Stereospecific uncatalyzed α-O-glycosylation and α-C- glycosidation by means of a new D-gulal-derived α vinyl oxirane

Article abstract of DOI:10.1021/jo0491152

The reaction of α vinyl oxirane 5, prepared through a new route to the D-gulal system, with O-nucleophiles (alcohols and di-O-isopropylidene- α-D-monosaccharides) and C-nucleophiles (lithium alkyls) affords, in a completely stereoselective way, the corres

Full text of DOI:10.1021/jo0491152

SCHEME 1
Ster eosp ecific Un ca ta lyzed
r-O-Glycosyla tion a n d r-C-Glycosid a tion by
Mea n s of a New D-Gu la l-Der ived r Vin yl
Oxir a n e
Valeria Di Bussolo, Micaela Caselli,
Maria Rosaria Romano, Mauro Pineschi, and
Paolo Crotti*
Dipartimento di Chimica Bioorganica e Biofarmacia,
Universita` di Pisa, Via Bonanno 33, 56126 Pisa, Italy
crotti@farm.unipi.it
Received May 26, 2004
SCHEME 2
Abstr a ct: The reaction of R vinyl oxirane 5, prepared
through a new route to the D-gulal system, with O-nucleo-
philes (alcohols and di-O-isopropylidene-R-D-monosaccha-
rides) and C-nucleophiles (lithium alkyls) affords, in a
completely stereoselective way, the corresponding 2-unsat-
urated R O- and C-glycosides having the same configuration
as the starting epoxide.
Alkyl 2,3-dideoxy-2-hexenopyranosides (pseudoglycals)
are useful synthetic intermediates because the presence
of the unsaturation allows the introduction of further
functionalities.1 One of the most common procedures for
the synthesis of pseudoglycals is the Ferrier allylic
rearrangement of glycals.2 However, the drawbacks of
this reaction are often its incomplete stereoselectivity (R/â
ratio) and the use of a Lewis acid as the necessary
catalyst.2,3 As a consequence, methods for the stereose-
lective synthesis of O- and C-glycosides, whose impor-
tance in natural products synthesis and as mimics is well-
documented, constitute an important synthetic challenge.
Recently, we have found that vinyl oxiranes 2a and 2b
simply prepared from D-glucal are useful intermediates
for the synthesis of pseudoglycals and derivatives: the
reaction of 2a and 2b (obtained in situ by cyclization of
the corresponding hydroxy mesylates 1a and 1b) with
alcohols (O-nucleophiles)3a and lithium alkyls (C-nucleo-
philes)3b afforded the corresponding 2-unsaturated â-O-
(3â) and â-C-glycosides (4â) in a completely 1,4-regio- and
â-stereoselective conjugate addition process (Scheme 1).3,4
The observation that the â-stereoselectivity obtained
in the nucleophilic addition to epoxides 2a and 2b
corresponded to the â-configuration of the oxirane ring
led us to consider it interesting to prepare epoxide 5, the
R-diastereoisomer of the previously examined epoxide 2b,
and to study the corresponding regio- and stereochemical
behavior in nucleophilic addition reactions (Scheme 2).
For the synthesis of 5 it was considered useful to have
6-(O-benzyl)-D-gulal (trans diol 7) as the starting material
(Scheme 2). Diol 7 could be reasonably prepared in a
simple way by the opening reaction of epoxide 2b with
an alkaline hydroxide such as KOH (an O-nucleophile)
through a SN2 addition process and attack of the nucleo-
phile on the allylic C(3) oxirane carbon. Actually, the
reaction of 2b with aqueous KOH afforded only a very
complex reaction mixture not containing any trace of the
desired diol 7. Diol 7 could be prepared only by reaction
of epoxide 2b with a new reagent, tetrabutylammonium
trimethylsilanolate (Bu4N+Me3SiO-), in which the nu-
cleophilic alcoholate moiety is a synthetic analogue of
OH-. This reagent was prepared by exchange, in a THF
solution, between Bu4NBr and Me3SiOK (commercially
available) followed by filtration to eliminate KBr. The
THF solution containing the new reagent was then added
to epoxide 2b. A clean reaction occurred and the trans
diol 7 was obtained as the only reaction product. Reason-
ably, in these reaction conditions, the corresponding
O-TMS derivative 6, derived by an 1,2-anti attack of
Me3SiO-, constitutes the primary reaction product, sub-
sequently hydrolyzed to diol 7, the reaction product, in
the aqueous workup (Scheme 2). In this way, a new
procedure for the synthesis of the D-gulal system has been
found.5
(1) (a) Takhi, M.; Abdel-Rahman, A. A.-H.; Schmidt, R. R. Synlett
2001, 427 and references therein. (b) Linde, R. G., II; Egbertson, M.;
Coleman, R. S.; J ones, A. B.; Danishefsky, S. J . J . Org. Chem. 1990,
55, 2771.
