Chemoselectivity issues of the asymmetric interaction between cyclohexanone, β-nitrostyrene, and benzoic acid under 5-aryl prolinate's organocatalysis

Article abstract of DOI:10.1002/chir.23212

4-l-menthyloxycarbonyl 5-aryl prolinates were studied as organocatalysts of a novel three-component reaction of cyclohexanone, benzoic acid, and β-nitrostyrene. The presence of ortho-halogen atom in 5-aryl fragment of the catalyst is favored for driving the formation of chiral 7a-hydroxyoctahydro-2H-indol-2-one scaffold. 5-(o-Chlorophenyl) prolinate selectively afforded 3-phenyl-7a-hydroxyoctahydro-2H-indol-2-one with ee 63%, whereas 5-phenyl prolinate led to conjugation of β-nitrostyrene to cyclohexanone (the Michael adduct). Plausible chlorine effect is accounted for the specific interaction of the 5-aryl prolinate enamine intermediate with β-nitrostyrene in the transition state.

Full text of DOI:10.1002/chir.23212

Received: 3 January 2020
DOI: 10.1002/chir.23212
Revised: 6 February 2020
Accepted: 11 February 2020
S H O R T C O M M U N I C A T I O N
Chemoselectivity issues of the asymmetric interaction
between cyclohexanone, β-nitrostyrene, and benzoic acid
under 5-aryl prolinate's organocatalysis
Polina M. Ivantcova | Konstantin V. Kudryavtsev
Department of Chemistry, Lomonosov
Abstract
Moscow State University, Moscow,
Russian Federation
4-L-menthyloxycarbonyl 5-aryl prolinates were studied as organocatalysts of
a novel three-component reaction of cyclohexanone, benzoic acid, and β-
nitrostyrene. The presence of ortho-halogen atom in 5-aryl fragment of the
catalyst is favored for driving the formation of chiral 7a-hydroxyoctahydro-2H-
indol-2-one scaffold. 5-(o-Chlorophenyl) prolinate selectively afforded
3-phenyl-7a-hydroxyoctahydro-2H-indol-2-one with ee 63%, whereas 5-phenyl
prolinate led to conjugation of β-nitrostyrene to cyclohexanone (the Michael
adduct). Plausible chlorine effect is accounted for the specific interaction of
the 5-aryl prolinate enamine intermediate with β-nitrostyrene in the transition
state.
Correspondence
Konstantin V. Kudryavtsev, Department
of Chemistry, Lomonosov Moscow State
University, Leninskie Gory 1/3, Moscow
119991, Russian Federation.
Email: kudr@med.chem.msu.ru
Funding information
scholarship of the President of the
Russian Federation, Grant/Award
Number: SP-1278.2018.4
K E Y W O R D S
enamine catalysis, multicomponent reactions, proline, β-peptides
1 | INTRODUCTION
ketones, carboxylic acids, and nitroalkenes catalyzed by
5-aryl prolinate I (X = trans-NO2; Y = cis-Ph; R = H;
Functionalized 5-aryl prolinates I (5-ArPro, Figure 1)
contain the structural fragment of L-proline, well recog-
nized as an efficient organocatalyst of the important and
widely known C─C bond-forming transformations,1 that
determines some unique catalytic properties of this
unnatural α-amino acid organocatalyst's class.2 Most of
the transformations catalyzed by 5-ArPro species are
based on covalent enamine catalysis3 and comprise
aldol4,5 and Michael6,7 condensations. Formation of the
iminium intermediate of 5-ArPro with α,β-unsaturated
aldehydes provides a basis for efficient organocatalytic
asymmetric cycloadditions.8 Additional substituents in
the pyrrolidine cycle of 5-ArPro scaffold would be benefi-
cial for the interaction with coupled molecular com-
ponents and/or for the preferential shielding of one face
of the catalyst as in the case of 5-ArPro derivatives II
(Figure 1). Very recently, Cossío et al reported an
unusual three-component reaction between cyclic
R1 = CH3) (Scheme 1A).9 An unexpected synthetic result
of this interaction is the generation in one preparative
step of the 7a-hydroxyoctahydro-2H-indol-2-one scaffold
III with three novel chiral centers (Scheme 1A). The ste-
ric and electronic features of the used 5-aryl prolinate
I are highly crucial for the Cossío reaction, and all known
amine organocatalysts different from 5-ArPro induced
only conjugate addition of nitroalkene to ketone and did
not reproduce the formation of substituted 7a-
hydroxyoctahydro-2H-indol-2-ones.9
In the current work, we studied a three-component
interaction of cyclohexanone, benzoic acid, and β-
nitrostyrene as the simplest model system of the
Cossío reaction9 in the presence of chiral 4-L-
menthyloxycarbonyl 5-aryl prolinates II (Figure 1) and
observed the unique influence of the ortho-substituent
in the 5-aryl fragment of organocatalysts II on chemo-
and enantioselectivities of the investigated process
Chirality. 2020;1–9.
wileyonlinelibrary.com/journal/chir
© 2020 Wiley Periodicals, Inc.
1

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IVANTCOVA AND KUDRYAVTSEV
mixture
of
corresponding
iminoester
ArCH═NCH2CO2Me (11 mmol), AgOAc•2PPh311 (2.28 g,
3.3 mmol), L-menthyl acrylate (2.31 g, 11 mmol) in 75 mL
of dry toluene under an inert atmosphere. Reaction flask
was protected from the light with aluminum foil. Reac-
tion mixture was stirred at room temperature for 48 hours.
Then, the reaction mixture was filtered through Celite.
Filtrate was washed with H2O (50 mL) and saturated
NH4Cl solution (50 mL). Organic phase was dried under
Na2SO4 and concentrated under reduced pressure. The
crude products were purified by column chromatography
on silica gel using hexane/AcOEt 3:1 as an eluent.10-12
FIGURE 1 Structural formulae of 5-ArPro organocatalysts
I and II
(Scheme 1B). The catalyst's selection was based on the
synthetic availability of 5-ArPro II via highly
diastereoselective
1,3-dipolar
cycloaddition
of
azomethine ylides with L- or D-menthyl acrylates10 and
the hypothesis of favorable shielding effects of all three
cis-substituents of the pyrrolidine cycle with an addi-
tional menthyl chiral fragment.
