Peptide-catalyzed stereoselective Michael addition of aldehydes and ketones to heterocyclic nitroalkenes

Article abstract of DOI:10.1007/s00706-017-2126-2

Abstract: Stereoselective Michael addition of enolizable carbonyl compounds to a furane-derived nitroalkene was catalyzed by di- and tripeptide organocatalysts. The most competent catalysts were tripeptides possessing Pro–Pro–Glu structure. With aldehydes

Full text of DOI:10.1007/s00706-017-2126-2

Monatsh Chem
https://doi.org/10.1007/s00706-017-2126-2
ORIGINAL PAPER
Peptide-catalyzed stereoselective Michael addition of aldehydes
and ketones to heterocyclic nitroalkenes
1
Viera Polackova Patrıcia Cmelova Renata Gorova Radovan Sebesta
1
2
•
1
ˇ
ˇ
•
•
´ˇ
´
´
´
´
´
´
Received: 8 November 2017 / Accepted: 3 December 2017
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2017
Abstract Stereoselective Michael addition of enolizable
carbonyl compounds to a furane-derived nitroalkene was
catalyzed by di- and tripeptide organocatalysts. The most
competent catalysts were tripeptides possessing Pro–Pro–
Glu structure. With aldehydes, Michael adducts were
obtained in high yields and with medium-to-high diastereo-
(up to 13:1 d.r.) and enantiomeric purities (up to 99% ee).
The reaction was less stereoselective with cyclic ketones
than with aldehydes.
Introduction
Heterocyclic compounds, including chiral ones, are
broadly distributed in nature [1]. Heteroaromatics, as well
as saturated heterocycles, belong among the most impor-
tant pharmacophores [2]. Asymmetric organocatalysis
gives access to numerous chiral heterocyclic compounds
[3–5]. Michael addition is one of the principal C–C bond
building strategies [6–8].
Graphical abstract
Short-chain peptides have found many uses in asym-
metric catalysis [9–12]. Peptides proved valuable
alternatives to enzymes for modifications of complex nat-
ural products [13]. Seminal Miller’s discoveries of
nucleophilic peptide-based catalysts for acylations [14] and
later on phosphorylations [15, 16] and sulfinylations [17]
stimulated the interest of the organic chemistry community
in catalytic peptides. Short-chain peptides or peptide-based
catalysts can also catalyze many other reactions. Peptides
possessing a free primary or secondary amine group can
activate enolizable carbonyl compounds via enamine for-
mation. In this way, peptides served as catalysts for
numerous aldol-type reactions [18–28]. Similarly, peptides
engage in several Michael additions. In 2006, Cordova and
co-workers showed that di- and tripeptides can catalyze
Michael addition of ketones to nitroalkenes [29]. Wen-
nemers et al. developed N-terminal proline tripeptides as
excellent catalysts for 1,4-additions of aldehydes to
nitroalkenes [30–36]. These type of catalysts proved robust
enough even for immobilization on solid supports [37, 38].
Peptide catalysts found use also in 1,4-additions to other
types of Michael acceptors, such as maleimides [39] or
enals [40, 41]. In addition, modified peptides, such as
diketopiperazines, dipeptide-derived phosphonium salts,
and tetrahydropyran-based dipeptides, are competent cat-
alysts for Michael additions [42–44]. The catalytic activity
Keywords Catalysis Á Peptides Á Michael addition Á
Carbonyl compounds Á Heterocycles
ˇ
& Radovan Sebesta
radovan.sebesta@uniba.sk
1
Department of Organic Chemistry, Faculty of Natural
´
Sciences, Comenius University in Bratislava, Mlynska
ˇ
dolina, Ilkovicova 6, 842 15 Bratislava, Slovakia
2
Institute of Chemistry, Faculty of Natural Sciences,
´
Comenius University in Bratislava, Mlynska dolina,
ˇ
Ilkovicova 6, 842 15 Bratislava, Slovakia
123

´ˇ ´
V. Polackova et al.
of peptides is closely linked with their secondary structures
[45, 46].
Although large attention has already been focused on
organocatalytic Michael additions, substrates containing
heterocyclic moieties were studied only sparingly. Given
the importance and widespread occurrence of the hetero-
cyclic skeleton in biologically active compounds, we have
decided to investigate Michael addition of carbonyl com-
pounds to heterocyclic nitroalkenes. In this paper, we
present the results of our studies of asymmetric 1,4-addi-
tions of aldehydes and ketones to heterocyclic nitroalkenes
catalyzed by short-chain peptides.
Fig. 2 Heterocyclic nitroalkenes used in this study
Scheme 1
Results and discussion
Nitroalkenes 1 and 3 proved to be unreactive in Michael
additions of enolizable aldehydes. Despite several attempts
under various conditions, we were not able to isolate cor-
responding Michael adducts using none of peptidic
catalysts. On the other hand, furane-derived nitroalkene 2
afforded corresponding Michael adduct 5a in the reaction
with 3-phenylpropanal (4a) (Scheme 1).
We have started our investigation by synthesis of peptides.
Using the literature procedures, we have synthesized six
short-chain peptides containing N-terminal proline residue
(Fig. 1). This proline moiety is important for the supposed
enamine-forming activity of catalysts. Catalyst C1 is
composed of two L-proline moieties. Catalysts C2 and C3
contain D-proline and a glutamic acid having both protected
and free carboxylic functions. Catalyst C4 is a tripeptide
comprising L-Pro-L-Pro-L-Glu. Catalysts C5 and C6 pos-
sess D-Pro-L-Pro motive combined with either protected or
unprotected glutamic acid. Glutamic acid can act as an
additional Bronsted acid, which can accelerate Michael
additions. This idea has been suggested by Wennemers for
similar peptides containing either aspartic or glutamic acid
[30, 38].
