Highly modular dipeptide-like organocatalysts for direct asymmetric aldol reactions in brine

Article abstract of DOI:10.1039/c5ra07019h

A novel series of dipeptide-like organocatalysts derived from proline, amino acids and primary amines have been prepared for direct asymmetric aldol reactions between various aromatic aldehydes and acetone to afford aldol products in good yields (up to 82%) and moderate enantioselectivities (up to 67% ee) with only 1 mol% of catalyst-loading in brine. Under the same conditions, the direct asymmetric aldol reactions of aromatic aldehydes and cyclohexanone give aldol products with high yields (up to 91%) and moderate to good enantioselectivities (up to 88% ee) and excellent diastereoselectivities (up to 99% dr). These organocatalysts are easily synthesized from commercially available materials in multi-gram scale with high modularity in their structural and stereogenic properties.

Full text of DOI:10.1039/c5ra07019h

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Highly modular dipeptide-like organocatalysts for
direct asymmetric aldol reactions in brine†
Cite this: RSC Adv., 2015, 5, 39557
*
*
Xiao-Mu Hu, Dong-Xu Zhang, Sheng-Yong Zhang and Ping-An Wang
A novel series of dipeptide-like organocatalysts derived from proline, amino acids and primary amines have
been prepared for direct asymmetric aldol reactions between various aromatic aldehydes and acetone to
afford aldol products in good yields (up to 82%) and moderate enantioselectivities (up to 67% ee) with
only 1 mol% of catalyst-loading in brine. Under the same conditions, the direct asymmetric aldol
reactions of aromatic aldehydes and cyclohexanone give aldol products with high yields (up to 91%) and
moderate to good enantioselectivities (up to 88% ee) and excellent diastereoselectivities (up to 99% dr).
These organocatalysts are easily synthesized from commercially available materials in multi-gram scale
with high modularity in their structural and stereogenic properties.
Received 18th April 2015
Accepted 24th April 2015
DOI: 10.1039/c5ra07019h
www.rsc.org/advances
loading (usually 10–30 mol%) and additives are necessary
to ensure good yields and enantioselectivities in most cases,
Introduction
and the low-loading organocatalysts without any additive for
the direct asymmetric aldol reactions under aqueous condi-
tions are rare.
In this paper, we have presented the preparation and
application of a novel class of highly modular dipeptide-like
The direct aldol reaction is one of the most fundamental reac-
tions for carbon–carbon bond formation.1,2 Many efforts are
devoted to develop a highly efficient asymmetric version of this
important reaction both in metal3 or metal-free catalytic
conditions.4 Since the prominent achievements of List and
Barbas III on proline catalysis,5 a large number of organo-
catalysts have been prepared and applied in direct aldol reac-
tions between various aldehydes and ketones to achieve
excellent yields and enantioselectivities.6–19
Peptides are common bio-molecules and constituents in
living organisms, and play vital roles in variously biological
activities. In modern organic synthesis, small peptides can be
used as catalysts and ligands for enantioselective trans-
formations20 such as acylation,21 epoxidation,22 and cyclo-
propanation.23 Undoubtedly, the research of organic
synthesis in or on aqueous medium is attractive to chemists
by its environmentally benign property and easily handled
process.24 Since Janda's25 pioneering work on direct asym-
metric aldol reactions in water, Barbas III,26 Hayashi,27 and
Singh28 et al. have independently developed enantioselective
aldol reactions in aqueous media to achieve excellent results.
Small peptides are also utilized as organocatalysts for direct
asymmetric aldol reactions in water or brine to afford aldols
in good yields and enantioselectivities,29 and some elegant
examples30 are listed in Fig. 1. However, the high catalyst-
Department of Medicinal Chemistry, School of Pharmacy, The Fourth Military Medical
University, Changle West Road 169, Xi'an, 710032, P. R. China. E-mail:
ping_an1718@outlook.com; syzhang@fmmu.edu.cn; Fax: +86-29-84776945; Tel:
+86-29-84776807 ext. 605
† Electronic supplementary information (ESI) available: 1H, 13C NMR and HRMS
of compounds 14a–i, HPLC charts of aldol products 3a–j and 15a–k can be found
in the ESI. See DOI: 10.1039/c5ra07019h
Fig. 1 Typical small peptides catalysed direct aldol reactions.
RSC Adv., 2015, 5, 39557–39564 | 39557
This journal is © The Royal Society of Chemistry 2015

View Article Online
RSC Advances
Paper
organocatalysts 14 (Fig. 3). Only one column chromatographic
purication of the intermediates 13 needed in the third step.
The organocatalysts 14b–e derived from L-proline and (S)-
methylbenzylamine but containing different amino acid motifs
in the middle part of the structures, are prepared for the
detection of the steric effect on their chiral induction abilities in
the direct aldol reactions. The family of 14f–h are synthesized
from chiral methylbenzylamine, valine and proline but with
different congurations to investigate the effect of the tunably
stereogenic centers on aldol reactions. The organocatalyst 14i
with the ending group of benzylamine is used in the direct aldol
reaction to show the necessity of the chiral or achiral primary
amine group in these dipeptide-like analogues. The catalyst 14a
[from L-proline and (S)-methylbenzylamine] are used as cata-
lysts for the comparison with the performance of the above
dipeptide-like organocatalysts 14b–i in the direct aldol
reactions.
Fig. 2 Dipeptide-like organocatalysts in this study.
Direct aldol reactions by using dipeptide-like organocatalysts
With these above dipeptide-like organocatalysts 14b–i in hand,
the direct aldol reaction of 4-nitrobenzyaldehyde and acetone
was chosen as the model reaction for the test of the activities of
catalysts. Initially, the reaction was performed under neat
conditions at room temperature (r.t.) with catalysts L-proline (30
mol%), and 14a–e (5 mol% respectively), and the results are
shown in the Table 1. From the Table 1, it was found that L-
proline was the effective catalyst to give moderate yield (76%)
and relatively good enantioselectivity (67% ee) of aldol product
(Table 1, entry 1) but with a large amount of catalyst-loading.