2.1.1 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-phenylpyrrolidine-2,4-dicarboxylate IIa
2 | MATERIALS AND METHODS
Yield 81%; 1.30 g; colorless crystals; mp 103–105ꢀC;1Н
NMR (400 MHz, CDCl3, δ): 7.30-7.42 (m, 5H), 4.57 (d,
J 7.4 Hz, 1H), 4.37 (td, J 10.8, 4.3 Hz, 1H), 4.09 (t,
J 8.0 Hz, 1H), 3.84 (s, 3H), 3.36 (dt, J 7.6, 5.4 Hz, 1H),
2.53 (dt, J 12.8, 8.1 Hz, 1H), 2.40 (ddd, J 12.8, 8.1, 6.2 Hz,
1H), 1.46-1.53 (m, 3H), 1.04-1.21 (m, 2H), 0.87-0.95 (m,
1H), 0.79-0.86 (m, 1H), 0.79 (d, J 6.9 Hz, 3H), 0.72 (d,
J 6.9 Hz, 3H), 0.60-0.70 (m, 1H), 0.52 (d, J 6.9 Hz, 3H),
0.19-0.28 (m, 1H).10
Nuclear magnetic resonance (NMR) spectra were
recorded on Bruker AM-400 and Agilent 400 MR spec-
trometers for solutions in CDCl3 and DMSO-d6 with tet-
ramethylsilane (TMS) as internal standard (See
Supporting Information for spectra images). Optical rota-
tions were determined at 589 nm (sodium D line) by
using a Jasco DIP-360 polarimeter; [α]D and c values are
given in units of deg cm3 g−1 dm−1 and gcm−3, respec-
tively. Chiral high-performance liquid chromatography
(HPLC) was performed on a SHIMADZU SPD-10A vp
series with chiral columns (Chiralpak AS-H, OD-H col-
umns 4.6 × 250 mm; Daicel Chemical Ind., Ltd.). High-
resolution mass spectra (HRMS) were recorded with a
HP-5989 instrument.
2.1.2 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(2-fluorophenyl)pyrrolidine-
2,4-dicarboxylate IIb
Yield 67%; 1.10 g; colorless crystals; mp 103-105ꢀC;1Н
NMR (400 MHz, CDCl3, δ): 7.44 (dt, J 7.5, 1.0 Hz, 1H),
7.24 (tdd, J 7.3, 5.3, 1.7 Hz, 1H), 7.12 (td, J 7.6, 1.1 Hz,
1H), 7.01 (ddd, J 10.5, 8.2, 1.2 Hz, 1H), 4.66 (d, J 7.2 Hz,
1H), 4.33 (td, J 10.9, 4.4 Hz, 1H), 3.98 (dd, J 9.2, 7.3 Hz,
1H), 3.84 (s, 3H), 3.41 (tdd, J 7.9, 4.3, 1.6 Hz, 1H), 2.79
(br.s, 1H), 2.51 (ddd, J 13.4, 9.2, 8.0 Hz, 1H), 2.39 (ddd,
2.1 | General procedure for the synthesis
of 4-L-menthyloxycarbonyl 5-aryl prolinates
IIa to j
A solution of triethylamine (1.90 mL, 1.40 g, 14 mmol) in
15 mL of toluene was added dropwise to the stirred
SCHEME 1 (A) Three-component reaction promoted by
organocatalyst I.9 (B) Screening process of L-menthyl
organocatalysts II

IVANTCOVA AND KUDRYAVTSEV
3
J 13.3, 7.3, 4.3 Hz, 1H), 1.68 (dtd, J 13.9, 7.0, 2.7 Hz, 1H),
1.51-1.58 (m, 2H), 1.06-1.25 (m, 2H), 0.85-0.94 (m, 2H),
0.83 (d, J 7.0 Hz, 3H), 0.70 (d, J 6.5 Hz, 3H), 0.63 (d,
J 7.0 Hz, 3H), 0.09 (dd, J 23.3, 12.2 Hz, 1H).6
(m, 2H), 0.84-0.95 (m, 1H), 0.83 (d, J 7.0 Hz, 3H), 0.68 (d,
J 6.5 Hz, 3H), 0.66 (d, J 7.0 Hz, 3H), 0.06-0.08 (m, 1H);13С
NMR (400 MHz, CDCl3, δ): 172.47, 172.25, 136.09,
132.94, 129.41, 127.89, 127.80, 124.13, 74.56, 64.81, 59.17,
52.74, 46.43, 46.08, 39.29, 33.86, 33.16, 30.91, 26.16, 23.23,
21.69, 20.65, 16.29. Anal. calcd. for C24H34BrNO4: C
60.00, H 7.13, N 2.92; found: C 60.16, H 7.17, N 3.10.
