Tert-Butyl esters of peptides as organocatalysts for the asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2014.12.007

Enantioselective aldol reactions between ketones and aldehydes were shown to be catalysed by a variety of tert-butyl esters of peptides. Amongst the peptides tested, Pro-Glu(O^tBu)-O^tBu proved to be the best, affording the product in

Full text of DOI:10.1016/j.tetasy.2014.12.007

Tetrahedron: Asymmetry 26 (2015) 102–108
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
tert-Butyl esters of peptides as organocatalysts for the asymmetric
aldol reaction
⇑
Aikaterini Bisticha, Ierasia Triandafillidi, Christoforos G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis 15771, Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 November 2014
Accepted 15 December 2014
Enantioselective aldol reactions between ketones and aldehydes were shown to be catalysed by a variety
of tert-butyl esters of peptides. Amongst the peptides tested, Pro-Glu(OtBu)-OtBu proved to be the best,
affording the product in good to excellent yields, diastereoselectivities and enantioselectivities.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
or a urea moiety,6h were excellent organocatalysts in promoting
the aldol reaction; however these molecules were only active in
Since List, Lerner and Barbas employed proline, a natural amino
acid, as a catalyst for intermolecular aldol reactions,1 organocatal-
ysis has flourished to such an extent that it is nowadays recognized
as the third major pillar of asymmetric catalysis, alongside transi-
tion metal complex catalysis and biocatalysis.2,3 Amongst the var-
ious reactions for the enantioselective formation of a C–C bond, the
asymmetric aldol reaction is one of the most important.4 Thus,
researchers have designed and synthesized a number of proline
derivatives, either containing bioisosteric groups such as sulfona-
mides and tetrazoles,5 or prolinamides which contain additional
chiral functionalities that are able to act as hydrogen bond donors.6
The family of peptides has also been studied for their potential as
organocatalysts.7 Peptides were amongst the first molecules to be
used as catalysts in asymmetric aldol reactions, however, they led
to low to moderate enantioselectivities in most cases.8,9 In most of
the above cases, DMSO or an organic solvent was utilized as the
reaction medium. Over the last few years, water has attracted
attention as the reaction medium, since it is an abundant, safe
and environmentally friendly solvent. Hayashi et al. and Barbas
et al. were amongst the first to report on successful organocatalytic
protocols in the presence of water.10 Since then, a variety of proline
derivatives11 and amino acid derivatives12 have been designed and
employed successfully in aqueous environments.
organic solvents. More recently, we introduced a number of Pro-
Phe tripeptides bearing a tert-butyl ester of an amino acid at the
C-terminus, where depending on the amino acid employed, these
molecules could catalyse the aldol reaction either in an organic sol-
vent or in an aqueous medium.13 Bearing these results in mind and
our previous involvement in organocatalysis,14 we further ques-
tioned whether we could employ tert-butyl esters of dipeptides
or tripeptides as potential organocatalysts. The synthesis of these
peptides is shown in Scheme 1.
Starting from the Cbz-protected amino acid at the N-terminus, a
standard peptide coupling employing carbodiimide chemistry led
to protected dipeptides or tripeptides; after hydrogenation under
Pd/C, the deprotected peptides 1a–4b were obtained in moderate
to high yields in two steps. To fully demonstrate the potential of
peptides bearing tert-butyl esters, we tested four different catego-
ries of peptides: (i) dipeptides bearing the primary amine of phen-
ylalanine and an amide at the
a
-carboxylic acid, H-Phe-Phe-OtBu
1a, H-Phe-Phg-OtBu 1b and H-Phe-Glu(OtBu)-OtBu 1c; (ii) dipep-
tides bearing the primary amine of
a-tert-butyl aspartate and an
amide at the b-carboxylic acid, H-Asp(Phe-OtBu)-OtBu 2a, H-
Asp(Gly-OtBu)-OtBu 2b and H-Asp(Val-OtBu)-OtBu 2c; (iii) tripep-
tides bearing the primary amine of aspartic acid and two amides
at the
a
- and the b-carboxylic acids, H-Asp[Asp(OtBu)-OtBu]-
Asp(OtBu)-OtBu 3a and H-Asp[Glu(OtBu)-OtBu]-Glu(OtBu)-OtBu
3b and finally (iv) dipeptides bearing the secondary amine of pro-
line, Pro-Ala-OtBu 4a and Pro-Glu(OtBu)-OtBu 4b. In order to test
organic solvents and aqueous media, all of the catalysts were
tested under both reaction conditions (Table 1).
2. Results and discussion
In our previous endeavours on enantioselective aldol reactions,
we have concluded that prolinamides bearing either a thiourea6f,g
The dipeptides based on phenylalanines 1a–c afforded the aldol
products in excellent yields in almost all cases, however, the
diastereoselectivity and the enantioselectivity were low (entries
1–6, Table 1). We had previously shown that the tripeptide
⇑
Corresponding author. Fax: +30 210 7274761.
