Synthesis of sialic acid derivatives based on chiral substrate-controlled stereoselective aldol reactions using pyruvic acid oxabicyclo[2.2.2]octyl orthoester

Article abstract of DOI:10.1039/c6ob02412b

The synthesis of sialic acids and their analogs was accomplished based on substrate-controlled asymmetric aldol reactions between sterically complicated aldehydes easily prepared from commercially available carbohydrates and a novel pyruvic acid oxabicyclo[2.2.2]octyl orthoester. Systematic aldol reaction studies using chiral aldehydes revealed that α,β,γ-benzyloxy-substituted aldehydes with an α,β-anti relative configuration preferentially provided the Felkin products with the 4,5-anti configuration with high diastereoselectivity. The relative β,γ-configuration in α,β,γ-benzyloxy-substituted aldehydes with an α,β-syn arrangement exerted a secondary effect on the diastereoselectivity of the stereogenic center formed in aldol reactions, and α,β-syn-β,γ-anti benzyloxyaldehyde exhibited superior diastereoselectivity to α,β-syn-β,γ-syn benzyloxyaldehyde to yield the Felkin products.

Full text of DOI:10.1039/c6ob02412b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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ARTICLE
Synthesis of sialic acid derivatives based on chiral substrate-
controlled stereoselective aldol reactions using pyruvic acid
oxabicyclo[2.2.2]octyl orthoester
Received 00th January 20xx,
Accepted 00th January 20xx
Yusuke Norimura, Daisuke Yamamoto, Kazuishi Makino*
DOI: 10.1039/x0xx00000x
The synthesis of sialic acids and their analogs was accomplished based on substrate-controlled asymmetric aldol reactions
between sterically complicated aldehydes easily prepared from commercially available carbohydrates and a novel pyruvic
acid oxabicyclo[2.2.2]octyl orthoester. Systematic aldol reaction studies using chiral aldehydes revealed that α,β,γ-
benzyloxy-substituted aldehydes with an α,β-anti relative configuration preferentially provided the Felkin products with
4,5-anti configuration with high diastereoselectivity. The relative β,γ-configuration in the α,β,γ-benzyloxy-substituted
aldehydes with an α,β-syn arrangement exerted a secondary effect on the diastereoselectivity of the stereogenic center
formed in the aldol reactions, and α,β-syn-β,γ-anti benzyloxyaldehyde exhibited superior diastereoselectivity to yield the
Felkin products than α,β-syn-β,γ-syn benzyloxyaldehyde.
www.rsc.org/
Introduction
HO
HO
HO
H
OH
H
OH
Sialic acids are a family of monosaccharides containing a
common 3ꢀdeoxyꢀ2ꢀulosonic acid structure of which more than
50 natural derivatives have been identified, including
acetylneuraminic acid (Neu5Ac,
galactoꢀ2ꢀnonulosonic acid (KDN,
O
O
HO
COOH
HO
COOH
HO
HO
AcHN
N
D
ꢀ
ꢀ
1
), 3ꢀdeoxyꢀ
D
ꢀglyceroꢀ
D
OH
OH
2), and 3ꢀdeoxyꢀ
ꢀmannoꢀ
1 NeuAc
2 KDN
2ꢀoctulosonic acid (KDO,
most common sialic acid, is frequently observed at the
ketosidically linked nonreducing terminal end
3) (Figure 1). Neu5Ac, which is the
HO
H
OH
α
ꢀ
HO
O
COOH
of
glycoconjugates such as glycoproteins, glycolipids, and
oligosaccharides, in the cell membranes of various living
organism, and plays a vital role in numerous biological
processes including cellꢀtoꢀcell recognition, neurobiological
functions, tumor metastasis, and viral infections.1 The most
HO
OH
3 KDO
Figure 1 Representative natural octulo- and nonulosonic acids.
abundant sialic acid, Neu5Ac, is synthesized in vivo from
acetylmannosamineꢀ6ꢀphosphate and phosphoenolpyruvate by
ꢀacetylneuraminic acid 9ꢀphosphate synthase (Neu5Acꢀ9ꢀP
Nꢀ
OPO3H2
OH
3
OH
1
1
O
*
CO2H
3
N
(HO)n
O
(HO)n
synthase), followed by
Nꢀacetylneuraminic acid 9ꢀphosphate
phosphoenolpyruvate
O
4
phosphatase (Neu5Acꢀ9ꢀP phosphatase).1ꢀ3
OH
C9 or C8
3-deoxy-2-ulosonic acids
OH
Owing to their biological and medical significance coupled
with their polyfunctionalized molecular structures, this unique
class of carbohydrate and its analogs are recognized as highly
attractive and important targets for chemical synthesis.4ꢀ21 In
this context, one of the most straightforward synthetic
approaches toward sialic acids such as Neu5Ac, KDN, and
carbohydrates
(RO)n
OR
pyruvic acid
equivalent
O
+
4
H
KDO is the direct carbon–carbon bond forming reaction at the
C4 position between an electrophilic sixꢀ or fiveꢀcarbon moiety
C3 unit
C6 or C5 unit
Figure 2 Biomimetic synthetic approach to 3-deoxy-2-ulosonic acids.
derived from hexose or pentose, and a nucleophilic pyruvate
equivalent such as an oxobutanedioic acid derivative,5 an
a 2ꢀacetylthiazole
derivative,9,10 propargyl bromide,11 and pyruvaldehyde
αꢀ
(bromomethyl)acrylic acid derivative,6ꢀ8
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dimethyl acetal,12,13 among others14 (Figure 2). However,
despite much pioneering work, the reaction yield and the
stereoselectivity at the C4 position induced by addition of a
pyruvate equivalent remain problematic. Moreover, lengthy
synthetic routes involving multiple protective group
manipulations are often necessary both for the preparation of an
electrophilic coupling partner derived from aldose, and/or the
transformations of the coupling product to the desired sialic
acid through selective oxidation of the C1 position to a
carboxylic acid. Very recently, Kanai and Shimizu et al.
reported the highly efficient synthesis of sialic acids via the
chiral copper catalystꢀcontrolled stereoselective propargylation
of unprotected aldoses and subsequent stepwise oxidations of
OH
OAc
O
a) AcCl
90%
b) HO
OH
OH
EDCI, DMAP
76%
O
O
9
-lactic acid
rac
OAc
OAc
d) NaH
O
O
O
c) BF3•OEt2
83%
MeOH
95%
O
O
O
11
10
e) SO3•pyridine
Et3N
OH
O
O
O
DMSO
the carbon
We herein describe a versatile synthesis of sialic acids, the
key step of which is based on substrateꢀcontrolled
–
carbon triple bond at the C1 and C2 position.15
CH 2Cl2
99%
O
O
O
O
12
8
a
stereoselective aldol reaction between the chiral aldehydes
easily prepared from commercially available carbohydrates and
a novel pyruvate equivalent.
