Organocatalyzed Asymmetric Aldol Reaction of α-Keto Amides with A Tripeptide Catalyst

Article abstract of DOI:10.1055/a-1380-6436

An organocatalyzed asymmetric aldol reaction of α-keto amides was developed. An N-terminal 4- trans -siloxyproline-based tripeptide with an l - tert -leucine unit adjacent to the 4- trans -siloxyproline residue was used to catalyze the reaction between various α-keto amides and acetone, to produce the corresponding aldol adducts with up to 99% yield and 91% ee.

Full text of DOI:10.1055/a-1380-6436

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 829–832
letter
829
en
K. Kon et al.
Letter
Synlett
Organocatalyzed Asymmetric Aldol Reaction of -Keto Amides
with A Tripeptide Catalyst
Kazumasa Kon
O
Hiromu Takai
O
Takumu Kobayashi
Yoshihito Kohari*
Miki Murata
NH HN
O
0
0
0
0
-
0
0
0
2
-
5
8
4
9
-
6
9
0
5
O
HO
NH
(20 mol%)
O
OH
O
O
TBDPSO
H
H
N
N
Ar
R
Ar
R
+
Division of Applied Chemistry, Faculty of Engineering, Kitami
Institute of Technology, 165 Koencho, Kitami 090-8507,
Japan
MeOH
–40 °C
O
R = alkyl
(20 equiv)
up to 99% yield
up to 91% ee
kohari@mail.kitami-it.ac.jp
YDeMoivsaihsiClihookinrotrohoeafsKprAoio@hpnpamdrliiaenidgl.kCAihtuaetmhmoii-rsittr.ayc, .Fjpaculty of Engineering, Kitami Institute of Technology, 165 Koencho, Kitami 090-8507, Japan
Received: 28.12.2020
Accepted after revision: 02.02.2021
Published online: 02.02.2021
the nucleophilic addition of keto groups to yield endo- or
exocyclic optically active amides.3,4 To the best of our
knowledge, there are only two reports of asymmetric and
chemoselectively nucleophilic addition to the keto group of
acyclic -keto amides to synthesize acyclic ,-disubstitut-
ed -hydroxy amides.5 In 2015, Feng and co-workers re-
ported a magnesium-catalyzed asymmetric carbonyl–ene
reaction of ,-unsaturated -keto amides with 5-methy-
leneoxazoline [Scheme 1(a)].5a However, this reaction ex-
hibits shortcomings in terms of its efficacy and substrate
scope. In 2011, Xu and Wolf reported a copper-catalyzed
asymmetric Henry reaction of various -keto amides with
nitromethane to prepare 2-substituted 2-hydroxy-3-nitro-
propanamides with high yields and enantioselectivities
[Scheme 1(b)].5b
Although these two reported metal-catalyzed asym-
metric reactions are excellent synthetic methods, no or-
ganocatalyzed asymmetric and chemoselective nucleophil-
ic addition to the keto group of acyclic -keto amides to
construct acyclic ,-disubstituted -hydroxy amides has
been reported. Furthermore, the asymmetric addition of
simple ketones such as acetone, which have lower nucleo-
philicities than nitromethane (that is, the asymmetric aldol
reaction of -keto amides with simple ketones) is still diffi-
cult. Therefore, the organocatalyzed asymmetric aldol reac-
DOI: 10.1055/a-1380-6436; Art ID: st-2020-u0467-l
Abstract An organocatalyzed asymmetric aldol reaction of -keto
amides was developed. An N-terminal 4-trans-siloxyproline-based
tripeptide with an L-tert-leucine unit adjacent to the 4-trans-siloxypro-
line residue was used to catalyze the reaction between various -keto
amides and acetone, to produce the corresponding aldol adducts with
up to 99% yield and 91% ee.