E-mail address: ckokotos@chem.uoa.gr (C.G. Kokotos).
http://dx.doi.org/10.1016/j.tetasy.2014.12.007
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

A. Bisticha et al. / Tetrahedron: Asymmetry 26 (2015) 102–108
103
1) H-AA2-OtBu, WSCI, HOBt,
CH2Cl2, Et3N, r.t., 24 h
H-AA1-AA -OtBu
Cbz-AA1-OH
2
2) H2, Pd/C, MeOH, r.t., 24 h
33-92%
Ph
Ph
Ph
O
O
O
H
N
H
N
H
N
OtBu
Ph
H2N
H2N
OtBu
H2N
OtBu
O
1a
O
O
O
Ph
Ph
1b
1c
CO2tBu
tBuO
H2N
O
tBuO
H2N
tBuO
O
O
O
O
OtBu
OtBu
OtBu
N
H
N
H
H2N
O
N
H
O
O
O
2a
2b
2c
tBuO
O
tBuO
HN
O
OtBu
O
O
HN
OtBu
O
O
O
O
H2N
NH
OtBu
H2N
NH
OtBu
O
tBuO
O
O
tBuO
O
3b
3a
CO2tBu
O
OtBu
OtBu
O
N
H
N
H
N
H
O
N
H
4b
4a
Scheme 1. Synthesis of tert-butyl esters of peptides 1a–4b.
Pro-Phe-Phg-OtBu was an excellent catalyst for aldol reactions
both in organic and aqueous media.13 Unfortunately, the high
importance of the proline unit is evident, since catalyst 1b lost
its ability to provide high diastereo- and enantiocontrol. Moving
ketone/aldehyde ratio or lower catalyst loading proved to be
dentrimental for the efficiency of the reaction (entries 22–25,
Table 1
forward to the
a-tert-butyl aspartate peptides 2a–c, where the
Catalyst screening for the enantioselective aldol reaction
O
amide bond is one carbon atom further away, poor selectivities
were also obtained in aqueous solvents, while in toluene, the reac-
tions were sluggish (entries 7–12, Table 1). It has been shown that
more having than one hydrogen bond site in an organocatalyst has
a positive effect on the properties of the catalyst.6,13 Unfortunately,
although catalysts 3a and 3b provided the aldol product with
higher enantioselectivities than catalysts 2a–c, the selectivities
were moderate (entries 13–16, Table 1). In order to recover the
high levels of diastereoselectivity and enantioselectivity, the priv-
ileged structure of proline had to be employed (entries 17–20,
Table 1). Although Pro-Ala-OtBu 4a proved to be sluggish in pro-
moting the aldol reaction, Pro-Glu(OtBu)-OtBu 4b provided the
aldol product with high enantiomeric excess under both reaction
conditions. In particular, utilizing brine as the reaction medium,
a quantitative yield of the product was obtained along with high
diastereoselectivity (entry 20, Table 1). It should be noted that sim-
ilar high yields and selectivities have been reported using
tripeptides.13
After identifying the optimum catalyst, the reaction conditions
were scrutinized (Table 2). Amongst the various solvents tested,
acetonitrile provided the best results, while aqueous media led to
slightly inferior selectivities (entries 1–14, Table 2). The acid addi-
tive was next studied (entries 15–20, Table 2). Strong acids did not
provide any product, because they deactivate the catalyst via salt
formation, while it seems that there is a small window of pKa for
the acid to provide both high diastereoselectivity and enantioselec-
tivity. Furthermore, the beneficial role of water was highlighted
(entry 5 vs 21, Table 2). Finally, a lower temperature, lower
O
O
OH
catalyst (20 mol%),
4-NBA (20 mol%)
H
+
NO2 conditions, H2O,
r.t.
NO2
7a
5a
6a
Catalyst
Entry
Conditions
Yielda (%)
drb
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
2a
2a
2b
2b
2c
2c
3a
3a
3b
3b
4a
4a
4b
4b
Toluene, 48 h
Brine, 24 h
Toluene, 48 h
Brine, 24 h
Toluene, 48 h
Brine, 24 h
Toluene, 48 h
Brine, 24 h
Toluene, 72 h
Brine, 72 h
Toluene, 72 h
Brine, 72 h
Toluene, 48 h
Brine, 24 h
Toluene, 48 h
Brine, 24 h
22
97
100
100
90
98
100
95
n.r.
43
n.r.
35
43
97
90
94
26
69:31
54:46
50:50
38:62
50:50
39:61
30:70
36:64
—
80
49
8
38
9
30
16
37
—
39
—
33
67
66
40
37
70
—
9
10
11
12
13
14
15
16
17
18
19
20
38:62
—
42:58
45:55
42:58
33:67
50:50
70:30
—
Toluene, 72 h
Brine, 72 h
Toluene, 48 h
Brine, 24 h
n.r.
38
100
76:24
90:10
90
87
a
Isolated yield.
The diastereomeric ratio (dr) anti:syn was determined by 1H NMR spectroscopy
b
of the crude reaction mixture.
c
The enantiomeric excess (ee) for the anti-diastereomer was determined by
chiral HPLC. 4-NBA: 4-nitrobenzoic acid.

104
A. Bisticha et al. / Tetrahedron: Asymmetry 26 (2015) 102–108
Table 2
Table 3
Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using
Enantioselective aldol reaction between ketones and aldehydes using catalyst 4b
catalyst 4b
O
O
OH
O
4b (20 mol%),
4-NBA (20 mol%)
O
O
O
OH
4b (20 mol%),
H
+
Ar
Ar
additive (20 mol%)
H
MeCN:H2O (10:1),
r.t., 48 h
+
n
n
NO2 conditions, H2O,
r.t.