(2) (a) Ferrier, R. J .; Zubkov, O. A. In Organic Reactions; Overman,
L. E., Eds.; Wiley: New York, 2003; Vol. 62, p 569. (b) Ferrier, R. J .
Top. Curr. Chem. 2001, 215, 153.
(3) (a) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett.
2002, 4, 3695. (b) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P.
Org. Lett. 2003, 5, 2173 and references therein.
(4) Control experiments carried out on epoxide 2b with alcohols
(MeOH and i-PrOH) and diacetone-D-glucose under protocol B showed
that the regio- and stereoselective behavior of 2b is superimposable
to that of 2a .3a
Following the procedure previously utilized for the
synthesis of epoxide 2b , the reaction of diol 7 with
(5) For alternative procedures for the construction of the D-gulal
system, see: (a) Engstrom, K. M.; Mendoza, M. R.; Navarro-Villalobos,
M.; Gin, D. Y. Angew. Chem., Int. Ed. 2001, 40, 1128. (b) Wittman, M.
D.; Halcomb, R. L.; Danishefsky, S. J .; Golik, J .; Vyas, D. J . Org. Chem.
1990, 55, 1979.
10.1021/jo0491152 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/14/2004
J . Org. Chem. 2004, 69, 7383-7386
7383

SCHEME 3
furanose (diacetone-D-glucose) and 1,2;3,4-di-O-isopro-
pylidene-R-D-galactopyranose, as the glycosyl acceptors,
showed that our protocol is also useful for the construc-
tion of disaccharides. Following protocol B, after 1 h at
room temperature, the corresponding R-linked disaccha-
rides 15R and 16R were obtained in a satisfactory yield
(Table 1, entries 9 and 10).11
As for C-nucleophiles, lithium alkyls such as MeLi,
BuLi, s-BuLi, t-BuLi, and PhLi (3 equiv) were added to
epoxide 5, previously prepared in Et2O from hydroxy
mesylate 10 (protocol C). In all cases, a complete 1,4-
regioselective and R-stereoselective addition of the alkyl
group occurred with the exclusive formation of the
corresponding R-C-glycosides 17-21R (Table 1, entries
11-15).6,9
The complete 1,4-regio- and R-stereoselectivity ob-
served in the reaction of epoxide 5 with alcohols, di-O-
isopropylidene monosaccharides, and RLi (the glycosyl
acceptors) can be rationalized by a possible coordination
between the oxirane oxygen and the nucleophile through
a hydrogen bond, in the case of alcohols and di-O-
isopropylidene monosaccharides, and of a coordination
through the metal, in the case of RLi, as shown in
structures 22 and 23 in Scheme 4. In this way, the
nucleophile can be effectively transported onto the R-face
of the vinyl oxirane system and appropriately disposed
for a R-direct attack on the C(1) carbon to give the
corresponding R-glycoside, as experimentally observed.
