Novel carbohydrate-based thioureas as organocatalysts for asymmetric michael addition of 1,3-dicarbonyl compounds to nitroolefins

Article abstract of DOI:10.1016/j.tet.2020.131339

A series of novel carbohydrate-derived thioureas were synthesized and examined as catalysts for the asymmetric Michael addition of symmetrical 1,3-dicarbonyl compounds, including dimethyl malonate, to several trans-β-nitrostyrenes. High enantioselectiviti

Full text of DOI:10.1016/j.tet.2020.131339

Journal Pre-proof
Novel carbohydrate-based thioureas as organocatalysts for asymmetric michael
addition of 1,3-dicarbonyl compounds to nitroolefins
Róbert Rončák, Monika Tvrdoňová, Jozef Gonda, Ján Elečko
PII:
S0040-4020(20)30494-4
https://doi.org/10.1016/j.tet.2020.131339
TET 131339
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 May 2020
Revised Date: 8 June 2020
Accepted Date: 10 June 2020
Please cite this article as: Rončák Ró, Tvrdoňová M, Gonda J, Elečko Já, Novel carbohydrate-
based thioureas as organocatalysts for asymmetric michael addition of 1,3-dicarbonyl compounds to
nitroolefins, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131339.
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Graphical Abstract
Novel carbohydrate-based thioureas as organocatalysts for asymmetric Michael addition of 1,3-dicarbonyl
compounds to nitroolefins
Róbert Rončák, Monika Tvrdoňová *, Jozef Gonda †, Ján Elečko

Novel carbohydrate-based thioureas as organocatalysts for asymmetric
Michael addition of 1,3-dicarbonyl compounds to nitroolefins
Róbert Rončák a, Monika Tvrdoňová a, , Jozef Gonda a,†, Ján Elečko a
aInstitute of Chemical Sciences, Department of Organic Chemistry, P.J. Šafárik University, Moyzesova
11, 040 01 Košice, Slovak Republic
†This work is dedicated to the memory of Professor Jozef Gonda (1957-2019)
ARTICLE INFO
Article history:
Received
Accepted
Available online
Keywords:
Organocatalysis; Carbohydrate thiourea; Michael addition; Enantioselectivity
ABSTRACT
A series of novel carbohydrate-derived thioureas were synthesized and examined as catalysts
for the asymmetric Michael addition of symmetrical 1,3-dicarbonyl compounds, including
dimethyl malonate, to several trans-β-nitrostyrenes. High enantioselectivities (up to 94% ee)
as well as high yields (up to 98%) were attained using a bifunctional organocatalyst bearing a
cinchona-based alkaloid unit.
1. Introduction
Chiral bifunctional organocatalysts, which combine a thiourea group as a hydrogen-bond
donor moiety with a Lewis base, are commonly used in asymmetric catalysis.1 In 2003
Takemoto and coworkers1f,2 described the prototype of such a catalyst and evaluated in
Michael reaction of malonates to nitroolefins (Fig. 1). The high stereocontrol of the reaction is
explained as a synergistic effect of both parts of the catalyst cooperatively activating the
Corresponding author.
e-mail address: monika.tvrdonova@upjs.sk (M. Tvrdoňová).
1

nucleophile and the electrophile simultaneously.2 The effectivity of Takemoto’s catalyst2a
inspired several synthetic groups and many different chiral scaffolds have been employed in
the synthesis of related structures1e,1g,2b,3 (Fig. 1).
Figure 1. Several examples of thiourea-based bifunctional catalysts bearing chiral scaffolds.
In the last decade, growing attention has been focused on the preparation of thiourea-based
bifunctional organocatalysts having a monosaccharide unit.4 In general, carbohydrates are
very useful chiral precursors due to their optical purity and stereodiversity as well as their
high degree of functionality for optimizing catalyst performance. Ma and coworkers4a
published the synthesis of the first thiourea catalysts bearing carbohydrate core scaffold and a
primary amino group (Fig. 2). The promising catalytic potential was later extended by the
2

synthesis of related catalysts bearing various amine basic moiety and monosaccharide or
disaccharide part.4b,4g,4j-k Most of Ma’s group catalysts have been evaluated successively in
direct Michael additions.4a-b,4g Various groups have been working on bifunctional
carbohydrate-based catalysts (some of them are illustrated in Figure 2) and their catalytic
potential has been evaluated in various asymmetric transformations, including Michael,4a-i,4l-
n,5a,5c,5e
Mannich4h,4j and Biginelli5b reactions, cyanation of carbonyl compounds5d and a one-
pot sequential conjugate addition/dearomative fluorination process.4k
Figure 2. Examples of thiourea-derived bifunctional catalysts with carbohydrate units.
Inspired by the various sugar-derived bifunctional thiourea conjugates in several asymmetric
catalytic processes,4,5 we decided to synthesize novel thiourea catalysts 2-6 that combined a
bulky
D-glucofuranose scaffold with a chiral amino unit, including cinchona alkaloid moieties
3