7a-t
NO2
Entry
Ketone
Ar
Product Yielda (%)
drb
eec (%)
6a
7a
5a
O
1
2
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CF3C6H4
3-CNC6H4
4-FC6H4
7a
7b
7c
7d
7e
7f
7g
7h
7i
7g
7k
7l
100
98
91:9
92:8
86:14
93:7
92
90
Entry
Conditions
Yielda (%)
drb
eec (%)
1
2
3
4
5
6
7
8
Toluene, 4-NBA, rt, 48 h
Pet. Ether, 4-NBA, rt, 48 h
Et2O, 4-NBA, rt, 24 h
THF, 4-NBA, rt, 48 h
MeCN, 4-NBA, rt, 48 h
CHCl3, 4-NBA, rt, 48 h
CH2Cl2, 4-NBA, rt, 48 h
AcOEt, 4-NBA, rt, 48 h
DMSO, 4-NBA, rt, 48 h
MeOH, 4-NBA, rt, 48 h
Neat, 4-NBA, rt, 48 h
H2O, 4-NBA, rt, 24 h
Brine, 4-NBA, rt, 24 h
aq NaBr, 4-NBA, rt, 24 h
MeCN, PhCOOH, rt, 48 h
MeCN, 4-Fphenol, rt, 48 h
MeCN, AcOH, rt, 48 h
MeCN, TFA, rt, 48 h
38
37
100
100
100
95
76:24
87:13
86:14
88:12
91:9
85:15
83:17
85:15
80:20
83;17
65:35
77:23
90:10
77:23
83:17
—
77:23
—
—
85:15
77:23
89:11
89:11
91:9
90
86
78
76
92
72
74
76
73
80
54
71
87
78
85
—
79
—
—
85
80
90
80
89
88
3
97
76
77
52
97
42
78
61
83
78
100
25
97
90
95
88
99
90
94
80
95
94
91
81
4d
5e
94:6
6d
86:14
90:10
86:14
87:13
85:15
91:9
90:10
78:22
85:15
7e
2-FC6H4
8d
4-BrC6H4
2-BrC6H4
4-ClC6H4
2-ClC6H4
C6H5
9e
97
95
10d
11e
12f
13e
14e
9
100
100
100
100
100
100
78
n.r.
98
n.r.
n.r.
100
68
88
54
48
27
10
11
12
13
14
15
16
17
18
19
20
21d
22
23e
24f
25g
4-Pyridinyl
3-Thiophenyl
7m
7n
O
15f
4-NO2C6H4
4-NO2C6H4
7o
7p
77
97
90:10
89:11
85
93
O
O
MeCN, CSA, rt, 48 h
16d
MeCN, 4-CF3BA, rt, 48 h
MeCN, 4-NBA, rt, 48 h
MeCN, 4-NBA, 0 °C, 48 h
MeCN, 4-NBA, rt, 48 h
MeCN, 4-NBA, rt, 48 h
MeCN, 4-NBA, rt, 48 h
S
O
90:10
17d
4-NO2C6H4
7q
7r
54
92
98:2
95
97
a
Isolated yield.
The diastereomeric ratio (dr) anti:syn was determined by 1H NMR spectroscopy
of the crude reaction mixture.
The enantiomeric excess (ee) for the anti-diastereomer was determined by
chiral HPLC.
O
O
O
b
c
d
18
4-NO2C6H4
84:16
No H2O.
5 equiv of cyclohexanone.
10 mol % of catalyst.
5 mol % of catalyst. 4-NBA: 4-nitrobenzoic acid. CSA: camphorsulfonic acid. 4-
e
f
g
O
O
CF3BA: 4-trifluoromethylbenzoic acid.
19
4-NO2C6H4
4-NO2C6H4
7s
7t
100
100
40:60
—
>99
73
20d
Table 2). We next turned our attention to exploring the substrate
scope of the enantioselective aldol reaction (Table 3).
a
A variety of substituted aromatic aldehydes were employed
with cyclohexanone to provide the aldol product (entries 1–14,
Table 3). Electron-withdrawing groups at any position of the aro-
matic group gave high to excellent yields and excellent selectivities
(entries 1–5, Table 3). Aromatic aldehydes bearing halogen substit-
uents either at the para- or the ortho-position led to lower yields
and selectivities in general (entries 6–11, Table 3). Benzaldehyde
required prolonged reaction times to afford the product in high
yield and selectivities, while heteroaromatic aldehydes could be
employed with some success (entries 12–14, Table 3). In particular,
4-pyridinyl carboxaldehyde led to lower diastereoselectivity, while
3-thiophenyl carboxaldehyde led to low yield and lower enantiose-
lectivity. Tetrahydropyran-4-one and tetrahydrothiopyran-4-one
required longer reaction times to afford the product in high yields
and selectivities (entries 15 and 16, Table 3). Disubstituted cyclo-
hexanone (at the 4-position) provided the product in lower yield,
but both the diastereoselectivity and enantioselectivity were
excellent, while desymmetrization of ketones is also possible, since
4-methyl-cyclohexanone gave the product in excellent yield and
enantioselectivity and high diastereoselectivity (entries 17 and
18, Table 3). Cyclopentanone, which is a difficult substrate to use
in the organocatalysed aldol reactions, was also utilized with some
success (entry 19, Table 3). Moreover, acetone was also investi-
Isolated yield.
