Stereoselective preparation of 2,3-dideoxy-3-C-[(α-D- galactopyranosyl)methyl]-D-arabino-hexopyranose and 2,3-dideoxy-3-C-[(α-D- galactopyranosyl)methyl]-L-arabino-hexopyranose

Article abstract of DOI:10.1135/cccc20080690

The diastereomeric substituted 2H-dihydropyran derivatives 2b and 3b were obtained by the stereoselective cycloaddition of (E)-4-(tetra-O-benzyl-a-D- galactopyranosyl)-1-(thiazol-2-yl)but-2-en-1-one (1) with either of the enantiomeric chiral vinyl ethers (R)-4 or (S)-4. Reduction of the ester group, transformation of the thiazole ring into an aldehyde group and reaction with an excess of borane afforded the final C-(1→3)-disaccharide structures. The obtained C-(1→3)-disaccharides, containing an L- or D-deoxy-arabino- hexopyranose moiety at the reducing end, were characterized as peracetylated methyl glycosides 9a, 9b and 12a, 12b.

Full text of DOI:10.1135/cccc20080690

690
Parkan, Vích, Dvořáková, Kniežo:
STEREOSELECTIVE PREPARATION OF 2,3-DIDEOXY-3-C-[(α-D-GALACTO-
PYRANOSYL)METHYL]-D-a ra bin o-HEXOPYRANOSE AND
2,3-DIDEOXY-3-C-[(α-D-GALACTOPYRANOSYL)METHYL]-
L-a ra bin o-HEXOPYRANOSE
b
a3,
Kamil PARKANa1, Ondřej VÍCHa2, Hana DVOŘÁKOVÁ and Ladislav KNIEŽO
*
a
Department of Chemistry of Natural Compounds, Institute of Chemical Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic; e-mail: kamil.parkan@vscht.cz,
1
2
3
ondrej.vich@vscht.cz, ladislav.kniezo@vscht.cz
b
NMR Laboratory, Institute of Chemical Technology, Prague, Technická 5, 166 28 Prague 6,
Czech Republic; e-mail: hana.dvorakova@vscht.cz
Received May 23, 2008
Accepted July 2, 2008
Publish ed on lin e July 25, 2008
Th e diastereom eric substituted 2H-dih ydropyran derivatives 2b an d 3b were obtain ed by th e
stereoselective cycloaddition of (E)-4-(tetra-O-ben zyl-α-D-galactopyran osyl)-1-(th iazol-2-yl)but-
2-en -1-on e (1) with eith er of th e en an tiom eric ch iral vin yl eth ers (R)-4 or (S)-4. Reduction of
th e ester group, tran sform ation of th e th iazole rin g in to an aldeh yde group an d reaction
with an excess of boran e afforded th e fin al C-(1→3)-disacch aride structures. Th e obtain ed
C-(1→3)-disacch arides, con tain in g an L- or D-deoxy-arabino-h exopyran ose m oiety at th e re-
ducin g en d, were ch aracterized as peracetylated m eth yl glycosides 9a, 9b an d 12a, 12b.
Keyw ord s: C-Disacch arides; Stereoselective syn th esis; Sacch aride ch em istry.
As a result of th eir great structural variability, sacch arides represen t very
suitable “structural un its” for th e con struction of th e so-called sugar codes1.
Th e in teraction s of sugar codes with protein receptors play a key role in
cell/cell or cell/path ogen com m un ication an d, in ter alia, even con trol such
im portan t processes as cell adh esion , fertilization , in flam m ation , im m un e
respon se an d can cer m etastasis. A deeper un derstan din g of m olecular details
of th ese recogn ition processes h as led to th e discovery of various sacch aride
derivatives of sign ifican t th erapeutic poten tial2. However, th e search for
n ew carboh ydrate-based th erapeutics or vaccin es is often com plicated by
th e fact th at oligosacch arides used in form in g th e sugar codes are labile
com poun ds in vivo, because th ey un dergo h ydrolysis by ubiquitous
glycosidases. Th e solution to th is problem m ay rest in th e use of stable car-
boh ydrate m im icks, such as C-disacch arides, wh ich n om in ally preserve th e
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700
© 2008 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20080690

Stereoselective Preparation of C-Disaccharides
691
structural in form ation of n atural disacch arides but are ch em ically as well as
en zym atically n on -h ydrolyzable3.
Recen tly we described a sh ort an d efficien t syn th esis of α-C-(1→3)-di-
sacch arides in wh ich D-glucopyran ose was lin ked to an L- or D-2-deoxy-
arabino-h exopyran ose m oiety4. Later on , we foun d th at th e stereoselectivity
of th e key step in our syn th esis, n am ely th e cycloaddition of th e substi-
tuted oxadien e with eth yl vin yl eth er, can be m arkedly in creased by th e use
of ch iral vin yl eth ers. Th is h as m ade possible th e facile stereoselective prep-
aration of furth er C-(1→3)-disacch aride derivatives5. As an exam ple of th is
approach we n ow report th e preparation of previously un kn own
disacch aride m im etics, in wh ich th e α-D-galactopyran osyl m oiety is lin ked
by a m eth ylen e bridge to C-3 of an L- or D-2-deoxy-arabino-h exopyran ose.