2.1.3 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(2-chlorophenyl)pyrrolidine-
2,4-dicarboxylate IIc
2.1.6 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(4-bromophenyl)pyrrolidine-
2,4-dicarboxylate IIf
Yield 77%; 1.20 g; colorless crystals; mp 118-120ꢀC;
[α]D = 26.1 (c = 1.24 in MeOH);1Н NMR (400 MHz,
20
CDCl3, δ): 7.53 (d, J 7.5 Hz, 1H), 7.34 (d, J 6.5 Hz, 1H),
7.15-7.29 (m, 2H), 4.74 (d, J 7.8 Hz, 1H), 4.29 (td, J 10.8,
4.4 Hz, 1H), 3.96 (t, J 8.0 Hz, 1H), 3.83 (s, 3H), 3.57 (dd,
J 11.7, 7.3 Hz, 1H), 2.87 (br.s, 1H), 2.38-2.56 (m, 2H),
1.61-1.77 (m, 1H), 1.54 (d, J 10.9 Hz, 1H), 1.03-1.24 (m,
2H), 0.82-0.89 (m, 5H), 0.65-0.69 (m, 7H), 0.02 (q,
J 11.9 Hz, 1H). Anal. calcd. for C23H32ClNO4: C 65.47, H
7.64, N 3.32; found: C 65.17, H 7.72, N 3.45.6
Yield 83%; 1.23 g; colorless crystals; mp 120-122ꢀC;1Н
NMR (400 MHz, DMSO-d6, δ): 7.43-7.47 (m, 2H),
7.25-7.29 (m, 2H), 4.44 (d, J 7.8 Hz, 1H), 4.21 (td, J 10.8,
4.4 Hz, 1H), 3.87 (t, J 7.8 Hz, 1H), 3.68 (s, 3H), 3.27-3.33
(m, 1H), 2.31 (dt, J 12.7, 8.1 Hz, 1H), 2.17 (ddd, J 12.7, 8.1,
6.2 Hz, 1H), 1.45-1.53 (m, 3H), 1.13-1.23 (m, 1H),
1.04-1.11 (m, 1H), 0.81-0.91 (m, 2H), 0.75 (d, J 6.9 Hz,
6H), 0.61-0.70 (m, 1H), 0.53 (d, J 6.9 Hz, 3H), 0.17-0.26
(m, 1H).11
2.1.4 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(2,6-dichlorophenyl)pyrrolidine-
2,4-dicarboxylate IId
2.1.7 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(2-iodophenyl)pyrrolidine-
2,4-dicarboxylate IIg
Yield 75%; 1.06 g; colorless crystals; mp 118-120ꢀC;
[α]D = 13.5 (c = 1.10 in MeOH);1Н NMR (400 MHz,
20
CDCl3, δ): 7.24-7.32 (m, 2H), 7.09-7.17 (m, 1H), 5.25 (d,
J 10.1 Hz, 1H), 4.41 (td, J 10.8, 4.2 Hz, 1H), 3.87 (dd,
J 10.4, 4.7 Hz, 1H), 3.82 (s, 3H), 3.52 (dd, J 18.6, 8.6 Hz,
1H), 2.50-2.62 (m, 1H), 2.39-2.50 (m, 1H), 1.73 (dtd,
J 14.0, 7.0, 2.5 Hz, 1H), 1.49-1.58 (m, 2H), 1.18-1.32 (m,
2H), 0.99-1.11 (m, 1H), 0.85-0.97 (m, 1H), 0.83 (d,
J 7.0 Hz, 3H), 0.71 (d, J 6.3 Hz, 3H), 0.67 (d, J 7.0 Hz, 3H),
0.02 (q, J 12.4 Hz, 1H). Anal. calcd. for C23H31Cl2NO4: C
60.53, H 6.85, N 3.07; found: C 60.45, H 6.66, N 3.01.
Yield 65%; 0.97 g; colorless crystals; mp 118-120ꢀC;
[α]D = 20.1 (c = 1.2 in MeOH);1Н NMR (400 MHz,
20
CDCl3, δ): 7.79 (dd, J 7.9, 1.1 Hz, 1H), 7.50 (dd, J 7.8,
1.6 Hz, 1H), 7.29-7.35 (m, 2H), 6.94 (td, J 7.6, 1.6 Hz, 1H),
4.60 (d, J 8.0 Hz, 1H), 4.27 (td, J 10.9, 4.4 Hz, 1H), 3.94 (t,
J 8.2 Hz, 1H), 3.81 (s, 3H), 3.60 (td, J 7.7, 6.0 Hz, 1H),
2.44-2.51 (m, 2H), 1.74 (dtd, J 14.0, 7.0, 2.6 Hz, 1H),
1.45-1.58 (m, 2H), 1.06-1.22 (m, 2H), 0.82-0.93 (m, 6H),
0.58-0.74 (m, 7H), 0.03 (dd, J 23.3, 12.2 Hz, 1H);13С NMR
(400 MHz, CDCl3, δ): 173.41, 172.28, 141.14, 139.18,
133.69 129.25, 128.21, 100.53, 74.16, 69.22, 59.35, 52.19,
46.48, 45.98, 39.22, 33.94, 33.21, 30.90, 26.18, 23.32, 21.73,
20.69, 16.40. Anal. calcd. for C23H32INO4: C 53.81, H
6.28, N 2.73, found: C 53.90, H 6.30, N 2.81.
2.1.5 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(2-bromophenyl)pyrrolidine-
2,4-dicarboxylate IIe
Yield 76%; 1.13 g; colorless crystals; mp 118-120ꢀC;
2.1.8 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(o-tolyl)pyrrolidine-2,4-dicarboxylate IIh
[α]D = 40.7 (c = 1.04 in MeOH);1Н NMR (400 MHz,
20
CDCl3, δ): 7.49-7.57 (m, 1H), 7.23-7.38 (m, 2H), 7.11 (td,
J 7.7, 1.6 Hz, 1H), 7.72 (d, J 7.7 Hz, 1H), 4.28 (td, J 10.9,
4.4 Hz, 1H), 3.96 (t, J 8.3 Hz, 1H), 3.82 (s, 3H), 3.60 (td,
J 7.7, 5.3 Hz, 1H), 2.75 (br.s, 1H), 2.41-2.53 (m, 2H), 1.73
(dtd, J 14.1, 7.0, 2.7 Hz, 1H), 1.49-1.58 (m, 2H), 1.07-1.23
Yield 70%; 0.870 g; colorless crystals;1Н NMR (400 MHz,
CDCl3, δ): 7.37-7.39 (m, 1H), 7.07-7.17 (m, 3H), 4.57 (d,
J 7.8 Hz, 1H), 4.25 (td, J 10.9, 4.4 Hz, 1H), 3.92 (t,

4
IVANTCOVA AND KUDRYAVTSEV
J 8.3 Hz, 1H), 3.81 (s, 3H), 3.34 (td, J 7.8, 5.5 Hz, 1H),
2.81 (br.s, 1H), 2.41-2.48 (m, 2H), 2.36 (s, 3H), 1.62-1.70
(m, 1H), 1.48-1.53 (m, 2H), 1.03-1.19 (m, 2H), 0.83-0.91
(m, 1H), 0.80 (d, J 7.1 Hz, 3H), 0.74-0.77 (m, 1H),
0.64-0.69 (m, 1H), 0.65 (d, J 6.6 Hz, 3H), 0.62 (d, J 7.1 Hz,
3H), −0.13 Ä −0.04 (m, 1H).12
IIb or IIj (2.0 mmol) in 20 mL of CH2Cl2 at 0 ꢀС.