Scheme 1 Synthesis of pyruvic acid orthoester 8. Reagents and conditions: a) AcCl (2.0
equiv), THF (0.1 M), 0 °C to rt, 1 h, 90%; b) 3-methyl-3-oxetanemethanol (1.2 equiv),
EDCI (1.1 equiv), DMAP (0.10 equiv), CH2Cl2 (0.5 M), 0 °C to rt, 4 h, 76%; c) BF3·Et2O (0.1
equiv), CH2Cl2 (0.4 M), 0 °C to rt, 4 h, 83%; d) NaH (0.1 equiv), MeOH (0.3 M), 0 °C to
rt, 3 h, 95%; e) SO3·pyridine (4.0 equiv), Et3N (12 equiv), DMSO (4.0 equiv), CH2Cl2 (0.6
M) 0 °C to rt, 1.5 h, 99%.
Results and discussion
We began our preliminary investigations on the aldol reaction
between the chiral aldehyde 14e prepared from
commercially available ethyl pyruvate or pyruvaldehyde
dimethyl acetal under strong basic conditions using lithium
hexamethyldisilazane (LiHMDS) in THF at −78 °C (Figure 3).
However, the use of ethyl pyruvate as a nucleophilic pyruvate
equivalent resulted in the recovery of aldehyde 14e, and the
desired aldol adduct is not obtained. This result suggests the
occurrence of the retroꢀaldol reaction by the coupling products
under basic conditions due to the strong electronꢀwithdrawing
Dꢀmannose and
aldol product
To overcome these problems, we designed pyruvic acid
oxabicyclo[2.2.2]octyl (OBO) orthoester as a novel pyruvate
7.
4
5
8
equivalent. We predicted that the existence of the highly
electronꢀdonating and more stable OBO orthoester adjacent to
the carbonyl carbon (instead of the ethoxycarbonyl group)
would not only suppress the retroꢀaldol reaction but also inhibit
the formation of the selfꢀaldol product (derived from the ketone
as a nucleophile) owing to the steric hindrance of the OBO
structure. Additionally, installation of the orthoester, which is
in the same oxidation state with carboxylic acid, avoids the
need for troublesome oxidative transformations after the aldol
coupling reaction.
property of the
Conversely, the aldol reaction of pyruvaldehyde dimethyl acetal
(in which the ꢀketo ester structure is masked) with aldehyde
14e partially proceeded, but the yield of aldol adduct was
very low (28% yield, dr = 6:1) and 42% of the pyruvaldehyde
αꢀketo ester structure in ethyl pyruvate.
5
α
6
The preparation of pyruvic acid OBO orthoester
8 is shown
dimethyl acetal
5
was consumed by the formation of the selfꢀ
in Scheme 1. The protection of the hydroxy group of racꢀlactic
acid as the acetate22 followed by the esterification of the
carboxylic acid with 3ꢀhydroxymethylꢀ3ꢀmethyloxetane using
1ꢀethylꢀ3ꢀ(3ꢀdimethylaminopropyl) carbodiimide hydrochloride
(EDC•HCl) afforded ester 10 in high yield, which on treatment
with 0.1 equivalent of BF3•OEt2,23 yielded the OBO orthoester
11 in 83% yield. The deprotection of the acetate in 11 using
4 (1.2 equiv)
88% recovery of aldehyde 14e
LiHMDS
(1.3 equiv)
THF, –78 °C
BnO BnO
BnO
O
BnO BnO
HO
*
O
H
BnO
OMe
OMe
OBn OBn
5 (1.2 equiv)
14e
OBn OBn
LiHMDS
(1.3 equiv)
THF, –78 °C
6
28% (dr = 6 : 1)
NaOMe and subsequent Parikh
–Doering oxidation provides
O
pyruvic acid OBO orthoester
storable powder.
8 as nonhygroscopic, stable, and
OH
+
MeO
OMe
OMe
D
-mannose
The synthesis of the aldehyde 14b as a coupling partner for
pyruvic acid OBO orthoester in the aldol reaction is shown in
MeO
7
8
42% of 5 was consumed
as the self-aldol adducts.
Scheme 2.24 Considering both the shortꢀstep syntheses of
aldehydes from commercially available carbohydrates and the
removal step of the hydroxyꢀprotecting groups to yield a highly
polar product after the aldol coupling reaction, we decided to
protect all the hydroxy groups as benzyl ethers. The aldehydes
O
O
O
OEt
OMe
O
O
O
O
OMe
4
5
8
pyruvic acid equivalents
pyruvic acid OBO orthoester
14a
carbohydrate in three steps via the temporary masking of the
aldehyde group with ꢀmethylhydroxylamine, benzyl
–14f were easily prepared from the corresponding
Figure 3 Aldol reactions between the chiral aldehyde 14e and pyruvic acid equivalents
4 or 5.
O
2 | J. Name., 2012, 00, 1-3
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diastereoselectivity relative to syn
ꢀ
α
,
β
ꢀbisalkoxy aldehydes to
afford the 3,4ꢀanti diastereomer (Felkin product) as the major
product, according to the Cornforth–Evans transitionꢀstate
model (Figure 4).25 However, stereoselectivity in substrateꢀ
controlled aldol reactions between more stereochemically
complicated chiral aldehydes and pyruvate equivalents, which
is the key reaction to synthesize biologically and medicinally
valuable sialic acids and their analogs, remains to be achieved.