(Scheme 1). The successful application of the furanose- and pyranose- derived
organocatalysts reported in literature4m,6 leads us to examine the effect of substituents attached
to designed glucofuranose-thiourea linkage and investigate their catalytic performance.
Recently, we reported a catalytic activity of the prepared bifunctional hybrids in the
enantioselective Michael addition of symmetrical 1,3-dicarbonyl compounds 11, 14, and
dimethyl malonate 15 to both unsubstituted 12a and substituted β-nitrostyrenes 12b-d (vide
infra).
2. Results and discussion
As shown in Scheme 1, the preparation of catalysts 2-6 was achieved in a single-step
procedure by treatment of the known 3-deoxy-1,2:5,6-di-O-isopropylidene-3-isothiocyanato-
3-C-vinyl-α-D
-glucofuranose 17 with the corresponding commercially available amines 7-10
in very good yields (75-98%, Scheme 1).
Scheme 1. Reagents and conditions: (a) (R)-7, THF, rt, 1 h; (b) (S)-7, THF, rt, 1 h; (c) 8, CH2Cl2, rt, 1.5 h; (d)
9.3 HCl, E3N, THF, rt, 48 h; (e) 10.3 HCl, Et3N, THF, rt, 24 h.
With thioureas 2-6 in hand, we started our investigation of their catalytic activity on the
model Michael addition. The screening of the reaction was carried out with pentane-2,4-dione
4

11, trans-nitrostyrene 12a, and 20 mol% of the prepared catalysts in CH2Cl2 at room
temperature. The obtained results are summarized in Table 1.
Table 1. Catalyst and solvent screening of the asymmetric Michael addition of pentane-2,4-dione 11 to trans-
nitrostyrene 12a
Catalyst
Time
Yielda
eeb (%)
config.c
6 (R)
rac.d
rac.d
Entry
Solvent
(days)
13a (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeOH
MeCN
THF
7
7
7
1
1
1
1
1
1
1
1
4
2
3
4
5
5
5
5
5
5
5
6
2
3
3
7
4
98
87
70
80
73
63
83
75
88 (R)
88 (R)
93 (R)
87 (R)
21 (R)
66 (R)
66 (R)
60 (S)
5e
6f
7
8
9
10
11
CH2Cl2
a Isolated yield. b Determined by chiral HPLC analysis. c Determined by comparison of the HPLC retention times
d
e
and optical rotations values with reported data (Ref.8). Racemic sample. In the presence of 5 mol% of the
catalyst 5. f Reaction was performed at -20 °C.
Model Michael reaction catalyzed by 2-4 was very slow and afforded the corresponding
addition product 13a in very low yield as a racemic mixture (Table 1, entries 2-3) or with only
6% enantiomeric excess after seven days (Table 1, entry 1). Among the tested catalysts
cinchona-based catalyst 5 emerged as the most effective catalyst, affording (R)-configured
adduct 13a in an excellent yield (98%) and high 88% ee with a significant shortening of the
reaction time to one day (Table 1, entry 4). On the other hand, its diastereoisomeric partner 6
was found to be less-active in terms of enantioselectivity (60% ee, Table 1, entry 11),
providing the Michael product 13a in only 75% yield with the opposite (S)-stereochemistry.
The screening of solvents revealed dichloromethane as the most suitable solvent from all
5