Then acryloyl chloride (220 μL, 250 mg, 2.6 mmol)
was added dropwise to the reaction mixture under an
inert atmosphere. Cooling bath was removed after
15 minutes of completion of acryloyl chloride addi-
tion. The reaction mixture was stirred at room
temperature for additional 24 hours, then washed wit-
h H2O (10 mL), brine (10 mL). Organic phase was
dried under Na2SO4 and concentrated at reduced pres-
sure. Acrylamides were isolated by column chromatog-
raphy on silica gel using hexane/AcOEt 3:1 as an
eluent.11
2.1.9 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(2-(trifluoromethyl)phenyl)pyrrolidine-
2,4-dicarboxylate IIi
Yield 84%; 1.20 g; colorless crystals;1Н NMR
(400 MHz, CDCl3, δ): 7.78 (d, J 7.7 Hz, 1H), 7.59 (d,
J 7.7 Hz, 1H), 7.49 (t, J 7.7 Hz, 1H), 7.31 (t, J 7.7 Hz,
1H), 4.84 (d, J 8.6 Hz, 1H), 4.24 (td, J 10.9, 4.5 Hz,
1H), 3.91 (t, J 8.2 Hz, 1H), 3.79 (s, 3H), 3.31 (td, J 8.4,
6.6 Hz, 1H), 2.61 (br.s, 1H), 2.48-2.55 (m, 1H),
2.39-2.44 (m, 1H), 1.62-1.71 (m, 1H), 1.47-1.52 (m, 2H),
1.01-1.20 (m, 2H), 0.81-0.89 (m, 1H), 0.78 (d, J 7.0 Hz,
3H), 0.71-0.78 (m, 1H), 0.64 (d, J 6.6 Hz, 3H), 0.62 (d,
J 7.0 Hz, 3H), 0.55-0.62 (m, 1H), 0.14 (q, J 12.1 Hz,
1H).12
2.2.1 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
1-acryloyl-5-(2-fluorophenyl)pyrrolidine-
2,4-dicarboxylate IIb_A
Yield 64%; colorless crystals; mp 75-77 ꢀC; [α]D
= −46.7 (c = 0.82 in CH2Cl2);1Н NMR (400 MHz,
25
DMSO-d6, δ): 7.88 (t, J 7.3 Hz, 1H), 7.34 (dd, J 13.2,
6.3 Hz, 1H), 7.10-7.27 (m, 2H), 5.96-6.12 (m, 2H), 5.72
(d, J 8.9 Hz, 1H), 5.56-5.67 (m, 1H), 4.40 (dd, J 10.7,
7.1 Hz, 1H), 4.32 (td, J 10.7, 3.8 Hz, 1H), 3.78-3.85 (m,
1H), 3.72 (s, 3H), 2.30 (dd, J 23.7, 12.2 Hz, 1H),
1.45-1.63 (m, 3H), 1.11-1.31 (m, 3H), 0.82-0.99 (m, 2H),
0.59-0.80 (m, 10H), 0.54 (d, J 6.9 Hz, 3H);13С NMR
(100 MHz, DMSO-d6, δ): 172.50, 168.97, 164.46, 160.90,
158.41, 130.43, 130.04, 129.44, 128.05, 127.07, 125.15,
115.60, 74.46, 59.20, 54.91, 52.52, 48.26, 46.57, 34.00,
30.99, 29.69,. 26.80, 25.95, 23.22, 22.23, 20.98, 16.53;
HRMS (ESI, m/z): [M + H]+ calcd. for C26H35NO5F,
460.2494; found, 460.2494.
2.1.10 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
5-(4-fluorophenyl)pyrrolidine-
2,4-dicarboxylate IIj
Yield 80%, colorless crystals, mp 97-99 ꢀC, [α]D20 = −46.7
(c = 0.82 in CH2Cl2);1Н NMR (400 MHz, DMSO-d6, δ):
7.35 (dd, J 8.1, 5.8 Hz, 2H), 7.09 (t, J 8.6 Hz, 2H), 4.46 (br.
s, 1H), 4.21 (td, J 10.8, 4.2 Hz,1H), 3.87 (br.s, 1H), 3.69 (s,
3H), 3.29 (dd, J 15.5, 7.7 Hz,1H), 3.18 (br.s, 1H), 2.31 (dt,
J 12.7, 8.0 Hz, 1H), 2.11-2.23 (m, 1H), 1.50-1.53 (m, 3H),
1.18 (br.s, 1H), 1.09 (t, J 11.5 Hz, 1H), 0.79-0.98 (m, 2H),
0.60-0.80 (m, 7H), 0.54 (d, J 6.8 Hz, 3H), 0.24 (q,
J 11.9 Hz, 1H);13С NMR (100 MHz, DMSO-d6, δ) 173.96,
171.21, 163.15, 160.74, 137.18, 137.15, 131.15, 129.77,
129.69, 115.04, 114.83, 73.37, 63.73, 59.16, 52.21, 48.77,
45.45, 33.98, 32.98, 30.89, 25.93, 23.18, 22.12, 20.94, 16.47;
HRMS (ESI, m/z): [M + H]+ calcd. for C23H33NO4F,
406.2388; found, 406.2386.