The catalyst 14a with slightly positive result of aldol reaction
has good yield (87%) but with very low enantioselectivity (Table
1, entry 2, 20% ee). The catalyst 14b from L-proline, L-alanine
and (S)-methylbenzylamine (L-Pro-L-Ala-S-amine) gives 82%
organocatalysts derived from proline, amino acids and
primary amines for direct aldol reactions between various
aromatic aldehydes and ketones in brine to provide aldol
products in excellent yields and moderate to good enantiose-
lectivities with only 1 mol% of catalyst-loading (Fig. 2).
Different amino acid tethered proline-skeletons were
compared and their catalytic behaviour was also evaluated in
this study.
Results and discussion
Synthesis of dipeptide-like organocatalysts
The synthesis of these dipeptide-like organocatalysts is very yield and 37% ee of aldol product (Table 1, entry 3). With the
straightforward and shown in Scheme 1. The coupling of the increase of the steric hindrance of the middle part of the cata-
chiral (or achiral) primary amines 9 with different Boc-protected lysts, the yield and the enantioselectivity of aldol adduct is also
amino acids 10 under the mixed-anhydride conditions provides signicantly increased (Table 1, entries 3–5). To our surprise,
the intermediates 11 in high yields which directly followed the the most hindered t-Bu in the middle part of catalyst 14d affords
deprotection of Boc-group to afford the amines 12. The lower yield and enantioselectivity than the catalyst 14c (L-Pro-L-
connection of 12 with Boc-proline can produce 13 which Val-S-amine, LLS, Table 1, entry 4 vs. 5). The catalyst 14e with L-
undergo the deprotection to yield the nal dipeptide-like Phe in the middle part results the lower enantioselectivity than
Scheme 1 The synthetic route to 14c.
39558 | RSC Adv., 2015, 5, 39557–39564
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
Fig. 3 The structures of organocatalysts 14a–i.
ꢁ
Table 1 The direct aldol reactions catalyzed by dipeptide-like orga-
nocatalysts 14 under neat conditions
(ꢀ40 C, with catalyst 14f, Table 1, entry 4 vs. 7). Switching the
conguration of proline motif of catalysts from L- to D-, the
congurations of aldol product are also changed to be their
opposite congurations (Table 1, entries 4, 7 vs. 8, 9). When the
terminal amine is achiral (catalyst 14i), the enantioselectivity of
aldol product is decreased (Table 1, entry 10). These results
indicate that the different stereogenic centers in these
dipeptide-like catalysts can produce the obviously different
enantioselective inductions and 14f is the best choice both at
r.t.b
ꢀ40 ꢁCc
ꢁ
r.t. and ꢀ40 C on the direct aldol reactions.
To the environmental benign concern, the direct aldol
reaction was undertaken in brine at r.t. with the catalysts 14c,
14f–i. There is a decrease of at least 10% ee for every entry when
changing from neat conditions to brine (Table 2, entries 1–5).
The catalyst-loading is also investigated. Interestingly, the
enantioselectivity of aldol product is obviously decreased to be
23% ee with 10 mol% of catalyst-loading of 14f (Table 2, entry 6
vs. entry 2), and this may due to the reaction switching from
kinetic-control to thermodynamic-control.31 To our delight,
when the amount of 14f is reduced to be 1 mol%, the aldol
Entrya,b
Orgcat.
Yield (%)
ee (%)d
Yield (%)
ee (%)d
1e
2
3
4
5
L-Pro
14a
14b
14c
14d
14e
14f
76
87
82
92
84
84
92
94
93
90
67(R)
20(R)
37(R)
57(R)
45(R)
41(R)
55(R)
57(S)
57(S)
49(R)
—
67
62
68
65
67
63
57
61
59
—
39(R)
59(R)
75(R)
61(R)
57(R)
80(R)
53(S)
49(S)
47(R)
6
7
8
9
10
14g
14h
14i
a
b
0.5 mmol of aldehyde 1a in 1.0 mL of acetone for every entry. The
c
d
reaction time is 24 h. The reaction time is
3
days.
The
enantiomeric excess (ee) of aldol product was determined by chiral
HPLC with Chiralpak AS-H column. 30 mol% of L-proline was used
Table 2 The direct aldol reactions in brine
e
in entry 1.
14c (ꢁTable 1, entry 6 vs. 4). When the reaction is performed at
ꢀ40 C in neat acetone, the yield of aldol product is decreased
but with the increase of the enantioselectivity (Table 1, entry 4
with 14c, 75% ee vs. 57% ee) and the sacrice of reaction time
(up to 3 days).
In order to investigate the effect of the tunable stereogenic
centers of catalysts on aldol reactions, 14f (L-Pro-L-Val-R-amine,
LLR), 14g (D-Pro-D-Val-S-amine, DDS), 14h (D-Pro-D-Val-R-amine,
DDR) and 14i (L-Pro-L-Val-Bn, LLBn) were prepared respectively.
The direct aldol reactions of 4-nitrobenzyaldehyde and acetone
under neat condition at r.t. or at ꢀ40 ꢁC were performed by
using these above catalysts. It was found that the conguration
of the chiral carbon atom in the terminal amine of catalysts is
Entrya
Orgcat. (mol%)
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8c
14c(5)
14f(5)
14g(5)
14h(5)
14i(5)
14f(10)
14f(1)
14f(1)
79
80
83
82
89
85
80
77
44(R)
45(R)
45(S)
45(S)
35(R)
23(R)
45(R)
7.5(R)
a
0.5 mmol of aldehyde 1a and 0.5 mL of acetone in 1.0 mL of brine for
b
every entry. The enantiomeric excess (ee) of aldol product was
changed from (S)- to (R)-, the enantioselectivity of aldol product determined by chiral HPLC with Chiralpak AS-H column, the
conguration of aldol product was assigned by comparison to the
is slightly increased from 75% (r.t., with catalyst 14c) to 80% ee
literature data. c The reaction was performed in water.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 39557–39564 | 39559

View Article Online
RSC Advances
Paper
Table 4 The direct aldol reactions between various aromatic alde-
hydes 1a–k and cyclohexanone in brine with 1 mol% of catalyst 14f
product is afforded in slightly lower yield (80%) but with rela-
tively stable enantioselectivity (45% ee) comparison to 5 mol%
of catalyst-loading (Table 2, entry 7 vs. entry 2). However, when
the reaction was performed in water with 1 mol% of catalyst 14f,
the enantioselectivity is decreased dramatically to 7.5% ee
(Table 2, entry 8 vs. entry 7). This shows that these dipeptide-like
organocatalysts are highly efficient for the direct aldol reactions
in brine but with very poor performance in water.
