Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls

Article abstract of DOI:10.1021/acs.orglett.0c01407

β-Turn tetrapeptides were demonstrated to catalyze asymmetric aldol reaction of α-branched aldehydes and α-carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to biomimetically synthesize acyclic all-carbon quaternary center-bearing 1,4-dicarbonyls in high yield and excellent enantioselectivity under mild conditions. The spatially restricted environment of the tetrapeptide warrants high enantioselectivity and yield with broad substrates. Using this protocol, (R)-pantolactone, the key intermediate of vitamin B5, was readily accessed in a practical, efficient, and environmentally benign process from inexpensive starting materials.

Full text of DOI:10.1021/acs.orglett.0c01407

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Letter
Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of
Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls
Zhi-Hong Du, Bao-Xiu Tao, Meng Yuan, Wen-Juan Qin, Yan-Li Xu, Pei Wang, and Chao-Shan Da*
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ABSTRACT: β-Turn tetrapeptides were demonstrated to catalyze asymmetric aldol reaction of α-branched aldehydes and α-
carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to biomimetically synthesize acyclic all-carbon quaternary center-bearing
1,4-dicarbonyls in high yield and excellent enantioselectivity under mild conditions. The spatially restricted environment of the
tetrapeptide warrants high enantioselectivity and yield with broad substrates. Using this protocol, (R)-pantolactone, the key
intermediate of vitamin B5, was readily accessed in a practical, efficient, and environmentally benign process from inexpensive
starting materials.
limited α-branched aldehydes in insufficient enantioselectiv-
ldol reaction is commonly used in preparing diverse chiral
Abioactive compounds and thus has always been widely ity.4,5 Mahrwald and co-worker made a seminal contribution in
studied.1 Catalytic asymmetric cross-aldol reaction of α-
performing the cross-aldol reaction of ethyl glyoxylate with
enolizable aldehydes, achieving good yields and enantioselec-
tivity (85% yield and 79% ee) with 10% L-His as an
organocatalyst.4 Additionally, Hayashi’s group employed
diphenylprolinol silyl ether to catalyze the same reaction to
construct all-carbon quaternary stereogenic centers in moder-
ate to good enantioselectivity but with poor diastereoselectiv-
ity.5 And notably, the reaction of α-branched aldehydes and α-
ketoaldehydes for 1,4-dicarbonyls has not been disclosed to
date. Therefore, it is highly anticipated to develop a new
efficient strategy to synthesize highly enantioenriched 1,4-
dicarbonyls by cross-aldol reaction of α-branched aldehydes
with glyoxylates and especially with α-ketoaldehydes.
branched aldehydes and α-carbonyl aldehydes can directly
produce chiral 2-hydroxy-3,3-disubstituted 1,4-dicarbonyls
bearing an acyclic all-carbon quaternary center. These 1,4-
dicarbonyl motifs are commonly found in natural products as
well as biologically and pharmaceutically active compounds,
such as extensively biologically and pharmaceutically active
coenzyme A (AC-1, Figure 1) and glucocorticoids AC-3 and
AC-4.2,3
To the best of our knowledge, catalytically asymmetric
preparation of these 1,4-dicarbonyls is rarely reported, except
for the recently disclosed reaction of ethyl glyoxylate and
Synthetic short peptides are ideal surrogates of enzymes and
have been utilized to biomimetically catalyze numerous highly
enantioselective organic transformations.6,7 In comparison to
enzymes, peptides are more easily accessible, modifiable, and
well compatible to varied conditions.8 Although they
reportedly catalyze asymmetric Aldol reactions, the successful
substrates are mainly limited to acetone and cyclohexanone as
Received: April 27, 2020
Figure 1. Bioactive compounds bearing 2-hydroxy-3,3-disubstituted
1,4-dicarbonyl motif.