Key words aldol reaction, asymmetric catalysis, peptide catalysis, or-
ganocatalysis, keto amides, hydroxy amides
Optically active acyclic ,-disubstituted -hydroxy
amides are skeletons that frequently occur in natural prod-
ucts and biologically active compounds.1 Therefore, new
methods for the stereoselective preparation of these com-
pounds are useful. Asymmetric nucleophilic addition to
acyclic -keto amides is a representative method for the
synthesis of these compounds. Although the use of asym-
metric nucleophilic additions to cyclic -keto amides (e.g.,
isatins) to synthesize optically active 3,3-disubstituted 2-
oxindoles is frequently reported,2 reports on reactions in-
volving acyclic -keto amides are relatively scarce.3–5 Also,
most reports involve asymmetric polyfunctionalization and
tBuHN
HO
(a)
O
N
Mg(OTf)2 (10 mol%)
chiral N,N’-dioxide (10 mol%)
O
H
N
N
tBu
Ph
Ph
Ph
(b)
+
O
O
CH2Cl2, 40 h
18% yield, >99% ee
Ph
O
Cu(OTf)2 (10 mol%)
chiral bisoxazolidine (10 mol%)
Et3N (20 mol%)
O
O2N
OH
O
H
H
N
N
R
Ph
R
Ph
MeNO2
+
MeCN, 0 °C, 24 h
up to 93% yield, 90% ee
O
Scheme 1 Catalytic asymmetric reactions to synthesis acyclic ,-disubstituted -hydroxy amides: (a) Feng and co-workers, (b) Wolf and co-workers
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 829–832
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

830
K. Kon et al.
Letter
Synlett
tion of -keto amides with simple ketones as nucleophiles
continues to be necessary and challenging.
Table 1 Optimization of the Reaction Conditions and Catalyst
O
We recently reported a tripeptide-catalyzed asymmetric al-
dol reaction of activated ketones with acetone to produce
optically active tertiary alcohols.6 In particular, H-Pro-Tle-
Gly-OH (1a) was an efficient catalyst for the reaction of -
keto esters, which exhibit an analogous acyclic 1,2-dicar-
bonyl structure to -keto amides [Scheme 2(a)].6c During
the course of our studies on the tripeptide-catalyzed asym-
metric aldol reactions of activated ketones, we expanded
the application of the tripeptide catalysts to the reaction of
-keto amides [Scheme 2(b)]. Here, we report an organocat-
alyzed asymmetric aldol reaction of -keto amides with ac-
etone in the presence of a tripeptide catalyst to synthesize
acyclic ,-disubstituted -hydroxy amides.
O
O
OH
H
H
N
1 (20 mol%)
+
N
Ph
Me
Ph
Me
solvent (0.1 mL)
0 °C, 3 d
O
O
4a
2a
3
(0.1 mmol)
(20 equiv)
R
O
O
O
1a: R = tBu
1b: R = Me
1c: R = H
O
1d: R = TBDPS
1e: R = H
NH HN
NH HN
HO
O
O
HO
NH
NH
RO
Entry
Catalyst
Solvent
Yield (%)a
eeb (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
MeOH
DMF
>99
16
11
19
–
65
25
38
29
–
2
3
CHCl3
THF
O
(a)
O
O
1a (20 mol%)
acetone (100 equiv)
4
OH
O
O
OR2
O
R1
R1
R2
NH HN
5
toluene
H2O
THF, 0 °C, 6 d
up to 95% yield, 88% ee
O
O
HO
NH
6
46
70
54
94
6
78
43
32
87
89
–
1a
7
EtOH
(b)
O
O
OH
8
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
O
H
H
N
N
1a-based tripeptide catalyst
R1
R2
R1
R2
9c,d
10c,e
11c,d,f
12c,d
13c,d
14c,d
15c,d
+
O
O
Scheme 2 (a) Our previous work: tripeptide-catalyzed direct asym-
metric aldol reaction of -keto esters. (b) This work: organocatalytic
asymmetric aldol reaction of -keto amides with acetone in the pres-
ence of a tripeptide catalyst to synthesize acyclic ,-disubstituted -
hydroxy amides.