By using only 1 mol% of dipeptide-like organocatalyst 14f, Entrya
Substrate
Product
Yield (%)
Anti : syn
ee (%)d
the direct aldol reactions of acetone and various aromatic
aldehydes (Table 3) with electron-withdrawing or electro-
donating group are suitable to brine medium at r.t. to
produce aldol adducts in good yields (up to 82%) and moderate
enantioselectivities (up to 67% ee).
The direct aldol reaction of 4-nitrobenzyaldehyde and
cyclohexanone (Table 4, entry 1) in water with 1 mol% of 14f
afforded 15a in excellent diastereoselectivity (d.r. > 98%) and
moderate enantioselectivity of anti-product (54% ee). However,
switching the reaction solvent of water to brine, the enantio-
selectivity of 15a is signicantly increased to 88% ee (Table 4,
entry 2). The direct aldol reactions between various aromatic
aldehydes 1a–k and cyclohexanone in brine with 1 mol% of
catalyst 14f were smoothly performed at r.t. to furnish aldols
15a–k with moderate to good enantioselectivities (except benz-
aldehyde 1f, entry 7, 28% ee) and excellent diastereoselective
ratios (Table 4, entries 2–12).
1b
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
15a
15a
15b
15c
15d
15e
15f
15g
15h
15i
81
82
89
92
85
86
72
87
76
81
80
91
98 : 2
96 : 4
99 : 1
99 : 1
98 : 2
99 : 1
98 : 2
99 : 1
95 : 5
97 : 3
89 : 11
91 : 9
54
88
68
65
77
76
28
78
84
67
66
81
9
10
11
12c
1j
1k
15j
15k
a
0.5 mmol of aldehyde 1 and 0.5 mL of acetone in 0.5 mL of brine for
entries 2 to 12. b The reaction was performed in 0.5 mL of acetone with
c
0.5 mL of water for entry 1. For entry 12, the substrate 1k is 4-
chlorobenzyaldehyde. The enantiomeric excess (ee) of aldol products
15a–k was determined by chiral HPLC with Chiralpak AD-H column,
the conguration of aldol product was assigned by comparison to the
literature data.
d
From the above reaction results, we have noticed that not
only acetone but also cyclohexanone react with various aromatic
aldehydes in brine to afford aldol adducts with superior enan-
tioselectivities to those in water (Table 2, entry 7 vs. entry 8;
Table 4, entry 2 vs. entry 1). This observation may due to the
“salting-out effect” increasing “hydrophobic effect” which was
found in the previous reports by Barbas III,26 Hayashi27 and
Singh28 et al. The OH groups of the surface water molecules in
brine may form the proper amount of additional hydrogen
bonds with two amide oxygen atoms to make the amidic NH
more acidic resulting in a tight transition state in hydrophobic
micro-surroundings to ensure the good enantioselectivity.
When the aldol reaction was performed in water, a large
amount of hydrogen bonds might form not only with two amide
oxygen atoms but also with amidic NH groups to deteriorate the
stable transition state leading to poor enantioseletivity. The
proposed transition states are shown in Fig. 4.
Table 3 The direct aldol reactions between various aromatic alde-
hydes and acetone in brine with 1 mol% of catalyst 14f
In summary, we have prepared a novel series of dipeptide-
like organocatalysts for the direct asymmetric aldol reactions
of various aromatic aldehydes and acetone in brine with only 1
mol% of catalyst-loading to provide aldol products in good
Entrya
Substrate
Product
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
1a R ¼ 4-NO2
1b R ¼ 2-NO2
1c R ¼ 3-NO2
1d R ¼ 4-Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
82
80
75
78
60
67
61
65
78
45(R)
60(R)
56(R)
51(R)
52(R)
54(R)
41(S)
54(R)
67(R)
47(R)
1e R ¼ 3-Br
1f R ¼ H
1g R ¼ 2,4-dichloro
1h R ¼ 4-Me
1i R ¼ 3-OMe
1j R ¼ 3,4,5-(OMe)3
10
3j
a
0.5 mmol of aldehyde 1 and 0.5 mL of acetone in 0.5 mL of brine for
b
every entry. The enantiomeric excess (ee) of aldol products 3a–j was
determined by chiral HPLC with Chiralpak AD-H, OD-H and AS-H
columns, the conguration of aldol product was assigned by
comparison to the literature data.
Fig. 4 The proposed transition states in brine and in water.
39560 | RSC Adv., 2015, 5, 39557–39564
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
yields (up to 82%) and moderate enantioselectivities (up to 67% yield the crude 13c as yellow wax (Alternatively, the crude 13c
ee). Additionally, under the same reaction conditions, the direct can be puried by a ash column chromatography with n-
asymmetric aldol reactions of various aromatic aldehydes with hexane/ethyl acetate ¼ 1/1, V/V). This crude 13c was directly
cyclohexanone afford the corresponding aldol adducts in high undergone the deprotection of Boc-group via TFA (4 mL, 52
yields (up to 92%) and moderate to good enantioselectivities (up mmol) in anhydrous DCM (30 mL) produced the crude product
to 88% ee) with excellent diastereoselectivitives (d.r. up to 99%). 14c which was puried by a ash column chromatography (n-
These dipeptide-like organocatalysts are easily synthesized in hexane/ethyl acetate/Et3N ¼ 1/5/0.05, V/V) to provide the nal
multi-gram scale with high tunability in their structural and dipeptide-like organocatalyst 14c (1.87 g, total yield 59% based
stereogenic properties. The more complex dipeptide-like orga- on Boc-L-Val-OH).
nocatalysts with multi-hydrogen bonding sites are investigated
in due course.