Th e α-D-galactopyran osyl m oiety, attach ed by a (1→3) glycosidic bon d to
th e oligosacch aride ch ain , is presen t as th e term in al m on osacch aride, e.g.,
in th e B blood group an tigen an d in th e so-called α-galactosyl epitope,
wh ich is respon sible for th e h yperacute rejection of organ s in xen otran s-
plan tation 6. Th e syn th esized com poun ds represen t n on -h ydrolyzable
m im etics of th is structural m otif, an d furth er syn th etic tran sform ation s of
th e deoxy-arabino-h exopyran ose rin g (i.e., via th e correspon din g glycals)
m ake possible th eir lin kage in to oligosacch aride ch ain s an d th e syn th esis of
n on -h ydrolyzable an alogs of n atural epitopes. A stereoisom eric com poun d,
2,3-dideoxy-3-C-[(β-D-galactopyran osyl)m eth yl]D-lyxo-h exopyran ose, was re-
cen tly prepared from isolevoglucosen , usin g a lon ger an d m ore laborious
procedure7.
Usin g our origin al procedure4, th e reaction of (E)-4-(tetra-O-ben zyl-
α-D-galactopyran osyl)-1-(th iazol-2-yl)but-2-en -1-on e (1) with eth yl vin yl
eth er led to a 1:1 m ixture of two diastereom eric en do cycloadducts 2a an d
3a wh ich were in separable by preparative ch rom atograph y (Sch em e 1).
SCHEME 1
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

692
Parkan, Vích, Dvořáková, Kniežo:
On th e con trary, cycloaddition with th e en an tiopure vin yl eth ers (R)-4
an d (S)-4, easily obtain able from th e ch eap an d com m ercially accessible en -
an tiom ers of m an delic acid, was h igh ly stereoselective5. Th e reaction with
en an tiom er (R)-4 afforded alm ost pure cycloadduct 2b, wh ile th e reaction
with en an tiom er (S)-4 led to alm ost pure cycloadduct 3b (Sch em e 2).
SCHEME 2
Un fortun ately, prelim in ary experim en ts dem on strated th at th e subse-
quen t tran sform ation of th e th iazole rin g in cycloadducts 2b an d 3b in to
an aldeh yde fun ction ality (un like th e sim ilar con version in cycloadducts 2a
an d 3a) proceeded with problem s. Th e desired aldeh ydes were obtain ed in
on ly low yields an d were accom pan ied by oth er un iden tified com poun ds.
Origin ally, we in ten ded to circum ven t th is syn th etic problem by replacin g
th e ch iral m oiety of m an delic acid in cycloadducts 2b an d 3b with sim pler
substituen ts (e.g., m eth oxy or eth oxy). However, all such attem pts led on ly
to m ixtures of several com poun ds. Th e attem pted acid-catalyzed tran s-
glycosidation was probably accom pan ied by cleavage of th e un saturated
dih ydropyran rin g an d subsequen t decom position of th e in term ediates.
To avoid th is problem , we reduced th e ester group in cycloadducts 2b
an d 3b with LiAlH4 an d protected th e resultin g prim ary alcoh ols by
ben zylation (Sch em e 3). Th e ben zyl eth ers 5 an d 6 th en un derwen t tran s-
form ation of th e th iazole rin g to an aldeh yde in th e usual m an n er with out
difficulty. Com poun d 5 gave pure aldeh yde 7 (yield 70%) wh ich , on reac-
tion with excess of boran e an d ben zylation of th e n ewly gen erated h ydroxy
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

Stereoselective Preparation of C-Disaccharides
693
(i) 1. LiAlH4, THF, 2. NaH, Bn Br, THF; (ii) 1. TfOMe, MeCN, 2. NaBH4, MeOH, 3. AgNO3,
H2O, MeCN; (iii) 1. BH3·Me2S, THF, 30% NaOH, 30% H2O2, 2. NaH, Bn Br, THF; (iv) 1. MeOH,
3
M HCl, THF, 2. H2, Pd/C, 3. Ac2O, pyridin e
SCHEME 3
Syn th esis of (1→3)-C-disacch arides
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

694
Parkan, Vích, Dvořáková, Kniežo:
groups, afforded th e desired structure, C-disacch aride 8, as th e sole reaction
product. Alth ough th e m ass spectrum of th e com poun d obtain ed agreed
with th e assum ed structure 8, it was n ot possible to con firm th e relative
1
con figuration of th e n ew deoxypyran ose directly from its com plex H NMR
spectrum . However, th e ch iral aglycon was easily exch an ged by treatm en t
of com poun d 8 in tetrah ydrofuran with m eth an olic solution of HCl, th e re-
action afforded a m ixture of on ly two an om ers, wh ich , after exch an ge of
th e ben zyl protectin g groups for acetates, was ch aracterized as a m ixture of
th e peracetyl m eth yl glycosides 9a an d 9b. As determ in ed from th e NMR
spectra, th e an om eric m eth yl glycosides 9a an d 9b were form ed in th e 4:1
ratio (as estim ated by in tegration of th e 1H NMR sign als of th e m eth oxy
group at 3.27 ppm in th e m ajor an om er an d at 3.41 ppm in th e m in or
on e). Th e couplin g con stan ts of th e m ajor an om er 9a un equivocally sh ow
th at th e substituen ts on carbon atom s 4 an d 5 of th e n ew deoxyh exo-
pyran ose are in th e equatorial position s ( J(H-4,H-5) = 9.9 Hz). Th e con figu-
ration s of th e rem ain in g carbon atom s in th is com poun d were determ in ed
usin g NOE experim en ts: a m arked NOE was observed between proton s H-3
an d H-5, but th ere was n o in teraction with proton H-1. On th e con trary,
proton s H-3 an d H-5 sh owed a stron g NOE with th e m eth oxy group in th e
an om eric position . Th ese results con firm th at th e substituen ts at position s
3, 4 an d 5 are equatorial wh ereas th e an om eric m eth oxy group is axial. Th is
m ean s th at th e m ajor stereoisom er 9a is th e α-m eth yl glycoside of th e sub-
stituted 2-deoxy-arabino-h exopyran ose. As follows from th e couplin g con -
1
stan ts of th e H NMR spectrum of th e m in or an om er 9b, th e substituen ts
on carbon atom s 1, 4 an d 5 of th is deoxyh exopyran ose are in equatorial po-
sition (J(H-1,H-2ax) = 9.4 Hz, J(H-1,H-2eq) = 1.8 Hz, J(H-4,H-5) = 9.6 Hz).