–
10
55
94 (94)g
6
78
31
91
78
At the outset, we investigated the reaction conditions
for the asymmetric aldol reaction of N-methyl-2-oxo-2-
phenylacetamide (2a) with acetone (3) catalyzed by tripep-
tide 1a (Table 1, entries 1–11). The 1a-catalyzed reaction in
MeOH at 0 °C gave the corresponding -hydroxy amide 4a
in quantitative yield and 65% ee (entry 1). When an aprotic
solvent such as DMF, CHCl3, THF, or toluene was used, the
reaction rate and enantioselectivity declined compared
with the reaction in MeOH (entries 2–5). In contrast, with
H2O as the reaction medium, although the enantioselectivi-
ty improved, the reaction rate decreased (entry 6). Further-
more, the reaction rates and enantioselectivities of the re-
action in EtOH and i-PrOH were lower than those of the re-
a Determined by 1H NMR analysis with 1,1,2,2-tetrachloroethane as inter-
nal standard.
b Determined by HPLC analysis.
c For 5 days.
d At –40 °C.
e At –70 °C.
f In the presence of trifluoroacetic acid (20 mol%).
g Isolated yield after silica gel column chromatography.
Next, we investigated the efficacy of catalysts for the re-
action between 2a and acetone (3) under the optimized re-
action conditions (Table 1, 12–15). Catalysts 1b and 1c, in
which the tert-butyl group of 1a was replaced by a Me
group and a H atom, respectively, were used as catalysts, re-
vealing the effect of the tert-butyl group of 1a in the 1a-cat-
alyzed reaction (entries 12 and 13). 1b- and 1c-catalyzed
reactions produced 4a with lower yields and enantioselec-
tivities than did the 1a-catalyzed reaction. These results in-
dicate that the tert-butyl group of 1a plays an important
role in the reaction rate and enantioselectivity. Further-
more, the reaction catalyzed by the 4-trans-siloxyproline-
based catalyst 1d progressed with a similar reaction rate
and a higher enantioselectivity compared with the 1a-cata-
lyzed reaction (entry 14). However, the rate and enantiose-
lectivity of reaction with the 4-trans-hydroxyproline-based
catalyst 1e were considerably lower (entry 15). Therefore,
action in MeOH (entries
7 and 8). Additionally, the
enantioselectivity was considerably improved when the re-
action was conducted in MeOH at –40 °C compared with
that in MeOH at 0 °C (entry 9). However, the reaction at –70
°C yielded only a small amount of 4a (entry 10). The reac-
tion hardly progressed in the presence of trifluoroacetic
acid (entry 11). On the basis of these investigation (entries
1–11), we chose the reaction between 2a and acetone (3;
20 equiv) in MeOH at –40 °C for five days as the best reac-
tion conditions (entry 9).
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 829–832

831
K. Kon et al.
Letter
Synlett
4-trans-siloxyproline-based tripeptide 1d was found to be
the best catalyst for this reaction, and the 1d-catalyzed re-
action under the optimized reaction conditions afforded 4a
with a 94% yield and a 91% ee (entry 14).
O
(a)
(b)
OH
H
O
O
H
N
1d (20 mol%)
N
+
Me
Me
MeOH (0.1 mL)
–40 °C, 5 d
O
O
4i
82% yield, 16% ee
2i
3
The substrate scope of this reaction under the optimized re-
action conditions was then studied (Scheme 3). -Keto am-
ides 2a–c with various alkyl groups on the secondary amide
nitrogen were subjected to the reaction. The N-methyl am-
ide 2a reacted with acetone (3) to give the corresponding -
hydroxy amide 4a with high chemical yield and high enan-
tioselectivity. The reactions of the N-ethyl amide 2b and of
the N-isopropyl amide 2c similarly gave products 4b and
4c, respectively, in good chemical yields and high enantio-
selectivities. Further, -keto amides with sterically more
compact alkyl groups on the secondary amide group pro-
vided the corresponding -hydroxy amides 4a–c with high-
er chemical yields and enantioselectivities. N,N-Dimethyl-
2-oxo-2-phenylacetamide did not react with acetone (3).