The diastereomeric ratio (dr) anti:syn was determined by 1H NMR spectroscopy
of the crude reaction mixture.
b
c
The enantiomeric excess (ee) for the anti-diastereomer was determined by
chiral HPLC.
d
Reaction time: 96 h.
Reaction time: 72 h.
Reaction time: 120 h.
e
f
CO2tBu
O
N
O
N
H
R1
O
O
H
R2
R
Figure 1. Proposed transition state model for the aldol reaction.
gated as the ketone counterpart, leading to excellent yield but
moderate enantioselectivity (entry 20, Table 3). In comparison to
tripeptides as organocatalysts to promote the enantioselective

A. Bisticha et al. / Tetrahedron: Asymmetry 26 (2015) 102–108
105
aldol reaction,13 Pro-Glu(OtBu)-OtBu, which is faster and easier to
synthesize, led to similar yields and selectivities.
4.1.1. (S)-tert-Butyl-2-[(S)-2-amino-3-phenylpropanamido]-3-
phenylpropanoate 1a15
A plausible transition state model is proposed in Figure 1. The
free amine from the dipeptide activates the ketone via enamine
formation, while the electrophile is activated via hydrogen bonding
from the amide proton.
To a stirring solution of Cbz-phenylalanine (0.56 g, 2.00 mmol)
in dry CH2Cl2 (25 mL) at 0 °C, HClꢀH-Phe-OtBu (0.52 g, 2.00 mmol),
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
(WSCIꢀHCl) (0.38 g, 2.00 mmol), 1-hydroxybenzotriazole (HOBt)
(0.27 g, 2.00 mmol) and Et3N (1.06 mL, 8.00 mmol), were added
consecutively. The reaction mixture was left stirring at 0 °C for
1 h, and then warmed to room temperature and left stirring for
18 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and
washed with aq HCl 1 M (2 ꢁ 30 mL), brine (30 mL), aq NaOH
1 M (2 ꢁ 30 mL) and brine (30 mL). The solvents were evaporated
in vacuo and the crude product was used in the next reaction.
The crude product was dissolved in MeOH (15 mL) and 10% Pd/
C (10 mol %) was added and the reaction mixture was left stirring
at room temperature for 24 h under a hydrogen atmosphere. After
filtration through Celite, the solvent was evaporated in vacuo and
the crude product was purified by column chromatography eluting
with CHCl3/MeOH (95:5) (0.49 g, 66% yield); Colourless oil;
3. Conclusion
In conclusion, the synthesis of four different groups of dipep-
tides and tripeptides based either on phenylalanine,
a-tert-butyl
aspartate, aspartic acid or proline and a series of tert-butyl
esters of amino acids was carried out. The design was based
on the propensity of primary and secondary amines to activate
ketones via enamine formation, while the amide proton could
activate the electrophile. All compounds in these families pro-
moted the aldol reaction, however proline dipeptides provided
the best results with the dipeptide Pro-Glu(OtBu)-OtBu affording
the best results both in organic and aqueous media. After
screening various reaction conditions, wet acetonitrile provided
the best results. A variety of aromatic aldehydes and ketones
were utilized successfully leading to products in mediocre to
excellent yields, and with good to excellent diastereoselectivi-
ties and enantioselectivities. These results build on our previous
results, where tripeptides were found to be excellent organocat-
alysts.13 Herein we have highlighted that even proline dipep-
tides can lead to excellent organocatalytic results and provide
better catalytic properties than proline itself, since they can
[a
]
D
25 = ꢂ9.8 (c 1.0, CH3OH); 1H NMR (200 MHz, CD3OD): d 7.38–
7.17 (10H, m, ArH), 4.58 (1H, t, J = 6.9 Hz, NCH), 4.17–4.02 (1H,
m, NCH), 3.28–2.92 (4H, m, 2ꢁ PhCH2), 1.38 [9H, s, C(CH3)3]; 13C
NMR (50 MHz, CD3OD): d 170.5, 169.3, 136.8, 134.7, 129.5, 129.3,
128.9, 128.4, 127.6, 126.8, 82.0, 54.9, 54.4, 37.9, 37.5, 27.1; MS
(ESI) 369 (M+H+, 100%).
4.1.2. (S)-tert-Butyl-2-[(S)-2-amino-3-phenylpropanamido]-2-
phenylacetate 1b
Same procedure as above utilizing (S)-H-Phg-OtBu (0.44 g, 62%
be employed in
a variety of organic solvents and aqueous
yield); Colourless oil; [a]
25 = +57.0 (c 0.33, CH3OH); 1H NMR
D
media leading to high yields and selectivities.