Moreover, th e spectrum of th is an om er displayed m arked NOEs between
proton s H-1, H-3 an d H-5; th us con firm in g th at in th is case all th e substitu-
en ts are equatorial an d th us 9b is th e β-m eth yl glycoside of th e substituted
2-deoxy-arabino-h exopyran ose. Sin ce th e absolute con figuration of th e
startin g com poun d 2b was un equivocally determ in ed by X-ray diffraction
in our previous study5, th e deoxy-arabino-h exopyran ose in m eth yl
glycosides 9a an d 9b m ust h ave th e L-con figuration .
Usin g th e sam e reaction sch em e as above, we con verted th e diastereo-
isom eric com poun d 6 in to aldeh yde 10, wh ich , via in term ediate 11 (in th is
case n ot isolated), was con verted in to a m ixture of peracetylated m eth yl
glycosides 12a an d 12b. Th e NMR spectra of th e obtain ed m ixture of 12a
an d 12b were alm ost iden tical with th ose of com poun ds 9a an d 9b. Also in
th is case, th e two m eth yl glycosides were form ed in th e ca. 4:1 ratio (as
1
determ in ed by in tegration of H NMR sign als of OMe at 3.34 ppm for th e
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

Stereoselective Preparation of C-Disaccharides
695
m ajor an om er an d at 3.49 ppm for th e m in or on e). As in th e precedin g
case, th e in teraction con stan ts an d NOE experim en ts un equivocally con -
firm th at th e m ajor stereoisom er 12a is th e α-m eth yl glycoside of th e sub-
stituted 2-deoxy-arabino-h exopyran ose wh ereas th e m in or stereoisom er 12b
is th e β-m eth yl glycoside. As follows from th e absolute con figuration 5 of
th e startin g com poun d 3b, th e n ew deoxy-arabino-h exopyran ose in th e
m eth yl glycosides 12a, 12b m ust h ave th e D-con figuration .
In con clusion , we h ave dem on strated th at stereoselective cycloaddition
of th e en an tiom eric vin yl eth ers (R)-4 an d (S)-4 with th e suitably substi-
tuted oxadien e 1 en ables a facile an d sim ple preparation of th e previously
un kn own (1→3)-disacch aride m im etics, con tain in g an α-D-galactopyra-
n osyl m oiety at th e n on -reducin g en d an d a 2-deoxy-arabino-h exopyran ose
m oiety of L- or D-con figuration at th e reducin g en d. Com poun ds 12a an d
12b m ay serve as precursors for th e syn th esis of n on -h ydrolyzable
glycoprotein or glycolipid epitopes con tain in g th e α-D-galactopyran osyl-
(1→3)-structural m otif.
EXPERIMENTAL
Th e syn th esis of com poun ds 2b an d 3b h as already been described in our previous paper5.
Th e m eltin g poin ts are un corrected. TLC was perform ed on HF254 plates (Merck), detec-
tion was by UV ligh t or by sprayin g with a solution of Ce(SO4)2(H2O)4 (5 g) in 10% H2SO4
(500 m l) an d subsequen t h eatin g. Flash colum n ch rom atograph y was perform ed on silica gel
(MERCK, 100–160 µm ) in solven ts, distilled prior to use. Optical rotation s were m easured at
25 °C on a JASCO DIP-370 spectropolarim eter. 1H an d 13C NMR spectra were taken on a Bruker
DRX 500 Avan ce spectrom eter at 500.132 MHz (1H NMR) an d at 125.767 MHz (13C NMR)
usin g tetram eth ylsilan e as in tern al stan dard. Ch em ical sh ifts in th e 1H an d 13C NMR spectra
are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. 1H an d 13C NMR sign al assign m en ts
were con firm ed by 2D COSY an d HMQC wh en n ecessary. NOE con n ectivities were obtain ed
usin g th e 1D 1H DPFGSE-NOE experim en t. For n um berin g of atom s see Sch em e 3. Mass
spectra an d HPLC were perform ed on a 250 × 4.6 m m colum n packed with 5 µm Supelco BDS
Hypersil C-18, m obile ph ase m eth an ol–water, usin g an HP 1100 in strum en t equipped with a
gradien t pum p, colum n th erm ostat, an d in addition to a UV detector, also with an Agilen t
G1956B sin gle quadrupole system as an MS detector.