Our investigation into the aldol reaction between the chiral
OMe
H
O
OH
OH
OBn
N
a) NH2OMe•HCl
pyridine
BnO
HO
OH
b) NaH
BnBr, Bu4NI
OBn OBn
D-arabinose
85% (2 steps)
OBn
13b
O
c) TsOH•H 2O
aldehydes 14a
presented in Table 1. The reaction of
–
14f and pyruvic acid OBO orthoester
syn
8
are
syn
BnO
H
aq HCHO
THF
75%
α
,
β
ꢀ
ꢀ
β
,
γ
ꢀ
OBn OBn
benzyloxyaldehyde 14a with the Li enolate prepared from
pyruvic acid OBO orthoester
and LiHMDS26 in THF at −78
14b
8
Scheme 2 Synthesis of O-benzyl-protected aldehydes 14b. Reagents and conditions:
(a) NH2OMe·HCl (1.2 equiv), pyridine (0.7 M), rt to 70 °C, 12 h; (b) NaH (7.0 equiv), BnBr
(6.0 equiv), Bu4NI (0.1 equiv), DMF (0.1 M), 0 °C to rt, 18 h, 85 % (two steps); (c)
TsOH·H2O (1.0 equiv), aq HCHO–THF (1:2.5, 0.1 M), rt, 12 h, 75%.
°C provided aldol 18a as a 2:1 diastereomeric mixture of the
4,5ꢀanti and 4,5ꢀsyn adducts in 58% yield (entry 1). Under the
same conditions, the aldol reaction of
α,βꢀsynꢀβ,γꢀanti
benzyloxyaldehyde 14b with pyruvic acid OBO orthoester
resulted in increased diastereoselectivity (4,5ꢀanti:4,5ꢀsyn
8
=
7:1) and a 67% yield (entry 3). The addition of ZnCl2 to the
aldol reaction of syn anti benzyloxyꢀsubstituted
aldehyde 14b improved the diastereoselectivity to 4,5ꢀanti:4,5ꢀ
syn = 11:1 in 60% yield (entry 4), whereas low conversion was
OMe
H
a) NH2OMe•HCl
pyridine
O
OH
OBn OBn
N
α
,
β
ꢀ
ꢀβ,γꢀ
HO
BnO
2
b) BaO, Ba(OH)2
BnBr
2
HO
NHAc
OBn NHAc
HO
observed in the case of
(entry 2) Conversely, the use of
14c and 14d in the aldol reaction with pyruvic acid OBO
orthoester provided the 4,5ꢀanti aldol adduct (Felkin product)
as the major product with excellent diastereoselectivity (4,5ꢀ
anti:4,5ꢀsyn = >20:1) and in good yields (entries 5 8).
These results indicate that the major controlling factor for
the diastereoselectivity is the relative configuration of the
and ꢀpositions in the aldehydes (entries 1 and 3 vs 5 and 7).
That is to say, anti benzyloxyaldehydes exhibit higher
diastereoselectivity than syn benzyloxyaldehydes in the
aldol reaction with pyruvic acid OBO orthoester to
This is in good
α
,
β
ꢀsyn
ꢀ
β
,γ
ꢀ
syn benzyloxyaldehyde 14a
15b 2R: GlcNAc
15d 2S: ManNAc
16b 55% (2 steps)
16d 69% (2 steps)
.
α,βꢀanti benzyloxyaldehydes
BnO BnO
O
8
c) TsOH•H 2
O
BnO
2
H
aq HCHO
THF
–
OBn NHAc
17b
17d
α
ꢀ
Scheme 3 Synthesis of O-benzyl-protected N-acetylaldehydes 17b and 17d. Reagents
and conditions: (a) NH2OMe·HCl (1.2 equiv), pyridine (0.7 M), rt to 70 °C, 12 h; (b) BaO
(9.4 equiv), Ba(OH)2 (3.2 equiv), BnBr (13 equiv), DMF (0.2 M), 0 °C to rt, 24 h, 55% for
16b (two steps), 69% for 16d (two steps); (c) TsOH·H2O (1.0 equiv for 16b, 18 equiv for
16d), aq HCHO–THF (1:2.5, 0.1 M), rt, 15 min. The crude product was passed through a
short silica gel column before the aldol reaction.
β
α,βꢀ
α,βꢀ
8
preferentially afford the Felkin products
.
agreement with the previous work by Evans.25 In addition, our
systematic examination indicates that the relative configuration
of the
influence on the
aldehydes with
substrates to provide the Felkin product with higher
diastereoselectivity than those with syn configuration (entry
vs 2). The reactions of the more stereochemically complicated
aldehydes 14e and 14f with the Li enolate from pyruvic acid
OBO orthoester afforded the aldol adducts 18e and 18f in
β
ꢀ and
γ
ꢀpositions in the aldehydes exerts as a secondary
ꢀface selectivity in the aldol reaction, and
anti configuration are more favorable as
P2O
O
P2O
O
1
HO
O
π
β,γꢀ
LDA
3
α
+
4
R1
H
THF
–78 °C
R2
R1
5
*
R2
β
P1O
P1O
R2 = Me, i-Pr,
t-Bu
R1 = Et, i-Pr, CH2OTBS
β,γꢀ
3,4-anti
P1, P2 = i-Pr, Bn, PMB,
Felkin product
1
TBS
dr >99 :1 ~ 95 : 5
Figure 4 Studies on asymmetric induction in methyl ketone aldol additions to α,β-
bisalkoxy aldehydes by Evans et al. (Ref. 25).