(200 MHz, CDCl3): d 8.24 (1H, d, J = 7.2 Hz, NH), 7.38–7.06 (10H,
m, ArH), 5.46 (1H, d, J = 7.2 Hz, NCH), 3.81–3.57 (1H, m, NCH),
3.22–3.05 (1H, m, PhCHH), 2.79–2.51 (1H, m, PhCHH), 1.85 (2H,
br s, NH2), 1.38 [9H, s, C(CH3)3]; 13C NMR (50 MHz, CDCl3): d
173.0 (173.2), 169.8 (169.6), 137.4 (137.8), 137.1 (137.2), 129.3
(129.0), 128.7 (128.6), 128.0, 127.0, 126.9, 126.7, 82.4, 56.5, 56.1,
40.6, 28.0; MS (ESI) 355 (M+H+, 100%); HRMS exact mass calcd
for [M+H]+ (C21H27O3N2)+ requires m/z 355.2016, found m/z
355.2017.
4. Experimental
4.1. General
Organic solutions were concentrated under reduced pressure
on a Büchi rotary evaporator. Chromatographic purification of
the products was accomplished using forced-flow chromatogra-
phy on Merck Kieselgel 60 F254 230–400 mesh. Thin-layer
chromatography (TLC) was performed on aluminium backed
silica plates (0.2 mm, 60 F254). Visualization of the developed
chromatogram was performed by fluorescence quenching using
phosphomolybdic acid stains, anisaldehyde or ninhydrin stains.
Optical rotations were measured on a Perkin Elmer 343 polar-
imeter. 1H NMR spectra were recorded on Varian Mercury
(200 MHz) and are internally referenced to residual protio sol-
vent signals. Data for 1H NMR are reported as follows: chem-
ical shift (d ppm), integration, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad
signal), coupling constant and assignment. 13C NMR spectra
were recorded on Varian Mercury (50 MHz) and are internally
referenced to residual protio solvent signals. Data for 13C NMR
are reported in terms of chemical shift (d ppm). Wherever
rotamers exist, they are cited in parenthesis. 19F NMR spectra
were recorded on Varian Mercury (188 MHz) and are internally
referenced to trifluoroacetic acid. Mass spectra were recorded
on a Finnigan Surveyor MSQ Plus, with only molecular ions
and major peaks being reported with intensities quoted as per-
centages of the base peak. HRMS spectra were recorded on
ThermoÒ Orbitrap Velos spectrometer. Chiral High Performance
Liquid Chromatography (HPLC) analyses were performed using
an Agilent 1100 Series apparatus and ChiralpakÒ AD-H, OD-H
and AS-H columns. The configuration of the products has been
assigned by comparison to the literature data or assigned by
analogy.
4.1.3. (S)-Di-tert-butyl-2-[(S)-2-amino-3-phenylpropanamido]
pentanedioate 1c
Same procedure as above utilizing HClꢀH-Glu(OtBu)-OtBu
(0.40 g, 49% yield); Colourless oil; [
a
]
25 = ꢂ11.8 (c 0.33, CH3OH);
D
1H NMR (200 MHz, CD3OD): d 7.38–7.06 (5H, m, ArH), 4.42–4.23
(1H, m, NCH), 4.18–3.71 (1H, m, NCH), 3.46–3.13 (1H, m, PhCHH),
3.07–2.78 (1H, m, PhCHH), 2.32–1.67 (4H, m, 2ꢁ CH2), 1.45 [18H, s,
C(CH3)3]; 13C NMR (50 MHz, CD3OD): d 172.5 (172.6), 172.4
(172.5), 170.3 (170.8), 135.2 (134.9), 129.5 (129.7), 128.7 (128.5),
126.7 (127.0), 82.0, 80.7, 52.5, 52.4, 42.9, 31.3, 27.4, 27.3, 22.4;
MS (ESI) 407 (M+H+, 100%); HRMS exact mass calcd for [M+H]+
(C22H35O5N2)+ requires m/z 407.2540, found m/z 407.2544.
4.1.4. (S)-tert-Butyl 2-amino-4-{[(S)-1-(tert-butoxy)-1-oxo-3-
phenylpropan-2-yl]amino}-4-oxobutanoate 2a
To a stirred solution of Cbz-Asp-OtBu (0.32 g, 1.00 mmol) in dry
CH2Cl2 (15 mL) at 0 °C, HClꢀH-Phe-OtBu (0.26 g, 1.00 mmol), 1-(3-
dimethylaminopropyl)-3-ethyl
carbodiimide
hydrochloride
(WSCIꢀHCl) (0.19 g, 1.00 mmol), 1-hydroxybenzotriazole (HOBt)
(0.14 g, 1.00 mmol) and Et3N (0.53 mL, 4.00 mmol), were added
consecutively. The reaction mixture was left stirring at 0 °C for
1 h, and then warmed to room temperature and left stirring for
18 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and
washed with aq HCl 1 M (2 ꢁ 20 mL), brine (20 mL), aq NaOH
1 M (2 ꢁ 20 mL) and brine (20 mL). The solvents were evaporated
in vacuo and the crude product was used in the next reaction step.

