Efficient Synthesis of Diverse Monosaccharide Derivatives in the Solid Phase

Full text of DOI:10.1021/jo9802776

4868
J . Org. Chem. 1998, 63, 4868-4869
Sch em e 1. Solid -P h a se Syn th esis of
Efficien t Syn th esis of Diver se
Mon osa cch a r id e Der iva tives in th e Solid
P h a se
6-O-Ben zyl-2-d eoxy-L-gu lose (8)
Shuj Kobayashi,*,† Takeshi Wakabayashi, and
Masaru Yasuda
Department of Applied Chemistry, Faculty of Science,
Science University of Tokyo (SUT), and CREST, J apan Science
and Technology Corporation (J ST), Kagurazaka, Shinjuku-ku,
Tokyo 162, J apan
Received February 18, 1998
While there are many biologically important compounds
containing sugars, monosaccharides are the smallest sugar
unit and are known to play important roles in their biological
activities.1 To obtain compounds having unique biological
activity as well as to refine specific molecular interactions,
it is desirable to be able to easily optimize the structure of
monosaccharides, and therefore, development of new meth-
ods for the synthesis of diverse monosaccharide derivatives
is in great demand.
While monosaccharides have rather simple structures,
they may contain four, five, six, or seven (higher sugars)
asymmetric centers, and the combination of various sub-
stituents at each chiral center provides a great number of
structurally different monosaccharide derivatives. Three
major methods have been reported so far for the synthesis
of monosaccharides. The first method is the traditional one,
that is, the synthesis of rare sugars from the common sugars
such as glucose, mannose, galactose, etc.2 One drawback
of this method is that it requires tedious long transforma-
tions and protection and deprotection of the hydroxyl groups
of the monosaccharides. The second method is to utilize
stereoselective reactions of three-carbon or four-carbon
alkoxyaldehydes (glyceraldehyde or threose derivatives pre-
pared from mannitol or tartaric acids) with carbon nucleo-
philes such as allylmetals or enolates3 or hetero Diels-Alder
reactions.4 Finally, efficient methods for the synthesis of
monosaccharides from simple achiral compounds using
asymmetric synthesis have been reported recently.5 While
these syntheses provide useful methods for the preparation
of specific rare sugars, much time and manpower are
required for the synthesis of a diverse monosaccharide
library according to these methods.
Our approach reported herein is based on solid-phase
synthesis.6 Organic synthesis on solid supports has advan-
tages over conventional liquid-phase approaches in its
particularly simple reaction procedures. Therefore, applica-
tion to automated systems and library construction are
promising using solid-phase protocols. An example, the
synthesis of a rare sugar, 6-O-benzyl-2-deoxy-L-gulose, is
shown in Scheme 1. The starting material, chlorometh-
ylated resin 1 or thiol resin 2, was converted to thioester
resin 3a . Treatment of 3a with tert-butyldimethylsilyl
triflate (TBSOTf) and triethylamine in dichloromethane at
room temperature (rt) provided polymer-supported silyl enol
ether (PSSEE) 4a .7 A key reaction is the aldol condensation
of 4a with a chiral aldehyde (5a ) using a Lewis acid
promoter,8 which proceeded smoothly in dichloromethane at
-78 °C (20 h) to afford the desired adduct with perfect
stereoselectivity (>98/2). Deprotection of the TBS group of
the aldol adduct (6) using tetrabutylammonium fluoride
(TBAF)/acetic acid in THF at 40 °C for 6 h induced
spontaneous lactone formation and, hence, cleavage from the
polymer support. The yield was determined to be 61% from
1 (four steps) at this stage. It is noted that all transforma-
tions in the solid-phase were carried out in one pot. Finally,
reduction of 7 with diisobutylaluminum hydride (DIBAL)
gave 6-O-benzyl-2-deoxy-L-gulose (>80%).
Similarly, four monosaccharide derivatives (lactones) were
prepared using the combination of chiral alkoxy aldehydes
and PSSEEs in the solid-phase (Scheme 2). The 2-deoxy
series and 2-benzyloxy series were prepared from PSSEE
4a and 4b, respectively. It is noted that the stereochemistry
of the stereogenic center at the C-3 position can be controlled
by choice of the protective groups of the alkoxyaldehydes.
The diversity of the monosaccharide derivatives obtained
according to this protocol depends on the numbers and kinds
of alkoxy aldehydes and PSSEEs. We have already reported
a preparation method for PSSEEs, according to which
various types can be prepared.7 On the other hand, many
alkoxy aldehydes have been synthesized from natural sources
such as mannitol and tartaric acid.3,9 Alternatively, we have
developed an efficient method for the synthesis of alkoxy
aldehydes using asymmetric aldol reactions. Recently, we
have developed tin(II)-mediated highly diastereo- and enan-
† Present address: Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, J apan.
(1) For leading references, see: Trends in Synthetic Carbohydrate
Chemistry; Horton, D., Hawkins, L. D., McGarvey, G., Eds.; ACS Symposium
Series 386; Amrican Chemical Society: Washington, DC, 1989. Thiem, J .;
Klaffke, W. Top. Curr. Chem. 1990, 154, 285. Recent Progress in the
Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer:
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Chem. 1984, 3, 125. Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
Tetrahedron 1990, 46, 265.
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Synthetic Carbohydrate Chemistry; Horton, D., Hawkins, L. D., McGarvey,
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(5) Ko, S. Y.; Lee, W. M.; Masamune, S.; Reed, L. A., III; Sharpless, K.
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(7) Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki, M. Tetrahedron Lett.
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S0022-3263(98)00277-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/27/1998