A similar hydrogen bond or coordination with the nu-
cleophile necessarily developed on the â-face was con-
sidered to be responsible for the complete 1,4-regio- and
â-stereoselectivity observed with epoxides 2a and 2b
under the same conditions.3
TBDMS-Cl (1 equiv) afforded the monoprotected deriva-
tive 8 in a completely regioselective way. Subsequent
mesylation (MsCl/Py) of 8 afforded the O-protected
mesylate 9, which was then deprotected by the usual
protocol (TBAF/THF) to give the hydroxy mesylate 10,
which constitutes the ultimate precursor of epoxide 5
(Scheme 3). As previously observed in the case of epoxides
2a and 2b, epoxide 5 is not sufficiently stable to be
isolated, but can be prepared in situ by cyclization of
hydroxy mesylate 10 under alkaline conditions (t-BuOK)
and made to react immediately with a nucleophile.
To enable a direct comparison with the diastereoiso-
meric epoxide 2b under the same conditions, the regio-
and stereoselectivity of epoxide 5 in opening reactions
with nucleophiles was examined in the addition reaction
of simple O-nucleophiles and C-nucleophiles.3 As for
O-nucleophiles, MeOH, EtOH, i-PrOH, and t-BuOH were
used following two protocols, A and B, which differ only
in the amount of nucleophile (alcohol) present: in protocol
A, the alcohol is the solvent of the reaction, and repre-
sents a large amount of the nucleophile present, whereas
in the alternative procedure (protocol B), the alcohol is
added in a very small amount (only 3 equiv) to epoxide
5, previously formed from 10 in a benzene solution.
Under protocol A, the results obtained indicate that
the addition reaction is completely 1,4-regioselective, but
with an R/â stereoselectivity depending on the type of
alcohol used: with MeOH and EtOH an 81:19 and a 97:3
mixture of the corresponding R- and â-glycosides, 11R,â
and 12R,â, was obtained, respectively, whereas with
i-PrOH and t-BuOH the corresponding R-glycosides 13R
and 14R are practically the only reaction products (Table
1, entries 1, 3, 5, and 7).6,7 In the alternative protocol B,
a completely 1,4-regio- and R-stereoselective result is
observed with the obtainment of the corresponding
R-glycosides 11-14R, as the only addition products, with
all the alcohols examined (Table 1, entries 2, 4, 6, and
8).8,9 The use of 1,2;5,6-di-O-isopropylidene-R-D-gluco-
The comparison of the results obtained with R epoxide
5 and with previously studied â epoxides 2a and 2b3,4 in
their reactions with alcohols, di-O-isopropylidene-R-D-
monosaccharides, and lithium alkyls indicates that, in
these glycal-derived vinyl oxirane systems, the configu-
ration R or â of the oxirane ring and the related
coordination or chelation effects could be responsible for
the complete R- or â-stereoselectivity respectively ob-
served in the completely regioselective conjugate addition
of O- and C-nucleophiles.13 In this way, R- (from 5) and
â-O- and C-glycosides (from 2a ,b) can be stereospecifi-
cally obtained by a simple and efficient protocol that does
not need a catalyst, but only smoothly basic conditions
(9) The R-configuration of glycosides 11-21R was established (i) by
appropriate NOE experiments, where possible (14R and 20R), (ii) by
the presence of chemical shift values for C(5) lower than 75 ppm in
the 13C NMR spectra of C-glycosides 17-21R, as a diagnostic tool for
a 1,5-trans relationship between substituents at C(1) and C(5) (R
anomer) in these 2-unsaturated C-glycopyranosyl compounds,10 and
(iii) by comparison of the chemical shift of the anomeric proton in both
11
R- (11-13R and 15-16R) and â-anomers (11-13â and 15-16â),7,
which indicate, in accordance with previously reported data,12 that the
value for H-1 in the R-anomer is upfield with respect to the value for
the H-1 proton in the corresponding â-anomer.
(10) Ramnauth, J .; Poulin, O.; Rakhit, S.; Maddaford, S. P. Org. Lett.
2001, 3, 2013 and pertinent references therein.
(6) Under protocols A and C, the reaction crude products are
particularly simple and clean, showing the exclusive presence of the
corresponding 1,4-addition product(s).
