Totally Stereoselective Synthesis of 1,3-Disaccharides through Diels-Alder Reactions

Article abstract of DOI:10.1021/jo034556r

A nonclassical, totally stereoselective synthesis of orthogonally protected 1,3-disaccharides is reported. Enantiomerically pure β-keto-δ-lactones, efficiently obtained from glucal and galactal, are transformed into electron-poor heterodienes and chemo-,

Full text of DOI:10.1021/jo034556r

Tota lly Ster eoselective Syn th esis of 1,3-Disa cch a r id es th r ou gh
Diels-Ald er Rea ction s†
Alessandra Bartolozzi,‡ Stefania Pacciani, Cecilia Benvenuti, Martina Cacciarini,
Francesca Liguori, Stefano Menichetti, and Cristina Nativi*
Dipartimento di Chimica Organica “Ugo Schiff”, Universita’ di Firenze, and CNR-ICCOM,
via della Lastruccia, 13 I-50019 Sesto Fiorentino (FI), Italy
cristina.nativi@unifi.it
Received April 30, 2003
A nonclassical, totally stereoselective synthesis of orthogonally protected 1,3-disaccharides is
reported. Enantiomerically pure â-keto-δ-lactones, efficiently obtained from glucal and galactal,
are transformed into electron-poor heterodienes and chemo-, regio-, and stereoselectively cycloadded
to glycals as electron-rich dienophiles, to directly afford 2-thiodisaccharides. The reductive desul-
furization of the latter smoothly gave the corresponding 2,2′-dideoxydisaccharides.
1. In tr od u ction
The increased interest in glycobiology and the expan-
sion of knowledge of the role of oligosaccharides1 sets the
stereocontrol in O-glycosylation as a central matter in
carbohydrate chemistry.
The biological activity of entire classes of oligo- and
polysaccharides are nowadays widely studied and com-
plex oligosaccharide-containing molecules of considerable
pharmaceutical interest are an important target for many
research groups. Many of these active molecules, such
as anthracyclines, aureolic acids, or cardiac glycosides,
present deoxy oligosaccharide moieties as common and
essential parts2 (Figure 1).
Efficient and stereoselective methods affording disac-
charides have often been reported.3 Most of them concern
the formation of 1,6-linked disaccharides and rely on the
use of Lewis acids as promoters, while the stereochemical
control is obtained making use of the anchimeric assis-
tance of a neighboring group adjacent to the anomeric
center.
F IGURE 1. Structure of Chromomycin A3 (a member of
aureolic acid family).
lack of a neighboring group and the associated lessened
stability of suitable glycosyl donors. This explains well
the few general and efficient methods existing for the
direct stereoselective synthesis of this class of compounds.
To circumvent these problems “tailored” transformations4
are required.
A few years ago we published the effective synthesis
for R- and â-O-glycosides based on the chemo-, regio-, and
stereoselective [4+2] cycloadditions between “in situ”
generated R,R′-dioxothiones 15 (electron-poor dienes) and
differently substituted or unsubstituted glycals 2 (electron-
rich dienophiles)6 (Scheme 1).
In the synthesis of 2-deoxyglycosides (and 2-deoxydi-
saccharides) the most evident problems consist of the
* Address all correspondence to this author at the Universita’ di
Firenze. Phone: +39-055-4573540. Fax: +39-055-4573570.
† Dedicated to Prof. Giuseppe Capozzi on the occasion of his
retirement.
‡ Present address: Surface Logix, Inc., 50 Soldiers Field Place,
Brighton, MA 02135.
Taking advantage of the easily and selectively re-
movable sulfur atom, the R- and â-2-deoxy-2-thio-O-gly-
cosides 3 and 4 were transformed into the corre-
(1) (a) Yarema, K. J .; Bertozzi, C. R. Curr. Op. Chem. Biol. 1998, 2,
49. (b) Galli-Stampino, L.; Meinjohanns, E.; Frische, K.; Meldal, M.;
J ensen, T.; Werdelin, O.; Mouritsen, S. Cancer Res. 1997, 57, 3214.