(2S,4S)-2-[(2R)-2-(Ben zyloxy)-1-ph en yleth oxy]-4-[(2,3,4,6-tetra-O-ben zyl-α-D-galacto
pyran osyl)m eth yl]-6-(th iazol-2-yl)-3,4-dih ydro-2H-pyran (5)
Lith ium alum in um h ydride (0.3 g, 7.95 m m ol) was added portion wise un der n itrogen to a
solution of com poun d 2b (2.3 g, 2.65 m m ol) in tetrah ydrofuran (50 m l), cooled to 0 °C, an d
th e reaction m ixture was stirred at room tem perature for 2 h . Th e m ixture was th en
quen ch ed by th e cautious addition of 1 M NaOH (5 m l), th e solid salts were rem oved by fil-
tration an d th e filtrate was taken down . Th e residue was partition ed between eth yl acetate
an d water. Th e organ ic ph ase was dried, th e solven t evaporated an d th e residue flash -
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

696
Parkan, Vích, Dvořáková, Kniežo:
ch rom atograph ed on a sh ort colum n of silica gel in petroleum eth er–eth yl acetate (5:1). A
solution of th e obtain ed alcoh ol (2.1 g, RF 0.4 in petroleum eth er–eth yl acetate (2:1), m/z
841.8 [M + H]+) in tetrah ydrofuran (60 m l) was stirred with NaH (0.2 g, 5 m m ol; 60% sus-
pen sion in m in eral oil) at room tem perature for 1 h . Ben zyl brom ide (0.49 m l, 3.75 m m ol)
an d tetrabutylam m on ium iodide (0.23 g, 0.63 m m ol) were added, an d th e reaction m ixture
was stirred at 40 °C for 15 m in an d th en at room tem perature for 14 h . After th e addition of
m eth an ol (3 m l), th e solven t was evaporated in vacuo an d th e residue was partition ed be-
tween dich lorom eth an e an d saturated solution of NaHCO3. Th e organ ic ph ase was dried an d
th en evaporated. Th e residue was ch rom atograph ed on silica gel in petroleum eth er–eth yl
acetate (4:1). Yield 1.97 g (80%) of com poun d 5, RF 0.65 (petroleum eth er–eth yl acetate 2:1).
[α]D +52.2 (c 1.02, CHCl3). 1H NMR (CDCl3): 1.78 m , 1 H (H-1′′a); 1.92 ddd, 1 H, J(3ax,3eq) =
13.7, J(3ax,4) = 6.8, J(3ax,2) = 6.8 (H-3ax); 2.00 ddd, 1 H, J(1′′a,1′′b) = 15.1, J(1′′b,1′) = 10.3,
J(1′′b,4) = 5.5 (H-1′′b); 2.24 ddd, 1 H, J(3eq,3ax) = 13.7, J(3eq,4) = 6.6, J(3eq,2) = 1.4 (H-3eq);
2.62 m , 1 H (H-4); 3.59–3.75 m , 5 H (Bn OCH2CHPh , H-2′, H-3′, H-6a′); 3.92 m , 1 H (6b′);
4.02 m , 1 H (H-4′); 4.11 m , 1 H (H-5′); 4.25 bd, 1 H, J(1′′b,1′) = 10.3 (H-1′); 4.47–4.80 m , 10 H
(5 × OCH2Ph); 5.00 dd, 1H, J = 8.1, 3.6 (BnOCH2CHPh); 5.50 dd, 1 H, J(2,3eq) = 1.4, J(2,3ax) =
6.8 (H-2); 6.01 d, 1 H, J(5,4) = 3.4 (H-5); 7.12 d, 1 H, J = 3.2 (H-th iazole); 7.19–7.41 m , 30 H
(6 × Ph ); 7.71 d, 1 H, J = 3.2 (H-th iazole). 13C NMR (CDCl3): 27.61 (C-4), 34.15 (C-1′′), 34.17
(C-3), 67.61 (C-6′), 72.40 (C-1′), 72.95, 73.07, 73.27, 73.34, 73.52 (5 × OCH2Ph ), 74.35,
76.78, 77.01, 77.24 (C-2′, C-3′, C-4′, C-5′), 76.92 (Bn OCH2CHPh ), 81.16 (Bn OCH2CHPh ),
100.78 (C-2), 103.76 (C-5), 118.49 (CH-th iazole), 126.56–128.29 (25 × C6H5), 138.16, 138.32,
138.41, 138.50, 139.75 (5 × ipso C6H5), 142.79 (CH-th iazole); 143.58 (C-6) 164.46 (C-2
th iazole). For C58H59NO8S calculated relative m olecular m ass 930.16. MS (ESI), m/z: 931.4
[M + H]+.
(2S,4S)-2-[(2R)-2-(Ben zyloxy)-1-ph en yleth oxy]-4-[(2,3,4,6-tetra-O-ben zyl-α-D-galacto
pyran osyl)m eth yl]-6-form yl-3,4-dih ydro-2H-pyran (7)
Molecular sieves (4Å, 1.5 g) were added to a solution of com poun d 5 (1.5 g, 1.6 m m ol) in
aceton itrile (10 m l), an d m eth yl triflate (0.24 m l, 2.1 m m ol) was added dropwise. After
stirrin g at room tem perature for 15 m in , m eth an ol (3 m l) was added an d th e solven t was
evaporated in vacuo. Th e residue was treated with m eth an ol (20 m l) an d th en NaBH4 (0.20 g,
5.2 m m ol) was added in portion s. After stirrin g at room tem perature for 15 m in , aceton e (5 m l)
was added, th e reaction m ixture was filtered th rough Supercel an d th e filtrate was evapo-
rated in vacuo. Th e residue was dissolved in aceton itrile (15 m l) an d a solution of AgNO3
(0.41 g, 2.4 m m ol) in water (1.5 m l) was added under vigorous stirring. After stirring for 10 m in,
ph osph ate buffer (10 m l, pH 7) was added an d after an addition al 10 m in th e aceton itrile
was evaporated in vacuo an d th e residue was partition ed between dich lorom eth an e an d
ph osph ate buffer (pH 7). Th e organ ic ph ase was dried an d evaporated. Th e resultin g residue
was flash -ch rom atograph ed th rough a sh ort colum n of silica gel in petroleum eth er–eth yl
acetate (4:1). Yield 1.14 g (70%) of aldeh yde 7, RF 0.4 (petroleum eth er–eth yl acetate 3:1).