The effects of the addition of electron-withdrawing and -
donating groups at the 4-position of the phenyl group in 2a
were then investigated. The reaction of 2d with a bromo
group as a weakly electron-withdrawing group produced
4d with a high chemical yield and enantioselectivity. Simi-
larly, amide 2e, which contained a trifluoromethyl group
instead of the bromo group in 2d, reacted smoothly and
stereoselectively with 3. The reaction of 2f with an elec-
tron-donating methyl group afforded 4f with a high enantio-
selectivity and medium chemical yield. Furthermore, the al-
dol reaction of 2g, which had a bromo group at the 3-posi-
(0.1 mmol)
(20 equiv)
O
H
O
O
1d (20 mol%)
MeOH (0.1 mL)
no reaction
+
or
N
Me
O
–40 °C, 5 d
2a
5
6
(0.1 mmol)
(20 equiv)
(20 equiv)
Scheme 4 Failed reactions: (a) the reaction of ,-unsaturated -keto
amides 2i and 3; (b) the reactions of 2a with cyclohexanone (5) or bu-
tan-2-one (6)
tion of the phenyl group, afforded 4g. The reaction of N-
methyl-2-(2-naphthyl)-2-oxoacetamide (2h) was highly
stereoselective, producing 4h. Thus, the 1d-catalyzed reac-
tions of various -keto amides 2a–h afforded the corre-
sponding -hydroxy amides 4a–h with high enantioselec-
tivities.
Next, the reaction between the ,-unsaturated -keto
amide 2i and acetone (3) was examined [Scheme 4(a)]. Al-
though this reaction progressed smoothly, the enantiose-
lectivity of this reaction was lower than that of the reaction
of 2a. We believe that the reason for the lower enantioselec-
tivity of the former reaction compared with the latter is re-
lated to the difference in the steric environment of the sty-
ryl group in 2i and the phenyl group in 2a. Next, cyclohexa-
none (5) and butan-2-one (6) were used as nucleophiles
[Scheme 4(b)]; however, these reactions did not afford cor-
responding aldol adducts, probably, because of the bulki-
ness of 5 and 6.
O
O
O
OH
O
H
N
1d (20 mol%)
H
N
+
R1
R2
R1
R2
MeOH (0.1 mL)
–40 °C, 5 d
O
2
3
4
The catalytic cycle of this reaction was assumed to be
similar to that of the proline-catalyzed asymmetric aldol re-
action (Figure 1).7 Therefore, acetone (3) is activated by
enamine formation through reaction with the amino group
of 1d. The C–C bond is then formed by nucleophilic addition
of the enamine to 2, generating the iminium–aldol interme-
diate. Finally, the aldol adduct is formed by hydrolysis of the
(0.1 mmol)
(20 equiv)
O
O
O
OH
O
OH
H
OH
O
H
N
H
N
N
Me
Et
iPr
O
4a
4b
4c
94% yield, 91% ee
82% yield, 85% ee
79% yield, 68% ee
O
O
O
OH
H
OH
H
OH
H
1d
4
3
N
N
N
Me
Me
Me
H2O
H2O
enamine
formation
O
O
O
hydrolysis
Br
F3C
Me
4d
4e
4f
92% yield, 90% ee
99% yield, 90% ee
34% yield, 91% ee
TBDPSO
O
O
O
O
OH
O
OH
O
N+
H
N
H
O
N
HN
HO
R
Me
Me
NH HN
O
O
CONHR’
HN
HO
N
Br
TBDPSO
–O
4g
90% yield, 86% ee
4h
76% yield, 89% ee
O
C–C bond formation
2
Scheme 3 Substrate scope. Isolated yields are reported; the ee was de-
termined by HPLC analysis.
Figure 1 A plausible catalytic cycle
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 829–832

832
K. Kon et al.
Letter
Synlett
iminium cation. In this reaction, the absolute configuration
of the aldol adduct 4 is determined at the C–C bond-forma-
tion step.
(3) For reactions using -keto amides as substrates, see: (a) Di
Sanza, R.; Nguyen, T. L. N.; Iqbal, N.; Argent, S. P.; Lewis, W.;
Lam, H. W. Chem. Sci. 2020, 11, 2401. (b) Xia, A.-B.; Pan, G.-J.;
Wu, C.; Liu, X.-L.; Zhang, X.-L.; Li, Z.-B.; Du, X.-H.; Xu, D.-Q. Adv.