2.2.2 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
1-acryloyl-5-(4-fluorophenyl)pyrrolidine-
2,4-dicarboxylate IIj_A
Yield 87%; colorless crystals; mp 110-112ꢀC; [α]D
= −54.3 (c = 0.69 in CH2Cl2);1Н NMR (400 MHz,
25
DMSO-d6, δ): 7.64 (dd, J 8.3, 5.6 Hz, 2H), 7.14 (t,
J 8.7 Hz, 2H), 6.15 (dd, J 16.7, 9.9 Hz, 1H), 6.05 (dd,
J 16.6, 2.2 Hz, 1H), 5.55 (dd, J 9.9, 2.3 Hz, 1H), 5.51
(d, J 8.8 Hz, 1H), 4.38 (dd, J 11.0, 6.8 Hz, 1H), 4.31
(td, J 10.9, 4.2 Hz, 1H), 3.64-3.83 (m, 4H), 2.37 (dt,
J 12.8, 6.5 Hz, 1H), 2.20 (dd, J 24.0, 12.3 Hz, 1H), 1.54
(t, J 12.9 Hz, 2H), 1.11-1.35 (m, 3H), 0.65-0.97 (m,
10H), 0.47 (d, J 6.8 Hz, 3H);13С NMR (100 MHz,
DMSO-d6, δ): 172.73, 172.55, 168.45, 164.55, 160.77,
131.97, 130.57, 130.48, 129.00, 128.70, 115.56, 115.35,
2.2 | General procedure for the synthesis
of acrylamides IIb_A, IIj_A from 5-aryl
prolinates IIb and IIj
Triethylamine (420 μL, 303 mg, 3.0 mmol) was added
to a stirred solution of corresponding 5-aryl prolinate

IVANTCOVA AND KUDRYAVTSEV
5
74.45, 61.49, 59.16, 52.51, 49.09, 46.51, 33.96, 31.06,
28.92, 26.80, 25.73, 23.13, 22.23, 21.00, 16.47; HRMS
(ESI, m/z): [M + H]+ calcd. for C26H35NO5F, 460.2494;
found, 460.2495.
2.3.2 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
1-((2S,3R,5R)-2-(2-chlorophenyl)-
5-(methoxycarbonyl)pyrrolidine-
3-carbonyl)-5-(2-fluorophenyl)pyrrolidine-
2,4-dicarboxylate Vb
2.3 | General procedure for the synthesis
of dimers Va and Vb
Yield 72%; colorless crystals; mp 98-100 ꢀC; [α]D
25
= −37.6 (c = 0.88 in CH2Cl2);1Н NMR (400 MHz,
A solution of triethylamine (315 μL, 227 mg, 2.3 mmol)
in 3 mL of toluene was added dropwise to the
DMSO-d6, δ): 7.46 (ddd, J 12.3, 7.8, 1.4 Hz, 2H), 7.27-7.42
(m, 4H), 7.07-7.25 (m, 2H), 5.23 (d, J 8.6 Hz, 1H), 4.71 (t,
J 7.7 Hz,1H), 4.24 (td, J 10.8, 4.0 Hz,1H), 3.69-3.81 (m,
2H), 3.59-3.70 (m, 7H), 3.17 (t, J 8.4 Hz, 1H), 2.97-3.07
(m, 1H), 2.62 (dt, J 11.9, 7.6 Hz, 1H), 2.01-2.20 (m, 2H),
1.90-1.98 (m, 2H), 1.47-1.63 (m, 4H), 1.16-1.31 (m, 4H),
0.69-1.01 (m, 10H), 0.57 (d, J 6.9 Hz, 3H);13С NMR
(100 MHz, DMSO-d6, δ): 173.55, 171.64, 171.23, 168.39,
137.23, 132.43, 130.70, 130.62, 129.92, 129.63, 129.42,
127.47, 125.06, 115.85, 115.65, 99.99, 74.58, 61.58, 58.93,
58.87, 54.88, 52.47, 52.17, 48.19, 46.64, 45.39, 34.01, 33.76,
30.93, 28.99, 26.10, 23.36, 22.24, 20.99, 16.73; HRMS (ESI,
m/z): [M + H]+ calcd. for C36H45O7N235ClF, 671.2894;
found, 671.2892.
stirred
solution
of
corresponding
iminoester
11
ArCH═NCH2CO2Me (1.6 mmol), AgOAc•2PPh3
(311 mg, 0.45 mmol) and acrylamide IIj_A or IIb_A
(1.5 mmol) in 20 mL of dry toluene under an inert
atmosphere. Reaction flask was protected from the
light with aluminum foil. The reaction mixture
was stirred at room temperature for 48 hours. Then,
toluene was removed by evaporation under
reduced pressure. The solid residue was suspended in
CH2Cl2 (50 mL) and the precipitate was removed
by filtration. Organic phase was washed with H2O
(25 mL), brine (25 mL) and dried under Na2SO4.
Filtrates were evaporated under reduced pressure.
The products were isolated by column chromatography
on silica gel using hexane/AcOEt from 3:1 to 1:1 as
an eluent.11
2.4 | General procedure for the three-
component interaction of cyclohexanone,
benzoic acid, and Β-nitrostyrene in the
presence of organocatalysts II and V
2.3.1 | 4-((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl) 2-methyl (2S,4S,5R)-
1-((2S,3R,5R)-2-(4-chlorophenyl)-
5-(methoxycarbonyl)pyrrolidine-
3-carbonyl)-5-(4-fluorophenyl)pyrrolidine-
2,4-dicarboxylate Va
A solution of benzoic acid (135 mg, 1.1 mmol), β-
nitrostyrene (150 mg, 1.0 mmol), and 5-aryl prolinate
organocatalyst II or V (20-50 mol%) in 1 mL of cyclohex-
anone was stirred at certain temperature for necessary
time (Tables 1–3). The progress of the reactions was mon-
itored by thin-layer chromatography (TLC). The crude
products were purified by column chromatography on
silica gel using CH2Cl2/MeOH from 100:1 to 50:1 as an
eluent. Organocatalysts II or V were recovered from reac-
tion mixtures in all cases by column chromatography
process.