(c) Dwek, R. A. Chem. Rev. 1996, 96, 683. (d) Varki, A. Glycobiology
1993, 3, 97.
(2) (a) Kirschning, A.; Bechtold, A. F. W.; Rohr, J . Top. Curr. Chem.
1997, 188, 2. (b) Thiem, J .; Klaffke, W. Top. Curr. Chem. 1990, 154,
285.
(3) (a) Capozzi, G.; Menichetti, S.; Nativi, C. In New Trend in
Synthetic Medicinal Chemistry. Methods and Principles in Medicinal
Chemistry; Gualtieri, Ed.; Wiley-VCH: Weinheim RFG, Germany,
2000; Vol. 7, pp 221-259. (b) Hanessian, S.; Lou, B. Chem. Rev. 2000,
100, 4443. (c) Danishefsky, S. J .; Bilodeau, M. T. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1380.
(4) (a) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000, 56, 8385.
(b) Hallis, T. M.; Liu, H. Acc. Chem. Res. 1999, 32, 579. (c) Toshima,
K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503.
(5) For the synthesis of R,R′-dioxothiones see: Capozzi, G.; Franck,
R. W.; Mattioli, M.; Menichetti, S.; Nativi, C.; Valle, G. J . Org. Chem.
1995, 60, 6416.
(6) (a) Capozzi, G.; Dios, A.; Franck, R. W.; Geer. A.; Marzabadi,
C.; Menichetti, S.; Nativi, C.; Tamarez, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 777. (b) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.;
Raffaelli, B. Chem. Eur. J . 1999, 5, 1748.
10.1021/jo034556r CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/09/2003
J . Org. Chem. 2003, 68, 8529-8533
8529

Bartolozzi et al.
SCHEME 1. Diels-Ald er Rea ction s betw een
r,r′-Dioxoth ion es 1 a n d Glyca ls 2
SCHEME 2. Retr osyn th esis for
â-Keto-r-th ion o-δ-la cton es 8
We wish to report here on the extension of the efficient
synthesis of alkyl- or aryl-O-glycosides, to prepare enan-
tiomerically pure O-disaccharides directly through an
inverse electron-demand Diels-Alder reaction between
R,R′-dioxothiones deriving from monosaccharides and
suitable glycals. This nonclassical approach to disaccha-
rides stereoselectively affords O-glycosyl linkages under
mild, neutral conditions.
CHART 1. Str u ctu r e of o-Th ioqu in on es 7 a n d
BE-12406B.
2. Resu lts a n d Discu ssion
Disaccharides can be obtained in a single step by
cycloadding glycals to appropriately substituted R,R′-
dioxothiones. A possible retrosynthetic scheme to achieve
our target molecules, capitalizing on the chemo-, regio-,
and stereochemical properties of the above-described
inverse-electron demand Diels-Alder reactions, can be
envisaged as depicted in Scheme 2. The R,R′-dioxothione
8 can be formed by the base treatment of the phthalimido
derivative 9 obtained, in turn, from the enantiomerically
pure â-keto-δ-lactones 10 (Scheme 2).
Looking in the literature for the synthesis of â-keto-
δ-lactones such as 10, we realized that the drawbacks
presented by known methods12 (undesired side lacton-
izations or low selectivity in the formation of new
stereocenters) made them unreliable for our purposes.
A new procedure for the preparation of enantiomeri-
cally pure â-keto-δ-lactones seemed to be advisable and
dealing with our target, carbohydrates appeared highly
attractive chiral sources.13
The stereoselective and efficient transformation of
monosaccharides into â-keto-δ-lactones was realized14
from glycals 11, selectively protected to give 12, which
smoothly afforded 13, the key intermediates to the
desired â-keto-δ-lactones 10 (Scheme 3).
