Enantioselective Synthesis of Monosaccharide Analogues by Two-Step Sequential Enamine Catalysis: Benzoyloxylation and Aldol Reaction

Article abstract of DOI:10.1002/ejoc.202000073

An efficient route to synthesize monosaccharide analogues in an enantio- and diastereoselective manner is described. Three contiguous stereocenters can be constructed via enantioselective benzoyloxylation of aldehydes using a chiral secondary amine catalyst and a subsequent aldol reaction of the resulting α-benzoyloxyaldehydes with the protected dihydroxyacetones using chiral amino acid catalysts, and single diastereomers were obtained with excellent enantioselectivity.

Full text of DOI:10.1002/ejoc.202000073

A Journal of
Accepted Article
Title: Enantioselective synthesis of monosaccharide analogues by two-
step sequential enamine catalysis: benzoyloxylation and aldol
reaction
Authors: Mio Shimogaki, Aika Takeshima, Taichi Kano, and Keiji
Maruoka
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000073
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000073
Supported by

10.1002/ejoc.202000073
European Journal of Organic Chemistry
COMMUNICATION
Enantioselective synthesis of monosaccharide analogues by two-
step sequential enamine catalysis: benzoyloxylation and aldol
reaction
Mio Shimogaki,[a] Aika Takeshima,[a] Taichi Kano*[a] and Keiji Maruoka*[a,b,c]
Abstract: An efficient route to synthesize monosaccharide analogues
in an enantio- and diastereoselective manner is described. Three
contiguous stereocenters can be constructed via enantioselective
benzoyloxylation of aldehydes using a chiral secondary amine
catalyst and a subsequent aldol reaction of the resulting α-
benzoyloxyaldehydes with the protected dihydroxyacetones using
chiral amino acid catalysts, and single diastereomers were obtained
with excellent enantioselectivity
.
Monosaccharides are widespread in nature and play important
roles in an organism. Among them, hexoses, which are roughly
divided into aldohexose and ketohexose, are the most widely
distributed monosaccharides which also exist as glycosides,
oligosaccharides and polysaccharides. They are one of the
materials that living organisms use most frequently as energy
sources. Aldohexoses serve as an energy source and also form
a complex with polysaccharides, lipids and proteins to perform
various functions in vivo. Ketohexoses also offer great potential
for pharmaceutical and synthetic chemistry applications as well
as nutrients of food.[1] However, they are defined as rare sugars
except for D-fructose and their natural abundance is low.
Therefore, the development of efficient methodologies for
synthesis of ketohexoses and their analogues is highly desirable.
De novo synthesis of hexoses from simple aldehydes using
amino acid catalysts has attracted much attention over the last
two decades.[2–6] In 2004, MacMillan and co-workers reported the
two-step synthesis of protected aldohexoses through the proline-
catalyzed enantioselective aldol reaction followed by the Lewis
acid-mediated diastereoselective Mukaiyama aldol reaction
(Scheme 1a).[3] Córdova and co-workers described the proline-
catalyzed cross-aldol reaction, in which aldohexose analogues
were formed by assembling three aldehydes with excellent
chemo-, diastereo-, and enantioselectivity (Scheme 1b).[4c]
Scheme 1. Enantioselective organocatalyzed synthesis of hexoses.
Dihydroxyacetone-based aldol reaction is a powerful tool for the
construction of carbohydrates,[7,8] and this method is widely used
for ketohexose synthesis. In the previous reports, the aldol
reaction of dihydroxyacetone derivatives was carried out using
chiral α,β-dioxyaldehydes with an α-stereogenic center (Scheme
1c).[5–7] Meanwhile, we have developed novel chiral
tritylpyrrolidines, which were found to be efficient secondary
amine catalysts for enantioselective benzoyloxylation of
aldehydes.[9–11] We conceived that stereoselective synthesis of
ketohexose analogues can be achieved through the
enantioselective benzoyloxylation and the aldol reaction of the
[a]
[b]
M. Shimogaki, A. Takeshima, Prof. Dr. T. Kano
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: kano@kuchem.kyoto-u.ac.jp
http://kuchem.kyoto-u.ac.jp/yugo/
Prof. Dr. K. Maruoka
Graduate School of Pharmaceutical Sciences
Kyoto University, Sakyo, Kyoto 606-8501, Japan
Guangdong University of Technology, Guangzhou 510006 (China)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
http://www.pharm.kyoto-u.ac.jp/orgcat/index.html
School of Chemical Engineering and Light Industry
Guangdong University of Technology, Guangzhou 510006 (China)
[c]
Supporting information for this article is given via a link at the end of
the document.