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© XXXX American Chemical Society
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aldol donors.9 Challengingly, the new arena of alkyl aldehydes,
especially α-branched alkyl aldehydes, as aldol donors is
expected to be explored with catalytic peptides. β-Turn
tetrapeptides constitute a range of successful artificial enzymes
in organic transformations.10 X-ray analysis of a novel β-turn
tetrapeptide, designed and synthesized by us based on our
previous work,11 shows that the catalytic terminal NH2 and
COOH groups both locate on the same side of the turn plane
(Figure 2). The terminal bulky i-Bu and t-Bu groups position
a
Table 1. Optimization of Reaction Conditions
cat./
mol %
1a
(mmol)
yield
b
ee
(%)
c
entry
solvent
t (h)
(%)
1
2
3
4
5
6
7
8
A/5
A/5
A/5
B/5
C/5
D/5
E/5
F/5
B/5
B/5
B/5
B/5
B/5
B/5
B/2.5
B/1
G/5
H/5
I/5
2.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
72
72
72
72
72
72
72
72
48
72
48
48
24
24
36
48
72
48
48
24
24
120
120
74
79
70
85
80
59
80
84
87
86
91
90
84
98
98
77
34
43
65
50
44
26
94
94
89
97
91
75
91
84
95
98
86
98
91
99
99
95
70
48
75
93
97
78
55
Figure 2. X-ray of a tetrapeptide (ent-B, NH2-DTle-Pro-Gly-DLeu-
OH, CCDC 1940092).
9
roughly on the same side as the NH2 and COOH groups and
effectively shade the two ends of the tetrapeptide. In the
reaction of α-branched aldehydes and α-carbonyl aldehydes,
the plane and the two bulky alkyl groups should form an
idealistic spatially restricted chiral environment and thus
largely limit the conformation freedom of the transition state
complex and the attacking direction from the α-branched
aldehyde nucleophile to the α-carbonyl aldehyde electrophile,
probably enabling a highly asymmetric induction. Herein, we
disclose our initial results of asymmetric cross-aldol reaction of
α-branched aldehydes with glyoxylates and first with α-
ketoaldehydes biomimetically catalyzed by low-loading β-turn
tetrapeptides with excellent enantioselectivity and high yield.
The work was initiated with the typical reaction of
isobutyraldehyde and ethyl glyoxylate at room temperature
catalyzed by β-turn tetrapeptide A (Table 1, entry 1). The
reaction proceeded smoothly with good yield and excellent
enantioselectivity (74% yield and 94% ee), indicating the
tetrapeptide was suitable for this reaction. Investigation of the
loading of isobutyraldehyde revealed 2.0 equiv of isobutyr-
aldehyde was ideal in view of the yield and enantioselectivity
(entries 1−3). Subsequently, five other tetrapeptides B−F
were tested. All of the peptides smoothly catalyzed the reaction
with good to high enantioselectivity. Notably, self-aldol side-
reaction of isobutyraldehyde was not detactable.4a Tetrapep-
tide B, bearing the largest t-Bu side chain group at the N-
terminus, achieved the highest enantioselectivity (entries 2, 4−
8), confirming our postulation about the positive effect of the
bulky side chain group on the asymmetric induction. For the
solvent, MeCN is optimal (entries 4, 9−14). Tetrapeptide B
loading can be reduced to 2.5 mol % without erosion of the
yield and enantioselectivity (entries 14−16).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
ClC2H4Cl
MeOH
THF
MeOtBu
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
J/5
K/5
L/5
M/5
17
a
b
Ethyl glyoxylate 2a (0.5 mmol, 50% in toluene). Isolated yield.
c
Determined with the p-nitrobenzoate of 3a by chiral HPLC. The
configuration was assigned by comparing the optical rotation
direction of 3a with its reported datum.4a
To demonstrate the structural superiority of tetrapeptide B,
tert-leucine G, dipeptide H, and tripeptide I were investigated
(Table 1, entries 14 vs 17−19). tert-Leucine made the reaction
very sluggish and resulted in moderate enantioselectivity and a
very low yield, with the self-aldol side-reaction of isobutyr-
aldehyde detectable. Dipeptide H sharply decreased the
enantioselectivity although it achieved a higher yield than
tert-leucine G. Tripeptide I apparently displayed superior
efficiency to tert-leucine and dipeptide H in view of the yield
and enantioselectivity although its C-terminal amino acid
residue is an achiral glycine.12 But tripeptide I obtained a much
lower yield and enantioselectivity than tetrapeptide B, probably
B
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because tripeptide I cannot form a spatially restricted chiral
environment like tetrapeptide B.
