Practical syntheses of enantiopure carbasugars: Carba-β-altrose, carba-β-mannose, carba-β-idose, and carba-β-talose derivatives

Article abstract of DOI:10.1016/j.tetasy.2003.12.042

D and L forms of carba-β-altrose 8, carba-β-mannose 10a, carba-β-idose 12, carba-β-talose 14 derivatives were prepared from (±)-3-cyclohexene-1-carboxylic acid 1. Homochiral diol compounds D-5a and L-5a, which were prepared from 1 via enzyme resolution of

Full text of DOI:10.1016/j.tetasy.2003.12.042

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 581–584
Practical syntheses of enantiopure carbasugars: carba-b-altrose,
carba-b-mannose, carba-b-idose, and carba-b-talose derivatives
Seok-Ho Yu and Sung-Kee Chung*
Department of Chemistry, Division of Molecular and Life Sciences, Pohang University of Science and Technology,
Pohang 790-784, South Korea
Received 22 November 2003; accepted 29 December 2003
Dedicated to Professor D. H. Kim on the occasion of his 70th birthday
Abstract—
D
and
from ( )-3-cyclohexene-1-carboxylic acid 1. Homochiral diol compounds
L
forms of carba-b-altrose 8, carba-b-mannose 10a, carba-b-idose 12, carba-b-talose 14 derivatives were prepared
-5a and -5a, which were prepared from 1 via enzyme
D
L
resolution of ( )-4a, were efficiently transformed to carba-b-altrose derivatives 8 by stereoselective introduction of hydroxyl groups.
Oxidation (PCC)/reduction (NaBH4) of 3-OH and/or 4-OH of 8a efficiently gave 10a, 12, and 14 with good stereoselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
Carbohydrate–protein interactions are known to initiate
or mediate important cell–cell recognition processes
such as immune response, fertilization, cell growth, cell–
cell adhesion, viral infection, and inflammation.1 Cur-
rently, oligosaccharides or their analogues are emerging
as potential therapeutic agents,2 because they are pos-
sible regulators of these biological processes. Nonhy-
drolyzable analogues of oligosaccharides such as carba-
oligosaccharides3 are thought to be more desirable drug
candidates than natural sugars because they are stable to
hydrolysis by ubiquitous glycosidases.4
such as carbasugar 1,2-epoxide derivatives.3 We envi-
sioned that a series of operations involving (1) synthesis
of a suitable carbasugar stereoisomer followed by (2)
conversion to its ÔC3 and C4 variantsÕ, and then (3)
conversion of these four stereoisomers to 1,2-epoxides
and ÔC1 and C2 variantsÕ might be a more practical route
to all possible carbasugar building blocks (Fig. 1).
OR1
R6'O
R4'O
R6O
R4O
O
OR2
OR3'
Glycosyl Donor Mimic Glycosyl Acceptor Mimic
8(16) stereoisomers
16(32) stereoisomers
OR3
Recently, we have investigated a practical synthetic
route to carbasugar derivatives that can be used as
building blocks for nonhydrolyzable oligosaccharide
analogues. Although various synthetic routes to carba-
sugar stereoisomers have been developed since 1966,5;6
there is no reported general protocol to provide all ste-
reoisomers (glycosyl acceptor mimics). Ten out of 16
possible stereoisomers were synthesized by one of the
more representative routes,7 developed by Ogawa et al.
but most of them were generated as mixtures.8 Rather
than using a specific route for each stereoisomer, stereo-
selective conversion of carbasugar stereoisomers to their
epimers can be a more practical way to obtain other
stereoisomers. Furthermore, carbasugar building blocks
should also be made available as glycosyl donor mimics
C1 & C2 variation
5a
3
OR1
OR2
OR1
R6O
R4O
R6O
R4O
R6'O
R4'O
1
OR2
OR3
C3 & C4 variants
4 (8) stereoisomers
OR3
OR3'
1,2-olefin derivatives
4 (8) stereoisomers
one stereoisomer
of carbasugar
Figure 1.