resulting
α-benzoyloxyaldehydes
with
dihydroxyacetone
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Table 1. Syn-selective aldol reaction of the 1 with (rac)–2a.[a]
derivatives. In the amine-catalyzed aldol reaction, Z-enamine and
E-enamine intermediates afford syn- and anti-adducts,
respectively.[12] The stereochemistry of the enamine intermediate
can be controlled by the combination of the amine catalyst and
substrate. It is considered that several ketohexose analogues with
controlled three stereogenic centers can be synthesized by
performing the aldol reaction between each enamine intermediate
and chiral α-benzoyloxyaldehydes formed by the enantioselective
benzoyloxylation. Herein, we report an efficient enantioselective
synthesis of ketohexose analogues by two-step sequential
enamine catalysis consisting of chiral amine-catalyzed
benzoyloxylation of aldehydes followed by the amino acid-
catalyzed aldol reaction with dihydroxyacetones.
First, since the synthetic method for optically enriched α-
benzoyloxyaldehydes has already been established, the aldol
reaction between a dihydroxyacetone derivative and an α-
benzoyloxyaldehyde was investigated. We chose the TBS-
protected dihydroxyacetone 1 as a donor and primary amines as
a catalyst to form the Z-enamine intermediate effectively (Table
1).[13] In the presence of L-tryptophan, the reaction of 1 with
racemic α-benzoyloxyaldehyde 2a in DMSO, DMF or N-
methylpyrrolidone (NMP) was carried out (entries 1–3).[12d,14]
Among the solvent tested, NMP showed the highest yield and was
selected for further study. The reactions using other amino acid
catalysts gave the products in low yield due to the low solubility of
catalysts (entries 4–6). Therefore, highly soluble catalysts were
then employed. Use of the TBS-protected L-threonine (O-TBS-L-
Thr) gave the major product 3a in 43% yield and two other
diastereomers were obtained in total 29% yield (entry 7).[15] The
reaction using 3,3-diphenyl-L-alanine hardly proceeded in spite of
high solubility (entry 8). Reducing the amount of 1 from two
equivalents to one equivalent decreased the yield (entry 9). Use
of 5 equivalents of 1 increased the yield and 3a was obtained in
49% yield with 93% ee along with a mixture of minor
diastereomers in total 41% yield (entry 10). This result indicated
that there is matched/mismatched relationship between α-
benzoyloxyaldehydes and the catalyst. Almost all (S)-
benzoyloxyaldehyde (ca. 46%) was preferentially consumed
through the enantioselective syn–selective aldol reaction.
Therefore, the other minor diastereomers would be formed from
(R)-benzoyloxyaldehyde through the enantioselective syn- and
anti-selective aldol reaction. Incidentlly, the reaction using tBu-
protected L-threonine (O-tBu-L-Thr) gave a similar result (entry
11).[6c,12d] In terms of accessibility, O-TBS-L-Thr was selected for
further study. The reaction with O-TBS-D-Thr proceeded to give
Entry
1
Catalyst
Solvent
DMSO
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
t (h)
63
Yield [%][b] (dr)
9 (9:0:0:0)
L-tryptophan
L-tryptophan
L-tryptophan
L-phenylalanine
L-valine
2
63
24 (14:7:3:0)
44 (24:14:6:0)
10 (10:0:0:0)
Trace
3
110
42
4
5
52
6
L-threonine
110
39
Trace
7
O-TBS-L-Thr
3,3-diphenyl-L-alanine
O-TBS-L-Thr
O-TBS-L-Thr
O-tBu-L-Thr
O-TBS-D-Thr
O-TBS-DL-Thr
72 (43:20:9:0)
5 (5:0:0:0)
8
72
9[c]
10[d,e]
11[d]
12[d]
13[d]
101
112
112
60
62 (38:15:9:0)
90 (49:27:14:0)
91 (49:26:16:0)
76 (46:21:9:0)
82 (69:9:4:0)
41
[a] Reactions were performed on a 0.1 mmol scale in 0.1 mL of NMP. [b] 1H
NMR yield utilizing 1,1,2,2-tetrachloroethane as an internal standard. [c] Use
of 1 (1 eq.). [d] Use of 1 (5 eq.). [e] Enantiomeric excess of major isomer
was 93%.
peroxide (BPO) in the presence of tritylpyrrolidine (S,R)-5 as a
catalyst in THF at 0 °C. After the reaction, NMP was added to
the mixture and THF was removed under reduced pressure.