Table 2. Optimization of Aldol Reaction Conditions of
Phenyl Glyoxal
a
To investigate the roles of the terminal COOH and NH2
groups of tetrapeptide B, tetrapeptides J−M were investigated
(entries 14 vs 20−23). Tetrapeptide J, with C-terminal COOH
protected by benzyl ester, similarly realized excellent 93%
enantioselectivity but sharply decreased the yield. While the C-
terminal COOH was changed into a secondary amide,
tetrapeptide K slightly increased the enantioselectivity to
97%, but the yield was not accompanyingly increased. These
two cases apparently reveal the indispensability of the C-
terminal COOH in tetrapeptide B to the transformation.13
Tetrapeptide L, with a N-terminal secondary amine group,
abruptly decreased both the yield and enantioselectivity,
unambiguously indicating the importance of the N-terminal
NH2 to both the yield and enantioselectivity. Tetrapeptide M,
with a N-terminal secondary amine group and C-terminus
benzyl ester, further diminished the yield and enantioselectivity
in comparison with tetrapeptide L. Therefore, the N-terminus
NH2 and C-terminus COOH groups are both essential to high
yield and enantioselectivity.
b
c
entry
additive (mg)
solvent
t (h)
yield (%)
ee (%)
1
2
3
4
5
−
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
72
48
48
24
12
16
53
60
55
85
95
99
99
99
99
99
99
4 Å (50)
MgSO4 (50)
Na2SO4 (50)
Na2SO4 (100)
Na2SO4 (100)
d
6
92
b
a
1.0 mmol of 1a and 0.5 mmol of 4a were used. Isolated yield.
Determined with the acetal of 5a and 2,2-dimethyl-1,3-propanediol
c
d
by chiral HPLC. 2.5 mol % B was used.
reduced the yield and prolonged the reaction time (entries 5 vs
6).
With this reoptimized reaction conditions, α-ketoaldehydes
were extensively explored with symmetric α-branched
aldehydes without a stereocenter (Scheme 2). Excitingly, the
Under the optimized reaction conditions, the substrate
scope was explored (Scheme 1). Clearly, this protocol is
Scheme 2. Catalytic Enantioselective Aldol Reaction of α-
Ketoaldehydes
Scheme 1. Catalytic Enantioselective Aldol Reactions of
Glyoxylates
a
a
a
1.0 mmol of 1 and 0.5 mmol of 2 were used. Isolated yield. Ee was
b
determined with the p-nitrobenzoate of 3 by chiral HPLC. The
enantiomer of B, ent-B, was used.
particularly suitable to this aldol reaction with very high
enantioselectivity to all investigated aldehydes. While ent-B
(the enantiomer of tetrapeptide B) was used, enantiomers of
all the 1,4-dicarbonyl products were similarly realized with the
same high yield and enantioselectivity. Thus, ent-3a−ent-3c,
the intermediates of vitamin B5 and coenzyme A, can be
prepared in very high yield and enantioselectivity in an eco-
friendly manner through a catalytic asymmetric reaction for the
first time.
a
1.0 mmol of 1, 0.5 mmol of 4, and 100 mg of anhydrous Na2SO4
were used. Isolated yield. Ee was determined with the acetal of 5 and
2,2-dimethyl-1,3-propanediol by chiral HPLC. ent-B was used. Ee
was directly determined by chiral HPLC.