106
A. Bisticha et al. / Tetrahedron: Asymmetry 26 (2015) 102–108
The crude product was dissolved in MeOH (15 mL) and 10% Pd/C
(10 mol %) was added after which the reaction mixture was left
stirring at room temperature for 24 h under a hydrogen atmo-
sphere. After filtration through Celite, the solvent was evaporated
in vacuo and the crude product was purified by column chroma-
tography eluting with CHCl3/MeOH (98:2) (0.15 g, 37% yield); Col-
NMR (50 MHz, CD3OD): d 174.7 (174.3), 171.6 (171.5), 170.2
(170.3), 170.1 (170.2), 169.9 (170.0), 169.8 (169.7), 82.2, 82.0,
81.4, 81.2, 52.1, 49.8, 49.5, 40.3, 37.1, 37.0, 27.2, 27.0; MS (ESI)
588 (M+H+, 100%); HRMS exact mass calcd for [MꢂH]ꢂ (C28H48O10-
N3)ꢂ requires m/z 586.3340, found m/z 586.3341.
ourless oil; [
a]
25 = ꢂ1.2 (c 0.5, CH3OH); 1H NMR (200 MHz, CDCl3):
4.1.8. (2S,20S)-Tetra-tert-butyl 2,20-{[(S)-2-aminosuccinyl]
bis(azanediyl)}dipentanedioate 3b
D
d 7.77 (1H, br s, NH), 7.41–7.08 (5H, m, ArH), 4.71–4.61 (1H, m,
NCH), 4.25–4.08 (1H, m, NCH), 3.72 (2H, br s, NH2), 3.12–2.92
(2H, m, PhCH2), 2.88–2.31 (2H, m, COCH2), 1.42–1.37 [18H, m,
2 ꢁ C(CH3)3]; 13C NMR (50 MHz, CDCl3): d 171.7 (171.8), 170.9
(171.0), 169.8 (169.7), 136.3 (136.5), 129.4, 128.3, 126.8, 82.3
(82.5), 82.2 (82.1), 53.9 (52.7), 51.5 (51.4), 37.8 (38.3), 37.6
(38.0), 27.8; MS (ESI) 393 (M+H+, 100%); HRMS exact mass calcd
for [M+H]+ (C21H33O5N2)+ requires m/z 393.2384, found m/z
393.2394.
Same procedure as above utilizing HClꢀH-Glu(OtBu)-OtBu
(0.41 g, 67% yield); Colourless oil; [
a
]
25 = ꢂ16.0 (c 0.1, CH3OH);
D
1H NMR (200 MHz, CD3OD): d 4.38–4.24 (1H, m, NCH), 3.37–3.28
(2H, m, 2ꢁ NCH), 2.68–2.43 (2H, m, 2ꢁ CHH), 2.42–2.23 (4H, m,
4ꢁ CHH), 2.21–1.96 (2H, m, 2ꢁ CHH), 1.95–1.71 (2H, m, 2ꢁ
CHH), 1.48–1.38 [36H, m, 4ꢁ C(CH3)3]; 13C NMR (50 MHz, CD3OD):
d 175.8 (175.9), 173.6 (174.5), 174.0 (174.1), 173.8 (173.9), 173.7
(173.8), 173.0 (172.5), 83.1 (83.2), 83.0 (83.1), 81.8 (81.9), 81.8
(81.9), 60.2, 53.7, 53.4, 39.7, 32.5, 32.4, 28.3, 28.2, 22.6, 22.3; MS
(ESI) 616 (M+H+, 100%); HRMS exact mass calcd for [M+H]+
(C30H54O10N5)+ requires m/z 616.3809, found m/z 616.3782.
4.1.5. (S)-tert-Butyl 2-amino-4-{[2-(tert-butoxy)-2-oxoethyl]
amino}-4-oxobutanoate 2b
Same procedure as above utilizing HClꢀH-Gly-OtBu (0.28 g, 92%
yield); Colourless oil; [
a
]
D
25 = ꢂ0.95 (c 0.1, CH3OH); 1H NMR
4.1.9. (S)-tert-Butyl 2-[(S)-pyrrolidine-2-carboxamido]propanoate
4a
(200 MHz, CDCl3): d 7.85 (1H, br s, NH), 3.93 (2H, t, J = 5.0 Hz,
NCH2), 3.69 (1H, dd, J = 9.4 and 3.1 Hz, NCH), 2.67 (1H, dd,
J = 15.6 and 3.1 Hz, COCHH), 2.41 (1H, dd, J = 15.6 and 9.4 Hz,
COCHH), 1.89 (2H, br s, NH2), 1.48–1.38 [18H, m, 2ꢁ C(CH3)3];
13C NMR (50 MHz, CDCl3): d 173.5, 170.7, 169.2, 82.2, 81.9, 51.9,
41.9, 39.6, 28.0, 27.9; MS (ESI) 303 (M+H+, 100%); HRMS exact
mass calcd for [M+Na]+ (C14H26O5N2Na)+ requires m/z 325.1734,
found m/z 325.1737.