(7) In the case of the reaction of epoxide 5 with i-PrOH under
protocol A, a signal at δ 5.19 in the 1H NMR spectrum of the crude
reaction mixture, reasonably due to the isomeric â-anomer 13â (0.6%),
could be detected.
(8) Under protocol B, the reaction crude products obtained with all
alcohols showed the presence, beside the corresponding R-glycosides
(80-90%), of some amount (20-10%) of other products which, although
not identified, turned out not to be the corresponding â-1,4- or anti
1,2-adducts (1H NMR).
(11) In the case of the reactions of epoxide 5 with diacetone-D-glucose
and 1,2;3,4-di-O-isopropylidene-R-D-galactopyranose (protocol B) a
signal at δ 5.30 and 5.07 in the 1H NMR spectrum of the respective
crude reaction mixture, reasonably due to the corresponding isomeric
â-anomer 15â and 16â (less than 3%), respectively, could be detected.
(12) Achmatowicz, O., J r.; Bielski, R. Carbohydr. Res. 1977, 55, 165.
(13) For a recent catalyzed reagent-controlled O-glycosylation, see:
Kim, H.; Men, H.; Lee, C. J . Am. Chem. Soc. 2004, 126, 1336.
7384 J . Org. Chem., Vol. 69, No. 21, 2004

TABLE 1. Glycosyla tion of Alcoh ols a n d Lith iu m Alk yls by Ep oxid e 5
a
Protocol A: ROH as the solvent. Protocol B: benzene as the solvent, ROH ) 3 equiv; Protocol C: Et2O as the solvent, RLi ) 3 equiv.
Crude product. c Purified product (flash chromatography or preparative TLC).
b
SCHEME 4
Exp er im en ta l Section
Rea ction of Ep oxid e 5 w ith a n Alcoh ol a s th e Solven t/
Nu cleop h ile (P r otocol A). Gen er a l p r oced u r e: A solution
of hydroxy mesylate 10 (0.042 g, 0.13 mmol) in anhydrous alcohol
(2.5 mL) was treated with t-BuOK (0.017 g, 0.15 mmol) and the
reaction mixture was stirred at room temperature for 18 h.
Dilution with Et2O and evaporation of the washed (saturated
aqueous NaCl) solution afforded a crude oily product consisting
of a mixture of the corresponding R- and â-glycosides 11R,â and
12R,â, in the case of the reaction in MeOH and EtOH, respec-
tively, or containing only the corresponding R-glycoside 13R and
14R in the case of the reaction in i-PrOH and t-BuOH (1H NMR)
(Table 1), which was subjected to flash chromatography. Elution
with a 6:4 hexane/AcOEt mixture afforded pure R-glycosides 11-
14R (only in the case of the reaction in MeOH did the 81:19
mixture of R- and â-glycosides 11R and 11â turn out to be not
separable under any chromatographic conditions).
Rea ction of Ep oxid e 5 w ith a n Alcoh ol (3 equ iv) in
An h yd r ou s Ben zen e (P r ot ocol B). Gen er a l p r oced u r e:A
solution of hydroxy mesylate 10 (0.042 g, 0.13 mmol) in
anhydrous benzene (2.5 mL) was treated with t-BuOK (0.017 g,
0.15 mmol) and the reaction mixture was stirred at room
temperature for 15 min. Alcohol (3 equiv) was added and the
reaction mixture was stirred at room temperature for the time
to generate epoxides 5 and 2a ,b from the corresponding
hydroxy mesylates 10 and 1a ,b, respectively.
Studies are in progress to examine the chemical
behavior of the new epoxide 5 also with other nucleo-
philes, other than alcohols and lithium alkyls, as N- and
S-nucleophiles.
J . Org. Chem, Vol. 69, No. 21, 2004 7385

shown in Table 1. Dilution with Et2O and evaporation of the
washed (saturated aqueous NaCl) solution afforded a crude oily
product mostly consisting of the corresponding R-glycoside 11-
14R (1H NMR) (Table 1), which was purified by flash chroma-
tography with use of a 6:4 hexane/AcOEt mixture as the eluant.