Subsequently, O-TBS-L-Thr-catalyzed aldol reaction of 1 with
the resulting (S)-α-benzoyloxyaldehyde gave the product 3a as
a single diastereomer in moderate yield with excellent
enantioselectivity (entry 1). On the other hand, use of O-TBS-
D-Thr in the second step led to a significant decrease in yield
andenantioselectivity due to the mismatched combination of
the catalyst and α-benzoyloxyaldehyde (entry 2). Since O-
TBS-L-Thr was identified as the matched catalyst for the aldol
reaction of (S)-α-benzoyloxyaldehyde formed by (S,R)-5,
several other aldehydes were examined under these
conditions. The reactions of 3-phenylpropanal (4b) and
branched 3-methylbutanal (4c) also afforded single
diastereomers in good yields with excellent enantioselectivities
(entries 3 and 4). We also examined β-heteroaldehyde
substrates to synthesize L-fructose analogues. The reaction
using 3-benzyloxypropanal (4d) gave only a trace amount of
the target product, because the first step reaction hardly
proceeded (entry 5). Fortunately, use of β-oxyaldehyde 4e
which has a bis(4-fluorophenyl)methyl group instead of benzyl
the enantiomeric products in good yield with
a similar
diastereoselectivity (entry 12). Using the racemic catalyst O-TBS-
DL-Thr, the ratio of the major isomer against minor isomers was
improved due to increased amount of the matched pair of the
catalyst and benzoyloxyaldehyde (entry 13). Based on these
results, we considered that one diastereomer could be
preferentially formed with high enantioselectivity by use of the
optically enriched α-benzoyloxyaldehydes and the matched
catalyst in the aldol reaction.
We then investigated the sequential enantioselective
benzoyloxylation and aldol reaction with the TBS-protected
dihydroxyacetone
1
(Table 2). The enantioselective
benzoyloxylation of hexanal (4a) was carried out using benzoyl
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Table 2. Sequential enantioselective benzoyloxylation of various aldehydes 4
and syn-selective aldol reaction with 1.[a]
can be attributed to decomposition of 6 caused by benzoic acid
which is a side product of the first step reaction. To overcome this
problem, the acidic substances were removed by passing through
Amberlite IRA–93ZU, which is a weakly basic ion exchange resin,
after benzoyloxylation (See the Supporting Information for details).
Consequently, the benzoyloxylation and the subsequent aldol
reaction using L-proline proceeded to give 7a as a single
diastereomer in 52% yield with 99% ee (Scheme 2b). Similarly,
the reaction with D-proline at the second step afforded 7b as a
single diastereomer in 39% yield with 99% ee (Scheme 2c).
Entry
1
4 (R)
Yield [%][b]
3a 56
ee [%]
99
4a Bu
2[c]
3
4a Bu
3a 5[d]
3b 59
–53
99
4b Bn
4
4c iPr
3c 52
99
5
4d CH2OBn
4e CH2OCH(4-F-C6H4)2
4f CH2SiPhMe2
4g CH2NHCbz
4g CH2NHCbz
3d trace
3e 40
nd
6
99
7
3f 44[e]
3g 43
95
8
99
Figure 1. X–ray crystal structure of 3h. CCDC: 1955026.
9[f]
3h 46
99
[a] Reactions were performed on a 0.1 mmol scale. [b] Isolated yield. [c] O-
TBS-D-Thr was used instead of O-TBS-L-Thr. [d] Other two diastereomers
(total 14%) were obtained. [e] Another diastereomer (7%) was obtained. [f]
p-Bromobenzoyl peroxide was used instead of BPO.