tested (Table 1, entries 4-10). Catalyst loading was successfully reduced to 5 mol% without
any loss of enantioselectivity in slightly lower yield (Table 1, entry 5). Performing the
reaction at low temperature (-20 °C) were also investigated afforded the best enantioselective
results (93% ee) but only 70% of product was formed (Table 1, entry 6). The absolute
configuration of 13a was determined by comparison of the HPLC and optical rotation data in
the literature for both enantiomers of 13a.8
Having identified the bifunctional thiourea 5 as a promising catalyst, we focused our attention
on evaluating the synthetic potential of 5 in the Michael addition of the symmetrical 1,3-
dicarbonyl compounds 11 and 14, including dimethyl malonate 15, to both unsubstituted 12a
and substituted β-nitrostyrenes 12b-d with methyl-, methoxy- and bromo- groups on the
phenyl ring (Table 2). For this screening we used previously optimized reaction conditions of
the model study (20 mol% of catalyst, CH2Cl2, room temperature).
Table 2. Enantioselective 1,4-addition of Michael donors 11, 14 and 15 to various β-nitrostyrenes 12a-d
catalyzed by 5
Time
(h)
24
24
24
24
24
24
24
24
24
48
48
48
Yielda
eeb (%)
config.c
88 (R)
86 (R)
94 (R)
92 (R)
88 (R)
89 (R)
80 (R)
76 (R)
60 (R)
8 (R)
Entry
Nitroolefin
Michael donor
(%)
1
12a (R1 = H)
11 (R2 = Me)
11 (R2 = Me)
11 (R2 = Me)
11 (R2 = Me)
14 (R2 = Ph)
14 (R2 = Ph)
14 (R2 = Ph)
14 (R2 = Ph)
14 (R2 = Ph)
15 (R2 = OMe)
15 (R2 = OMe)
15 (R2 = OMe)
98 (13a)
96 (13b)
91 (13c)
81 (13d)
82 (16a)
73 (16a)
75 (16b)
80 (16c)
29 (16d)
14 (17a)
11 (17b)
42 (17c)
2
12b (R1 = Me)
12c (R1 = OMe)
12d (R1 = Br)
12a (R1 = H)
3
4
5
6e
12a (R1 = H)
7
12b (R1 = Me)
12c (R1 = OMe)
12d (R1 = Br)
12a (R1 = H)
8
9
10
11
12
12b (R1 = Me)
12c (R1 = OMe)
11 (R)
17 (R)
6

13
12d (R1 = Br)
15 (R2 = OMe)
48
27 (17d)
13d
b
c
a Isolated yield. Determined by chiral HPLC analysis. Determined by comparison with reported data - HPLC
retention times and optical rotation values (Refs.8,9). d The absolute configuration not assigned. e In the presence
of 5 mol% of the catalyst 5.
As given in Table 2, in the case of Michael addition of pentane-2,4-dione 11 to 12b-d, all of
the para-substituted nitroolefins used was found to furnish adducts 13b-d in very good yields
(81-96%) and enantioselectivities (86-94% ee). The best level of selectivity (94% ee) was
observed for the reaction between 11 and β-nitrostyrene 12c bearing an electron-donating
group on the phenyl core when compared to the model reaction (Table 1, entry 1 versus entry
3). On the other hand, 1,3-dicarbonyl compound 14 yielded with the corresponding olefins
12b-c products 16b-d with relatively lower enantioselectivities (76-80% ee). The chemical
yields were good and ranged from 75 to 80% (Table 2, entries 7-8). The ability of 5 to
catalyze the enantioselective 1,4-addition between 12d and 14 was significantly reduced and
expected product 16d was obtained in only 29% yield with 60% ee (Table 2, entry 9). A
promising result of the Michael addition regarding selectivity (88% ee) and effectivity (82%
yield) was observed in the case of the unsubstituted olefin 12a (Table 2, entry 5). It should be
noted that also in this case the amount of catalyst had no significant effect on the course of the
reaction. After reducing the catalyst loading from 20 mol% to 5 mol% the selectivity remains
the same and the chemical yield gently decreased (89% ee, 73%, Table 2, entry 6).
For extending the substrate scope of the Michael addition, we also investigated the reaction of
nitrostyrenes 12a-d with dimethyl malonate 15 as the Michael donor. The use of 15 as a
catalyst led to a dramatic loss of stereocontrol providing the corresponding products 17a-d in
very small yields ranged from 11 to 42% (Table 2, entries 10-13). The different reactivity of
malonate 15 toward the Michael addition by comparison with 1,3-dicarbonyl compounds 11
and 14 could be explained by the lower acidity of the methylene group protons in the case of
15.
To make a comparison between thioureas 5 and 6, we also turned our attention to the catalytic
activity of 6. The use of 6 allowed the conversion of both unsubstituted and substituted β-
nitrostyrenes 12a and 12c with the 1,3-diketones 11 and 14 into the corresponding adducts
13a, 13c, 16a and 16c in good yields (up to 85%), but a significant decrease of
enantioselectivity was noticed (16-60% ee, Table 3, entries 1-4).
7