(S)-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide32 (14a)
Compound 14a was prepared from Boc-L-Pro-OH and (S)-(ꢀ)-1-
Experimental
phenylethylamine. The same procedure as described above for
General
the preparation of compound 14c was used.
Yield 72%; white solid; m.p. 145–147 ꢁC; [a]D25 ¼ ꢀ91.8ꢁ (c ¼
0.50, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.96 (d, J ¼ 7.2 Hz,
1H), 7.36–7.34 (m, 5H), 5.11 (dd, J ¼ 7.2, 1.6 Hz, 1H), 3.75 (dd, J
¼ 5.6, 3.6 Hz, 1H), 3.07–3.01 (m, 1H), 2.96–2.90 (m, 1H), 2.21–
2.12 (m, 2H), 1.99–1.92 (m, 1H), 1.78–1.50 (m, 2H), 1.09 (d, J ¼
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 173.95, 143.52, 128.59,
127.18, 126.15, 60.58, 48.03, 47.24, 30.74, 26.16, 22.17;
HRMS(ESI+) calcd for C13H19N2O [M + H]+ ¼ 219.1497, found:
219.1498.
ꢁ
Melting points are uncorrected and expressed in C by MRS-2
melting point apparatus from Shanghai Apparatus Co., Ltd.
1H NMR and 13C NMR spectra were measured in CDCl3, solu-
tion on a Bruker AV-400 spectrometer using TMS as an internal
reference. Coupling constant (J) values are given in Hz. Multi-
plicities are designated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet.
High-resolution mass spectra were performed on a Bruker
microTOF-Q II Mass Spectrometer with ES ionization (ESI). All
commercially available reagents were used as received. Thin-
layer chromatography on silica (with GF254) was used to
monitor all reactions. Products were puried by ash column
chromatography on silica gel purchased from Qingdao Haiyang
Chemical Co., Ltd. Optical rotations were measured on a Perkin
Elmer 343 polarimeter. Chiral High Performance Liquid Chro-
matography (HPLC) analyses were performed using an Agilent
1200 series apparatus and Chiralpak AD-H, OD-H and AS-H
columns purchased from Daicel Chemical Industries. The
conguration of the products has been assigned by comparison
to the literature data or assigned by analogy. All reactions
involving air- or moisture-sensitive species were performed in
oven-dried Schlenk tubes under an inert atmosphere.
(S)-N-((S)-1-oxo-1-(((S)-1-phenylethyl)amino)propan-2-yl)
pyrrolidine-2-carboxamide29f (14b)
Compound 14b was prepared from Boc-L-Pro-OH, Boc-L-Ala-OH
and (S)-(ꢀ)-1-phenylethylamine. The same procedure as
described above for the preparation of compound 14c was used.
Yield 52%; white solid; m.p. 155–157 ꢁC; [a]D25 ¼ ꢀ216.7ꢁ (c ¼
0.50, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 8.11 (d, J ¼ 7.6 Hz,
1H), 7.37–7.26 (m, 5H), 6.96 (d, J ¼ 7.2 Hz, 1H), 5.07 (t, J ¼ 7.2
Hz, 1H), 4.44 (t, J ¼ 7.2 Hz, 1H), 3.78–3.73 (m, 1H), 3.05–3.01 (m,
1H), 2.95–2.91 (m, 1H), 2.15–1.91 (m, 2H), 1.90 (br, 1H), 1.77–
1.67 (m, 2H), 1.46 (d, J ¼ 6.8 Hz, 3H), 1.36 (d, J ¼ 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) d 175.62, 171.26, 143.34, 128.64, 127.23,
126.05, 60.39, 48.90, 48.50, 47.27, 30.69, 26.21, 22.13, 17.73;
HRMS(ESI+) calcd for C16H24N3O2 [M + H]+ ¼ 290.1869, found:
290.1871.
Typical synthetic procedure for preparation of dipeptide-like
organocatalyst 14c
A solution of Boc-L-Val-OH (10c, 2.17 g, 10 mmol), Et3N (1.52 g,
15 mmol) and isobutyl chloroformate (1.57 mL, 10 mmol) in
dichloromethane (DCM, 25 mL) at 0 ꢁC was stirred for 30 min,
aer which the (S)-(ꢀ)-1-phenylethylamine 9 (11 mmol) was
(S)-N-((S)-3-methyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-2-
yl)pyrrolidine-2-carboxamide22a (14c, LLS)
added and stirred at this temperature for 2 h aer which it was Compound 14c was prepared from Boc-L-Pro-OH, Boc-L-Val-OH
warmed to room temperature along with stirring overnight. The and (S)-(ꢀ)-1-phenylethylamine. Yield 59%; white solid; m.p.