The oxidation sequence of the two hydroxyl groups of
the lactols 15 was crucial for the successful formation of
10. In fact, when 15b was oxidized under Swern condi-
tions, to be directly transformed into 10b, the undesired
sponding R- and â-2-deoxy-O-glycosides 5 and 6 without
affecting the absolute configuration of the anomeric
center (Scheme 1).
The stereoselectivity of these cycloadditions can be
adequately modulated and R- or â-isomers can be ob-
tained as single stereoisomers if suitable glycals and
solvent are employed.6
Cycloadducts 3 have also been successfully employed
as glycosyl donors to prepare 2-deoxy-â-O-disaccharides.
As a matter of fact, after “remote activation”3b,7 3 ef-
ficiently react with appropriate glycosyl acceptors to
afford â-O-disaccharides with total stereoselectivity.8
Aryl R- or â-glycosides were analogously prepared em-
ploying o-thioquinones 79 as electron-poor dienes (Chart
1). The cycloaddition occurs with the same chemo-, regio-,
and stereoselectivity observed for R,R′-dioxothiones; more-
over, as we reported10 for the synthesis of the 2-deoxy
analogue of the antitumor antibiotic BE-12406B11
(Chart 1), the cycloaddition of o-thioquinones 7 to 6-de-
oxyglycals successfully affords aryl 2,6-dideoxy-O-glyco-
sides, naturally occurring and synthetically challenging
molecules.
(7) Hanessian, S. In Preparative Carbohydrate Chemistry; Hanes-
sian, Ed.; Marcel Dekker: New York, 1997; pp 381-388.
(8) Bartolozzi, A.; Capozzi, G.; Menichetti, S.; Nativi, C. Eur. J . Org.
Chem. 2001, 2083.
(9) For the synthesis of o-thioquinones see: Capozzi, G.; Falciani,
C.; Menichetti, S.; Nativi, C. J . Org. Chem. 1997, 62, 2611.
(10) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.; Franck, R.
W. Tetrahedron Lett. 1995, 36, 6755.
(12) (a) Ge, P.; Kirk, K. L. J . Org. Chem. 1996, 61, 8671. (b) Sato,
M.; Sugita, Y.; Abiko, Y.; Kaneko, C. Tetrahedron: Asymmetry 1992,
3, 1157. (c) Schlessinger, R. H.; Pettus, L. H. J . Org. Chem. 1998, 63,
9089. (d) Kashihara, H.; Shinoki, H.; Suemune, H.; Sakai, K. Chem.
Pharm. Bull. 1986, 34, 4527.
(13) For a described synthesis of â-keto-δ-lactones from carbohy-
drates see ref 12a.
(11) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. Tetrahe-
dron Lett. 1994, 35, 4591.
(14) Previous communication: Bartolozzi, A.; Capozzi, G.; Men-
ichetti, S.; Nativi, C. Org. Lett. 2000, 2, 251.
8530 J . Org. Chem., Vol. 68, No. 22, 2003

Stereoselective Synthesis of 1,3-Disaccharides
SCHEME 3. Syn th esis of â-Keto-δ-la cton es 10a
SCHEME 4. “In Situ ” Gen er a tion of Oxoth ion es 8
a n d Th eir Tr a p p in g w ith Eth yl Vin yl Eth er a
a
Reagents and conditions: (a) PhthNSCl, rt, CHCl3, >95%. (b)
Py, CHCl3. (c) Ethyl vinyl ether, CHCl3, rt, 8 h, (18a , 79%; 18b,
88%).
SCHEME 5. Syn th esis of Cycloa d d u cts 21-23a
a
Reagents and conditions: (a) t-BDMSOTf, py, CH2Cl2, 0 °C,
69% (12a ), >98% (12b). (b) BnBr, NaH, DMF, rt, 3 h. (c) TBAF,
DMF, rt, 4 h, 98% (13a ), 97% (13b) for two steps. (d) PivCl, py,
CH2Cl2, rt 20 h, 74% (14a ), 70% (14b). (e) 15a : HCl, THF/H2O,
40 °C, 6 h, 69%. 15b: Bu4NHSO4, CH3CN/H2O, 65 °C, 15 h, 72%.