Yield 67%; colorless crystals; mp 119-120 ꢀC; [α]D
= −13.6 (c = 1.37 in CH2Cl2);1Н NMR (400 MHz,
25
DMSO-d6, δ): 7.60 (dd, J 8.5, 5.5 Hz, 2H), 7.36-7.48 (m,
4H), 7.16 (t, J 8.8 Hz, 2H), 4.85 (d, J 8.5 Hz, 1H), 4.46
(d, J 4.5 Hz, 1H), 4.28 (td, J 10.8, 4.2 Hz, 1H), 3.53
(m, 8H), 2.95 (dd, J 12.9, 7.6 Hz, 1H), 2.64 (ddd,
J 13.1, 8.3, 6.5 Hz, 1H), 2.10-2.21 (m, 1H), 1.91-2.07
(m, 2H), 1.83 (dt, J 12.7, 8.3 Hz, 1H), 1.50-1.64 (m,
3H), 1.32-1.46 (m, 2H), 1.20-1.33 (m, 2H), 0.64-0.98 (m,
10H), 0.50 (d, J 6.9 Hz, 3H);13С NMR (100 MHz,
DMSO-d6, δ): 173.74, 172.29, 171.74, 168.17, 163.65,
161.21, 139.49, 134.87, 132.43, 130.63, 130.56, 129.61,
128.50, 115.58, 115.37, 74.49, 64.32, 61.41, 59.21, 58.78,
52.42, 52.15, 48.88, 46.95, 46.59, 33.97, 33.37, 31.04,
28.34, 25.73, 23.06, 22.23, 21.13, 16.40; HRMS (ESI,
m/z): [M + H]+ calcd. for C36H45O7N235ClF, 671.2894;
found, 671.2894.
2.4.1 | (3R,3aS,7aR)-7a-hydroxy-2-oxo-
3-phenyloctahydro-1H-indol-1-yl benzoate
IIIa
Colorless crystals, mp 150-152 ꢀC, [α]D20-18.6 (c = 0.86 in
CHCl3, ee − 63%); lit.9: [α]D25 = −35.0 (c = 0.35 in CHCl3,
ee − 97%).1Н NMR (400 MHz, CDCl3, δ): 8.13 (d,
J 7.9 Hz, 2H), 7.65 (t, J 7.4 Hz, 1H), 7.49 (t, J 7.8 Hz, 2H),
7.30-7.39 (m, 5H), 3.54 (d, J 9.6 Hz, 1H), 3.02 (br.s, 1H),
2.39-2.50 (m, 1H), 2.23 (d, J 13.1 Hz, 1H), 1.81-1.93 (m,

6
IVANTCOVA AND KUDRYAVTSEV
TABLE 1 Three-component interaction of cyclohexanone, benzoic acid, and β-nitrostyrene (Scheme 1B) at room temperature in the
presence of 20 mol% of organocatalysts II
R substituent in
the catalyst II
Catalyst II
Time, days
Ratio IIIa:IVa
Yield IIIab, %
ee IIIac, %
Yield IVb, %
ee IVc, %
−62
11
d
IIa
IIb
IIc
IId
IIe
IIf
IIg
Ih
H
2
3
4
3
6
6
3
6
6
1:25
3:1
–
–
78
20
–
2-F
70
90
51
31
45
22
–
−44
−63
−7
2-cl
99:1
99:1
1:2
–
2,6-diCl
2-Br
4-Br
2-I
–
–
nde
−70
−3
63
50
76
70
47
2:3
nd
2:7
−81
–
−79
−25
29
2-CH3
2-CF3
1:10
2:1
IIi
37
−63
aCalculated from 1H NMR spectra of the reaction mixtures.
bIsolated by chromatography.
cDetermined by chiral HPLC of pure isolated sample.
dNot isolated.
eNot determined.
TABLE 2 Three-component interaction of cyclohexanone, benzoic acid, and β-nitrostyrene (Scheme 1B) in the presence of
ortho-halogen substituted organocatalysts II
Catalyst II
(R substituent)
Temperature,
ꢀC
Ratio
II, mol% Time, days IIIa: IVa Yield IIIab, % ee IIIac, % Yield IVb,
%
ee IVc,
–
%
d
IIc (2-cl)
IIc (2-cl)
IIe (2-Br)
IIe (2-Br)
IIe (2-Br)
IIg (2-I)
25
20
50
20
50
40
20
30
4
99:1
99:1
1:2
90
20
31
50
26
22
–
−63
−87
−70
−84
−93
−81
–
–
−30
25
14
6
–
–
nde
63
49
–
25
4
1:1
nd
−30
25
14
3
99:1
2:7
–
76
81
−79
−89
IIg (2-I)
−30
20
1:99
aCalculated from 1H NMR spectra of the reaction mixtures.
bIsolated by chromatography.
cDetermined by chiral HPLC of pure isolated sample.
dNot isolated.
eNot determined.
TABLE 3 Three-component interaction of cyclohexanone, benzoic acid, and β-nitrostyrene (Scheme 1B) at room temperature in the
presence of β-proline dipeptides V
Catalyst V
V, mol%
Time, days
Ratio IIIa:IVa
Yield IIIab, %
ee IIIac, %
Yield IVb, %
ee IVc, %
d
Va
Vb
Vc
Vd
10
20
13
13
2
3
2
3
1:99
1:1
–
–
96
45
99
95
13
45
–
71
–
−45
17
1:99
1:99
–
–
95
aCalculated from 1H NMR spectra of the reaction mixtures.
bIsolated by chromatography.
cDetermined by chiral HPLC of pure isolated sample.
dNot isolated.