reaction was monitored by TLC, and then quenched with sat. 141–142 ꢁC; [a]D25 ¼ ꢀ98.2ꢁ (c ¼ 1.0, CH2Cl2); 1H NMR (400 MHz,
aq. NH4Cl (25 mL), and successively washed with H2O, and CDCl3) d 8.25 (d, J ¼ 8.8 Hz, 1H), 7.34–7.26 (m, 5H), 6.76 (d, J ¼
brine. Aqueous phase extracted with dichloromethane (3 ꢂ 25 7.6 Hz, 1H), 5.10 (t, J ¼ 7.2 Hz, 1H), 4.18 (t, J ¼ 8.2 Hz, 1H), 3.77
mL). The organic layers were dried over Na2SO4, ltered, and (dd, J ¼ 4.8, 4.4 Hz, 1H), 3.08–3.02 (m, 1H), 2.97–2.91 (m, 1H),
concentrated to give the crude 11c as light yellow glue which 2.19–2.10 (m, 3H), 1.97–1.89 (m, 1H), 1.76–1.69 (m, 2H), 1.47 (d,
was directly deprotected by using triuoroacetic acid (TFA, 4 J ¼ 6.8 Hz, 3H), 0.88 (d, J ¼ 6.8 Hz, 6H); 13C NMR (101 MHz,
mL, 52 mmol, 6 equiv.) in 30 mL of DCM to afford the crude CDCl3) d 175.36, 170.37, 143.26, 128.61, 127.27, 126.14, 60.48,
product 12c without further purication. The coupling of Boc-L- 58.47, 48.92, 47.31, 30.98, 30.68, 26.16, 21.92, 19.48, 18.12;
Pro-OH (1.72 g, 8 mmol) with crude 12c was performed HRMS(ESI+) calcd for C18H28N3O2 [M + H]+ ¼ 318.2182, found:
following the same procedure of the connection of 10c with 9 to 318.2188.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 39557–39564 | 39561

View Article Online
RSC Advances
Paper
Yield 53%; white solid; m.p. 122–123 ꢁC; [a]D25 ¼ +23.9ꢁ (c ¼
(S)-N-((S)-3,3-dimethyl-1-oxo-1-(((S)-1-phenylethyl)amino)
butan-2-yl)pyrrolidine-2-carboxamide (14d)
1
1.0, CH2Cl2); H NMR (400 MHz, CDCl3) d 8.21 (d, J ¼ 9.2 Hz,
1H), 7.30–7.20 (m, 5H), 6.93 (d, J ¼ 8.0 Hz, 1H), 5.11 (t, J ¼ 7.2
Hz, 1H), 4.23 (dd, J ¼ 7.6, 1.6 Hz, 1H), 3.61 (dd, J ¼ 5.2, 4.0 Hz,
1H), 3.04–2.98 (m, 1H), 2.94–2.90 (m, 1H), 2.23–2.05 (m, 3H),
1.93–1.85 (m, 1H), 1.70 (t, J ¼ 6.8 Hz, 2H), 1.50 (d, J ¼ 6.8 Hz,
3H), 0.99 (d, J ¼ 6.8 Hz, 3H), 0.93 (d, J ¼ 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 175.38, 170.23, 143.15, 128.57, 127.16,
126.11, 60.37, 58.34, 48.79, 47.24, 30.74, 26.12, 22.07, 19.51,
18.24; HRMS(ESI+) calcd for C18H28N3O2 [M + H]+ ¼ 318.2182,
found: 318.2187.
Compound 14d was prepared from Boc-L-Pro-OH, 3-Me-Boc-L-
Val-OH and (S)-(ꢀ)-1-phenylethylamine. The same procedure as
described above for the preparation of compound 14c was used.
Yield 62%; white solid; m.p. 86–88 ꢁC; [a]D25 ¼ ꢀ80.3ꢁ (c ¼ 0.50,
CH2Cl2); 1H NMR (400 MHz, CDCl3) d 8.45 (d, J ¼ 10.0 Hz, 1H),
7.37–7.26 (m, 5H), 6.94 (d, J ¼ 5.6 Hz, 1H), 5.10 (t, J ¼ 7.2 Hz,
1H), 4.31 (d, J ¼ 10.0 Hz, 1H), 3.85 (br, 1H), 3.11–2.97 (m, 2H),
2.21–2.11 (m, 1H), 1.97–1.72 (m, 2H), 1.49–1.47 (m, 2H), 1.46 (d,
J ¼ 6.8 Hz, 3H), 0.93 (s, 9H); 13C NMR (100 MHz, CDCl3) d
174.43, 169.67, 143.43, 128.52, 127.19, 126.32, 60.48, 60.12,
58.40, 48.96, 47.20, 34.98, 30.96, 26.60, 26.04, 21.89, 18.44;
HRMS(ESI+) calcd for C19H30N3O2 [M + H]+ ¼ 332.2338, found:
332.2337.
(R)-N-((R)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-
2-yl)pyrrolidine-2-carboxamide (14h, DDR)
Compound 14h was prepared from Boc-D-Pro-OH, Boc-D-Val-OH
and (R)-(+)-1-phenylethylamine. The same procedure as
described above for the preparation of compound 14c was used.
Yield 56%; white solid; m.p. 141–143 ꢁC; [a]D25 ¼ +98.8ꢁ (c ¼ 1.0,
(S)-N-((S)-1-oxo-3-phenyl-1-(((S)-1-phenylethyl)amino) propan-
2-yl)pyrrolidine-2-carboxamide (14e)
1
CH2Cl2); H NMR (400 MHz, CDCl3) d 8.27 (d, J ¼ 9.2 Hz, 1H),
Compound 14e was prepared from Boc-L-Pro-OH, Boc-L-Phe-OH
and (S)-(ꢀ)-1-phenylethylamine. The same procedure as
described above for the preparation of compound 14c was used.
Yield 53%; white solid, m.p. 107–109 ꢁC; [a]D25 ¼ ꢀ15.4ꢁ (c ¼
0.50, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 8.09 (d, J ¼ 7.8 Hz,
1H), 7.30–7.12 (m, 10H), 6.64 (d, J ¼ 29.3, 7.5 Hz, 1H), 5.02 (t, J ¼
7.2 Hz, 1H), 4.60 (q, J ¼ 8.0 Hz, 1H), 3.64 (dd, J ¼ 4.0, 5.2 Hz,
1H), 3.20–2.77 (m, 4H), 2.07–2.02 (m, 2H), 1.75–1.68 (m, 1H),
1.64–1.49 (m, 2H), 1.36 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 175.71, 169.81, 143.26, 137.21, 129.28, 128.56, 127.17,
126.78, 126.02, 60.23, 58.42, 48.81, 47.09, 30.65, 25.92, 21.97,
18.44; HRMS(ESI+) calcd for C22H28N3O2 [M + H]+ ¼ 366.2182,
found: 366.2179.