[α]D +33.6 (c 1.03, CHCl3). 1H NMR (CDCl3): 1.92–2.07 m , 4 H (H-1′′a, H-1′′b, H-3ax,
H-3eq); 2.57 m , 1 H (H-4); 3.54–3.65 m , 3 H (Bn OCH2CHPh , H-6a′); 3.71–3.78 m , 2 H (H-2′,
H-3′); 3.87 m , 1 H (H-6b′); 3.99 m , 1 H (H-4′); 4.02–4.10 m , 2 H (H-1′, H-5′); 4.45–4.77 m , 10 H
(5 × OCH2Ph ); 4.94 dd, 1 H, J = 8.0, 3.4 (Bn OCH2CHPh ); 5.56 m , 1 H (H-2); 5.81 d, 1 H,
J(5,4) = 4.2 (H-5), 7.14–7.37 m , 30 H (6 × Ph ); 8.74 s, 1 H (CHO). 13C NMR (CDCl3): 26.54
(C-4), 32.11 (C-1′′), 32.15 (C-3), 67.68 (C-6′), 72.01 (C-1′), 72.8, 73.04, 73.21, 73.24, 73.34 (5 ×
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

Stereoselective Preparation of C-Disaccharides
697
OCH2Ph ), 74.31, 76.78, 77.01, 77.26 (C-2′, C-3′, C-4′, C-5′), 76.84 (Bn OCH2CHPh ), 79.60
(Bn OCH2CH Ph ), 98.30 (C-2), 125.66 (C-5), 127.39–128.36 (25 × C6H5), 138.13, 138.20,
138.38, 139.47, 139.34 (5 × ipso C6H5), 148.72 (C-6), 186.40 (CHO). For C56H58O9 calculated
relative m olecular m ass 875.05. MS (ESI), m/z: 876.1 [M + H]+.
(2R)-2-(Ben zyloxy)-1-ph en yleth yl 2,3-Dideoxy-3-C-[(2,3,4,6-tetra-O-ben zyl-α-D-galacto
pyran osyl)m eth yl]-4,6-di-O-ben zyl-β-L-arabino-h exopyran oside (8)
A 2 M solution of BH3·Me2S in tetrah ydrofuran (2.1 m l, 4.1 m m ol) was added dropwise to a
cool (0 °C) solution of aldeh yde 7 (1.03 g, 1.18 m m ol) in tetrah ydrofuran (35 m l) an d th e
reaction m ixture was stirred at room tem perature for 16 h . Th e m ixture was quen ch ed by
th e gradual addition of 30% NaOH (2.2 m l) an d 30% H2O2 (2.2 m l), an d stirred at room
tem perature for 30 m in . Th e reaction m ixture was partition ed between dich lorom eth an e
an d a saturated aqueous NaCl solution . Th e organ ic ph ase was dried an d evaporated in
vacuo. Th e residue was dissolved in tetrah ydrofuran (20 m l) an d stirred with NaH (60% sus-
pen sion in m in eral oil; 0.21 g, 5.3 m ol) at room tem perature for 1 h . Ben zyl brom ide (0.56 m l,
4.7 m m ol) an d tetrabutylam m on ium iodide (0.13 g, 0.35 m m ol) were added, an d th e reac-
tion m ixture was h eated to 40 °C for 15 m in . After stirrin g at room tem perature for 14 h ,
m eth an ol (3 m l) was added an d th e solven t was evaporated in vacuo. Th e residue was par-
tition ed between dich lorom eth an e an d a saturated solution of NaHCO3. Th e organ ic layer
was dried, evaporated in vacuo, an d ch rom atograph ed on silica gel in petroleum eth er–eth yl
acetate (5:1). Yield 1 g (79%) of com poun d 8, RF 0.4 (petroleum eth er–eth yl acetate 3:1). [α]D
+45.6 (c 0.26, CHCl3). 1H NMR (CDCl3): 1.31–1.55 m , 2 H (H-1′′a, H-2ax); 2.02–2.35 m , 3 H
(H-1′′b, H-2eq, H-3); 3.40 m , 1 H (H-5), 3.49–3.58 m , 2 H (Bn OCH2aCHPh , H-6a); 3.60–3.79 m ,
6 H (Bn OCH2bCHPh , H-2′, H-3′, H-6′a, H-6b, H-5); 3.86 m , 1 H (H-6′b); 3.97 m , 1 H (H-4′);
4.10 m , 1 H (H-5′); 4.15 m , 1 H (H-1′); 4.34–4.84 m , 15 H (7 × OCH2Ph , H-1); 4.93 dd, 1 H,
J = 8.2, 3.5 (Bn OCH2CHPh ); 7.10–7.43 m , 40 H (8 × Ph ). 13C NMR (CDCl3): 29.70 (C-1′′),
35.44 (C-3), 35.68 (C-2), 69.35 (C-6′), 69.58 (C-6), 71.27 (C-1′), 72.85, 72.99, 73.05,
73.18, 73.36, 73.43, 73.53 (7 × OCH2Ph ), 74.18, 74.26, 74.49 (C-2′, C-3′, C-4′), 74.72
(Bn OCH2CHPh ), 76.79 (C-5), 76.85 (C-5′), 78.32 (C-4), 78.36 (Bn OCH2CHPh ), 93.90 (C-1),
127.18–128.46 (40 × C6H5), 138.11, 138.22, 138.26, 138.29, 138.32, 138.41, 138.51, 138.53 (8 ×
ipso C6H5). For C70H74O10 calculated relative m olecular m ass 1075.33. MS (ESI), m/z: 1076.6
[M + H]+.