Herein we report, as a part of our attempts to develop
practical synthetic routes to all stereoisomers of mono-
meric carbasugar, (1) a synthetic route to homochiral
5a-carba-b-altrose derivatives (D and L-8a) from race-
mic 3-cyclohexene-1-carboxylic acid 1 via enzymatic
resolution and stepwise introduction of hydroxyl groups
at C1ꢀC4 and (2) regio- and stereo-selective conversion
* Corresponding author. Tel.: +82-54-279-2103; fax: +82-54-279-3399;
e-mail: skchung@postech.ac.kr
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.042

582
S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 15 (2004) 581–584
of 8a to the other three (six as enantiomers) stereo-
isomers (Fig. 2, only
variantsÕ.
O
O
O
O
O
D
-form is shown) as ÔC3 and C4
HO
a
b
+
c
+
+
94%
93%
93%
I
1
2
3
O
OH
HO
HO
+
O
O
O
OH
OH
OAc
MeO
d
MeO
MeO
+
+
1
D-5a
L-4b
4a
D-4a
52%
48%
OTBDPS
OMOM
OTBDPS
OMOM
e
f, d, f, e
71%
75%
HO
OMOM
BzO
OMOM
OH
OH
HO
HO
OH
OH
carba-β-mannose (D-10a)
carba-β-idose (D-12b)
carba-β-talose (D-14)
carba-β-altrose (D-8a)
L-5a
D-5a
Scheme 1. Reagents and conditions: (a) NaHCO3, KI, I2, water, rt; (b)
DBU, THF, reflux; (c) NaHCO3, MeOH, reflux; (d) Novozym 435,
vinyl acetate, t-BuOMe, rt; (3) LAH, THF, 0 °C, crystallization; (f)
NaOMe (0.1 equiv) MeOH, rt.
Figure 2.
Homochiral diols,
the - and
synthetic scheme. Although
derived from optically active 3-cyclohexene-1-carboxylic
acid -1 and -1, preparation of homochiral -1 or -1
D
-5 and
L
-5 are key intermediates for
D
L
-form of carba-b-altrose derivative 8a in our
D
-5a9c and -5a10 can be
L
D
-5b with mCPBA gave the cis-epoxide D-6a as major
1
product (cis:trans ¼ 20:1 by H NMR) presumably due
to the directing effect of the allylic hydroxyl group.16
D
L
D
L
After protection of 1-OH of
cessive treatments with TMSBr, DBU, 1 M HCl, and
NaOMe–MeOH resulted in compound -7a via an
elimination reaction of the transient bromohydrin.15b
Treatment of -7a with MOMCl and diisopropylethyl-
amine gave compound -7b and the subsequent
D-6a as a benzoate, suc-
requires a stoichiometric amount of expensive chiral
auxiliaries.9 We therefore examined a synthetic route to
D
homochiral
-1 based on enzymatic kinetic resolution of com-
pound 4a with hydrolases (Scheme 1).11
-4a was
prepared by iodo-lactonization of -1 with sub-
D-5a and L-5a from commercially available
D/L
D
D/L
D
D/L
17
dihydroxylation with a catalytic amount of OsO4 and
N-methylmorpholine N-oxide in acetone–water (6:1)
sequent elimination and methanolysis according to the
literature procedures.9b We studied kinetic acetylation
gave compound
similarly prepared from L-5a.
D
-8a as the sole product.
L
-8a was
reactions of
acetate.12 Treatment of
10 mg/mmol of -4a) and vinyl acetate (9 equiv) in
D
/
L
-4a with available lipases and vinyl
D/L
-4a with Novozym 43513 (3–
D/L
t-BuOMe was found to give the best result at 52%
conversion. Depending on the reaction scale, the enan-
tiomeric excess of
and the acetylated product,
ee.14 Reduction of
-4a (ꢀ90% ee) with lithium alumi-
num hydride was followed by crystallization to obtain
D
-4a was in the range of 90–95% ee
OR
OR'
RO
L
-4b in the range of 80–85%
TBDPSO
c
d
b
D
96%
78%
O
24
enantiomerically pure
D
-5a in 75% yield {½aꢁ ¼ þ20:8
D
D-6a R = H
D-6b R = Bz
D-5a R, R' = H
D-5b R = TBDPS, R' = H
D-5c R, R' = TBDPS
23
D
L-4b resulted in low % ee, and
(c 1.46, MeOH), lit. ½aꢁ ¼ þ20:3 (c 1.46, MeOH)9c}.
a
98%
A direct reduction of
another cycle of enzyme acetylation was carried out.