8
good yields and acceptable diastereoselectivity (4,5ꢀanti:4,5ꢀ
syn = 7:1 for aldehyde 14e, 4,5ꢀanti:4,5ꢀsyn = 11:1 for aldehyde
protection of the hydroxy groups, and regeneration of the
14f
) favoring the Felkin products (entries 9 and 11).
aldehyde by transꢀoximation. The preparation of
Nꢀacetyl αꢀ
Furthermore, the use of 1.3 equivalents of ZnCl2 as an additive
provided the 4,5ꢀanti aldol product with excellent
diastereoselectivity (4,5ꢀanti:4,5ꢀsyn = >20:1 for aldehydes 14e
and 14f) (entries 10 and 12).
amino aldehydes 17b and 17d, which were precursors for
Neu5Ac and its analogs, was also achieved through similar
transformations (Scheme 3).24
Concerning asymmetric induction in diastereoselective
aldol reactions, Evans et al. have reported systematic studies on
We next examined the aldol reactions of chiral
acetylaminoaldehydes 17a 17d with pyruvic acid OBO
orthoester for the syntheses of Neu5Ac and its analogs (Table
2). The treatment of syn ꢀacetylaminoꢀ
benzyloxyaldehyde 17a with the Li enolate prepared from 2.2
αꢀ
–
π
ꢀface selectivity in the addition of lithium enolates prepared
from methyl ketones to ꢀbisalkoxy aldehydes, and
concluded that anti ꢀbisalkoxy aldehydes exhibit superior
8
α,β
α
,
β
ꢀ
α
βꢀ
ꢀα,β
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Table 1 The chiral substrate-controlled diastereoselective aldol reaction of O-benzyl-protected aldehydes 14a–14f with pyruvate orthoester 8.
O
HO
O
O
LiHMDS (1.3 equiv)
additive (1.3 equiv)
4
O
1
O
O
5
n
+
BnO
BnO
*
BnO
BnO
n
H
O
THF
O
OBn
O
OBn
–78 °C, 0.5 h
(1.2 equiv)
8
14a−14f
18a−18f
Entry
Aldehyde
Additives
―
Major adduct (Felkin product)
Yield (%)
58
dr
4,5-anti : 4,5-syn
2 : 1
1
2
BnO
HO
*
O
BnO
O
O
γ
α
BnO
BnO
β
H
O
ZnCl2
OBn OBn
O
< 10
2 : 1
BnO
OBn
O
anti-18a
14a
BnO
HO
O
BnO
3
4
―
67
60
7 : 1
O
BnO
*
OBn OBn
anti-18b
BnO
H
O
O
OBn OBn
ZnCl2
11 : 1
14b
5
6
BnO
O
―
54
50
> 20 : 1
> 20 : 1
BnO
HO
O
O
BnO
H
BnO
*
O
OBn OBn
OBn OBn
O
ZnCl2
14c
anti-18c
BnO
HO
*
O
BnO
O
7
8
―
51
52
> 20 : 1
> 20 : 1
O
BnO
BnO
BnO
H
O
OBn OBn
O
OBn OBn
ZnCl2
anti-18d
14d
BnO BnO
HO
*
O
BnO BnO
O
BnO
O
9
―
62
58
7 : 1
H
O
OBn OBn
O
OBn OBn
14e
anti-18e
10
ZnCl2
> 20 : 1
BnO
HO
*
O
11
12
―
51
47
11 : 1
BnO
O
O
BnO
H
BnO
O
OBn OBn
OBn OBn
O
ZnCl2
> 20 : 1
14f
anti-18f
equivalents of pyruvic acid OBO orthoester
8 and 2.3 as a substrate, the aldol reactions proceeded with good to high
equivalents of LiHMDS in THF at −78 °C afforded the aldol diastereoselectivity, furnishing the antiꢀFelkin product as the
adduct 19a in 65% yield with a moderate diastereomeric ratio major diastereomer (entry 3, 4,5ꢀanti:4,5ꢀsyn = 1:6; entry 4,
(entry 1, dr = 2:1). Low diastereoselectivity was also observed 4,5ꢀanti:4,5ꢀsyn = 1:>20)
in the aldol reaction using the more stereochemically C=O face selectivity was observed between the aldol reactions
complicated syn ꢀacetylaminoꢀ ꢀbenzyloxyaldehyde 17b of anti ꢀacetylaminoꢀ ꢀbenzyloxyaldehydes and those of
(entry 2, 4,5ꢀanti:4,5ꢀsyn = 3.5:1). Conversely, when ꢀbenzyloxyaldehydes.
anti ꢀacetylaminoꢀ ꢀbenzyloxyaldehyde 17c or 17d was used
. It should be noted that a reversal
α
,
β
ꢀ
α
β
α
,
β
ꢀ
α
β
α
,
β
ꢀ
α
α
β
4 | J. Name., 2012, 00, 1-3
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Table 2 The chiral substrate-controlled diastereoselective aldol reaction of O-benzyl-protected α-N-acetylaminoaldehydes 17a-17d with pyruvate orthoester 8.
O
HO
O
O
LiHMDS (2.3 equiv)
4
O
1
O
O
5
+
BnO
BnO
n
*
BnO
BnO
n
H
O
THF
O
NHAc
O
NHAc
–78 °C, 0.5 h
(2.2 equiv)
17a−17d
Aldehyde
8
19a−19d
Entry
1
Major adduct
Yield (%)
dr
4,5-anti : 4,5-syn
(2 : 1) a
65
BnO
O
BnO
HO
O
α
O
β
H
*
O
NHAc
NHAc
O
17a
19a
BnO BnO
HO
O
BnO BnO
O
2
3
76
71
3.5 : 1
γ
α
BnO
O
BnO
β
H
*
O
OBn NHAc
O
OBn NHAc
17b
anti-19b
BnO
HO
O
1 : 6
BnO
O
O
*
H
O
NHAc
O
NHAc
17c
-19c
syn
BnO BnO
HO
O
BnO BnO
O
BnO
O
4
82
1 : > 20
BnO
*
H
O
OBn NHAc
O
OBn NHAc
17d
syn-19d
a The stereochemistry of the newly formed stereogenic center C4 position of major aldol adducts was not determined.