7.35–7.25 (m, 5H), 7.02 (d, J ¼ 7.6 Hz, 1H), 5.10 (t, J ¼ 7.2 Hz,
1H), 4.24 (dd, J ¼ 7.6, 1.6 Hz, 1H), 3.74 (dd, J ¼ 4.8, 4.4 Hz, 1H),
3.07–3.01 (m, 1H), 2.96–2.91 (m, 1H), 2.17–2.06 (m, 3H), 1.96–
1.88 (m, 1H), 1.72 (t, J ¼ 6.8 Hz, 2H), 1.46 (d, J ¼ 7.2 Hz, 3H), 0.88
(d, J ¼ 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 175.04, 170.42,
143.44, 128.85, 128.56, 127.19, 126.17, 60.46, 58.35, 48.92,
47.27, 30.98, 30.96, 26.08, 22.01, 19.44, 18.15; HRMS(ESI+) calcd
for C18H28N3O2 [M + H]+ ¼ 318.2182, found: 318.2187.
(S)-N-((S)-1-(benzylamino)-3-methyl-1-oxobutan-2-yl)
pyrrolidine-2-carboxamide (14i)
Compound 14i was prepared from Boc-L-Pro-OH, Boc-L-Val-OH
and benzylamine. The same procedure as described above for
the preparation of compound 14c was used.
Yield 51%; white solid; m.p. 121–123 ꢁC; [a]D25 ¼ ꢀ61.3ꢁ (c ¼
(S)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-
yl)pyrrolidine-2-carboxamide (14f, LLR)
1
1.0, CH2Cl2); H NMR (400 MHz, CDCl3) d 8.23 (d, J ¼ 9.2 Hz,
1H), 7.35–7.32 (m, 5H), 6.75 (s, 1H), 4.49 (dd, J ¼ 9.2, 5.6 Hz,
1H), 4.40 (dd, J ¼ 9.2, 5.6 Hz, 1H), 4.19 (t, J ¼ 8.4 Hz, 1H), 3.68
(dd, J ¼ 4.2, 4.0 Hz, 1H), 3.06–3.00 (m, 1H), 2.96–2.91 (m, 1H),
2.28–2.19 (m, 1H), 2.15–2.07 (m, 1H), 1.93–1.86 (m, 2H), 1.75–
1.68 (m, 2H), 0.95 (t, J ¼ 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 172.25, 171.14, 138.12, 128.64, 127.74, 127.41, 60.33, 58.46,
47.21, 43.44, 30.88, 30.52, 28.27, 19.52, 18.45; HRMS(ESI+) calcd
for C17H26N3O2 [M + H]+ ¼ 304.2025, found: 304.2029.
Compound 14f was prepared from Boc-L-Pro-OH, Boc-L-Val-OH
and (R)-(+)-1-phenylethylamine. The same procedure as
described above for the preparation of compound 14c was used.
Yield 67%; white solid, m.p. 132–133 ꢁC; [a]D25 ¼ ꢀ23.5ꢁ (c ¼
1
1.0, CH2Cl2); H NMR (400 MHz, CDCl3) d 8.18 (d, J ¼ 9.2 Hz,
1H), 7.28–7.20 (m, 5H), 6.90 (d, J ¼ 8.0 Hz, 1H), 5.11 (t, J ¼ 7.2
Hz, 1H), 4.23 (dd, J ¼ 7.6, 1.6 Hz, 1H), 3.59 (dd, J ¼ 4.8, 4.4 Hz,
1H), 3.03–2.97 (m, 1H), 2.94–2.89 (m, 1H), 2.23–2.05 (m, 2H),
1.94–1.86 (m, 2H), 1.73–1.66 (m, 2H), 1.49 (d, J ¼ 6.8 Hz, 3H),
0.99 (d, J ¼ 6.8 Hz, 3H), 0.94 (d, J ¼ 6.8 Hz, 3H); 13C NMR (101
MHz, CDCl3) d 175.58, 170.28, 143.18, 128.58, 127.15, 126.11,
60.41, 58.22, 48.73, 47.26, 30.95, 30.68, 26.17, 22.07, 19.52,
18.23; HRMS(ESI+) calcd for C18H27N3O2 [M + H]+ ¼ 318.2182,
found: 318.2182.
Typical procedure for direct aldol reactions by using
dipeptide-like organocatalyst 14f in brine
To a mixed solvents of sat. aq. brine (0.5 mL) and ketone (0.5
mL) was added aldehyde (0.5 mmol), and the corresponding
catalyst 14f (1.6 mg, 0.005 mmol). The reaction mixture was
stirred at 25 ꢁC for 24 h. The mixture was then quenched with a
solution of saturated NH4Cl (0.5 mL), and extracted with ethyl
acetate (3 ꢂ 10 mL). The combined organic layer was washed
with brine and dried over anhydrous Na2SO4 and concentrated
(R)-N-((R)-3-methyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-
2-yl)pyrrolidine-2-carboxamide (14g, DDS)
Compound 14g was prepared from Boc-D-Pro-OH, Boc-D-Val-OH under reduced pressure to give a residue which was puried
and (S)-(ꢀ)-1-phenylethylamine. The same procedure as through a ash column chromatography with n-hexane/ethyl
described above for the preparation of compound 14c was used. acetate (1 : 1, V/V) to afford the pure aldol adduct. All these
39562 | RSC Adv., 2015, 5, 39557–39564
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
aldol products are known compounds29,33,34 and the enantio- 12 T. Kano, O. Tokuda and K. Maruoka, Tetrahedron Lett., 2006,
meric excess (ee) of the aldol adduct was determined by chiral 47, 7423.
HPLC analysis. For HPLC spectra of compounds 3a–j and 15a–k, 13 G. Guillena, M. del C. Hita and C. Najera, Tetrahedron:
´
please refer to ESI.†
Asymmetry, 2006, 17, 1493.
14 C. D. Maycock and M. R. Ventura, Tetrahedron: Asymmetry,
2012, 23, 1262.