Synth. Catal. 2016, 358, 3155. (c) Ishida, N.; Nečas, D.; Masuda,
Y.; Murakami, M. Angew. Chem. Int. Ed. 2015, 127, 7526.
(d) Hatano, M.; Nishimura, T. Angew. Chem. Int. Ed. 2015, 54,
10949. (e) Wang, L.; Ni, Q.; Blümel, M.; Shu, T.; Raabe, G.;
Enders, D. Chem. Eur. J. 2015, 21, 8033. (f) Joie, C.; Deckers, K.;
Raabe, G.; Ender, D. Synthesis 2014, 46, 1539. (g) Joie, C.;
Deckers, K.; Enders, D. Synthesis 2014, 49, 799.
(h) Goudedranche, S.; Pierrot, D.; Constantieux, T.; Bonne, D.;
Rodriguez, J. Chem. Commun. 2014, 50, 15605. (i) Shirai, T.; Ito,
H.; Yamamoto, Y. Angew. Chem. Int. Ed. 2014, 53, 2658.
(j) Raimondi, W.; del Mar Sanchez Duque, M.; Goudedranche,
S.; Quintard, A.; Constantieux, T.; Bugaut, X.; Bonne, D.;
Rodriguez, J. Synthesis 2013, 1659. (k) Yin, L.; Kanai, M.;
Shibasaki, M. Angew. Chem. Int. Ed. 2011, 50, 7620.
In conclusion, we have developed an organocatalyzed
asymmetric aldol reaction of -keto amides with acetone in
the presence of a tripeptide catalyst. The desired ,-disub-
stituted -hydroxy amides were obtained in up to 99% yield
and 91% ee. Further studies pertaining to the expansion of
the substrate scope, the determination of the absolute con-
figuration of the aldol adduct, and the investigation of the
origin of enantioselectivity are currently underway in our
group.
Funding Information
This work was supported by the Sasakawa Scientific Research Grant
(4) For reactions using ,-unsaturated -keto amides as substrates,
see: (a) Guo, Y.-J.; Guo, X.; Kong, D.-Z.; Lu, H.-J.; Liu, L.-T.; Hua,
Y.-Z.; Wang, M.-C. J. Org. Chem. 2020, 85, 4195. (b) Yang, X.-C.;
Liu, M.-M.; Mathey, F.; Yang, H.; Hua, Y.-Z.; Wang, M.-C. J. Org.
Chem. 2019, 84, 7762. (c) Liu, M.-M.; Yang, X.-C.; Hua, Y.-Z.;
Chang, J.-B.; Wang, M.-C. Org. Lett. 2019, 21, 2111. (d) Yao, Q.;
Yu, H.; Zhang, H.; Dong, S.; Chang, F.; Lin, L.; Liu, X.; Feng, X.
Chem. Commun. 2018, 54, 3375. (e) Lefranc, A.; Guénée, L.;
Contal, S. G.; Alexakis, A. Synlett 2014, 25, 2947. (f) Evans, D. A.;
Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem. Int. Ed.
1998, 37, 3372.
(2020-3029) from The Japan Science Society.
J
a
pa
n
S
c
i
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n
c
e
S
oc
i
ety(
2
0
2
0-3
0
2
9
)
Acknowledgment
We would like to thank Editage (www.editage.com) for English lan-
guage editing.
Supporting Information
Supporting information for this article is available online at
(5) (a) Luo, W.; Zhao, J.; Ji, J.; Lin, L.; Liu, X.; Mei, H.; Feng, X. Chem.
Commun. 2015, 51, 10042. (b) Xu, H.; Wolf, C. Angew. Chem. Int.
Ed. 2011, 50, 12249.
https://doi.org/10.1055/a-1380-6436.