We have screened peptide catalysts C1–C6 in the
Michael reaction of phenylpropanal (4a) with nitroalkene
2. Interestingly, all catalysts afforded product 5a in good
yield and medium-to-high diastereomeric and enantiomeric
purity. The best performance was achieved by tripeptide
catalysts C5 and C6 (Table 1, entries 10 and 11). Table 1
summarizes the results of catalysts screening in the reac-
tion of nitroalkene 2 with 3-phenylpropanal (4a).
We have also tested Michael additions of a series of
aliphatic aldehydes 4b–4e to nitroalkene 2 (Scheme 2).
Corresponding Michael adducts 5b–5e were isolated in
good yields but with compromised diastereomeric and
enantiomeric purities.
With peptidic catalysts in hands, we started to investi-
gate Michael additions to heterocyclic nitroalkenes 1–3
(Fig. 2). Pyridine-based nitroalkene 1 was commercially
available. Furane derivative 2 and indol-derived alkene 3
were synthesized by the nitro-aldol reaction between cor-
responding aldehydes and nitromethane [47].
With nitroalkene 2, we have also explored Michael
additions of cyclic ketones, cyclopentanone (6a) and
cyclohexanone (6b) (Scheme 3). Corresponding Michael
adducts 7a, 7b were obtained in good yields but in only
Fig. 1 Peptidic organocatalysts
used in this study
123

Peptide-catalyzed stereoselective Michael addition of aldehydes and ketones to heterocyclic…
Table 1 Screening of peptide catalysts in the Michael reaction of 3-phenylpropanal (4d) with nitroalkene 2
Entry
Catalyst
Additive/loading/mol%a
Time/h
Yield/%
d.r. (syn:anti)
ee/%c
1
2
H-L-Pro-L-Pro-OMe (TFA.C1)
–/10
18
72
36
24
24
24
72
72
36
36
93
20
67
95
95
93
61
69
71
69
3:1
84 (R,S)
96 (R,S)
99 (R,S)
99 (R,S)
99 (R,S)
67 (R,S)
99 (S,R)
99 (S,R)
99 (S,R)
[ 99 (S,R)
H-L-Pro-L-Pro-L-Glu(OMe)-OMe (TFA.C4)
H-L-Pro-L-Pro-L-Glu(OMe)-OMe (TFA.C4)
H-L-Pro-L-Pro-L-Glu(OMe)-OMe (TFA.C4)
H-L-Pro-L-Pro-L-Glu(OMe)-OMe (TFA.C4)
H-L-Pro-L-Pro-L-Glu(OMe)-OMe (TFA.C4)
H-D-Pro-L-Glu-OH (TFA.C3)b
H-D-Pro-L-Glu(OMe)-OMe (TFA.C2)b
H-D-Pro-L-Pro-L-Glu(OMe)-OMe (C5)
H-D-Pro-L-Pro-L-Glu-OH (TFA.C6)
–/1
5:1
3
–/3
5:1
4
PhCO2H/3
5:1
5
AcOH/3
4:1
6
(R)-mandelic a./3
4:1
7
–/5
–/5
–/5
–/5
13:1
9:1
8
9
11:1
13:1
10
aLoading of catalyst, NMM, as well as acidic additive
bSolvent CHCl3/i-PrOH 1:1
cEnantiomeric excesses determined by chiral HPLC; absolute configuration assigned by analogy with the literature [30]
Scheme 2
Scheme 3
Conclusion
Short-chain peptide organocatalysts possessing N-terminal
proline moiety are effective catalysts for Michael additions
of aldehydes to furan-derived nitroalkene. The corre-
sponding Michael adducts were obtained in high yields
(70–93%). The Michael addition of 3-phenylpropanal also
proceeded with high diastereo- and enantioselectivity (13:1
d.r., 99% ee), but aliphatic aldehydes reacted with only
moderate stereoselectivities. Peptidic catalysts were less
efficient in 1,4-additions of cyclic ketones.
medium or low enantiomeric purity. The results of Michael
addition of cyclic ketones with nitroalkene 2 are summa-
rized in Table 2.
Experimental
To gain insight into catalytic activities, we have calcu-
lated geometries of three most effective catalysts C3, C5,
and C6. DFT calculation at xB97X-D/6-31G* level
showed that all catalysts display typical hairpin structure
supported by intramolecular hydrogen bonds. Catalysts C3
and C5, which comprise D-Pro-L-Pro arrangement, have
hydrogen bond between N-terminal proline moiety and
glutamic acid (C3: N—HOOC; C5: NH—O=C). On the
other hand, catalyst C6 shows hydrogen bonding between
amide NH of glutamic acid and nitrogen of terminal proline
moiety (Fig. 3).
All chemicals and solvents were purchased from Alfa
Aesar or Sigma-Aldrich. All reactions were performed
under an Ar-atmosphere. The solvents were purified and
dried according to the standard techniques. Thin-layer
chromatography was performed on Merck TLC-plates sil-
ica gel 60, F-254, or on Al2O3 TLC-plates. Compounds
were visualized by irradiation with UV light and/or by
treatment with solutions of KMnO4 or ninhydrin reagent.