To a stirred solution of Cbz-Pro-OH (0.25 g, 1.00 mmol) in dry
CH2Cl2 (15 mL) at 0 °C, HClꢀH-Ala-OtBu (0.18 g, 1.00 mmol), 1-(3-
dimethylaminopropyl)-3-ethyl
carbodiimide
hydrochloride
(WSCIꢀHCl) (0.19 g, 1.00 mmol), 1-hydroxybenzotriazole (HOBt)
(0.14 g, 1.00 mmol) and Et3N (0.53 mL, 4.00 mmol), were added
consecutively. The reaction mixture was left stirring at 0 °C for
1 h, and then warmed to room temperature and left stirring for
18 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and
washed with aq HCl 1 M (2 ꢁ 20 mL), brine (20 mL), aq NaOH 1 N
(2 ꢁ 20 mL) and brine (20 mL). The solvents were evaporated in
vacuo and the crude product was used in the next reaction step.
The crude product was dissolved in MeOH (15 mL) and 10% Pd/
C (10 mol %) was added after which the reaction mixture was left
stirring at room temperature for 24 h under a hydrogen atmo-
sphere. After filtration through Celite, the solvent was evaporated
under vacuo and the crude product was purified by column chro-
matography eluting with CHCl3/MeOH (95:5) (0.18 g, 74% yield);
4.1.6. (S)-tert-Butyl 2-amino-4-{[(S)-1-(tert-butoxy)-3-methyl-
1oxobutan-2-yl]amino}-4-oxobutanoate 2c
Same procedure as above utilizing HClꢀH-Val-OtBu (0.11 g, 33%
yield); Colourless oil; [a]
25 = +2.8 (c 0.1, CHCl3); 1H NMR (200 MHz,
D
CDCl3): d 7.76 (1H, d, J = 8.3 Hz, NH), 4.45 (1H, dd, J = 8.8 and
4.4 Hz, NCH), 3.70–3.63 (1H, m, NCH), 2.70 (1H, dd, J = 15.9 and
3.1 Hz, COCHH), 2.40 (1H, dd, J = 15.9 and 9.6 Hz, COCHH), 2.22–
2.07 (1H, m, CH), 2.00 (2H, br s, NH2), 1.44 [18H, s, 2ꢁ C(CH3)3],
0.90 (3H, d, J = 6.8 Hz, CH3), 0.87 (3H, d, J = 6.8 Hz, CH3); 13C NMR
(50 MHz, CDCl3): d 173.5, 171.1, 170.4, 81.8, 57.2, 52.1, 39.7,
31.3, 28.0, 27.9, 19.0, 17.6; MS (ESI) 345 (M+H+, 100%); HRMS exact
mass calcd for [M+Na]+ (C17H31O5N2Na)+ requires m/z 366.2125,
found m/z 366.2130.
Colourless oil; [
a]
25 = ꢂ38.8 (c 0.2, CHCl3); 1H NMR (200 MHz,
D
CDCl3): d 8.12 (1H, d, J = 7.6 Hz, NH), 4.37 (1H, quint, J = 7.3 Hz,
NCH), 3.83 (1H, dd, J = 8.7 and 5.4 Hz, NCH), 3.41 (1H, br s, NH),
3.10–2.88 (2H, m, NCH2), 2.22–2.06 (1H, m, CHH), 1.98–1.61 (3H,
m, 3ꢁ CHH), 1.42 [9H, s, C(CH3)3], 1.33 (3H, d, J = 7.2 Hz, CH3);
13C NMR (50 MHz, CDCl3): d 173.9, 172.1, 81.6, 60.1, 48.1, 47.0,
30.6, 27.8, 25.8, 18.4; MS (ESI) 243 (M+H+, 100%); HRMS exact
mass calcd for [M+H]+ (C12H22O3N2Na)+ requires m/z 265.1523,
found m/z 265.1521.
4.1.7. (2S,20S)-Tetra-tert-butyl 2,20-{[(S)-2-aminosuccinyl]
bis(azanediyl)}disuccinate 3a
To a stirred solution of Cbz-Asp-OH (0.27 g, 1.00 mmol) in dry
CH2Cl2 (15 mL) at 0 °C, HClꢀH-Asp(OtBu)-OtBu (0.62 g, 2.20 mmol),
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
(WSCIꢀHCl) (0.42 g, 2.20 mmol), 1-hydroxybenzotriazole (HOBt)
(0.31 g, 2.20 mmol) and Et3N (0.53 mL, 4.00 mmol), were added
consecutively. The reaction mixture was left stirring at 0 °C for
1 h, and then warmed to room temperature and left stirring for
18 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and
washed with aq HCl 1 M (2 ꢁ 20 mL), brine (20 mL), aq NaOH
1 M (2 ꢁ 20 mL) and brine (20 mL). The solvents were evaporated
in vacuo and the crude product was used in the next reaction step.