(f) Ag2CO3-Celite, benzene, 80 °C, 2.5-5 h, 74% (17a ), 97% (17b).
(g) DMSO, Et3N, (CF3CO)2O, -70 °C, 1 h, 86% (10a ), 87% (10b).
R,â-unsaturated lactone 16 was isolated as the sole
product. On the other hand, when the same oxidation
was performed with PCC, PDC, or SO3‚py, we only
observed decomposition of the starting material. To
circumvent these problems, the hydroxyl groups were
transformed independently. In the first step, an oxidant
allowing the chemoselective oxidation of the anomeric
hydroxyl group in the presence of the unprotected OH
at C-3 was chosen. The hydroxyl lactols 15 were thus
treated with silver carbonate on Celite15 to give the
hydroxyl lactones 17 in high yield (17a , 74%; 17b, 97%).
The subsequent oxidation of 17 with Swern conditions
gave the diasteromerically pure â-keto-δ-lactones 10
(10a , 86%; 10b, 87%), without epimerization at C-4. The
oxidation of 17 was attempted under Dess-Martin
conditions16 as well, but unreacted starting material was
always recovered.
To test whether â-keto-δ-lactones could be employed
as precursors of disaccharides through cycloaddition
reactions, derivatives 10 were transformed into phthal-
imido derivatives 9, which upon addition of pyridine gave
the transient R,R′-dioxothiones 8, directly trapped “in
situ” by ethyl vinyl ether (Scheme 4).
The inverse electron-demand Diels-Alder reaction
between 8 and ethyl vinyl ether allowed for isolation of
the cycloadducts 18 as single chemo- and regioisomers5,6
in a 1/1 diasteromeric ratio (Scheme 4).
The cycloaddition of R,R′-dioxothiones 8 was success-
fully performed with other, more appealing, dienophiles,
as depicted in Scheme 5.
The 2-deoxy-2-thio-1,3-O-disaccharides 21 and 22 were
obtained by reacting the glucothione 8a with the triben-
a
Reagents and conditions: (a) CHCl3, rt, 1.5 h, 76%. (b) CHl3,
rt, 5 h, 52%. (c) CHCl3, rt, 5 h 76%.
zyl-D-glucal 19 and the dibenzyl-L-arabinal 20, respec-
tively, while 23 was formed by cycloaddition of the
galactothione 8b with 19. All cycloadducts were obtained
as diasteromerically pure compounds.17 The stereochem-
istry observed can be rationalized assuming that the
attack of the oxothiones occurred from the bottom face
(15) Fetizon, M.; Golfier, M.; Morgues, P. Tetrahedron Lett. 1972,
4445.
(16) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156.
J . Org. Chem, Vol. 68, No. 22, 2003 8531

Bartolozzi et al.
SCHEME 6. Syn th esis of Sp ir oth ioa ceta ls 25 a n d 26
SCHEME 7. P r ep a r a tion of Th iola cton e 27 a n d
of the dienophiles for 21 and 23 and from the top face of
the dienophile for 22.18
Syn th esis of Disa cch a r id e 28a
The protocol was also successfully extended to the
exoglycal 24,20 a product of interest for our research
toward the synthesis of an analogue of the GM3-ganglio-
side lactone.14,21 Compound 24 reacted with 8a affording
the spiro derivatives 25a and 26a and with 8b, affording
the spiro derivatives 25b and 26b. Compounds 25a /26a
and 25b/26b were obtained as 2/1 mixtures of diaster-
oisomers22 (Scheme 6).
As extensively reported,20 the preferred configuration
of the spirocenters was determined by the anomeric
effects and the structures 25a and 25b (i.e. the structures
with two anomeric effects23) were assigned to the major
isomers.24
To test the general applicability of the present proce-
dure, the cycloaddition was also performed between the
benzylglucal 19 and the bis-p-methoxybenzyl protected
thiolactone 27, which was prepared as reported in
Scheme 7. The cycloadduct 28 was obtained as diastero-
merically pure compound in 76% yield (Scheme 7).