Products Michael additions from reaction mixtures were
123

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V. Polackova et al.
Table 2 Michael addition of cyclic ketones to nitroalkene 2
Entry
Ketone
Catalyst
Catalyst loading/mol%a
Time/h
Yield/%
d.r. (syn/anti)
ee/%c
1
1
2
3
4
6a
6b
6b
6b
6b
C3
C1
C4
C4b
C3
5
10
5
72
18
31
83
95
45
20
4:1
6:1
10:1
6:1
7:1
19 (S,S)
26 (R,R)
36 (R,R)
9 (R,R)
24
3
72
5
120
16 (S,S)
aCatalyst as well as NMM loading
bPhCO2H (3 mol %) as additive
cEnantiomeric excesses determined by chiral HPLC; absolute configuration assigned by comparison of the sign of optical rotation with the
literature data [48]
Fig. 3 Lowest energy conformers of catalysts C3, C5, and C6 calculated at xB97X-D/6-31G* level
suspended in 10 cm3 dry CH2Cl2 and cooled an ice bath
after general work-up separated by flash chromatography
under
a
nitrogen atmosphere. DIPEA (iPrNEt2)
using Isolera Biotage FSKO-1107-0010. NMR spectra
were recorded on Varian NMR System 300 (300 or
600 MHz for 1H and 75 MHz for 13C). Chemical shifts (d)
are given in ppm relative to tetramethylsilane. Melting
points were measured on an M-656 Bu¨chi. High-resolution
mass spectra (HRMS) were recorded on Orbitrap Elite
Thermo Scientific Velos Pro, ionization mode: HESI
heated electrospray. Enantiomeric excesses were deter-
mined by chiral HPLC using Diacel Chiralcel OD-H, AD-
H, AS-H columns with isopropyl alcohol and hexane or
heptane as the eluents. Optical rotations were recorded on
Jasco P-2000 polarimeter.
(1.07 cm3) was added dropwise over 10 min, and the
resulting yellow solution was stirred for an additional
10 min, and then added 462 mg HClÁH-L-Pro-OMe
(2.8 mmol) as a solid. The resulting homogeneous yellow
reaction mixture was stirred at room temperature for 10 h
and diluted with 15 cm3 of 0.1 M HCl. The layers were
separated, and the aqueous phase extracted with EtOAc
(3 9 10 cm3). The combined organic phases were washed
with 15 cm3 1 M NaHCO3 solution, 15 cm3 water, and
15 cm3 brine, dried over MgSO4, and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography and visualized with
ninhydrin to afford the title compound. N-Cbz-protecting
peptides were prepared in analogously using N-Cbz-D-
Pro-OH.
Syntheses of peptidic catalysts
Peptides prepared by solution phase synthesis. The syn-
theses of peptide catalysts were carried out according to the
standard methods of solution phase synthesis of peptides
[36, 49–52].
N-Boc-D-Pro-L-Pro-OMe
It was observed as a mixture of conformers (77%), as a
clear colorless oil. 1H NMR (300 MHz, CDCl3):
d = 5.00–4.35 (m, 2H), 3.80–3.35 (m, 7H), 2.41–1.74
(m, 8H), 1.47–1.40 (4 9 s, 9H) ppm. Spectral data agree
with those in the literature [36].
N-Boc-D-Pro-L-Pro-OMe
N-Boc-D-Pro-OH (600 mg, 2.8 mmol), 639 mg EDCÁHCl
(3.3 mmol), and 512 mg HOBtÁH2O (3.3 mmol) were
123

Peptide-catalyzed stereoselective Michael addition of aldehydes and ketones to heterocyclic…
N-Boc-L-Pro-L-Pro-OMe
calculated for C25H33N3O8 [M ? H]? 504.23, found
It was observed as a mixture of conformers, as a clear
colorless oil (87%). 1H NMR (300 MHz, CDCl3):
d = 4.61–4.37 (m, 2H), 3.80–3.35 (m, 7H), 2.23–1.83
(m, 8H), 1.45 and 1.39 (2 9 s, 9H) ppm. Spectral data
agree with those in the literature [53].
504.2; Na-adduct calculated for C25H33N3O8 [M ? Na]?
526.2, found 526.2.
N-Boc-D-Pro-L-Pro-L-Glu(OMe)-OMe
It was obtained as a colorless oil (61%). 1H NMR
(300 MHz, CDCl3): d = 4.71–4.74 (m, 1H), 4.48–4.39
(m, 2H), 3.93–3.40 (m, 10H), 2.49–1.82 (m, 12H), 1.42 (s,
9H) ppm; 13C NMR (75 MHz, CDCl3): d = 173.0, 172.2,
171.6, 171.5, 79.7, 60.1, 57.8, 52.1, 52.0, 51.5, 47.1, 46.9,
30.5, 29.2, 28.3, 28.1, 26.3, 24.6, 24.3 ppm.