Communications
J . Org. Chem., Vol. 63, No. 15, 1998 4869
Sch em e 2. Syn th esis of Mon osa cch a r id e Der iva tives
(La cton es) in th e Solid P h a se
Sch em e 4. Syn th esis of 3-Am in o Su ga r Der iva tives
(La cton es) in th e Solid P h a sea -c
Sch em e 3. Solid -P h a se Syn th esis of 11
a
b
All yields are from 2. PMP ) p-MeOPh. c Diastereomer ratios
(major/minor) are shown in parentheses.
Sch em e 5. Solid -P h a se Syn th esis of Ald itol
Der iva tives
tioselective aldol reactions of silyl enol ethers with carbonyl
compounds.10 Various types of â-hydroxy thioesters have
been prepared starting from simple achiral compounds using
these asymmetric reactions. After protection of the â-hy-
droxy groups of the aldol adducts, treatment of these
protected adducts with DIBAL gave the desired alkoxy
aldehydes in excellent yields with excellent diastereo- and
enantioselectivities.11
We then synthesized 3-amino sugars in the solid-phase.
In nature, there are many biologically interesting compounds
containing 3-amino sugars such as daunosamine, acosamine,
ristosamine, etc.12 An example of our solid-phase synthesis
of 3-amino sugars is shown in Scheme 3. Thiol resin 2 was
converted to thioester resin 3b, which was silylated to give
PSSEE 4b. The key three-component reaction of an alde-
hyde, an amine, and 4b proceeded smoothly in the presence
of a catalytic amount of scandium triflate (Sc(OTf)3) in
dichloromethane at -78 °C to room temperature over 15 h
to afford the corresponding adduct (9) with perfect stereo-
selectivity (>98/2).13 Also in this case, deprotection of the
TBS group (rt, 12 h) induced a spontaneous cyclization to
give lactone 10, which was reduced with DIBAL to produce
3-amino sugar derivative 11 in an 82% yield. Similarly,
2-benzyloxy series, 2-deoxy series, and 2-deoxy-2-methyl
series of 3-amino sugars were successfully prepared in the
solid phase (Scheme 4).
Finally, the present method was successfully applied to
the synthesis of alditol derivatives (the reduced forms of
monosaccharides). Reductive cleavage from the support
instead of deprotection of the TBS groups gave alditol
derivatives in good yields (Scheme 5). Since we have already
demonstrated that basic cleavage (NaOMe) from the same
support affords carboxylic acids,8,13 uronic acid (the oxidized
forms of monosaccharides) formation would be possible
simply by changing the cleavage method.
In summary, a new method for the synthesis of monosac-
charide derivatives in the solid phase has been developed.
Several transformations in the solid phase have been
performed in one pot, and application to an automated
system is possible. Moreover, since various kinds of PSSEEs
and alkoxyaldehydes are available, this solid-phase synthe-
sis provides a useful method for the synthesis of monosac-
charide libraries.
Ack n ow led gm en t. This work was partially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, J apan, and a
SUT Special Grant for Research Promotion.
(9) Mukaiyama, T.; Yamada, T.; Suzuki, K. Chem. Lett. 1983, 173.
(10) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem. Lett. 1990, 1455.
Kobayashi, S.; Horibe, M. Chem. Eur. J . 1997, 3, 1472 and references
therein.
Su p p or tin g In for m a tion Ava ila ble: Text describing the
experimental procedure and selected physical data of products (7
pages).
(11) See the Supporting Information.
(12) Sibi, M. P.; Lu, J .; Edwards, J . J . Org. Chem. 1997, 62, 5864. Hauser,
F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35.
(13) Kobayashi, S.; Moriwaki, M.; Akiyama, R.; Suzuki, S.; Hachiya, I.
Tetrahedron Lett. 1996, 37, 7783.
J O9802776