The absolute configuration of the aforementioned products was assigned by comparison of the
HPLC retention times8, 9 and opposite optical rotation values with the published data8c (see
ESI), revealing the (S)-stereochemistry of the prevalent antipode in all cases (Table 3). Our
screening showed that the absolute configuration of the Michael products is controlled by the
(R)-configured C-9/C-8 stereocenters in the bulky 9-amino-9-deoxyquinidine moiety of 5
(Table 2). Surprisingly, thiourea 6 bearing the (8S,9S)-9-amino-9-deoxy-epiquinine fragment
was found to be a poorer catalyst for preferring the formation of the opposite enantiomer. The
obtained results indicate that the proper conformation of the cinchona alkaloid-derived
scaffolds is probably necessary for successful asymmetric induction, while a furanose
template is beneficial for the tuning of the catalyst.
Table 3. Bifunctional cinchona organocatalyst 6 catalyzed Michael reaction of nitrostyrenes 12a, 12c with
donors 11 and 14
Time
(h)
24
Yielda
eeb
Entry
Catalyst
Nitrostyrenes
Michael donor
(%)
(config.)c
60 (S)
44 (S)
16 (S)
40 (S)
1
2
3
4
12a (R1 = H)
11 (R2 = Me)
11 (R2 = Me)
14 (R2 = Ph)
14 (R2 = Ph)
75 (13a)
85 (13c)
78 (16a)
31 (16c)
6
6
6
6
12c (R1 = OMe)
12a (R1 = H)
24
24
12c (R1 = OMe)
24
b
c
a Isolated yield. Determined by chiral HPLC analysis. Determined by comparison with reported data - HPLC
retention times and optical rotation values (Refs.8,9).
3. Conclusion
In conclusion, five novel glucofuranose-based thiourea organocatalysts 2-6 were synthesized
from the commercially available amines 7-10 and the known isothiocyanate 1 developed in
our laboratory. The initial screening of their catalytic activity on the model Michael addition
showed the promising potential of the bifunctional catalyst 5, bearing a quinidine-derived
8

cinchona alkaloid scaffold. Thiourea 5 proved to be a highly efficient catalyst for the Michael
addition of 1,3-dicarbonyl compounds to nitrostyrenes to afford the corresponding adducts
with good-to-high enantioselectivities (up to 94% ee) in excellent yields (up to 98%), without
any additive. Catalyst loading screening study revealed that only 5 mol% is sufficient to
catalyze the reaction, and decrease the reaction temperature to -20 °C slightly improved the
enantiomeric enrichment but resulted in lower yield. Further studies, aimed at the reaction
mechanism and scope of this novel catalyst, are currently in progress.
4. Experimental section
4.1. General methods
All reagents bought from commercial sources (Aldrich or Acros Organics) were used as sold
without further purification. Solvents were dried and purified before use according to standard
procedures. Yields refer to chromatographically purified and spectroscopically pure
compounds, unless otherwise stated. All reactions were performed under an atmosphere of
nitrogen. Reactions were monitored by thin layer chromatography (TLC) using Merck silica
gel 60 F254 analytical plates and visualized by fluorescence quenching under UV light (254
nm). In addition, TLC plates were stained with a dipping solution of basic potassium
permanganate solution, or ethanolic acidic solution of p-anisaldehyde followed by heating.
Chromatographic purification was performed on silica gel, Kieselgel 60 (0.040‒0.063 mm,
230‒400 mesh, Merck). Solvents for chromatography (n-hexane, EtOAc, DCM, MeOH) were
13
distilled before use. 1H NMR and C NMR spectra were recorded on a Varian Mercury Plus
1
400 FT NMR (400.13 MHz for H and 100.61 MHz for 13C) spectrometer in deuterated
solvents (CDCl3 and CD3OD). NMR data are reported as follows: δ are given in parts per
million (ppm), for 1H relative to TMS (δ = 0.00 ppm) as the internal standard or to the solvent
signals CD3OD (δ = 4.84 ppm or δ = 3.31 ppm) and for 13C relative to CDCl3 (δ = 77.00 ppm)
13
13
or CD3OD (δ = 49.05 ppm). The multiplicity of the C NMR signals concerning the C-1H
coupling was determined by the HSQC and HMBC method. Chemical shifts (in ppm) and
coupling constants (in Hz) were obtained by first-order analysis; assignments were derived
from COSY and H/C correlation spectra. Infrared (IR) spectra were measured with a Nicolet
6700 FT-IR spectrometer and are listed in ν values (cm−1), only selected maximum
absorbances are reported. High-resolution mass spectra (HRMS) were recorded on a
micrOTOF-Q II quadrupoletime of flight hybrid mass spectrometer (Bruker Daltonics).
9