N-Boc-D-Pro-L-Glu(OMe)-OMe
It was obtained as a white powder (86%). M.p.: 55–57 °C;
1H NMR (300 MHz, CDCl3): d = 6.73 (s, 1H), 4.62 (td, d,
J = 8.1, 5.1 Hz, 1H), 4.29 (s, 1H), 3.74 (s, 3H), 3.67 (s,
3H), 3.46 (m, 2H), 3.49 (m, 2H), 2.50–1.85 (m, 8H), 1.47
(s, 9H) ppm; 13C NMR (151 MHz, CDCl3): d = 173.2,
172.2, 155.9, 154.7, 129.1, 128.9, 125.4, 125.2, 120.4,
120.3, 109.5, 105.1, 85.2, 80.7, 61.3, 60.2, 52.6, 51.9, 51.5,
47.2, 31.2, 29.9, 28.5, 27.5, 24.6, 23.8 ppm; HRMS: m/z
calculated for C17H29N2O7 [M ? H]? 373.1969, found
373.1968; for Na-adduct calc. for C17H28N2NaO7
[M ? Na]? 395.1789, found 395.1788.
N-Boc-L-Pro-L-Pro-L-Glu(OMe)-OMe
It was observed as a mixture of conformers (64%), as a
1
colorless oil. H NMR (300 MHz, CDCl3): d = 4.64–4.33
(m, 3H), 3.75–3.42 (m, 9H), 2.61–1.66 (m, 12H), 1.42 (s,
9H) ppm; 13C NMR (75 MHz, CDCl3): d = 173.2, 172.9,
172.7, 172.1, 171.9, 171.8, 171.5, 171.4, 171.0, 154.5,
80.0, 79.6, 60.9, 59.8, 58.0, 57.7, 57.6, 52.4, 52.1, 51.7,
51.5, 47.1, 46.9, 46.7, 31.4, 30.8, 29.9, 29.5, 29.3, 28.5,
28.4, 27.4, 27.1, 25.3, 24.7, 24.7, 24.1, 23.5, 22.2 ppm;
MM-ES ? APCI: m/z calculated for C22H35N3NaO8 Na-
adduct [M ? Na]? 492.2316, found 492.2318;
[a]2D0 = - 108 (c = 1, MeOH).
N-Cbz-D-Pro-L-Pro-OMe
It was observed as a mixture of rotamers (77%), as a
1
colorless oil. H NMR (300 MHz, CDCl3): d = 7.47–7.27
(m, 5H), 5.29–4.88 (m, 2H), 4.65–4.38 (m, 1H), 4.32–4.08
(m, 1H), 3.81–3.28 (m, 7H), 2.43–1.76 (m, 8H) ppm; 13C
NMR (151 MHz, CDCl3): d = 173.6, 173.1, 172.7, 172.8,
172.6, 172.5, 171.8, 171.8, 155.4, 155.1, 154.7, 154.3,
137.4, 137.3, 137.0, 136.7, 129.1, 129.0, 128.9, 128.8,
128.6, 128.3, 128.2, 128.2, 128.1, 67.9, 67.4, 67.3, 67.3,
59.8, 59.7, 59.7, 59.5, 58.6, 58.3, 58.3, 57.7, 52.9, 52.6,
52.5, 47.9, 47.5, 47.4, 47.2, 47.1, 47.0, 34.4, 31.8, 31.4,
31.2, 30.9, 30.4, 29.9, 29.4, 29.3, 26.5, 26.4, 26.1, 26.0,
25.8, 25.4, 25.3, 25.2, 25.1, 24.7, 24.3, 23.9, 23.1,
General procedure for deprotection of the carboxyl
group
To a solution of 130 mg N-Boc-D-Pro-L-Glu(OMe)-OMe
(0.28 mmol) in 3 cm3 MeOH was added 0.7 cm3 1 M
NaOH and the resulting solution was stirred at room tem-
perature 2 h. The reaction mixture was concentrated under
reduced pressure, and the resulting aqueous phase was
acidified to pH 1 with conc. HCl and extracted with CH2-
Cl2 (3 9 7 cm3). The combined organic layers were
washed with brine and dried over Na2SO4, and the solvent
was removed under reduced pressure to afford the title
compound.
ꢀ
22.7 ppm; IR (ATR): m = 3319, 2950, 2929, 2878, 2205,
2110, 1879, 1741, 1701, 1653, 1577, 1541, 1498, 1411,
1351, 1323, 1270, 1242, 1194, 1323, 1270, 1242, 1194,
1167, 1114, 1086, 1046, 986, 965, 917, 891, 766, 739,
698 cm-1
; HRMS: m/z calculated for C19H25N2O5
[M ? H]? 361.1758, found 361.1759; Na-adduct calcu-
lated for C19H24N2NaO5 [M ? Na]? 383.1577, found
383.1580; [a]2D0 = - 3.5 (c = 1, MeOH).
N-Boc-D-Pro-L-Glu(OH)-OH
It was obtained as a colorless oil (53%). 1H NMR
(600 MHz, CDCl3): d = 10.7 (br s, 2H), 4.49 (m, 1H),
4.31 (m, 1H), 3.52–3.43 (m, 2H), 2.50–1.87 (m, 8H), 1.41
(s, 9H) ppm; MS (ESI): m/z calculated for Na-adduct
C15H24N2NaO7 [M ? Na]? 367.1, found 367.1.