Thus, methanolysis of
-4b (ꢀ80% ee) with NaOMe
(0.1 equiv) in MeOH gave
-4a (ꢀ80% ee). The product
L
OMOM
OMOM
OR
f
TBDPSO
R'O
TBDPSO
L
99%
OR
L
-4a (ꢀ80% ee) upon treatment with Novozym 435 and
vinyl acetate again (ꢀ86% conversion), followed by
24
OR
D-7a R = H
deacetylation and reduction gave enantiomerically pure
e
D-8a R, R' = H
D-8b R = H, R' = Bz
D-8c R = Bz, R' = H
D-7b R = MOM
L
-5a even without recrystallization {½aꢁ ¼ ꢂ20:6
g and/or h
97-99%
D
99%
23
D
(c 1.57, MeOH), lit. ½aꢁ ¼ ꢂ20:5 (c 2.19, 99.5%
EtOH)10}. From these runs of operation, were obtained
Scheme 2. Reagents and conditions: (a) TBDPS-Cl (1.0 equiv), imid-
azole, DMF, 0 °C, -5b:
14.5 g (36% overall yield) of
overall yield) of L-5a starting from 49.8 g of
D
-5a and 15.2 g (37%
-4a.
D
D
-5c ¼ 70%: 14%; (b) mCPBA, CH2Cl2, 0 °C,
D/L
cis:trans ¼ 20:1; (c) BzCl (1.5 equiv), pyridine, 0 °C; (d) (i) TMSBr
(4 equiv), 0 °C, (ii) DBU (4 equiv), 80 °C, 5 days, (iii) 1 N HCl, rt, (iv)
NaOMe (0.1 equiv), MeOH, rt; (e) MOMCl (4 equiv), (i-Pr)2 NEt
(4 equiv), CH2Cl2, 40 °C; (f) OsO4 (cat.), NMO (2 equiv), rt; (g) (i)
triethyl orthobenzoate (2 equiv), p-TSA monohydrate (0.1 equiv),
CH2Cl2, rt, (ii) 80% aq AcOH; (h) TEA (2 equiv), Me2SnCl2 (2 mol %),
BzCl (1.2 equiv), 0 °C.
Synthesis of D-8a was accomplished from diol D-5a by
applying the modified ÔSharpless procedureÕ for trans-
forming an epoxide to an allyl alcohol (Scheme 2).15 The
primary hydroxyl group of
t-butyldiphenylsilyl group to
D
-5a was protected with
-5b and treatment of
D

S.-H. Yu, S.-K. Chung / Tetrahedron: Asymmetry 15 (2004) 581–584
583
The carba-b-altrose derivative
into its regioisomeric monobenzoates
Treatment of
-8a with triethyl orthobenzoate18 and p-
TSA, followed by hydrolysis in 80% aqueous AcOH
gave a mixture of benzoates ( -8b:
-8c ¼ 25:75) in 99%
yield. On the other hand, -8a upon treatment with
benzoyl chloride, triethylamine, and Me2SnCl2 gave 4-
O-benzoate -8b as the major product -8b:
-8c ¼ 88:12, 97%). Oxidation of 4-O-benzoate -8b
with PCC3b;20 gave the 3-keto compound
-9a, which
D
-8a was transformed
to the steric hindrance of the axial 2-OMOM groups.
Initially, we examined the reduction of the 4-OBn-3-keto
D
-8b and -8c.