Based on the results shown in Table 2, possible transition-
state models for the aldol reactions of (S)-α-benzoyloxyaldehydes
and the TBS-protected dihydroxyacetone 1 are proposed as
shown in Figure 2. In the nucleophilic addition to chiral α-
oxyaldehydes, the Cornforth model, which is based on dipole
minimization between the carbonyl group and the adjacent C–O
bond, is supported by recent theoretical and experimental
studies.[7b,17] The reaction of the mismatched pair turns out to be
slow and less stereoselective compared to that of the matched
pair because of the greater steric repulsion between the α-
group increased the yield drastically,[16] giving the product 3e in
moderate yield with high ee value (entry 6). The stereoselectivity
of the reaction using 3-(dimethyl(phenyl)silyl)propanal (4f) slightly
decreased and another diastereomer was also obtained (entry 7).
The reaction of the N-Cbz-protected β-amino aldehyde 4g
proceeded well to give 3g in moderate yield with high
enantioselectivity (entry 8). When p-bromobenzoyl peroxide was
used instead of BPO, a similar result was obtained (entry 9). The
absolute configuration of the product 3h was determined by X-ray
crystal structure analysis (Figure 1), and was consistent with the
expected stereochemistry in the reaction using (S,R)-5 and O-
TBS-L-Thr. Those of other products were assigned by analogy of
3h.
In order to provide other ketohexose analogues, the anti-
selective aldol reaction through the E-enamine intermediate was
examined. In the presence of D,L-proline catalyst, the aldol
reaction of racemic α-benzoyloxyaldehyde 2a with 2,2-dimethyl-
1,3-dioxane-5-one (6) (dioxanone) in dimethylsulfoxide afforded
two diastereomers in a ratio of approximately 1:1.[8a] This reaction
did not exhibit the match/mismatch effects between the chirality
of α-benzoyloxyaldehyde and that of the catalyst. The sequential
enantioselective benzoyloxylation of aldehyde 4a and the aldol
reaction with the dioxanone 6 using L-proline was then carried out
according to the previous method for the synthesis of 3. However,
the target product 7a was not observed (Scheme 2a). This result
Scheme 2. Enantioselective benzoyloxylation of aldehyde 4a and anti-selective
aldol reaction with the dioxanone 6.
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reaction of (S)-α-benzoyloxyaldehyde with 1.
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steric repulsion between the α-oxyaldehyde and the enamine
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enamine intermediate, and both diastereomers 7a and 7b can be
formed.
In summary, we have achieved a highly enantio- and
diastereoselective synthesis of ketohexose analogues through
enantioselective benzoyloxylation using the secondary amine
catalyst and the subsequent aldol reaction using amino acid
catalysts. In the second step,the primary amine catalyst and the
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TBS-protected
dihydroxyacetone
form
the
Z-enamine
intermediate, giving syn-aldol products as single diastereomers.
In this case, the stereogenic center formed in the first step
affected the reaction rate of the second step. On the other hand,
the proline catalyst and the dioxanone form the E-enamine
intermediate, giving anti-aldol products. The stereogenic center
formed in the first step had a small effect on the reaction rate in
the second step, and it was possible to provide two different
diastereomers, respectively, depending on the configuration of
the proline catalyst used.
[9]
M. Shimogaki, H. Maruyama, S. Tsuji, C. Homma, T. Kano, K. Maruoka,
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This work was supported by JSPS KAKENHI Grant Numbers
JP17H06450, JP26220803, JP18H01975, and JP18J01780. M. S.
is grateful for Fellowships for Young Scientists from the Japan
Society for the Promotion of Science (JSPS). We are grateful to
Mr. T. Yamakado for performing X-ray crystallographic studies.
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Keywords: asymmetric synthesis • aldol reaction •
benzoyloxylation • carbohydrates • organocatalysis
[13] The use of unprotected dihydroxyacetone as a donor resulted in a
complex mixture in the syn-selective aldol reaction.
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Entry for the Table of Contents
Key Topic
Organocatalysis
COMMUNICATION
Mio Shimogaki, Aika Takeshima, Taichi
Kano,* Keiji Maruoka*
Page No. – Page No.
Enantioselective synthesis of
monosaccharide analogues by two-
step sequential enamine catalysis:
benzoyloxylation and aldol reaction
Synthesis of monosaccharide analogues in an enantio- and diastereoselective manner
has been investigated. Asymmetric benzoyloxylation and subsequent aldol reaction
using two amine catalysts effectively give monosaccharide analogues with controlled
three stereogenic centers.
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