N-Cbz-D-Pro-L-Pro-L-Glu(OMe)-OMe
It was obtained as a colorless oil (64%). 1H NMR
(600 MHz, CDCl3): d = 7.66 (d, J = 8.2 Hz, 1H),
7.35–7.31 (m, 5H), 5.15 (d, J = 12.5 Hz, 1H), 5.00 (d,
J = 12.5 Hz, 1H), 4.71 (d, J = 8.0 Hz, 1H), 4.47 (m, 2H),
3.99 (m, 1H), 3.67 (s, 3H), 3.62 (s, 3H), 3.56 (m, 1H),
2.46–1.85 (m, 14 H) ppm; 13C NMR (151 MHz, CDCl3):
d = 173.5, 173.3, 172.1, 171.9, 171.6, 155.4, 136.8, 129.1,
129.0, 128.9, 128.8, 128.7, 128.7, 128.3, 128.2, 127.9,
125.5, 125.2, 120.5, 120.4, 109.6, 109.6, 85.3, 67.3, 60.6,
58.2, 52.4, 52.0, 51.8, 47.4,47.1, 30.6, 30.1, 30.0, 29.9,
29.4, 28.8, 27.5, 27.3, 26.7, 25.1, 24.4 ppm; MS (ESI): m/z
N-Boc-D-Pro-L-Pro-OH
It was obtained as a mixture of rotamers (87%), as a white
solid. M.p.: 191–192 °C recrystallized from ethyl acetate
(196–197 °C [54]); 1H NMR (300 MHz, CDCl3): d = 11.6
(br s, 1H), 4.65–4.62 (m, 1H), 4.47–4.42 (m, 1H),
3.79–3.42 (m, 4H), 2.62–1.85 (m, 8H), 1.44 and 1.40 (s,
9H) ppm. Spectral data agree with those in the literature
[36].
123

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V. Polackova et al.
N-Boc-L-Pro-L-Pro-OH
1989, 1735, 1649, 1542, 1439, 1371, 1343, 1164, 984, 916,
797, 722 cm-1; HRMS: m/z calculated for C17H28N3O6
[M ? H]? 370.1973, found 370.1977; [a]2D0 = - 0.6
(c = 1, MeOH).
It was obtained as a mixture of conformers (86%), as a
white solid. M.p.: 177–181 °C recrystallized from EtOAc
(177–180 °C [55]); 1H NMR (300 MHz, CDCl3):
d = 4.71–4.60 (m, 1H), 4.53–4.38 (m, 1H), 3.84–3.38
(m, 4H), 2.54–1.85 (m, 8H), 1.43 and 1.40 (s, 9H) ppm.
Spectral data agree with those in the literature [53].
[a]2D0 = - 150 (c = 1, MeOH) [55].
TFA.H-L-Pro-L-Pro-OMe (C1)
It was obtained as a pale brown oil (82%). 1H NMR
(300 MHz, CDCl3): d = 10.86 (s, 1H), 7.43 (s, 1H), 4.76
(s, 1H), 4.59 (m, 1H), 3.74 (s, 3H), 3.72–3.40 (m, 4H),
2.62–1.98 (m, 8H) ppm; 13C NMR (151 MHz, CDCl3,
N-Boc-D-Pro-L-Pro-L-Glu(OH)-OH
It was obtained as a colorless oil (78%). 1H NMR
(300 MHz, CDCl3): d = 8.81 (bs, 2H), 4.67–4.35 (m,
3H), 3.96–3.36 (m, 4H), 2.43–1.80 (m, 12H), 1.42 (s, 9H)
ppm; 13C NMR (75 MHz, CDCl3): d = 176.0, 175.9,
175.7, 173.4, 173.2, 173.0, 172.2, 172.0, 171.7, 80.8, 80.5,
80.4, 80.1, 60.8, 58.4, 58.1, 57.9, 53.5, 52.6, 52.3, 51.7,
47.3, 47.2, 30.7, 30.3, 29.7, 29.3, 28.8, 28.5, 28.2, 26.0,
24.7, 24.6, 24.4, 23.5 ppm.
POL-P204-13C):
d = 171.7,
J = 37.6 Hz), 114.4 (q, J = 286.9 Hz), 59.3, 58.7, 52.5,
167.3,
161.2
(q,
47.0, 46.8, 28.8, 28.7, 24.7, 24.6 ppm; IR (ATR):
ꢀ
m = 2962, 2324, 2118, 2096, 1742, 1655, 1459, 1368,
1260, 1078, 798, 705 cm-1; HRMS: m/z calculated for
C11H19N2O3 [M ? H]? 227.1390, found 227.1391;
[a]2D0 = - 10.6 (c = 1, MeOH). Spectral data agree with
those in the literature [56].