Optical rotations were measured on a P-2000 Jasco polarimeter and reported as follows: [α]D
(c in grams per 100 mL, solvent). Melting points were obtained on a Kofler hot block and are
uncorrected. The enantiomeric excesses were determined by HPLC analysis on chiral
columns (Chiralpak-IA, Lux 5μm i-Amylose-1) using n-hexane/i-PrOH as a mobile phase.
The corresponding HPLC analyses were performed on a Shimadzu HPLC system, including
the following instruments: LC-20AD pump and refractive index detector RID-10A.
Nitrostyrenes 12a-d were synthesized according to the known procedure10b and their
spectroscopic data and other relevant characteristics were in good accord with those reported
in the literature for the same compounds.10
4.1.1. Preparation of catalyst 2
To a solution of 17 (0.10 g, 0.305 mmol) in dry THF (4 mL) was added (R)-(+)-α-
methylbenzylamine (R)-7 (47 μL, 0.366 mmol). After being stirred for 1 h at room
temperature, the solvent was evaporated, and the residue was flash-chromatographed through
a short column of silica gel (n-hexane/EtOAc, 4:1) to give 0.13 g (96%) of compound 2 as a
white amorphous solid; [α]D21 +61.1 (c 1.12, CHCl3). IR (neat) ν 3340, 2984, 2931, 1531 cm-
1; 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.52
(s, 3H, CH3), 1.55 (d, J = 6.9 Hz, 3H, CH3), 4.02 (d, J = 7.8 Hz, 1H, H-4), 4.07 (dd, J = 8.7,
5.0 Hz, 1H, H-6), 4.09‒4.16 (m, 1H, H-6), 4.23‒4.30 (m, 1H, H-5), 4.49 (s, 1H, H-2), 5.47 (d,
J = 11.0 Hz, 1H, H-8), 5.50–5.64 (m, 2H, H-8, CH), 5.76 (s, 1H, H-1), 5.96 (d, J = 17.7, 11.0
13
Hz, 1H, H-7), 6.36 (s, 1H, NH), 6.87 (d, J = 7.2 Hz, 1H, NH), 7.23‒7.37 (m, 5H, Ph); C
NMR (101 MHz, CDCl3) δ 21.7 (CH3), 25.3 (CH3), 26.3 (CH3), 26.7 (CH3), 26.8 (CH3), 55.8
(CH), 67.3 (C-6), 70.1 (C-3), 73.1 (C-5), 81.6 (C-4), 86.7 (C-2), 103.7 (C-1), 110.5 (Cq),
113.1 (Cq), 121.1 (C-8), 126.4 (2 × CHPh), 127.6 (CHPh), 128.7 (2 × CHPh), 131.3 (C-7), 142.5
(Ci), 180.6 (C=S). ESI-HRMS: m/z calcd for C23H33N2O5S [M + H]+ 449.2105, found
449.2126.
4.1.2. Preparation of catalyst 3
Using the same procedure as described for the synthesis of 2, the corresponding
isothiocyanate 17 (0.10 g, 0.305 mmol) and (S)-(‒)-α-methylbenzylamine (S)-7 (47 μL, 0.366
mmol) afforded after flash chromatography on silica gel (n-hexane/EtOAc, 4:1) 0.13 g (96%)
of compound 3 as a white amorphous solid; [α]D21 +82.8 (c 0.92, CHCl3). IR (neat) ν 3354,
1
2984, 2932, 1536 cm-1; H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H, CH3), 1.34 (s, 3H, CH3),
1.44 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.54 (d, J = 6.9 Hz, 3H, CH3), 4.01 (d, J = 7.8 Hz, 1H,
10