Rea ction of Ep oxid e 5 w ith a Di-O-isop r op ylid en e-r-D-
m on osa cch a r id e in An h yd r ou s Ben zen e (P r otocol B).
Typ ica l p r oced u r e: A solution of hydroxy mesylate 10 (0.040
g, 0.13 mmol) in anhydrous benzene (2 mL) was treated with
t-BuOK (0.016 g, 0.14 mmol) and the reaction mixture was
stirred 15 min at room temperature. 1,2;5,6-Di-O-isopropylidene-
R-D-glucofuranose (diacetone D-glucose) (0.102 g, 0.39 mmol) was
added and the reaction mixture was stirred 1 h at room
temperature. Dilution with CH2Cl2 and evaporation of the
washed (saturated aqueous NaCl) organic solution afforded a
crude reaction product (0.113 g) consisting of a mixture of
disaccharide 15R and unreacted diacetone-D-glucose (1H NMR),
which was subjected to preparative TLC (an 8:2 hexane/AcOEt
mixture was used as the eluant). Extraction of the most intense
band afforded 3-O-(6-O-ben zyl-2,3-d id eoxy-R-D-er ith r o-h ex-
2-en op yr a n osyl)-1,2;5,6-d i-O-isop r op ylid en e-r-D-glu cofu r a -
n ose (15R) (0.037 g, 60% yield): Rf 0.30 (6:4 hexane/AcOEt);
128.1, 127.9, 125.8, 112.1, 109.3, 105.6, 95.8, 84.3, 81.7, 81.5,
74.0, 72.8, 71.1, 70.4, 67.9, 66.0, 27.1, 27.0, 26.4, 25.6. Anal. Calcd
for C25H34O9: C, 62.75; H, 7.16. Found: C, 62.59; H, 7.03.
Rea ction of Ep oxid e 5 w ith RLi (3 equ iv) in An h yd r ou s
Et2O (P r otocol C). Gen er a l p r oced u r e: A solution of hydroxy
mesylate 10 (0.034 g, 0.11 mmol) in anhydrous Et2O (2 mL) was
treated with t-BuOK (0.013 g, 0.12 mmol). After 15 min of
stirring at room temperature, the reaction mixture was cooled
at 0 °C and treated with a solution of commercially available
RLi (0.33 mmol, Table 1) and the resulting reaction mixture was
stirred at room temperature for 30 min. Dilution with Et2O (20
mL) and evaporation of the washed (saturated aqueous NaCl)
organic solution afforded a crude product consisting of the
corresponding practically pure R-C-glycoside 17-21R (1H NMR),
which was purified by flash chromatography, using a 7:3 hexane/
AcOEt mixture as the eluant.
Ack n ow led gm en t. This work was supported by the
University of Pisa and MIUR. P.C. gratefully acknowl-
edges Merck Research Laboratories for the generous
financial support derived from the 2002 ADP Chemistry
Award.
1
FTIR ν 3458, 1454, 1373, 1072, 1024 cm-1; H NMR (CDCl3) δ
7.27-7.39 (m, 5H), 5.95 (d, 1H, J ) 10.1 Hz), 5.86 (d, 1H, J )
3.5 Hz), 5.74 (dt, 1H, J ) 10.1, 2.3 Hz), 5.20 (br s, 1H, H-1),
4.68 (d, 1H, J ) 3.5 Hz), 4.62 (s, 2H), 4.27 (d, 1H, J ) 2.6 Hz),
4.12-4.24 (m, 2H), 4.08 (dd, 2H, J ) 8.3, 2.8 Hz), 3.97 (dd, 1H,
J ) 8.3, 5.3 Hz), 3.70-3.90 (m, 3H), 1.48 (s, 3H), 1.40 (s, 3H),
1.32 (s, 3H), 1.23 (s, 3H); 13C NMR (CDCl3) δ 137.8, 133.2, 128.7,
Su p p or tin g In for m a tion Ava ila ble: General information
and experimental details, as well as spectral and analytical
data for all compounds prepared in this study. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0491152
7386 J . Org. Chem., Vol. 69, No. 21, 2004