IVANTCOVA AND KUDRYAVTSEV
7
1H), 1.62-1.80 (m, 4H), 1.44-1.59 (m, 2H). HPLC
(Chiralcell OD-H, hexane/iPrOH = 90:10, flow rate 1 -/
min, λ = 210 nm), tR (minor) = 13.71 minutes, tR
(major) = 24.56 minutes, ee − 63%.
depending on the substituent in the aryl fragment of
5-ArPro organocatalyst II, definite chemoselectivities and
enantioselectivities were observed in the studied reaction
system (Table 1). Unsubstituted 5-aryl prolinate IIa
induced predominantly conjugate addition with good
yield and moderate enantioselectivity.
2.4.2 | (R)-2-((S)-2-nitro-1-phenylethyl)
cyclohexan-1-one IV
Introducing of the substituent advantageously of the
halogen nature in ortho-position of 5-aryl fragment of
compounds II dramatically biased the course of the
interaction to the three-component pathway (Table 1).
Despite the moderate enantiomeric purity of 7a-
hydroxyoctahydro-2H-indol-2-one IIIa, ortho-chloro cata-
lyst IIc induced only the Cossío product's formation
(Table 1). ortho-Halogenated catalysts IIc, IIe, and IIg,
which induced the highest enantiomeric purity of the
Cossío product IIIa, were studied further at different tem-
peratures and catalyst loadings (Table 2). Elevation of a
catalyst's loading from 20 mol% to 50 mol% led to increas-
ing of the yield and ee of the 7a-hydroxyoctahydro-2H-
indol-2-one IIIa in the case of ortho-bromo catalyst IIe
(Table 2). All low-temperature experiments were per-
formed in CH2Cl2 solution and scaled up to 30 mol% to
50 mol% quantities of 5-aryl prolinates IIc, IIe, and IIg.
ortho-Chloro compound IIc and ortho-bromo 5-ArPro IIe
at −30ꢀC exclusively induced three-component interac-
tion of cyclohexanone, benzoic acid, and β-nitrostyrene
and formation of 7a-hydroxyoctahydro-2H-indol-2-one
IIIa with high ee (87-93%) and low yield. The reaction
rate at these conditions was very low, and it took decades
to obtain an acceptable quantity of the product. Surpris-
ingly, ortho-iodine catalyst IIg at decreased temperature
led exclusively to the Michael adduct IV with good yield
and ee (Table 2).
In the course of our previous research, we have devel-
oped an efficient method of synthesis of well-defined chi-
ral oligomers consisted formally from 5-aryl prolinate
monomeric units.11,12 As these β-proline oligopeptides
represent structural analogs of 4-L-menthyloxycarbonyl
5-aryl prolinates II, we synthesized some dimeric species
V (Scheme 3) and elucidated them on the influence of the
interaction of cyclohexanone, benzoic acid, and β-
nitrostyrene (Scheme 1B, Table 3). Acryloylation of L-
menthyloxycarbonyl 5-aryl prolinates II and subsequent
1,3-dipolar cycloaddition with imino glycinates (as shown
20
Colorless crystals; mp 133-135 ꢀC; [α]D
= +20.3
(c = 1.40 in CHCl3, ee 95%); lit.13: [α]D25 = +28.1 (c = 0.99
in CHCl3, ee 93%).1Н NMR (400 MHz, CDCl3, δ):
7.30-7.36 (m, 2H), 7.24-7.30 (m, 1H), 7.15-7.21 (m, 2H),
4.95 (dd, J 12.5, 4.5 Hz, 1H), 4.65 (dd, J 12.5, 9.9 Hz, 1H),
3.78 (td, J 9.9, 4.5 Hz, 1H), 2.71 (ddd, J 25.0, 8.3, 4.8 Hz,
1H), 2.46-2.52 (m, 1H), 2.33-2.45 (m, 1H), 2.04-2.14 (m,
1H), 1.48-1.84 (m, 4H), 1.25 (ddd, J 25.0, 11.9, 3.4 Hz,
1H). HPLC (Chiralcell AS-H, hexane/iPrOH = 98:2, flow
rate 1 mL/min, λ = 210 nm), tR (major) = 17.89 minutes,
tR (minor) = 23.55 minutes, ee 95%.
3 | RESULTS AND DISCUSSION
4-L-menthyloxycarbonyl 5-aryl prolinates II were synthe-
sized as single diastereomers according previously
reported methods (Scheme 2).6,10,11 Besides the one
shown on Scheme 2, diastereoselective 1,3-dipolar cyclo-
addition with L-menthyl acrylate iminoglycinates
ArCH═NCH2CO2Me can interact with arynes14 or other
activated dipolarophiles.15 Realization of the interaction
of cyclohexanone, benzoic acid, and β-nitrostyrene under
conditions reported by Cossío9 (Scheme 1) in neat cyclo-
hexanone at room temperature in the presence of chiral
organocatalysts II has revealed very intriguing results
(Table 1). All reactions were conducted until the total
consumption of the β-nitrostyrene component. In most
cases, we registered two products of the studied interac-
tion: 7a-hydroxyoctahydro-2H-indol-2-one IIIa and the
Michael adduct IV (Scheme 1B, Table 1). It was demon-
strated by Cossío that nitroethyl cyclohexanone IV has
not been the intermediate of the compound IIIa
formation,9 indicating on the competing reactions path-
ways to both products (Scheme 1B). But in our case,
SCHEME 2 Synthesis of 5-ArPro organocatalysts II

8
IVANTCOVA AND KUDRYAVTSEV
SCHEME 3 Synthesis and molecular structures
of β-proline dipeptides V tested as organocatalysts
on Scheme 3) have produced desired compounds V.