Acknowledgements
15 L. Li, S.-H. Gou and F. Liu, Tetrahedron Lett., 2013, 54, 6358.
16 (a) P.-X. Zhou, S.-Z. Luo and J.-P. Cheng, Org. Biomol. Chem.,
2011, 9, 1784; (b) J. Huang, G.-D. Chen, X.-K. Fu, C. Li,
C.-L. Wu and Q. Miao, Catal. Sci. Technol., 2012, 2, 547; (c)
L. Peng, L.-L. Wang, J.-F. Bai, L.-N. Jia, Y.-L. Guo, X.-Y. Luo,
F.-Y. Wang, X.-Y. Xu and L.-X. Wang, Org. Biomol. Chem.,
2011, 9, 4774; (d) A. Kumar, S. Singh, V. Kumar and
S. S. Chimni, Org. Biomol. Chem., 2011, 9, 2731.
We thank the National Science Foundation of China (no.
21372259 and 21172262) for nancial support of this work.
Notes and references
1 (a) R. Kumar and E. V. Van der Eycken, Chem. Soc. Rev., 2013,
42, 1121; (b) M. Henrion, V. Ritleng and M. J. Chetcuti, ACS 17 T. He, K. Li, M.-Y. Wu, M.-B. Wu, N. Wang, L. Pu and
Catal., 2015, 5, 1283. X.-Q. Yu, Tetrahedron, 2013, 69, 5136.
2 (a) C.-L. Sun and Z.-J. Shi, Chem. Rev., 2014, 114, 9219; (b) 18 S. Eymur, E. Akceylan, O. Sahin, A. Uyanik and M. Yilmaz,
´
¨
Tetrahedron, 2014, 70, 4471.
S. Roscales and A. G. Csaky, Chem. Soc. Rev., 2014, 43,
8215; (c) V. Bisai, A. Bisai and V. K. Singh, Tetrahedron, 19 (a) J.-R. Chen, X.-L. An, X.-Y. Zhu, X.-F. Wang and W.-J. Xiao,
2012, 68, 4541.
J. Org. Chem., 2008, 73, 6006; (b) B.-L. Zheng, Q.-Z. Liu,
C.-S. Guo, X.-L. Wang and L. He, Org. Biomol. Chem., 2007,
5, 2913.
3 (a) G. L. Beutner and S. E. Denmark, Angew. Chem., Int. Ed.,
2013, 52, 9086; (b) B. M. Trost and C. S. Brindle, Chem. Soc.
Rev., 2010, 39, 1600; (c) J.-F. Zhao, B.-H. Tan and T.-P. Loh, 20 For small peptides catalysed organic reactions, see: (a) G. De
Chem. Sci., 2011, 2, 349.
Faveri, G. Ilyashenko and M. Watkinson, Chem. Soc. Rev.,
2011, 40, 1722; (b) E. A. C. Davie, S. M. Mennen, Y.-J. Xu
and S. J. Miller, Chem. Rev., 2007, 107, 5759; (c)
M. Akiyama, K. Akagawa, H. Seino and K. Kudo, Chem.
4 (a) B. List, Acc. Chem. Res., 2004, 37, 548; (b) Q.-Y. Zhang,
X.-L. Cui, L. Zhang, S.-Z. Luo, H. Wang and Y.-J. Wu,
Angew. Chem., Int. Ed., 2015, 54, 5210; (c) W. Notz,
F. Tanaka and C. F. Barbas III, Acc. Chem. Res., 2004, 37,
580; (d) T. Miura, H. Kasuga, K. Imai, M. Ina, N. Tada,
N. Imai and A. Itoh, Org. Biomol. Chem., 2012, 10, 2209.
5 (a) B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
´
Commun., 2014, 50, 7893; (d) J. Duschmale, S. Kohrt and
H. Wennemers, Chem. Commun., 2014, 50, 8109; (e)
A. F. de la Torre, D. G. Rivera, M. A. B. Ferreira,
ˆ
˜
A. G. Correa and M. W. Paixao, J. Org. Chem., 2013, 78, 10221.
¨
2000, 122, 2395; (b) B. List, J. Am. Chem. Soc., 2000, 122, 9336. 21 (a) C. E. Muller, D. Zell, R. Hrdina, R. C. Wende, L. Wanka,
6 (a) X.-H. Liu, L.-L. Lin and X.-M. Feng, Chem. Commun., 2009,
S. M. M. Schuler and P. R. Schreiner, J. Org. Chem., 2013,
78, 8465; (b) A. M. Vibhute, A. Vidyasagar, S. Sarala and
K. M. Sureshan, Chem. Commun., 2012, 48, 2448; (c)
´
6145; (b) C. Palomo, M. Oiarbide and J. M. Garcıa, Chem. Soc.
Rev., 2004, 33, 65; (c) K. Weidner, N. Kumagai and
M. Shibasaki, Angew. Chem., Int. Ed., 2014, 53, 6150; (d)
W. Wan, W. Gao, G.-B. Ma, L. Ma, F. Wang, J. Wang,
´
M. Matsumoto, S. J. Lee, M. R. Gagne and M. L. Waters,
Org. Biomol. Chem., 2014, 12, 8711.
H.-Z. Jiang, S.-Z. Zhu and J. Hao, RSC Adv., 2014, 4, 26563; 22 (a) D. K. Romney and S. J. Miller, Org. Lett., 2012, 14, 1138; (b)
(e) A. A. Elmekawy, J. B. Sweeney and D. R. Brown, Catal.
Sci. Technol., 2015, 5, 690; (f) S. Bhowmick, S. S. Kunte and
K. C. Bhowmick, RSC Adv., 2014, 4, 24311.
G. Peris, C. E. Jakobsche and S. J. Miller, J. Am. Chem. Soc.,
2007, 129, 8710.