TFA.H-D-Pro-L-Glu(OMe)-OMe (C2)
N-Cbz-D-Pro-L-Pro-OH
It was obtained as a brown oil (95%). 1H NMR (300 MHz,
CDCl3): d = 10.57 (bs, 1H), 8.57 (bs, 1H), 7.59 (s, 1H),
4.75–4.67 (m, 1H), 4.67–4.52 (m, 2H), 3.72 (s, 3H), 3.62
(s, 3H), 3.45 (m, 2H), 2.59–1.93 (m, 8H) ppm; 13C NMR
(75 MHz, CDCl3): d = 173.0, 171.8, 169.1, 163.8, 59.7,
52.7, 52.2, 51.9, 46.8, 41.9, 37.2, 32.1, 30.2, 29.8, 27.0,
It was obtained as a mixture of conformers (91%), as
a colorless oil. 1H NMR (600 MHz, CDCl3): d = 10.76 (s,
1H), 7.42–7.27 (m, 5H), 5.15–4.88 (m, 2H), 4.58–3.98 (m,
2H), 3.63–3.29 (m, 4H), 2.39–1.65 (m, 8H) ppm; 13C NMR
(75 MHz, CDCl3): d = 174.8, 174.6, 174.0, 173.3, 172.9,
172.8, 172.5, 172.3, 155.1, 155.1, 154.1, 154.0, 136.5,
136.4, 136.2, 128.6, 128.6, 128.5, 128.5, 128.4, 128.4,
128.3, 128.3, 128.1, 128.0, 127.9, 127.6, 120.2, 120.1,
67.6, 67.3, 67.1, 60.2, 59.4, 59.1, 58.3, 58.0, 57.8, 57.4,
53.5, 47.6, 47.4, 47.2, 47.1, 47.1, 46.9, 46.8, 46.7, 31.4,
31.1, 30.7, 30.3, 30.0, 29.3, 28.2, 27.6, 24.7, 24.6, 24.5,
ꢀ
26.5, 24.4 ppm; IR (ATR): m = 3075, 2959, 2578, 2489,
2330, 2120, 1882, 1730, 1664, 1560, 1438, 1347, 1257,
1160, 1133, 981, 835, 797, 721 cm-1; HRMS: m/z
calculated for C12H21N2O5 [M ? H]? 273.1445, found
273.1443; [a]2D0 = - 1.5 (c = 1, MeOH).
ꢀ
24.5, 23.9, 23.8, 22.5, 22.2 ppm; IR (ATR): m = 2956,
2879, 2514, 1877, 1701, 1654, 1608, 1412, 1351, 1266,
TFA.H-D-Pro-L-Glu(OH)-OH (C3)
It was obtained as a pale brown oil (78%). 1H NMR
(300 MHz, DMSO-d6): d = 9.48 (bs, 1H), 8.56 (bs, 1H),
4.39–4.05 (m, 2H), 3.33–3.06 (m, 2H), 2.40–1.70 (m, 8H)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 173.6, 172.7,
168.4, 158.3 (q, J = 35.4 Hz), 119.4 (q, J = 282.9 Hz),
59.1, 51.7, 45.7, 29.9, 29.8, 26.3, 23.5 ppm; IR (ATR):
1168, 1116, 1116, 1087, 913, 874, 824, 767, 730 cm-1
.
General procedure for deprotection Boc-protecting
group
To 222 mg of the N-Boc-L-Pro-L-Pro-L-Glu(OMe)-OMe
(0.47 mmol) in 5 cm3 CH2Cl2 was added 0.6 cm3 TFA.
The solution was kept at room temperature for 2 h and the
TFA evaporated to dryness. The oily residue was evapo-
rated with toluene three times and washed with a solution
of Et2O/hexane (1:2) to afford the title compound.
ꢀ
m = 3442, 3072, 2959, 2568, 2324, 2117, 2092, 1905,
1719, 1663, 1560, 1411, 1141, 962, 797, 722, 703 cm-1
;
HRMS: m/z calculated for C10H17N2O5 [M ? H]?
245.1132, found 245.1130; [a]2D0 = - 2.9 (c = 1, MeOH).
TFA.H-D-Pro-L-Pro-L-Glu-OH (C6)
It was obtained as a pale brown oil (91%). 1H NMR
(300 MHz, CDCl3): d = 4.56–4.38 (m, 2H), 3.79–3.24 (m,
5H), 2.65–1.78 (m, 11H) ppm; 13C NMR (75 MHz):
d = 172.6, 170.7, 170.4, 164.4, 157.6 (q, J = 35.5 Hz),
118.7 (q, J = 280.9 Hz), 57.9, 56.7, 49.2, 43.6, 27.3, 26.8,
TFA.H-L-Pro-L-Pro-L-Glu(OMe)-OMe (C4)
It was obtained as a pale brown oil (91%). 1H NMR
(300 MHz, CDCl3): d = 11.56 (s, 1H), 9.96 (s, 1H), 4.81–
4.70 (m, 1H), 4.58–4.45 (m, 2H), 3.76–3.36 (m, 10H),
2.60–1.97 (m, 12H) ppm; 13C NMR (151 MHz, CDCl3):
d = 173.2, 171.8, 171.6, 167.7, 160.9 (q, J = 38.8 Hz),
115.64 (q, J = 288.0 Hz), 60.6, 58.6, 52.5, 51.83, 51.82,
47.5, 47.1, 29.9, 29.0, 28.7, 27.0, 24.9, 24.6 ppm; IR
ꢀ
25.6, 24.1, 21.7, 21.4 ppm; IR (ATR): m = 3510, 3070,
2980, 2715, 2363, 2118, 1998, 1888, 1780, 1719, 1639,
1550, 1451, 1374, 1343, 1144, 797, 722, 699 cm-1
HRMS: m/z calculated for C15H24N3O6 [M ? H]?
342.1660, found 342.1661; [a]2D0 = - 0.6 (c = 1, MeOH).
;
ꢀ
(ATR): m = 3323, 3072, 2958, 2713, 2437, 2331, 2114,
123

Peptide-catalyzed stereoselective Michael addition of aldehydes and ketones to heterocyclic…
Deprotection of the N-Cbz protecting group
3-(Furan-2-yl)-2-methyl-4-nitrobutanal (5b)
Yellow oil. 1H NMR (300 MHz, CDCl3): d = 9.71 (s, 1H),
9.64 (d, J = 1.30 Hz, 1H), 7.36 (s, 1H), 6.32–6.28 (m, 1H),
6.22–6.16 (m, 1H), 4.80–4.66 (m, 2H), 4.12–3.96 (m, 1H),
2.90–2.73 (m, 1H), 1.24–1.05 (dd, J = 36.0, 7.5 Hz, 3H)
ppm. Spectral data agree with those in the literature [57].