The crude product was dissolved in MeOH (15 mL) and 10% Pd/
C (10 mol %) was added after which the reaction mixture was left
stirring at room temperature for 24 h under a hydrogen atmo-
sphere. After filtration through Celite, the solvent was evaporated
in vacuo and the crude product was purified by column chroma-
tography eluting with CHCl3/MeOH (95:5) (0.45 g, 77% yield); Col-
4.1.10. (S)-Di-tert-butyl 2-[(S)-pyrrolidine-2-carboxamido]
pentanedioate 4b
Same procedure as above utilizing HClꢀH-Glu(OtBu)-OtBu
(0.22 g, 63% yield); Colourless oil; [
a]
25 = ꢂ25.8 (c 0.5, CHCl3); 1H
D
NMR (200 MHz, CDCl3): d 8.60 (1H, br s, NH), 4.97–4.64 (1H, m,
NCH), 4.46–4.19 (1H, m, NCH), 3.63–3.34 (2H, m, NCH2), 2.71–
2.45 (1H, m, CHH), 2.45–2.24 (3H, m, 3ꢁ CHH), 2.22–1.83 (5H, m,
4ꢁ CHH and NH), 1.40 [18H, s, 2ꢁ C(CH3)3]; 13C NMR (50 MHz,
CDCl3): d 172.5, 170.1, 168.7, 82.0, 80.9, 59.5, 53.1, 46.7, 31.7,
30.4, 28.0, 27.9, 26.5, 24.3; MS (ESI) 357 (M+H+, 100%); HRMS exact
mass calcd for [M+H]+ (C18H33O5N2)+ requires m/z 357.2384, found
m/z 357.2393.
4.2. General procedure for the enantioselective aldol reaction
ourless oil; [
a
]
25 = ꢂ14.0 (c 1.0, CH3OH); 1H NMR (200 MHz,
D
CD3OD): d 4.78–4.61 (2H, m, 2ꢁ NCH), 4.30–3.84 (1H, m, NCH),
To
a
round-bottomed flask, Pro-Glu(OtBu)-OtBu (10 mg,
2.98–2.58 (6H, m, 3ꢁ CH2CO), 1.44 [36H, s, 4ꢁ C(CH3)3]; 13C
0.028 mmol), 4-NBA (4.7 mg, 0.028 mmol) and aldehyde

A. Bisticha et al. / Tetrahedron: Asymmetry 26 (2015) 102–108
107
(0.14 mmol) were added. After the addition of MeCN (1 mL) and
H2O (0.1 mL), the ketone (1.40 mmol) was added and the reaction
mixture was stirred for 24–120 h at room temperature. The solvent
was evaporated and the crude product was purified using flash col-
umn chromatography eluting with the appropriate mixture of
petroleum ether (40–60 °C)/ethyl acetate to afford the desired
product.
126.0, 125.9, 122.2, 70.6, 57.1, 42.6, 30.8, 27.8, 24.7; HPLC analysis:
Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate 1.0 mL/min,
retention time: 15.88 (minor) and 21.54 (major).
4.2.15. (S)-3-[(R)-Hydroxy-(4-nitrophenyl)methyl]dihydro-2H-
pyran-4(3H)-one 7o
See Ref. 13.
4.2.16. (S)-3-[(R)-Hydroxy-(4-nitrophenyl)methyl]dihydro-2H-
thiopyran-4(3H)-one 7p
4.2.1. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-cyclohexanone
7a
See Ref. 13.
See Ref. 13.
4.2.17. (S)-7-[(R)-Hydroxy-(4-nitrophenyl)methyl]-1,4-dioxospiro
[4.5]decan-8-one 7q
4.2.2. (S)-2-[(R)-Hydroxy-(3-nitrophenyl)methyl]-cyclohexanone
7b
See Ref. 13.
See Ref. 13.
4.2.18. (2S,4R)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-4-methyl
cyclohexanone 7r
4.2.3. (S)-2-[(R)-Hydroxy-(2-nitrophenyl)methyl]-cyclohexanone
7c
See Ref. 13.
See Ref. 13.
4.2.4. (S)-2-[(R)-Hydroxy-(4-trifluoromethylphenyl)methyl]-
cyclohexanone 7d
4.2.19. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-cyclopenta
none 7s
See Ref. 13.
See Ref. 13.
4.2.5. (R)-3-[Hydroxy-(2-(S)-oxocyclohexyl)methyl]-benzonitrile
7e
4.2.20. (R)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one 7t
See Ref. 13.
See Ref. 13.
Acknowledgments
4.2.6. (S)-2-[(R)-Hydroxy-(4-fluorophenyl)methyl]-cyclohexanone
7f
C.G.K. gratefully acknowledges the Operational Program ‘Educa-
tion and Lifelong Learning’ for financial support through the NSRF
See Ref. 13.
program ‘ENIRXYRH METADIDAKTOPXm EPEYNHTXN (PE 2431)’
co-financed by ESF and the Greek State and ORCA COST Action
CM0905.
4.2.7. (S)-2-[(R)-Hydroxy-(2-fluorophenyl)methyl]-cyclohexanone
7g
See Ref. 13.
References
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See Ref. 18.
4.2.11. (S)-2-[(R)-Hydroxy-(2-chlorophenyl)methyl]-
cyclohexanone 7k
See Ref. 18.
4.2.12. (S)-2-[(R)-Hydroxy-(phenyl)methyl]-cyclohexanone 7l
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7n
25% yield; [a]
25 = +9.2 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3):
D
anti d 7.36–7.26 (1H, m, ArH), 7.19 (1H, d, J = 2.4 Hz, ArH), 7.08 (1H,
d, J = 5.0 Hz, ArH), 4.92 (1H, d, J = 8.4 Hz, OCH), 3.90 (1H, br s, OH),
2.74–2.22 (3H, m, COCH and CHH), 2.17–2.04 (1H, m, CHH), 1.86–
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