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p
p
orti
n
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n
f
orm
a
ti
o
nS
u
p
p
orti
n
gInform
a
ti
o
n
(6) (a) Kon, K.; Kohari, Y.; Murata, M. Tetrahedron Lett. 2019, 60,
415. (b) Kon, K.; Kohari, Y.; Murata, M. Heterocycles 2019, 99,
841. (c) Kon, K.; Takai, H.; Kohari, Y.; Murata, M. Catalysts 2019,
9, 514.
(7) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122,
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References and Notes
(1) (a) Schneider, C. H.; Kasper, M. F.; De Weck, A. L.; Rolli, H.;
Angst, B. D. Allergy 1987, 42, 597. (b) Matumoto, N.; Momose, I.;
Umekita, M.; Kinoshita, N.; Chino, M.; Iinuma, H.; Sawa, T.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1998, 51, 1087. (c) Lu, S.-H.;
Yamagata, T.; Atuki, K.; Sun, L.; Smith, C. P.; Yoshimura, N.;
Chancellor, M. B.; De Groat, W. C. Brain Res. 2002, 946, 72.
(d) Schäcke, H.; Schottelius, A.; Döcke, W.-D.; Strehlke, P.;
Jaroch, S.; Schmees, N.; Rewinkel, H.; Hennekes, H.; Asadullah,
K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 227. (e) Oku, N.;
Krishnamoorthy, R.; Benson, A. G.; Ferguson, R. L.; Lipton, M. A.;
Phillips, L. R.; Gustafson, K. R.; McMahon, J. B. J. Org. Chem. 2005,
70, 6842. (f) Cantarini, M.; Fuhr, R.; Morris, T. Pharmacol. 2006,
77, 171. (g) Xie, W.; Ding, D.; Zi, W.; Li, G.; Ma, D. Angew. Chem.
Int. Ed. 2008, 47, 2844. (h) Lu, Z.; Van Wagoner, R. M.; Harper, M.
K.; Baker, H. L.; Hooper, J. N. A.; Bewley, C. A.; Ireland, C. M.
J. Nat. Prod. 2011, 74, 185.
(8) Aldol Products 4a–h; General Procedure
A mixture of 1d (20 mol, 10.7 mg), MeOH (0.1 mL), and
acetone (3; 2 mmol, 0.15 mL) was stirred at –40 °C for 10 min.
The appropriate -keto amide 2 (0.1 mmol) was added, and the
mixture was stirred at –40 °C for 5 d then concentrated under
reduced pressure. The aldol product was purified by column
chromatography (silica gel, hexane–EtOAc). The enantiomeric
excess of the aldol adduct was determined by chiral HPLC.
2-Hydroxy-N-methyl-4-oxo-2-phenylpentanamide (4a)
White solid, 20.8 mg (94%, 91% ee); mp 71–73 °C; []D23 +169.4
(c = 0.13, CHCl3). HPLC [Daicel CHIRALPAK AD-H, hexane–i-
PrOH (90:10), 1.0 mL/min, 254 nm, 35 °C]: tR (minor) = 10.9
min; tR (major) = 12.3 min. 1H NMR (600 MHz, CDCl3):  = 7.59–
7.57 (m, 2 H), 7.37–7.32 (m, 2 H), 7.28 (tt, J = 7.3, 1.5 Hz, 1 H),
6.78 (br s, 1 H), 5.34 (s, 1 H), 3.67 (d, J = 17.6 Hz, 1 H), 2.79 (d, J =
17.6 Hz, 1 H), 2.76 (d, J = 5.0 Hz, 3 H), 2.24 (s, 3 H). 13C NMR (150
MHz, CDCl3):  = 212.2, 174.1, 141.3, 128.4, 127.8, 124.4, 78.2,
50.8, 31.3, 26.1. HRMS (EI): m/z [M+] calcd for C12H15NO3:
221.1052; found: 221.1029.
(2) For selected reviews, see: (a) Brandão, P.; Burke, A. J. Tetrahe-
dron 2018, 74, 4927. (b) Yu, B.; Xing, H.; Yu, D.-Q.; Liu, H.-M.
Beilstein J. Org. Chem. 2016, 12, 1000. (c) Kumar, A.; Chimni, S. S.
RSC Adv. 2012, 2, 9748.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 829–832