HPLC: Chiralcel OD-H, hexan/i-PrOH 92:8, 0.8 cm3/min,
k = 250 nm, tR1 = 26.3, tR2 = 37.8 min; [a]2D0 = 2.8
(c = 1, CHCl3) ([a]D20 = 17.2 (93% ee, c = 1, CHCl3
[58]).
The N-Cbz-D-Pro-L-Pro-L-Glu(OMe)-OMe was dissolved
in 10 cm3 of methanol and 5.8 mg palladium (0.054 mmol,
10 wt% on activated carbon) was added. The reaction
mixture was stirred under hydrogen atmosphere at room
temperature 48 h. The solution was filtered over Celite, the
solvent was evaporated under reduced pressure, and H-D-
Pro-L-Pro-L-Glu(OMe)-OMe was obtained in 93% yield.
H-D-Pro-L-Pro-L-Glu(OMe)-OMe (C5)
It was obtained as a mixture of conformers (93%), as
a colorless oil. 1H NMR (300 MHz, CDCl3):
d = 4.71–4.41 (m, 3H), 3.86–3.26 (m, 10H), 2.59–1.87
(m, 12H) ppm; 13C NMR (151 MHz): d = 173.4, 173.1,
172.9, 172.5, 172.2, 172.0, 171.8, 171.7, 171.6, 171.2,
125.3, 67.3, 61.0, 60.4, 59.7, 59.4, 58.9, 55.8, 52.3, 52.0,
51.8, 51.7, 51.6, 51.6, 47.7, 47.3, 47.3, 46.6, 46.5, 40.3,
32.0, 30.4, 30.3, 30.0, 29.7, 29.1, 28.5, 28.3, 28.1, 27.1,
26.9, 26.2, 25.9, 24.8, 24.6, 24.3, 22.9, 22.1 ppm; IR
2-Ethyl-3-(furan-2-yl)-4-nitrobutanal (5c)
Yellow oil. 1H NMR (300 MHz, CDCl3): d = 9.72 (d,
J = 2.0 Hz, 1H), 9.61 (d, J = 2.60 Hz, 1H), 7.38–7.35
(dd, J = 1.9, 0.7 Hz, 1H), 6.33–6.18 (dd, J = 3.1, 1.9 Hz,
1H), 6.22–6.18 (d, J = 3.3 Hz, 1H), 4.76–4.60 (m, 2H),
4.05–3.95 (dt, J = 8.8, 5.5 Hz, 1H), 2.80–2.71 (m, 1H),
1.22 (d, 3H), 1.08 (d, 3H), 0.91 (t, J = 7.5 Hz, 3H) ppm.
Spectral data agree with those in the literature [50]. HPLC:
Chiralcel OD-H, hexane/i-PrOH 95:5, 0.8 cm3/min,
k = 250 nm, tR1 = 33.0, tR2 = 50.2 min; [a]2D0 = 0.4
(c = 1, CHCl3).
ꢀ
(ATR): m = 3447, 3199, 2952, 2880, 2782, 2427, 2352,
2253, 2115, 2093, 1933, 1733, 1647, 1541, 1437, 1365,
1341, 1257, 1199, 1168, 1123, 1093, 1039, 1007, 982, 918,
851, 821, 752 cm-1
C17H28N3O6 [M ? H]? 370.1973, found 370.1975;
[a]2D0 = - 20.7 (c = 1, MeOH).
2-[1-(Furan-2-yl)-2-nitroethyl]pentanal (5d)
;
HRMS: m/z calculated for
Yellow oil. 1H NMR (300 MHz, CDCl3): d = 9.71 (d,
J = 2.1 Hz, 1H), 9.60 (d, J = 2.7 Hz, 1H), 7.36 (d,
J = 1.7 Hz, 1H), 6.31 (dd, J = 3.1, 1.8 Hz, 1H), 6.19
(dd, J = 3.4 Hz, 1H), 4.77–4.61 (m, 1H), 4.07–3.92 (m,
1H), 2.83–2.57 (m, 1H), 1.56–1.34 (m, 4H), 0.88 (t,
J = 7.0 Hz, 1H) ppm. Spectral data agree with those in the
literature [59]. [a]2D0 = - 6.3 (c = 1, CHCl3).
General procedure for Michael addition
Peptide catalyst (0.022 mmol) and 2.2 mg NMM
(0.022 mmol) were dissolved in 1.2 cm3 solution mixture
of CHCl3/i-PrOH (9:1), and after 10 min, nitroalkene
(0.43 mmol) was added and, if applicable, 3 mol% of an
acidic additive was added. Again, after 10 min, stirring
aldehyde (1.29 mmol) was added dropwise and the
resulting reaction mixture was stirred at room tempera-
ture. The reaction time was monitored by TLC, followed
by concentration in vacuo. The crude product was purified
by flash chromatography using Isolera Biotage FSKO-
1107-0010 (silica gel, hexane: ethyl acetate gradient
35:1–15:1). The product was obtained in the reported
2-[1-(Furan-2-yl)-2-nitroethenyl]octanal
(5e, C14H21NO4)
Yellow oil. 1H NMR (300 MHz, CDCl3): d = 9.65 (d,
J = 1.9 Hz, 1H), 9.60 (d, J = 2.6 Hz, 1H), 7.40–7.32 (m,
1H), 6.31 (m, 1H), 6.19 (m, 1H), 4.76–4.60 (m, 2H), 4.00
(m, 1H), 2.83–2.54 (m, 1H), 1.74–1.13 (m, 10H), 0.86 (t,
J = 6.4 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d = 202.4, 150.1, 142.6, 110.5, 108.8, 76.1, 52.3, 37.0,
31.4, 29.2, 26.9, 26.6, 22.5, 14.0 ppm; IR (ATR):
ꢀ
m = 2926, 2857, 2727, 2090, 1720, 1553, 1506, 1459,
1431, 1376, 1191, 1148, 1075, 968, 915, 810, 736, 645,
yields
with
a defined
diastereoselectivity
and
enantioselectivity.