Absolute configurations of β-proline dipeptides Va,b rep-
resented at Scheme 3 are deduced from our previous
exhaustive studies.11 β-Proline dipeptides Vc,d with
(trifluoromethyl)phenyl substituents were synthesized by
us earlier.12 Dipeptides Va-c possess alternating structure
of chiral centers of monomeric pyrrolidine units, and
both pyrrolidine cycles in dipeptide Vd have the same
configuration of stereogenic centers.11,12 Symmetry of the
catalytically active pyrrolidine unit in dipeptides Va,b,d
is opposite to the corresponding fragment in 4-L-
menthyloxycarbonyl 5-aryl prolinates II (Figure 1,
Schemes 2 and 3). para-Substituted dimer Va induced
only the conjugate addition of β-nitrostyrene to cyclohex-
anone, while changing of substituents positions to ortho
in dipeptide Vb led to the formation of the products IIIa
and IV in equimolar ratio (Table 3).
provided compound IV with both high yield and high
ee (Table 3).
Plausible explanation of fine structural features of
5-aryl prolinates II and their dimeric analogs V causing
different reaction pathways may be proposed based on
the three-component reaction mechanism that has been
offered and computed by Cossío.9 An initial step of the
observed Cossío process is the interaction of 5-ArPro
cyclohexanone enamine (black) with protonated β-
nitrostyrene (magenta) as shown on Figure 2A. An
As could be supposed from the absolute configura-
tion of pyrrolidine units, 7a-hydroxyoctahydro-2H-indol-
2-one IIIa formed under catalysis by Vb is enriched with
the mirror enantiomer comparing with the processes
induced by 4-L-menthyloxycarbonyl 5-aryl prolinates II
(Tables 1 and 3). Homochiral CF3-substituted dipeptide
Vd efficiently catalyzed the Michael addition and
FIGURE 2 Transition states of the first-step interactions of
protonated β-nitrostyrene (magenta) with enamines formed from
4-trans-nitro 5-ArPro catalyst (A)9 and ortho-chloro 5-ArPro
catalyst (B)

IVANTCOVA AND KUDRYAVTSEV
9
organocatalysts in the Michael reaction. J Serb Chem Soc. 2014;
79:767-778.
important stabilization of this transition state is provided
by trans-4-nitro group of the catalyst I (Figure 2A, right
red dish line). ortho-Halogenated cis-aryl fragment in
5-aryl prolinates II could be considered as the stereo-
electronic mimic of the trans-4-nitro group under the def-
inite conformation of the 5-aryl substituent and affords
the required interaction with protonated β-nitrostyrene
as shown on Figure 2B (right dash green line).
7. Ruiz-Olalla A, de Gracia RM, Cossío FP. Densely substituted L-
proline esters as catalysts for asymmetric Michael additions of
ketones to nitroalkenes. J Org Chem. 2015;80(11):5588-5599.
8. Gerosa GG, Spanevello RA, Suárez AG, Sarotti AM. Joint
experimental, in silico, and NMR studies toward the rational
design of iminium-based organocatalyst derived from renew-
able sources. J Org Chem. 2015;80:7626-7634.
9. de Gracia RM, Ruiz-Olalla A, Bello T, de Cózar A, Cossío FP. A
three-component enantioselective cyclization reaction cata-
lyzed by an unnatural amino acid derivative. Angew Chem Int
Ed. 2018;57:668-672.
4 | CONCLUSION
10. Barr DA, Dorrity MJ, Grigg R, et al. Thornton-Pett M. X=Y-ZH
compounds as potential 1,3-dipoles. Part 43. Metal ion
catalysed asymmetric 1,3-dipolar cycloaddition reactions of
imines and menthyl acrylate. Tetrahedron. 1995;51:273-294.
11. Kudryavtsev KV, Ivantcova PM, Muhle-Goll C, et al. Menthols
as chiral auxiliaries for asymmetric cycloadditive oligomeriza-
tion: syntheses and studies of β-proline hexamers. Org Lett.
2015;17(24):6178-6181.
12. Kudryavtsev KV, Mantsyzov AB, Ivantcova PM, et al. Control
of azomethine cycloaddition stereochemistry by CF3 group:
structural diversity of fluorinated β-proline dimers. Org Lett.
2016;18:4698-4701.
To conclude, we observed an unusual sophisticated effect
of a distal halogen substituent in 5-aryl prolinate catalysts
on the course of the three-component interaction of
cyclohexanone, benzoic acid, and β-nitrostyrene. Theo-
retical and experimental proofs of the detected data are
under investigation in our laboratory as well as the
design of novel efficient organocatalysts for important
C─C bond-forming transformations.
ACKNOWLEDGMENTS
PMI's work was supported by a scholarship of the Presi-
dent of the Russian Federation (grant SP-1278.2018.4).
Professor Stefan Bräse (Karlsruhe Institute of Technol-
ogy) is gratefully acknowledged for providing of chiral
HPLC analysis.
13. Mahato CK, Kundu M, Pramanik A. Solvent free, fast and
asymmetric Michael additions of ketones to nitroolefins using
chiral pyrrolidine–pyridone conjugate bases as organocatalysts.
Tetrah: Asymm. 2017;28:511-515.
14. Swain SP, Shih YC, Tsay SC, et al. Aryne-induced novel tan-
dem
1,2-addition/(3+2)
cycloaddition
to
generate
imidazolidines and pyrrolidines. Angew Chem Int Ed. 2015;
54(34):9926-9930.
ORCID
Konstantin V. Kudryavtsev https://orcid.org/0000-0002-
6363-5842
15. Xu H, Golz C, Strohmann C, Antonchick AP, Waldmann H.
Enantiodivergent combination of natural product scaffolds
enabled by catalytic enantioselective cycloaddition. Angew
Chem Int Ed. 2016;55(27):7761-7765.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Ivantcova PM,
Kudryavtsev KV. Chemoselectivity issues of the
asymmetric interaction between cyclohexanone, β-
nitrostyrene, and benzoic acid under 5-aryl
prolinate's organocatalysis. Chirality. 2020;1–9.
https://doi.org/10.1002/chir.23212
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6. Jovanovic P, Ranđelovic J, Ivkovic B, Suteu C, Tokic
ꢀ
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Vujoševic Z, Savic V. Substituted proline derivatives as