Having established the utility of substrateꢀcontrolled
diastereoselectivity using chiral aldehydes and pyruvic acid OBO
Conclusion
In summary, we have developed a synthetic strategy for sialic acids
and their analogs based on the substrateꢀcontrolled asymmetric aldol
reactions between sterically complicated aldehydes easily prepared
from commercially available carbohydrates, and pyruvic acid OBO
orthoester 8, we examined the transformation of the aldol adducts to
the desired sialic acids and their analogs. Deprotection of the benzyl
ether groups and the hemi ketalization of aldol adduct 18b by
treatment with wetꢀtype Pd–C in THF under hydrogen atmosphere,
orthoester 8, which was employed as
a novel pyruvic acid
followed by hydrolysis of the ester under mild basic conditions,
afforded the triethylammonium salt 21b. The purification of the
equivalent. Systematic studies on the aldol reaction using chiral
aldehydes derived from pentoses revealed that α,β,γꢀbenzyloxyꢀ
substituted aldehydes with an α,βꢀanti relative configuration
preferentially provided the Felkin products with 4,5ꢀanti
configuration in high diastereoselectivity. In addition, the relative
β,γꢀconfiguration in the α,β,γꢀbenzyloxyꢀsubstituted aldehydes with
product was performed by recrystallization from H2O–EtOH of the
corresponding ammonium salts 22b (Scheme 4).6a Other aldol
adducts 19c and 19d were also converted to triethylammonium salts
23c and 25d by a sequence of hydrogenolysis and hydrolysis, and
the characterizations of these products were performed using the an α,βꢀsyn arrangement exerted
a secondary effect on the
corresponding methyl esters 24c and 26d (Scheme 5).
diastereoselectivity of the stereogenic center formed in the aldol
reactions with pyruvic acid OBO orthoester 8, and α,βꢀsynꢀβ,γꢀanti
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benzyloxyaldehyde exhibited superior diastereoselectivity to yield be transformed to sialic acids and their analogs in three steps without
the Felkin products (which could be further improved by the addition the need for oxidation reactions. The chiral substrateꢀcontrolled
stereoselective aldol reaction described here will provide not only a
convenient synthetic method for sialic acid derivatives but also a
guiding principle for asymmetric induction in aldol reactions using
stereochemically complicated aldehydes.
of ZnCl2) than α,βꢀsynꢀβ,γꢀsyn benzyloxyaldehyde. Conversely, we
also found that the aldol reactions of α,βꢀanti αꢀacetylaminoꢀβꢀ
benzyloxyꢀsubstituted aldehydes with pyruvic acid OBO orthoester 8
preferentially afforded antiꢀFelkin products with 4,5ꢀsyn
configuration. Moreover, some of the obtained aldol adducts could
Experimental
(3-Methyloxetan-3-yl)methyl 2-acetoxypropanoate (10)
BnO
HO
O
a) H2, Pd/C
O
To a stirred solution of 3ꢀmethylꢀ3ꢀoxetanemethanol (5.86 g, 57.4
mmol, 1.2 equiv), EDCI (10.1 g, 52.6 mmol, 1.1 equiv) and DMAP
(584 mg, 4.78 mmol, 0.10 equiv) in CH2Cl2 (96 mL, 0.50 M) at 0 °C
was added dropwise a solution of racꢀ2ꢀacetoxypropanoic acid 922
(6.31g, 47.8 mmol) in CH2Cl2 (30 mL, 1.6 M) under N2 atmosphere.
After the mixture was stirred for 4 h at room temperature, the
reaction was quenched with saturated aqueous NH4Cl (100 mL). The
resulting mixture was extracted with CHCl3 (3 x 100 mL). The
combined organic phases were washed with H2O (2 x 100 mL) and
brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. The obtained crude product was purified by
silica gel column chromatography (Hexane : AcOEt = 4 : 1) to give
10 (7.85 g, 36.3 mmol, 76% yield) as colorless oil. Rf value on TLC
0.62 (Hexane : AcOEt = 1 : 1); 1HꢀNMR (400 MHz, CDCl3) δ 5.10
(q, J = 6.8 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 4.51 (d, J = 11.6 Hz,
1H), 4.38 (d, J = 6.0 Hz, 2H), 4.25 (d, J = 11.2 Hz, 1H), 4.21 (d, J =
11.2 Hz, 1H), 2.13 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H), 1.33 (s, 3H);
13CꢀNMR (100 MHz, CDCl3) δ 170.9, 170.4, 79.3, 79.3, 69.1, 68.6,
39.1, 21.0, 20.6, 16.9; IR (neat) 2965, 2944, 2874, 1744, 1451, 1382,
1374, 1238, 1202, 1132, 1100, 1052, 984 cm–1; HRMS (ESI) m/z
calcd for C10H16NaO5 [M+Na]+ 239.0895, found 239.0886.
BnO
HO
O
OBn OBn
O
18b
HO
H
OH
O
b) Et3N : H2O
= 1 : 4
O
O
OH
HO
HO
OH
20b
OH
HO
HO
H
OH
H
OH
O
HO
O
CO2H
• NH3
CO2H
• Et3N
c) aq NH3
78% (3 steps)
HO
HO
OH
OH
21b
22b KDO•NH3
Scheme 4 Transformation of the aldol adduct 18b to the KDO ammonium salt 22b.
Reagents and conditions: a) H2, 10% wet-type Pd/C (50% w/w), THF (0.1 M), rt, 1.5 h; b)
Et3N:H2O = 1:4 (0.2 M), rt, 2 h; c) aq 28% NH3, rt, 1 min, 78% (three steps) after
recrystallization.
H
OH
O
BnO
HO
O
CO2H
Et3N
1-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)ethyl acetate
(11)
O
O
AcHN
HO
NHAc
O
OH
a) H2, Pd/C
To a stirred solution of 10 (7.83 g, 36.2 mmol, 1.0 equiv) in CH2Cl2
(91 mL, 0.40 M) at 0 °C under N2 atmosphere was added dropwise
BF3·OEt2 (0.447 mL, 3.62 mmol, 0.10 equiv). After 4 h at room
temperature, the reaction was quenched with Et3N (0.756 mL, 5.43
mmol, 0.15 equiv) at 0 °C and the mixture was stirred for 15 min.
The resulting mixture was diluted with H2O (100 mL) and extracted
with CHCl3 (3 x 200 mL). The combined organic phases were
washed with H2O (2 x 100 mL) and brine (2 x 100 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The
obtained crude product was purified by silica gel column
chromatography (Hexane : AcOEt = 6 : 1) to give 11 (6.49 g, 30.0
mmol, 83% yield) as white solid. Mp 79–81 °C; Rf value on TLC
0.61 (Hexane : AcOEt = 1 : 1); 1HꢀNMR (400 MHz, CDCl3) δ 4.99
(q, J = 6.4 Hz, 1H), 3.92 (s, 6H), 2.09 (s, 3H), 1.24 (d, J = 6.4 Hz,
3H), 0.81 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ 170.1, 107.6, 72.7,
69.9, 30.6, 21.3, 14.5, 14.3; IR (KBr) 2993, 2970, 2946, 2883, 1729,
1478, 1457, 1432, 1402, 1383, 1373, 1357, 1259, 1214, 1194, 1105,
1081, 1051, 1027, 1007, 982 cm–1; HRMS (ESI) m/z calcd for
C10H16NaO5 [M+Na]+ 239.0895, found 239.0888.