Meth yl 2,3-Dideoxy-3-C-[(2,3,4,6-tetra-O-acetyl-α-D-galactopyran osyl)m eth yl]-
4,6-di-O-acetyl-α-L-arabino-h exopyran oside (9a) an d
Meth yl 2,3-Dideoxy-3-C-[(2,3,4,6-tetra-O-acetyl-α-D-galactopyran osyl)m eth yl]-
4,6-di-O-acetyl-β-L-arabino-h exopyran oside (9b)
Meth an ol (30 m l) an d 3 M HCl (3.6 m l) were successively added to a solution of com poun d
8 (0.6 g, 0.56 m m ol) in tetrah ydrofuran (15 m l) an d th e reaction m ixture was stirred at
room tem perature for 23 h . A saturated solution of NaHCO3 (10 m l) was added cautiously
an d th e resultin g m ixture was con cen trated in vacuo. Th e residue th us obtain ed was parti-
tion ed between dich lorom eth an e an d a saturated solution of NaHCO3. After dryin g an d
evaporation of th e solven t, th e residue was ch rom atograph ed on silica gel in petroleum
eth er–eth yl acetate (8:1). Th e obtain ed m ixture of m eth yl glycosides (425 m g), RF 0.3 (petro-
leum eth er–eth yl acetate 3:1), m/z 879.4 [M + H]+, was dissolved in m eth an ol (10 m l) an d
h ydrogen ated over Pd/C (10%; 100 m g) at room tem perature for 2 h . Th e catalyst was re-
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

698
Parkan, Vích, Dvořáková, Kniežo:
m oved by filtration , th e solven t was evaporated an d th e residue dissolved in pyridin e (2 m l).
Acetic an h ydride (2 m l) was added an d th e m ixture was stirred at room tem perature for 1 h .
Th e reaction m ixture was poured on to ice an d th en partition ed between water an d eth yl
acetate. Th e organ ic ph ase was dried an d evaporated in vacuo. Ch rom atograph y of th e resi-
due on silica gel in petroleum eth er–eth yl acetate (2:1) afforded 248 m g (75%) of product as
a m ixture of two an om ers 9a an d 9b in th e ratio 4:1, RF 0.7 (petroleum eth er–eth yl acetate
2:1).
Anomer 9a: 1H NMR (CDCl3): 1.37 m , 1 H (H-1′′a); 1.49–1.58 m , 2 H (H-2ax, H-1′′b); ca.
1.95 m , overlapped by Ac, 1 H (H-2eq); 1.95 s, 3 H (1 × Ac); 1.98 s, 3 H (1 × Ac); 2.00 s, 3 H
(1 × Ac); 2.01 s, 3 H (1 × Ac); 2.02 s, 3 H (1 × Ac); 2.05 s, 3 H (1 × Ac); 2.19 m , 1 H (H-3);
3.27 s, 3 H (OCH3); 3.77 ddd, 1 H, J(5,6a) = 2.3, J(5,6b) = 4.8, J(5,4) = 9.9 (H-5); 3.91 dd, 1 H,
J(6a,5) = 2.3, J(6a,6b) = 12.1 (H-6a); 3.93–4.03 m , 2 H (H-5′, H-6a′); 4.13–4.16 m , 2 H (H-1′,
H-6b′); 4.18 dd, overlapped, 1 H, J(6b,5) = 4.8, J(6b,6a) = 12.1 (H-6b); 4.61–4.71 m , 2 H (H-1,
H-4); 5.04 dd, 1 H, J(3′,4′) = 3.2, J(3′,2′) = 9.6 (H-3′); 5.10 dd, 1 H, J(2′,1′) = 5.0, J(2′,3′) = 9.6
(H-2′); 5.31 dd, 1 H, J(4′,3′) = 3.2, J(4′,5′) = 5.5 (H-4′). 13C NMR (CDCl3): 20.48, 20.57, 20.62,
20.63, 20.74, 20.76 (6 × CH3CO), 28.22 (C-1′′), 32.33 (C-3), 36.07 (C-2), 54.36 (OCH3), 61.67
an d 62.73 (C-6 an d C-6′), 67.48 an d 67.57 (C-3′ an d C-4′), 68.02 an d 68.22 (C-2′ an d C-5′),
68.53 (C-5), 71.35 (C-1′), 71.94 (C-4), 97.46 (C-1), 169.82, 169.88, 169.96, 170.43, 170.60,
170.74 (6 × CH3CO). For C26H38O15 calculated relative m olecular m ass 590.57. MS (ESI), m/z:
591.3 [M + H]+.
Anomer 9b: 1H NMR (CDCl3): 1.82 m , 1 H (H-3); 3.41 s, 3 H (OCH3); 3.49 ddd, 1 H, J(5,6a) =
2.5, J(5,6b) = 4.9, J(4,5) = 9.6 (H-5); 4.35 dd, 1 H, J(1,2ax) = 9.4, J(1,2eq) = 1.8 (H-1), oth er
reson an ces are overlapped by sign als of th e m ajor isom er. For C26H38O15 calculated relative
m olecular m ass 590.57. MS (ESI), m/z: 591.3 [M + H]+.