b
c
While replacing the glyoxylate to α-ketoaldehydes (in
monohydrate form), the reaction became slow and the yield
was moderate despite very high enantioselectivity (Table 2,
entry 1). Several additives were tested, and anhydrous Na2SO4
satisfactorily induced a remarkable effect on the yield (entries
2−4). An increase in Na2SO4 explicitly shortened the reaction
time and enhanced the yield without changing the
enantioselectivity (entries 4−5). Decreasing the tetrapeptide
B loading did not decrease the enantioselectivity but slightly
reaction is very idealistic for all of the investigated α-
ketoaldehydes. All the aryl glyoxals uniformly realized 99%
enantioselectivity (5a−5t and 5w−5x), including two hetero-
aryl glyoxals (5s, 5t). Even the alkenyl and alkyl glyoxals also
achieved high yield and enantioselectivity (5u, 5v). While
using ent-B instead of B, high yield and enantioselectivity of
the corresponding enantiomer of the 1,4-dicarbonyl were both
C
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maintained (5a vs ent-5a). Therefore, pairs of highly
enantiopure enantiomers of the 1,4-dicarbonyls should be
readily accessible by simply switching two tetrapeptides with
each other: B and its enantiomer ent-B.
Scheme 4. Practicality Observation of the Transformation
Then, the reaction was extended to explore the asymmetric
α-branched aldehyde with an α-carbon stereocenter to
construct 1,4-dicarbonyls bearing an acyclic all-carbon
quaternary stereocenter (Scheme 3). Highly enantioselective
Scheme 3. Catalytic Stereoselective Aldol Reaction of α-
a
Branched Aldehydes and α-Carbonyl Aldehydes
Scheme 4),8 the intermediate for synthesis of vitamin B5,2d
(R)-panthenol and (R)-pantetheine.15,16 Conventionally,
highly enantiopure (R)-pantolactone is achieved by biological
fermentation.17 In addition, ent-3a can be transformed into the
lactam 8 (iii, Scheme 4), the intermediate of the potent
inhibitor of cathepsin K.3a The 1,4-dicarbonyl 5i was readily
reduced into triol 9. X-ray analysis of the crystal of triol 9
(CCDC 1940111) enabled the absolute configuration of 5i to
be determined. Thus, the configuration of other 1,4-
dicarbonyls 5 in Scheme 2 is deduced from 5i (iv, Scheme 4).
Based upon our investigations in this work and previous
reports, the speculated reaction mechanism is shown in
Scheme 5.9,18 The β-turn plane and two terminal bulky side
Scheme 5. Speculated Reaction Mechanism
a
1.0 mmol of 1, 0.5 mmol of 4, and 100 mg of anhydrous Na2SO4
were used. Isolated yield. Ee and dr value were determined by chiral
b
HPLC, and the reported ee is anti/syn. Ethyl glyoxylate was used.
construction of an acyclic all-carbon quaternary stereocenter is
a big challenge for the numerous degrees of freedom of the
molecule structure.5,14 Under the reconstructed reaction
conditions (for data for reoptimization of the reaction
conditions, see p S4 in Supporting Information), all reactions
proceeded smoothly and uniformly achieved excellent
enantioselectivity. The predominant diastereomers are anti,
determined by X-ray analysis of the crystal of 6a. The
diastereoselectivities are moderate to good. Methyl and ethyl
groups are two alkyl groups that were the most difficult to
differentiate at one carbon. Herein, 1,4-dicarbonyls bearing this
motif achieved more than 3:1 diastereoselectivity (Scheme 3,
6a−6c). While the ethyl group was replaced by a bulkier or
longer alkyl group, the diastereoselectivity changed little and
the highest dr value is higher than 4:1 for 6g and 6h (6d−6k).
Notably, α-branched aldehydes bearing an alkenyl group
similarly achieved excellent enantioselectivity and a high yield
(6j). Finally, the diastereoselectivity can be raised to 8:1 with
ethyl glyoxylate as the electrophile (6l−6m).
chain groups of tetrapeptide B largely sterically constrain the
rotation of both planes of the enamine from isobutyraldehyde
with tetrapeptide B and the aldehyde group of ethyl glyoxylate
in the transition state II. In this spatially constrained chiral
environment, the attack only on the Si-face of ethyl glyoxylate
is sterically admitted, leading to highly enantiopure (S)-3a.
The intermediates were detected by HR-MS.