19c
23c
b) Et3N - H2O
BnO BnO
HO
O
H
OH
O
BnO
O
O
HO
CO2H
Et3N
HO
AcHN
OBn NHAc
O
OH
19d
25d
H
OH
O
CO2Me
24c 61% (3 steps)
AcHN
OH
HO
c) Dowex, MeOH
H
OH
O
HO
CO2Me
HO
AcHN
26d NeuAc1Me 58% (3 steps)
OH
Scheme 5 Transformation of the aldol adducts 19c and 19d to the ulosonic acids 24c
and 26d. Reagents and conditions: a) H2, 10% wet-type Pd/C (50% w/w), THF (0.1 M),
rt, 1.5 h; b) Et3N:H2O = 1:4 (0.2 M), rt, 2 h; c) Dowex 50WX8, MeOH, 61% (three steps)
for 24c, 58% (three steps) for 26d.
1-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)ethan-1-ol (12)
6 | J. Name., 2012, 00, 1-3
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To a stirred solution of 11 (6.47 g, 29.9 mmol, 1.0 equiv) in MeOH J = 8.0 Hz, 1H, ꢀNH), 5.02 (dt, J = 8.0, 4.8 Hz, 1H), 4.74 (d, J = 10.8
(100 mL, 0.30 M) at 0 °C was added portionwise NaH (55% Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.59 (d, J = 10.8 Hz, 1H), 4.56
dispersion in oil, 131 mg, 2.99 mmol, 0.10 equiv), and the mixture (d, J = 11.6 Hz, 1H), 4.54 (s, 2H), 4.51 (d, J = 11.6 Hz, 1H), 4.49 (d,
was stirred for 3 h at room temperature. After the solvent was J = 11.6 Hz, 1H), 3.97 (dd, J = 9.2, 4.8 Hz, 1H), 3.94–3.90 (m, 3H),
removed under reduced pressure, the obtained crude product was 3.85 (s, 3H), 3.75–3.70 (m, 1H), 1.66 (s, 3H); 13CꢀNMR (100 MHz,
purified by silica gel column chromatography (Hexane : AcOEt = 4 :
1 contained 1% Et3N) to give 12 (4.95 g, 28.4 mmol, 95%) as white
solid. Mp 63–66 °C; Rf value on TLC 0.28 (Hexane : AcOEt = 1 :
CDCl3) δ 169.7, 147.4, 138.4, 138.2, 137.9, 137.8, 128.5, 128.5,
128.4, 128.3, 128.3, 128.2, 128.0, 127.9, 127.7, 127.7, 127.6, 127.6,
80.1, 79.0, 74.3, 73.4, 72.9, 72.3, 69.1, 61.8, 49.5, 23.0; IR (neat)
1); 1HꢀNMR (400 MHz, CDCl3) δ 3.93 (s, 6H), 3.73 (q, J = 6.4 Hz, 3086, 3063, 3030, 3004, 2938, 2901, 2869, 2817, 1676, 1661, 1497,
1H), 2.13 (br s, 1H, ꢀOH), 1.19 (d, J = 6.4 Hz, 3H), 0.81 (s, 3H); 1454, 1370, 1305, 1210, 1103, 1069, 1043, 1027, 907 cm–1; HRMS
(ESI) calcd for C37H42N2NaO6 [M+Na]+ 633.2941, found 633.2934.
13CꢀNMR (100 MHz, CDCl3) δ 108.3, 72.7, 69.4, 30.6, 16.2, 14.3;
IR (KBr) 3529, 2992, 2969, 2943, 2884, 1475, 1458, 1399, 1363,
1281, 1195, 1132, 1077, 1048, 1023, 958 cm–1; HRMS (ESI) m/z
calcd for C8H14NaO4 [M+Na]+ 197.0790, found 197.0790.
N-((2S,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)-1-oxohexan-2-
yl)acetamide (17d)
To a stirred solution of 16d (600 mg, 0.982 mmol, 1.0 equiv) in THF
and 36ꢀ38% aqueous HCHO (2.5 : 1, 9.8 mL, 0.10 M) at room
temperature was added TsOH·H2O (3.37 g, 17.7 mmol, 18 equiv).
The progress of the reaction was checked by TLC analysis ever 5
min.27 After the mixture was stirred for 15 min at room temperature,
the reaction was quenched with saturated aqueous NaHCO3 and the
resulting mixture was extracted with AcOEt (2 x 50 mL). The
combined organic phases were washed with H2O (2 x 50 mL) and
brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. The obtained crude product was passed
through a short column of silica gel using as an eluent (Hexane :
AcOEt = 1 : 1). The obtained product 17d (593 mg, pale yellow oil)
was used for next reaction without further purification.28
1-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)ethan-1-one (8)
To a stirred solution of 12 (4.95 g, 28.4 mmol, 1.0 equiv), DMSO
(8.10 mL, 114 mmol, 4.0 equiv) and Et3N (47.5 mL, 341 mmol, 12
equiv) in CH2Cl2 (47 mL, 0.60 M) at 0 °C was added portionwise
SO3·Py (18.1 g, 114 mmol, 4.0 equiv). After the mixture was stirred
at room temperature for 1.5 h under N2 atmosphere, the reaction was
quenched with H2O (100 mL). The resulting mixture was extracted
with AcOEt (3 x 200 mL). The combined organic phases were
washed with H2O (2 x 200 mL) and brine (2 x 200 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The
obtained crude product was purified by silica gel column
chromatography (Hexane : AcOEt = 5 : 1) to give 8 (4.84 g, 28.1
mmol, 99% yield) as white solid. Mp 105–114 °C; Rf value on TLC
1
N-((3S,4R,5R,6S,7R)-5,6,7,8-tetrakis(benzyloxy)-3-hydroxy-1-(4-
methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)-1-oxooctan-4-
yl)acetamide (19d)
0.54 (Hexane : AcOEt = 1 : 1); HꢀNMR (400 MHz, CDCl3) δ 3.97
(s, 6H), 2.23 (s, 3H), 0.83 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ
196.5, 103.2, 73.0, 30.8, 24.4, 14.1; IR (KBr) 2975, 2960, 2941,
2920, 2892, 1737, 1480, 1459, 1424, 1369, 1351, 1329, 1301, 1190,
1135, 1061, 1024, 982 cm–1; HRMS (ESI) m/z calcd for C8H12NaO4
[M+Na]+ 195.0633, found 195.0639.
