.6 (H-5); 4.30 dd, 1 H, J = 3.7, 12.0 (H-6b); 2.70 dq, 1 H, J = 7.4, 7.4, 7.4, 12.9
(SCH2CH3); 2.62 dq, 1 H, J = 7.4, 7.4, 7.4, 12.9 (SCH2CH3); 2.14 s, 3 H (OCOCH3); 2.13 s,
3 H (OCOCH3); 2.00 s, 3 H (OCOCH3); 1.28 t, 3 H, J = 7.4 (SCH2CH3). 13C NMR: 170.7
(OCOCH3), 169.8 (OCOCH3), 168.2, 168.0, 167.7 (OCOCH3), 134.3 (2 C), 131.5 (2 C), 123.6
(2 C) (C-arom ., Bn , Ph t), 78.0 (C-1), 70.9 (C-5), 69.6 (C-3), 68.6 (C-4), 62.1 (C-6), 51.5 (C-2),
24.9 (SCH2CH3), 20.9, 20.8 (OCOCH3), 20.8 (OCOCH3), 14.9 (SCH2CH3). For C22H25NO9S
calculated: relative m olecular m ass 479.5, m on oisotopic m ass 479.1. FAB MS, m/z: 480 [M +
H]+, 502 [M + Na]+, 524 [M + 2 Na]+. For C22H25NO9S (479.5) calculated: 55.11% C, 5.26% H,
2.92% N, 6.69% S; foun d: 55.23% C, 5.31% H, 2.87% N, 6.58% S.
This work was supported by the Grant Agency of Czech Republic (grant No. 203/00/0071), by the
Ministry of Education, Youth and Sports (grant No. 1131 00001) and Research Project Z4/055/905.
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