(2R,4R)-2-[(2S)-2-(Ben zyloxy)-1-ph en yleth oxy]-4-[(2,3,4,6-tetra-O-ben zyl-α-D-galacto
pyran osyl)m eth yl]-6-(th iazol-2-yl)-3,4-dih ydro-2H-pyran (6)
Com poun d 3b (5 g) was treated in th e sam e m an n er as described for th e preparation of
com poun d 5, yieldin g 4.235 g (79%) of com poun d 6, RF 0.45 (petroleum eth er–eth yl acetate
3:1). [α]D +29.5 (c 1.0, CHCl3). 1H NMR (CDCl3): 1.73 m , 1 H (H-1′′a); 1.87 ddd, 1 H,
J(3ax,3eq) = 13.7, J(3ax,4) = 6.9, J(3ax,2) = 6.9 (H-3ax); 1.95 ddd, 1 H, J(1′′a,1′′b) = 15.2,
J(1′′b,1′) = 10.3, J(1′′b,4) = 5.4 (H-1′′b); 2.19 ddd, 1 H, J(3eq,3ax) = 13.7, J(3eq,4) = 6.8,
J(3eq,2) = 1.2 (H-3eq); 2.62 m , 1 H (H-4); 3.59–3.75 m , 5 H (Bn OCH2CHPh , H-2′, H-3′,
H-6a′); 3.87 m , 1 H (H-6b′); 3.98 m , 1 H (H-4′); 4.06 m , 1 H (H-5′); 4.20 bd, 1 H, J(1′′b,1′) =
10.3 (H-1′); 4.45–4.75 m , 10 H (5 × OCH2Ph ); 4.95 dd, 1 H, J = 7.9, 3.4 (Bn OCH2CHPh );
5.45 dd, 1 H, J(2,3eq) = 1.4, J(2,3ax) = 6.8 (H-2); 6.01 d, 1 H, J(5,4) = 3.2 (H-5); 7.12 d, 1 H,
J = 3.1 (H-th iazole); 7.19–7.35 m , 30 H (6 × Ph ); 7.66 d, 1 H, J = 3.1 (H-th iazole). 13C NMR
(CDCl3): 27.65 (C-4), 34.15 (C-1′′), 34.17 (C-3), 67.61 (C-6′), 72.40 (C-1′), 72.95, 73.07,
73.27, 73.34, 73.52 (5 × OCH2Ph ), 74.35, 76.78, 77.01, 77.24 (C-2′, C-3′, C-4′, C-5′), 76.92
(Bn OCH2CHPh ), 81.16 (Bn OCH2CHPh ), 100.78 (C-2), 103.76 (C-5), 118.49 (CH-th iazole),
126.56–128.29 (25 × C6H5), 138.16, 138.32, 138.41, 138.50, 139.75 (5 × ipso C6H5), 142.79
(CH-th iazole), 143.58 (C-6), 164.46 (C-2 th iazole). For C58H59NO8S calculated relative m o-
lecular m ass 930.16. MS (ESI), m/z: 931.4 [M + H]+.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

Stereoselective Preparation of C-Disaccharides
699
(2R,4R)-2-[(2S)-2-(Ben zyloxy)-1-ph en yleth oxy]-4-[(2,3,4,6-tetra-O-ben zyl-α-D-galacto
pyran osyl)m eth yl]-6-form yl-3,4-dih ydro-2H-pyran (10)
Com poun d 6 (2.25 g) was treated in th e sam e m an n er as described for th e preparation of
com poun d 7, yieldin g 1.60 g (75%) of aldeh yde 10, RF 0.4 (petroleum eth er–eth yl acetate
3:1). [α]D + 23.8 (c 0.92, CHCl3). 1H NMR (CDCl3): 1.90–2.06 m , 4 H (H-1′′a, H-1′′b, H-3ax,
H-3eq); 2.57 m , 1 H (H-4); 3.50–3.65 m , 3 H (Bn OCH2CHPh , H-6a′); 3.73–3.80 m , 2 H (H-2′,
H-3′); 3.87 m , 1 H (H-6b′); 3.99 m , 1 H (H-4′); 4.02–4.11 m , 2 H (H-1′, H-5′); 4.45–4.75 m ,
10 H (5 × OCH2Ph ); 4.94 dd, 1 H, J = 8.1, 3.5 (Bn OCH2CHPh ); 5.56 m , 1 H (H-2); 5.81 d,
1 H, J(5,4) = 4.2 (H-5); 7.12–7.40 m , 30 H (6 × Ph ); 8.74 s, 1 H (CHO). 13C NMR (CDCl3):
26.54 (C-4), 32.11 (C-1′′), 32. 15 (C-3), 67.68 (C-6′), 72.01 (C-1′), 72.8, 73.04, 73.21, 73.24,
73.34 (5 × CH2Ph ), 74.31, 76.78, 77.01, 77.26 (C-2′, C-3′, C-4′, C-5′), 76.84 (Bn OCH2CHPh ),
79.60 (Bn OCH2CHPh ), 98.30 (C-2), 125.66 (C-5), 127.39–128.36 (25 × C6H5), 138.13,
138.20, 138.38, 139.47, 139.34 (5 × ipso C6H5), 148.72 (C-6), 186.40 (CHO). For C56H58O9
calculated relative m olecular m ass 875.05. MS (ESI), m/z: 876.1 [M + H]+.