To a stirred solution of LiHMDS (1.0 M in THF solution, 1.69 mL,
1.69 mmol, 2.3 equiv) in THF (7.4 mL) at –78 °C was added
dropwise a solution of 8 (279 mg, 1.62 mmol, 2.2 equiv) in THF (1.8
mL) under N2 atmosphere. After 30 min at –78 °C, a solution of 17d
(428 mg, 0.736 mmol, 1.0 equiv) in THF (1.8 mL) was added, and
the resulting mixture was furthermore stirred for 30 min at –78 °C.
The reaction was quenched with phosphate buffer (pH 6.86, 10 mL),
and the mixture was allowed to gently warm up to room temperature.
The resulting mixture was extracted with AcOEt (3 x 50 mL). The
combined organic phases were washed with H2O (2 x 100 mL) and
brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. The obtained crude product was purified by
silica gel column chromatography (Hexane : AcOEt = 1 : 2) to give
19d (452 mg, 0.600 mmol, 82% yield, anti : syn = 1 : >20) as
N-((2R,3R,4S,5R,Z)-3,4,5,6-tetrakis(benzyloxy)-1-
(methoxyimino)hexan-2-yl)acetamide (16d)
A solution of NꢀacetylꢀDꢀmannosamine 15d (1.00 g, 4.52 mmol, 1.0
equiv) and Oꢀmethylhydroxylamine hydrochloride (453 mg, 5.42
mmol, 1.2 equiv) in pyridine (6.5 mL, 0.70 M) was stirred for 12 h at
70 °C under N2 atmosphere. The reaction mixture was concentrated
under reduced pressure to give colorless oil. To a stirred solution of
the above crude product in DMF (23 mL, 0.20 M) at 0 °C was
successively added BnBr (7.01 mL, 59.2 mmol, 13.1 equiv), BaO
(6.52 g, 42.5 mmol, 9.4 equiv) and Ba(OH)2·8H2O (4.57 g, 14.5
mmol, 3.2 equiv). After stirred at 0 °C for 6 h and then at room
temperature for 18 h under N2 atmosphere, the mixture was filtered
through a Celite pad® by rinsing with CHCl3. After the filtrate was
concentrated under reduced pressure, the resulting residue was
dissolved in AcOEt (100 mL) and washed with H2O (2 x 100 mL)
and brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. The obtained crude product was purified by
silica gel column chromatography (Hexane : AcOEt = 6 : 1) to give
16d (1.91 g, 3.13 mmol, 69% in 2 steps) as pale yellow oil. Rf value
27
colorless oil. Rf value on TLC 0.30 (Hexane : AcOEt = 1 : 2); [α]D
+7.35 (c 0.25, CHCl3); 1HꢀNMR (400 MHz, CDCl3) δ 7.34–7.22 (m,
20H), 5.99 (d, J = 9.2 Hz, 1H, ꢀNH), 4.73 (d, J = 11.6 Hz, 1H), 4.73
(d, J = 10.4 Hz, 1H), 4.65 (d, J = 10.4 Hz, 1H), 4.63 (d, J = 11.6 Hz,
1H), 4.56 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.52 (d, J
= 11.6 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.49–4.46 (m, 1H), 4.10
(ddd, J = 9.2, 6.0, 1.2 Hz, 1H), 3.96 (s, 6H), 3.91–3.82 (m, 4H), 3.72
(dd, J = 10.8, 4.8 Hz, 1H), 3.34 (br s, 1H, ꢀOH), 2.78 (dd, J = 18.4,
8.8 Hz, 1H), 2.70 (dd, J = 18.4, 3.6 Hz, 1H), 1.74 (s, 3H), 0.83 (s,
3H); 13CꢀNMR (100 MHz, CDCl3) δ 198.1, 170.3, 138.5, 138.3,
138.2, 138.0, 128.4, 128.3, 128.3, 128.3, 128.3, 128.1, 127.9, 127.8,
24
on TLC 0.32 (Hexane : AcOEt = 2 : 1); [α]D +3.23 (c 0.50,
CHCl3); 1HꢀNMR (400 MHz, CDCl3) δ 7.35–7.22 (m, 21H), 6.40 (d,
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127.7, 127.6, 127.5, 127.5, 103.2, 79.1, 79.0, 79.0, 74.2, 73.3, 73.0,
72.2, 69.1, 65.7, 53.0, 41.6, 30.8, 23.2, 14.1; IR (neat) 3401, 3086,
3064, 3030, 2922, 2881, 1746, 1659, 1496, 1454, 1371, 1209, 1082,
1032, 998 cm–1; HRMS (ESI) calcd for C44H51NNaO10 [M+Na]+
776.3411, found 776.3394.
4
5
For reviews on the synthesis of sialic acid derivatives, see: (a)
DeNinno, M. P. Synthesis, 1991, 583–593; (b) M. J. Kiefel and
M. von Itzstein, Chem. Rev. 2002, 102, 471–490; (c) A.
Banaszek and J. Mlynarski, Studies in Natural Products
Chemistry, 2005, 30, 419–482; (d) I. Hemeon and A. J.
Bennet, Synthesis, 2007, 1899–1926.
Syntheses of 3-deoxy-2-ulosonic acid by addition reaction of
oxobutanedioic acid derivative to aldose derivatives, see: (a)
J. W. Cornforth, M. E. Firth and A. Gottschalk, Biochem. J.
1958, 68, 57–61; (b) P. M. Carroll and J. W. Cornforth,
Biochim. Biophys. Acta, 1960, 39, 161–162; (c) R. Kuhn and
G. Baschang, Justus Liebigs Ann. Chem. 1962, 659, 156–163;
(d) I. A. Kozlov, S. Mao, Y. Xu, X. Huang, L. Lee, P. S. Sears, C.