The synthetic scheme for 27 presents some improve-
ments with respect to that reported for 8a , as a matter
of fact (a) p-methoxybenzyl protecting groups can be
selectively removed under mild conditions and (b) the
same synthetic scheme can be followed to orthogonally
protect hydroxyls at C-4 and C-6 (simply changing
step d).
a
Reagents and conditions: (a) p(CH3O)C6H4CH(OMe)2, PPTS,
CH3CN, rt, 4 h, 70% (29). (b) TIPSCl, IMI, DMAP, DMF, rt, 3 h,
95% (30). (c) DIBAL-H, CH2Cl2, -15 to 0 °C, 2 h, 73% (31). (d)
°
PMBCl, tBuOK, DMSO, 0 C to rt, 3 h, 84% (32). (e) HCl (8 N),
The removal of the two p-methoxybenzyl groups was
realized by treating 28 with 2.5 equiv of 2,3-dichloro-5,6-
dioxane-H2O, 1.5 h, 59% (33). (f) HF (40% in H2O), DMF, 93%
(34). (g) Ag2CO3-Celite, benzene, 80 °C, 18 h , 89% (35). (h) DMSO,
°
Et3N, (CF3CO)2O, -70 C, 1 h, 68% (36). (i) PhthNSCl, rt, CHCl3.
(l) Py, CHCl3. (m) 19, rt, 3 h, 76% (28).
(17) 1H NMR analysis allowed the determination of the structures
of cycloadducts 21-23 as reported below: indeed, 21 shows a doublet
(J H1-2 ) 2.6 Hz) at 5.75 ppm for H-1 and a doublet of doublets (J H2-3
) 10.4 Hz) at 3.31 ppm, 22 shows a doublet (J H1-2 ) 2.5 Hz) at 5.70
ppm for H-1 and a doublet of doublets (J H2-3 ) 11.0 Hz) at 3.71 ppm,
while 23 shows a doublet (J H1-2 ) 2.6 Hz) at 5.53 ppm for H-1 and a
doublet of doublets (J H2-3 ) 10.7 Hz) at 3.28 ppm.
dicyano-1,4-benzoquinone (DDQ) to give the diol 37
(68%), which was characterized as acetyl derivative 38
(Scheme 8).
Treatment of 28 with cerium(IV) ammonium nitrate
(CAN) (3.5 equiv, CH3CN/H2O-9/1 rt, 9 h) did not afford
the expected diol 37, in fact the monodeprotected deriva-
tive 39 (20%) was isolated with undesired side products
(Scheme 8).
The sulfur atom, regioselectively introduced by cy-
cloaddition at C-2 and C-2′ of 21-23, 25, and 26, can be
reductively removed to afford the corresponding 2,2′-
dideoxy derivatives. Desulfurization was carried out on
21-23 with Raney-Ni in tetrahydrofuran, at room
temperature, giving the 2-deoxy disaccharides 41-43
(Scheme 9).
All reactions were performed in wet tetrahydrofuran,
using commercially available activated Raney-Nickel,
with yields comparable with those reported in the
(18) These results are perfectly in agreement with those previously
reported.6,10,19
(19) (a) Li, B.; Franck, R. W.; Capozzi, G.; Menichetti, S.; Nativi, C.
Org. Lett. 1999, 1, 111. (b) Dios, A.; Geer, A.; Marzabadi, C. H.; Franck,
R. W. J . Org. Chem. 1998, 63, 6673.
(20) Bartolozzi, A.; Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi,
C.; Paolacci, A. J . Org. Chem. 1999, 64, 6490.