Meth yl 2,3-Dideoxy-3-C-[(2,3,4,6-tetra-O-acetyl-α-D-galactopyran osyl)m eth yl]-
4,6-di-O-acetyl-α-D-arabino-h exopyran oside (12a) an d
Meth yl 2,3-Dideoxy-3-C-[(2,3,4,6-tetra-O-acetyl-α-D-galactopyran osyl)m eth yl]-
4,6-di-O-acetyl-β-D-arabino-h exopyran oside (12b)
Com poud 10 (1.60 g) was treated in th e sam e m an n er as described for th e preparation of
com poun d 8, yieldin g com poun d 11 (1.69 g), RF 0.45 (petroleum eth er–eth yl acetate 3:1),
m/z 1076.6 [M + H]+, wh ich was im m ediately processed as described for th e preparation of
com poun ds 9a an d 9b, yieldin g 650 m g (60%) of a m ixture of an om ers 12a an d 12b in th e
ratio 4:1, RF 0.7 (petroleum eth er–eth yl acetate 2:1).
Anomer 12a: 1H NMR (CDCl3): 1.47 m , 1 H (H-1′′a); 1.56–1.66 m , 2 H (H-2ax, H-1′′b); ca.
2.00 m , overlapped by Ac, 1 H (H-2eq); 2.02 s, 3 H (1 × Ac); 2.05 s, 3 H (1 × Ac); 2.06 s, 3 H
(1 × Ac); 2.07 s, 3 H (1 × Ac); 2.08 s, 3 H (1 × Ac); 2.12 s, 3 H (1 × Ac); 2.26 m , 1 H (H-3);
3.34 s, 3 H (OCH3); 3.84 ddd, 1 H, J(5,6a) = 2.1, J(5,6b) = 4.6, J(5,4) = 9.7 (H-5); 3.99 dd, 1 H,
J(6a,5) = 2.1, J(6a,6b) = 12.2 (H-6a); 4.01–4.09 m , 2 H (H-5′, H-6a′); 4.20–4.25 m , 2 H (H-1′,
H-6b′); 4.27 dd, overlapped, 1 H, J(6b,5) = 4.6, J(6a,6b) = 12.2 (H-6b), 4.71–4.77 m , 2 H (H-1,
H-4); 5.10 dd, 1 H, J(3′,4′) = 3.2, J(3′,2′) = 9.5 (H-3′); 5.17 dd, 1 H, J(2′,1′) = 5.1, J(2′,3′) = 9.5
(H-2′); 5.38 m , 1 H (H-4′). 13C NMR (CDCl3): 20.48, 20.52, 20.57, 20.62, 20.64, 20.76 (6 ×
CH3CO), 28.25 (C-1′), 32.34 (C-3), 36.07 (C-2), 54.54 (CH3O), 61.64 an d 62.73 (C-6 an d
C-6′), 67.49 an d 67.55 (C-3′ an d C-4′), 68.04 an d 68.23 (C-2′ an d C-5′), 68.54 (C-5), 71.35
an d 71.94 (C-4 an d C-1′), 97.47 (C-1), 169.83, 169.90, 169.97, 170.45, 170.62, 170.77 (6 ×
CH3CO). For C26H38O15 calculated relative m olecular m ass 590.57. MS (ESI), m/z: 591.3 [M +
H]+.
Anomer 12b: 1H NMR (CDCl3): 1.86 m , 1 H (H-3); 3.49 s, 3 H (OCH3); 3.56 ddd, 1 H, J(5,6a) =
2.4, J(5,6b) = 5.0, J(4,5) = 9.6 (H-5); 4.42 dd, 1 H, J(1,2ax) = 9.5, J(1,2eq) = 1.9 (H-1), oth er
reson an ces are overlapped by sign als of th e m ajor isom er. For C26H38O15 calculated relative
m olecular m ass 590.57. MS (ESI), m/z: 591.3 [M + H]+.
This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic
(Grant No. 6046137305) and by the Czech Science Foundation (Grant No. 203/08/1124).
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700

700
Parkan, Vích, Dvořáková, Kniežo:
REFERENCES
1. Gabius H.-J.: Naturwissenschaften 2000, 87, 108.
2. Wong Ch.-H. (Ed.): Carbohydrate-Based Drug Discovery. Wiley, Weinheim 2003.
3. For recent approaches to C-disaccharides see: a) Postema M. H. D., Piper J. L., Betts R. L.:
Synlett 2005, 1345; b) Awad L., Demange R., Zhu Y.-U., Vogel P.: Carbohydr. Res. 2006,
341, 1235; c) Taylor R. J. K., McAllister G. D., Franck R. W.: Carbohydr. Res. 2006, 341,
1298; and references therein.
4. a) Štěpánek P., Kniežo L., Dvořáková H., Vojtíšek P.: Synlett 2003, 963; b) Štěpánek P.,
Vích O., Kniežo L., Dvořáková H., Vojtíšek P.: Tetrahedron: Asymmetry 2004, 15, 1033.
5. Štěpánek P., Vích O., Werner L., Kniežo L., Dvořáková H., Vojtíšek P.: Collect. Czech.
Chem. Commun. 2005, 70, 1411.
6. Fang J., Li J., Chen X., Zhang Y., Wang J., Guo Z., Zhang W., Yu L., Brew K., Wang P. G.:
J. Am. Chem. Soc. 1998, 120, 6635.
7. Demange R., Awad L., Vogel P.: Tetrahedron: Asymmetry 2004, 15, 3573.
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 690–700