598 cm-1. HRMS: m/z calculated for C14H21NO4 Na-
adduct
[M ? Na]?
290.1363,
found
290.1364;
2-Benzyl-3-(furan-2-yl)-4-nitrobutanal (5a)
[a]2D0 = - 18.7 (c = 1, CHCl3).
Pale yellow oil. 1H NMR (300 MHz, CDCl3): d = 9.72 (d,
J = 1.4 Hz, 1H), 9.69 (d, J = 1.8 Hz, 1H), 7.40 (dd,
J = 1.8, 0.8 Hz, 1H), 7.30 (m, 2H), 7.23–7.09 (m, 3H),
6.35 (m, 1H), 6.23 (m, 1H), 4.78–4.58 (m, 2H), 4.08(m,
1H), 3.96 (m, 1H), 3.21–3.04 (m, 1H), 2.94–2.70 (m, 2H)
ppm. Spectral data agree with those in the literature [42].
HPLC: Chiralcel AS-H, heptane/i-PrOH 90:10, 0.7 cm3/
2-[1-(Furan-2-yl)-2-nitroethyl]cyclopentanone (7a)
Yellow oil. 1H NMR (300 MHz, CDCl3): d = 7.33 (d,
J = 1.0 Hz, 1H), 6.33–7.26 (m, 1H), 6.14 (dd, J = 6.9,
3.2 Hz, 1H), 5.09–4.95 (dd, J = 13.1, 6.2 Hz, 1H),
4.96–4.72 (m, 2H), 4.04–3.91 (m, 1H), 2.54–1.55 (m,
6H) ppm; HPLC: Chiralcel AS-H, heptane/i-PrOH 90:10,
0.7 cm3/min, k = 230 nm, tR1 = 32.9, tR2 = 55.8 min.
Spectral data agree with those in the literature [60].
min,
k = 220 nm,
tR1 = 29.15,
tR2 = 39.5 min;
[a]2D0 = - 3.5 (c = 1, CHCl3).
123

´ˇ ´
V. Polackova et al.
25. Triandafillidi I, Bisticha A, Voutyritsa E, Galiatsatou G, Kokotos
CG (2015) Tetrahedron 71:932
2-[1-(Furan-2-yl)-2-nitroethyl]cyclohexanone (7b)
1
Pale yellow solid. M.p.: 82–84 °C; H NMR (300 MHz,
´
´
26. Vega-Pen˜aloza A, Sanchez-Antonio O, Avila-Ortiz CG, Escud-
ero-Casao M, Juaristi E (2014) Asian J Org Chem 3:487
27. Bisticha A, Triandafillidi I, Kokotos CG (2015) Tetrahedron
Asymmetry 26:102
CDCl3): d = 7.36–7.32 (m, 1H), 6.31–6.26 (dd, J = 3.2,
1.9 Hz, 1H), 6.17 (m, 1H), 4.82–4.76 (dd, J = 12.5,
4.9 Hz, 1H), 4.71–4.62 (dd, J = 12.5, 9.2 Hz, 1H),
4.02–3.92 (dt, J = 9.1, 4.9 Hz, 1H), 2.81–2.69 (m, 1H),
2.51–2.29 (m, 2H), 2.15–2.05 (m, 1H), 1.88–1.60 (m, 4H),
1.28 (m, 1H) ppm. Spectral data agree with those in the
literature [48]. HPLC: Chiralcel IA, hexane/i-PrOH 90:10,
0.7 cm3/min, k = 254 nm, tR1 = 17.1, tR2 = 21.0 min;
[a]2D0 = 0.5 (c = 1, CHCl3) using C4; [a]2D0 = - 11.2
(c = 1, CHCl3) using C3.
28. Revell JD, Gantenbein D, Krattiger P, Wennemers H (2006)
Biopolymers (Pept Sci) 84:105
´ ´
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30. Wiesner M, Revell JD, Wennemers H (2008) Angew Chem Int
Ed 47:1871
31. Wiesner M, Revell JD, Tonazzi S, Wennemers H (2008) J Am
Chem Soc 130:5610
32. Wiesner M, Wennemers H (2010) Synthesis 2010:1568
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Acknowledgements This work was supported by the Slovak
Research and Development Agency under the contract no. APVV-15-
0039.
36. Kastl R, Wennemers H (2013) Angew Chem Int Ed 52:7228
37. Arakawa Y, Wiesner M, Wennemers H (2011) Adv Synth Catal
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38. Arakawa Y, Wennemers H (2013) Chemsuschem 6:242
39. Gru¨nenfelder CE, Kisunzu JK, Wennemers H (2016) Angew
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