23 K. Akagawa, S. Takigawa, I. S. Nagamine, R. Umezawa and
K. Kudo, Org. Lett., 2013, 15, 4964.
7 (a) C. Shen, F.-Y. Shen, G.-B. Zhou, H.-J. Xia, X.-Z. Chen,
X.-G. Liu and P.-F. Zhang, Catal. Commun., 2014, 26, 6; (b) 24 For organic reactions in aqueous media, see:(a) J. Mlynarski
´
J. Agarwal and R. K. Peddinti, Eur. J. Org. Chem., 2012, 6390.
8 P. Revelou, C. G. Kokotos and P. Moutevelis-Minakakis,
Tetrahedron, 2012, 68, 8732.
9 (a) S. Fotaras, C. G. Kokotos, E. Tsandi and G. Kokotos, Eur. J.
Org. Chem., 2011, 1310; (b) K. Arnold, A. S. Batsanov,
and S. Bas, Chem. Soc. Rev., 2014, 43, 577; (b) J. Huang,
G.-D. Chen, X.-K. Fu, C. Li, C.-L. Wu and Q. Miao, Catal.
Sci. Technol., 2012, 2, 547; (c) S. Bhowmick, S. S. Kunte and
K. C. Bhowmick, RSC Adv., 2014, 4, 24311; (d) X.-L. Liu,
B.-W. Pan, W.-H. Zhang, C. Yang, J. Yang, Y. Shi,
T.-T. Feng, Y. Zhou and W.-C. Yuan, Org. Biomol. Chem.,
2015, 13, 601; (e) S. Bhowmick and K. C. Bhowmick,
Tetrahedron: Asymmetry, 2011, 22, 1945.
¨
B. Davies, C. Grosjean, T. Schutz, A. Whiting and
K. Zawatzkya, Chem. Commun., 2008, 3879.
10 A. S. Saiyed and A. V. Bedekar, Tetrahedron: Asymmetry, 2013,
24, 1035.
25 T. J. Dickerson and K. D. Janda, J. Am. Chem. Soc., 2002, 124,
3220.
11 (a) A. J. A. Cobb, D. M. Shaw and S. V. Ley, Synlett, 2004, 558;
´
´
(b) C. E. T. Mitchell, S. E. Brenner, J. Garcıa-Fortanet and 26 A. Cordova, W. Notz and C. F. Barbas III, Chem. Commun.,
S. Ley, Org. Biomol. Chem., 2006, 4, 2039; (c) L. Wynands, 2002, 3024.
S. Delacroix, A. N. Van Nhien, E. Soriano, J. Marco- 27 Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and
Contelles and D. Postel, Tetrahedron, 2013, 69, 4899.
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 39557–39564 | 39563

View Article Online
RSC Advances
Paper
28 V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007, 9, 2593.
29 For small peptides catalysed aldol reactions, see:(a) S. Bayat,
B. A. Tejo, E. Abdulmalek, A. B. Salleh, Y. M. Normia and
Tetrahedron:
Asymmetry,
2015,
26,
102;
(d)
S. Chandrasekhar, K. Johny and C. R. Reddy, Tetrahedron:
Asymmetry, 2009, 20, 1742.
M. B. A. Rahman, RSC Adv., 2014, 4, 38859; (b) P. Dziedzic, 31 For the increase of catalyst-loading leading to the decrease of
´
´
W.-B. Zou, J. Hafrenb and A. Cordova, Org. Biomol. Chem.,
2006, 4, 38; (c) S. Bhowmick, S. S. Kunte and
K. C. Bhowmick, RSC Adv., 2014, 4, 24311; (d) S. Fotaras,
C. G. Kokotos and G. Kokotos, Org. Biomol. Chem., 2012,
10, 5613; (e) C. Berdugo, B. Escuder and J. F. Miravet, Org.
Biomol. Chem., 2015, 13, 592; (f) F.-B. Chen, S. Huang,
H. Zhang, F.-Y. Liu and Y.-G. Peng, Tetrahedron, 2008, 64,
9585; (g) A. Psarra, C. G. Kokotos and P. Moutevelis-
enantioselectivity of the product in organocatalysis, by the
reaction from kinetic to thermodynamic-control, see: (a)
G. Rulli, N. Duangdee, K. Baer, W. Hummel, A. Berkessel
¨
and H. Groger, Angew. Chem., Int. Ed., 2011, 50, 7944; (b)
A. Kumar and S. S. Chimni, Tetrahedron, 2013, 69, 5197; (c)
By self-association phenomenon of the catalyst, see:
H. B. Jang, H. S. Rho, J. S. Oh, E. H. Nam, S. E. Park,
H. Y. Bae and C. E. Song, Org. Biomol. Chem., 2010, 8, 3918.
Minakakis, Tetrahedron, 2014, 70, 608; (h) E. Machuca, 32 (a) F. Kelleher, S. Kelly, J. Watts and V. McKee, Tetrahedron,
Y. Rojas and E. Juaristi, Asian J. Org. Chem., 2015, 4, 46; (i)
P. Krattiger, R. Kovasy, J. D. Revell, S. Ivan and
H. Wennemers, Org. Lett., 2005, 7, 1101.
2010, 66, 3525; (b) J.-G. Xin, L. Chang, Z.-R. Hou, D.-J. Shang,
X.-H. Liu and X.-M. Feng, Chem.–Eur. J., 2008, 14, 3177.
33 X.-X. Song, A.-X. Liu, S.-S. Liu, W.-C. Gao, M.-C. Wang and
J.-B. Chang, Tetrahedron, 2014, 70, 1464.
30 (a) I. Triandallidi, A. Bisticha, E. Voutyritsa, G. Galiatsatou
and C. G. Kokotos, Tetrahedron, 2015, 71, 932; (b) 34 L. Wynands, S. Delacroix, A. N. Van Nhien, E. Soriano,
A. J. Pearson and S. Panda, Org. Lett., 2011, 13, 5548; (c)
A. Bisticha, I. Triandallidi and C. G. Kokotos,
J. Marco-Contelles and D. Postel, Tetrahedron, 2013, 69,
4899.
39564 | RSC Adv., 2015, 5, 39557–39564
This journal is © The Royal Society of Chemistry 2015