Gao, A. R. Coyle, K. D. Janda and C.-H. Wong, CemBioChem
Methyl (4S,5R,6S)-5-acetamido-2,4-dihydroxy-6-((1R,2R)-1,2,3-
trihydroxypropyl)tetrahydro-2H-pyran-2-carboxylate (26d)
A mixture of 19d (300 mg, 0.398 mmol, 1.0 equiv) and wetꢀtype Pdꢀ
C (10% on carbon, 150 mg, 50% w/w) in THF (4.0 mL, 0.10 M) was
strongly stirred for 1.5 h under H2 atmosphere. The reaction mixture
was filtered through a filter paper by rinsing with MeOH. The
combined filtrate was concentrated under reduced pressure to give
the crude product as colorless amorphous. A solution of the above
crude product in H2O and Et3N (4 : 1, 2.0 mL, 0.20 M) was stirred
for 1.5 h at room temperature. After the reaction mixture was
concentrated under reduced pressure, the residue was passed through
a column of silica gel (CHCl3 : MeOH = 30 : 1 then only MeOH) to
remove 1,1,1ꢀtris(hydroxymethyl)ethane. The obtained product was
used for next reaction without purification. A solution of the above
product in anhydrous MeOH (4.0 mL, 0.10 M) was treated with
Dowex®50WX8 (400% w/w) at room temperature for 2 h. The
mixture was filtered through a cotton filter, and concentrated under
reduced pressure to give 26d (74.7 mg, 0.231 mmol, 58% yield) as
white solid. The physical data of the synthesized compound 26d
were good agreement with those reported in the references.29, 30 Mp
179–180 °C; Rf value on TLC 0.30 (CHCl3 : MeOH : AcOH : H2O =
2001,
Syntheses of 3-deoxy-2-ulosonic acid by addition reaction of
-(bromomethyl)acrylic acid or its esters using indium, see:
2, 741–746.
6
α
(a) D. M. Gordon and G. M. Whitesides, J. Org. Chem. 1993,
58, 7937–7938; (b) T.-H. Chan and M.-C. Lee, J. Org. Chem.
1995, 60, 4228–4232; (c) M. Warwel and W.-D. Fessner,
Synlett 2000, 865–867; (d) M. D. Chappell and R. L. Halcomb,
Org. Lett. 2000, 2, 2003–2005; (e) S. Matthies, P. Stallforth
and P. H. Seeberger, J. Am. Chem. Soc. 2015, 137, 2848–
2851.
Synthesis of 3-deoxy-2-ulosonic acid by addition reaction of
7
8
9
α
-(bromomethyl)acrylic esters using zinc, see: (a) R. Csuk, M.
Hugener and Vasella, A. Helv. Chim. Acta 1988, 71, 609–618;
(b) M. Banwell and C. D. Savi and K. Watson, J. Chem. Soc.,
Perkin Trans. 1, 1998, 2251–2252.
Syntheses of 3-deoxy-2-ulosonic acid by addition reaction of
ethyl
α-(bromomethyl)acrylic ethyl esters using indium to
aziridine, see: R. Lorpitthaya, S. B. Suryawanshi, S. Wang, K.
K. Pasunooti,; S. Cai, J. Ma and X.-W. Liu, Angew. Chem. Int.
Ed. 2011, 50, 12054–12057.
25
1
60 : 30 : 3 : 5); [α]D –24.3 (c 0.5, MeOH); HꢀNMR (400 MHz,
MeOD) δ 4.07–3.96 (m, 2H), 3.85–3.78 (m, 2H), 3.78 (s, 3H), 3.72–
3.68 (m, 1H), 3.62 (dd, J = 11.2, 5.6 Hz, 1H), 3.48 (dd, J = 8.8, 1.2
Hz, 1H), 2.22 (dd, J = 12.8, 5.2 Hz, 1H), 2.01 (s, 3H), 1.89 (dd, J =
12.8, 11.2 Hz, 1H); 13CꢀNMR (100 MHz, MeOD) δ 175.1, 171.8,
96.7, 72.1, 71.7, 70.2, 67.9, 64.9, 54.3, 53.1, 40.7, 22.6; IR (KBr)
3386, 2959, 2936, 1749, 1742, 1701, 1686, 1654, 1638, 1627, 1560,
1542, 1509, 1490, 1475, 1458, 1438, 1375, 1311, 1279, 1127, 1069,
1035, 946 cm–1; HRMS (ESI) calcd for C12H21NNaO9 [M+Na]+
346.1114, found 346.1120.
Syntheses of 3-deoxy-2-ulosonic acid by addition reaction of
2-acetylthiazole, see: A. Dondoni and P. Merino, J. Org.
Chem. 1991, 56, 5294–5301.
10 Syntheses of 3-deoxy-2-ulosonic acid by Wittig olefination of
thiazole-armed carbonyl ylide, and followed by Michael
addition of BnONa, see: (a) A. Dondoni, A. Marra and P.
Merino, J. Am. Chem. Soc. 1994, 116, 3324–3336; (b) A.
Dondoni, A. Marra, P. Merino and A. Boscarato, Chem. Eur. J.
1999, 5, 3562–3572.
11 Synthesis of 3-deoxy-2-ulosonic acid by addition reaction of
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12 Syntheses of 3-deoxy-2-ulosonic acid by a chiral secondary
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Acknowledgements
This work was partially supported by the Sasakawa Scientific
Research Grant from The Japan Society for Y. N. and a Kitasato
University Research Grant for Young Researchers for D. Y. We
thank Dr. K. Nagai and Ms. M. Sato at Kitasato University for
instrumental analyses.
13 Syntheses of 3-deoxy-2-ulosonic acid by a chiral tertiary
amine, chiral zinc complex or chiral lanthanium-lithium-
BINOL complex catalyzed aldol reaction using pyruvic
aldehyde dimethyl acetal, 2-acetylthiazole or pyruvic ester
see: (a) O. El-Sepelgy, D. Schwarzer, P. Oskwarek and J.
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.
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