(21) Regarding GM3 lactone and its biological role, see: (a) Hamilton,
W. B.; Helling, F.; Lloyd, K. O.; Livingstone, P. O. Int. J . Cancer 1993,
53, 566. (b) Kojima, N.; Hakomori, S. J . Biol. Chem. 1991, 266, 17552.
(22) Compounds 25b and 26b were perfectly separated by column
chromatography on silica gel.
(23) Deslongchamps, P.; Rowan, D. D.; Pothier, N.; Sauve’, T.;
Saunders, J . K. Can. J . Chem. 1981, 59, 1105.
(24) Structure assignment of 25a , 25b, 26a , and 26b was realized
by 1H NMR by comparison with reported data of related compounds.20
More detailed investigations for the direct demonstration of the
structure of the two couples of diasteroisomers are currently in progress
in our labs.
8532 J . Org. Chem., Vol. 68, No. 22, 2003

Stereoselective Synthesis of 1,3-Disaccharides
SCHEME 8. Dep r otection of
p-Meth oxyben zyld isa cch a r id e 28
reduced amounts of Raney-Nickel), the disaccharide 41
was isolated with amounts of the unsaturated derivative
44 (18%); on the contrary, 42 was always formed as the
major product with undesired side products. Attempts
to improve the yield of 41 (prolonged reaction times or
higher quantities of Raney-Nickel) failed, in fact the
presence of decomposition products was observed.
The formation of the unsaturated deoxy derivatives 43
(galacto series) and of the saturated dideoxy derivative
42 (arabino series) (see Scheme 9) was tentatively
explained considering a higher stability of 42 and 43 with
respect to the corresponding unsaturated or saturated
analogues.26
Compounds 41 and 42 were obtained as single stereo-
isomers and their stereochemistry, as depicted in Scheme
1
9, was unambiguously determined by H NMR analysis:
indeed, CH2-2′, δ 2.69 (41), 2.79 (42) appeared as the AB
part of ABX systems and H-3′ (41 and 42) is in the axial
position.
SCHEME 9. Syn th esis of 2-Deoxy Disa cch a r id es
41-43
3. Con clu sion s
In conclusion we have devised a new procedure to
prepare enantiomerically pure carbohydrate â-keto-pyra-
nolactones from carbohydrates and successfully employed
them to achieve new glycosyl acceptors for the synthesis
of 2-thio-2-deoxy- and 2-deoxy-O-disaccharides in an
enantiomerically pure form. The general applicability of
the present procedure together with the real possibility
of using a variety of protecting groups on carbohydrate
moieties make it a promising, general approach to the
synthesis of complex deoxy oligosaccharides.
Ack n ow led gm en t. The authors thank Prof. Richard
W. Franck, Hunter College of CUNY, New York, for
useful discussions. This research was carried out within
the framework of the National Project “Stereoselezione
in Sintesi Organica. Metodologie ed Applicazioni” sup-
ported by the Ministero della Ricerca Scientifica e
Tecnologica, Rome, and by the University of Florence.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for compounds 10, 12-18,
21-23, 25, 26, and 28-44. This material is available free of
charge via the Internet at http://pubs.acs.org.
literature.4a,25 Generally, when using an aged Raney-
Nickel sample, lower yields were observed.
Noteworthy, glucolactones 21 and 22 under standard
desulfurizating conditions underwent the conjugated
double bond reduction, affording the saturated 2,2′-
dideoxydisaccharides 41 and 42, respectively (Scheme 9).
Depending on reaction conditions (low temperature and
J O034556R
(26) Small amounts (5-10%) of starting glycals 19 and 20 (not
shown) also can be isolated during the treatment of cycloadducts 21-
23 with Ra-Ni. Studies on the elucidation of the desulfurization
reactions mechanism are still in progress in our laboratories. For a
related publication see: Tamarez, M. M.; Franck, R. W.; Geer, A.
Tetrahedron 2003, 59, 4249.
(25) Franck, R. W.; Marzabadi, C. H. J . Org. Chem. 1998, 63, 2197.
J . Org. Chem, Vol. 68, No. 22, 2003 8533