In summary, we first successfully demonstrated the peptide-
catalyzed biomimetic cross-aldol reaction of α-branched
aldehydes with glyoxylates and α-ketoaldehydes for enantioen-
riched 1,4-dicarbonyls bearing an acyclic all-carbon quaternary
center in high yield, excellent enantioselectivity, and good
The model aldol reaction of isobutyraldehyde and ethyl
glyoxylate was enlarged to gram scale without reduction in
yield and ee with ent-B as the catalyst (i, Scheme 4). The
product ent-3a was readily reduced into (R)-pantolactone (ii,
D
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diastereoselectivity under mild reaction conditions. This work
can be used to efficiently synthesize extensively utilized and
largely commercially demanded (R)-pantolactone in very high
enantioselectivity and yield from inexpensive and green
starting materials.
Lanzhou University State Key Laboratory of Applied Organic
Chemistry for helpful discussions on HPLC analysis.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01407.
Reoptimization of reaction conditions for acyclic all-
carbon quaternary stereocenter-bearing 1,4-dicarbonyls,
peptides synthesis, experimental procedures, character-
ization of compounds, NMR and HPLC spectra for
compounds (PDF)
Accession Codes
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supplementary crystallographic data for this paper. These
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data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
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AUTHOR INFORMATION
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Corresponding Author
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Heikinheimo, A.; Neuburger, M.; Gademann, K. Formal Total
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Isoleucine-Catalyzed Direct Asymmetric Aldol Addition of Enolizable
Aldehydes. Org. Lett. 2012, 14, 2180−2183. (c) Scheffler, U.;
Mahrwald, R. Histidine-Catalyzed Asymmetric Aldol Addition of
Enolizable Aldehydes: Insights into its Mechanism. J. Org. Chem.
2012, 77, 2310−2330. (d) Lam, Y.-h.; Houk, K. N.; Scheffler, U.;
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(e) Heidlindemann, M.; Hammel, M.; Scheffler, U.; Mahrwald, R.;
Chao-Shan Da − Institute of Biochemistry and Molecular
Biology, School of Life Sciences and State Key Laboratory of
Applied Organic Chemistry, and Key Lab of Preclinical Study
for New Drugs of Gansu Province, Lanzhou University,
Lanzhou 730000, China; orcid.org/0000-0003-1306-
4348; Email: dachaoshan@lzu.edu.cn
Authors
Zhi-Hong Du − Institute of Biochemistry and Molecular Biology,
School of Life Sciences, Lanzhou University, Lanzhou 730000,
China
Bao-Xiu Tao − Institute of Biochemistry and Molecular Biology,
School of Life Sciences, Lanzhou University, Lanzhou 730000,
China
Meng Yuan − Institute of Biochemistry and Molecular Biology,
School of Life Sciences, Lanzhou University, Lanzhou 730000,
China
Wen-Juan Qin − Institute of Biochemistry and Molecular
Biology, School of Life Sciences, Lanzhou University, Lanzhou
730000, China
Yan-Li Xu − Institute of Biochemistry and Molecular Biology,
School of Life Sciences, Lanzhou University, Lanzhou 730000,
China
Pei Wang − School of Basic Medical Sciences, Ningxia Medical
University, Yinchuan 750004, China
̈
Hummel, W.; Berkessel, A.; Groger, H. Chemoenzymatic Synthesis of
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01407
Vitamin B5-Intermediate (R)-Pantolactone via Combined Asymmet-
ric Organo- and Biocatalysis. J. Org. Chem. 2015, 80, 3387−3396.
(5) Hayashi, Y.; Shomura, H.; Xu, Q.; Lear, M. J.; Sato, I.
Asymmetric Aldol Reaction of α,α-Disubstituted Acetaldehydes
Catalyzed by Diphenylprolinol Silyl Ether for the Construction of
Quaternary Stereogenic Centers. Eur. J. Org. Chem. 2015, 2015,
4316−4319.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is financially supported by Hangzhou Xinfu Science
& Tech Co. Ltd. We thank engineer Hong-Yu Wang at
■
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Based Enzyme Models. In Amino Acids, Peptides and Proteins in
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