D
D
derivative
D
-9b in order to obtain the carba-b-mannose
-10b, but a poor stereoselectivity was
-10b: -10b:
-8d ¼ ꢀ1:2 with NaBH4,
-8d ¼ ꢀ1:1 with BH3–SMe2) (Fig. 3). Apparently, for
some reasons, the benzoyl groups of -9a and -11 do
not hinder the bottom-side approach by the hydride,
whereas the benzyl group of -9b substantially does. In
derivative
D
D
D
observed (
D
D
D
D
D
19
D
D
D
(D
D
D
D
D
a recent report by Chang et al.23 many examples were
described concerning the stereoselectivities versus vicinal
functional groups in the reduction of ketosugars
(hexosulose) with NaBH4. Several of these examples
also imply that vicinal benzoate might not affect the
steric approach of hydride even though there has been
no obvious explanation for these results.
was then reduced with NaBH4 (5 equiv) and MeOH
(50 equiv) in dichloromethane to give the carba-b-man-
nose derivative D-10a with a high stereoselectivity (D-
10a:
oxidation of 3-O-benzoate
D
-8b ¼ 96:4 by 1H NMR) (Scheme 3). Similarly,
D-8c with PCC gave the 4-
keto compound
with NaBH4 gave the carba-b-idose derivative
with a high stereoselectivity ( -12a:
-8c ¼ 95:5 by H
NMR). Benzoyl migration of -12a was effected in 60%
D
-11 and subsequent reduction of
D
-11
D
-12a
1
D
D
OTBDPS
OMOM
OTBDPS
OMOM
D
H-
aqueous pyridine for 4 days21;22 at 100 °C to give a
BnO
HO
BnO
OMOM
OMOM
mixture of
migration reaction of
D
-12a and
D
-12b (30:70). By repeating the
-12a, the 4-O-benzoate -12b
O
D-10b
D
D
H-
was obtained in 83% overall yield. Further inversion of
3-OH of the carba-b-idose derivative -12b by the
similar oxidation/reduction strategy provided the carba-
b-talose derivative -14 with a high stereoselectivity (
14:
-12b ¼ 95:5 by H NMR).
+
D-9b
OTBDPS
OMOM
D
BnO
OMOM
D
1
D-
OH
D-8d
D
Figure 3.
OMOM
OMOM
OMOM
OMOM
TBDPSO
HO
TBDPSO
BzO
OBz
D-8c
In conclusion, we have developed a practical route to
optically active carba-b-altrose derivative, and -8a,
from 3-cyclohexen-1-carboxylic acid via stepwise, ste-
reoselective introductions of hydroxyl groups and
enzymatic resolution. We have also developed facile
OH
D-8b
a
D
L
a
94%
99%
OMOM
OMOM
OMOM
TBDPSO
TBDPSO
BzO
transformation routes from 8a to other stereoisomers [
D
O
OMOM
and of carba-b-mannose 10a, carba-b-idose 12, carba-
L
O
D-9a
OBz
D-11
b-talose derivatives 14] via regio- and stereo-selective
inversions of the C3 and/or C4 stereochemistry of 8a.
We are currently examining these eight carbasugar ste-
reoisomers as convenient precursors to all other possible
carbasugar stereoisomers and their derivatives, as well
as the utility of these derivatives as building blocks
of carbasugar-containing oligosaccharide mimics as
potential drug candidates.
b
99%
b
97%
OMOM
OMOM
TBDPSO
R'O
TBDPSO
BzO
OMOM
OMOM
OR
OH
D-12a R = Bz, R' = H
D-12b R = H, R' = Bz
D-10a
c
a
95%
Acknowledgements
OMOM
OMOM
OMOM
b
97%
TBDPSO
BzO
TBDPSO
BzO
OMOM
Financial support from the Ministry of Education/BSRI
Fund is gratefully acknowledged.
OH
O
D-14
D-13
Scheme 3. Reagents and conditions: (a) PCC (3.0 equiv), molecular
ꢀ
sieve 4 A, CH2Cl2, reflux; (b) NaBH4 (5.0 equiv), MeOH (50 equiv),
References and notes
CH2Cl2, 0 °C; (c) 60% aq pyridine, 100 °C, 4 days,
-12b ¼ 27%:66%.
D-12a:
D
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D
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20
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14. Although we obtained
reaction (1 mmol scale), enantiomeric excess of
ꢀ90% ee from large scale reaction (150 mmol scale). The
enantiomeric purity of -4a was determined by measuring
the specific rotation of its oxidized compound, that is
D
-4a with ꢀ95% ee from small scale
D
-4a was
D