H-4), 4.05 (dd, J = 8.8, 5.0 Hz, 1H, H-6), 4.09‒4.16 (m, 1H, H-6), 4.23‒4.31 (m, 1H, H-5),
4.49 (s, 1H, H-2), 5.47 (d, J = 11.0 Hz, 1H, H-8), 5.51‒5.63 (m, 2H, H-8, CH), 5.75 (s, 1H,
H-1), 5.96 (dd, J = 17.8, 11.0 Hz, 1H, H-7), 6.32 (s, 1H, NH), 6.85 (d, J = 7.4 Hz, 1H, NH),
13
7.38‒7.23 (m, 5H, Ph); C NMR (101 MHz, CDCl3) δ 21.7 (CH3), 25.3 (CH3), 26.3 (CH3),
26.7 (CH3), 26.8 (CH3), 55.8 (CH), 67.3 (C-6), 70.1 (C-3), 73.1 (C-5), 81.6 (C-4), 86.7 (C-2),
103.7 (C-1), 110.6 (Cq), 113.1 (Cq), 121.1 (C-8), 126.5 (2 × CHPh), 127.6 (CHPh), 128.7 (2 ×
CHPh), 131.3 (C-7), 142.5 (Ci), 180.7 (C=S). ESI-HRMS: m/z calcd for C23H33N2O5S [M +
H]+ 449.2105, found 449.2131.
4.1.3. Preparation of catalyst 4
(1R,2R)-(−)-1,2-diaminocyclohexane 8 (0.17 g, 1.527 mmol) was added to a solution of
isothiocyanate 17 (0.10 g, 0.305 mmol) in dry CH2Cl2 (4 mL). After being stirred for 1.5 h at
room temperature, the mixture was concentrated, and the residue was chromatographed on
silica gel (CH2Cl2/MeOH, 10:1). This procedure yielded 0.10 g (75%) of compound 4 as
white crystals; mp 128‒130 °C; [α]D21 +68.6 (c 0.98, CHCl3). IR (neat) ν 3319, 3272, 2985,
2933, 2858, 1556 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.02‒1.37 (m, 10H, 2 × CH2, 2 × CH3),
1.44 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.64‒1.76 (m, 2H, CH2), 1.92‒2.09 (m, 2H, CH2), 2.31
(br s, 2H, NH2), 2.44‒2.55 (m, 1H, CH), 3.99‒4.16 (m, 4H, H-4, 2 × H-6, CH), 4.27‒4.36 (m,
1H, H-5), 4.59 (br s, 1H, H-2), 5.47‒5.60 (m, 2H, 2 × H-8), 5.88 (d, J = 3.4 Hz, 1H, H-1),
13
5.97 (dd, J = 17.7, 11.0 Hz, 1H, H-7), 6.40 (br s, 1H, NH), 6.61 (br s, 1H, NH); C NMR
(101 MHz, CDCl3) δ 24.9 (CH2), 25.0 (CH2), 25.3 (CH3), 26.4 (CH3), 26.7 (CH3), 26.9 (CH3),
32.3 (CH2), 34.7 (CH2), 55.8 (CH), 62.8 (CH), 67.4 (C-6), 70.0 (C-3), 73.0 (C-5), 81.8 (C-4),
86.7 (C-2), 103.8 (C-1), 110.5 (Cq), 113.0 (Cq), 120.8 (C-8), 131.3 (C-7), 181.5 (C=S). ESI-
HRMS: m/z calcd for C21H36N3O5S [M + H]+ 442.2370, found 442.2379.
4.1.4. Preparation of catalyst 5
A solution of (9R)-6'-methoxycinchonan-9-amine trihydrochloride 9.3 HCl (0.10 g, 0.231
mmol) in dry THF (9 mL) was treated with Et3N (96 μL, 0.693 mmol) at room temperature.
Then isothiocyanate 17 (83 mg, 0.254 mmol) was added and stirring was continued for 48 h at
the same temperature. After completion of the reaction, the solvent was evaporated, and the
residue was subjected to flash chromatography on silica gel (CH2Cl2/MeOH, 98:2) to afford
0.135 g (90%) of compound 5 as a white amorphous solid; [α]D21 +154.5 (c 0.92, CHCl3). IR
1
(neat) ν 3315, 2983, 2935, 1621 cm-1; H NMR (400 MHz, CD3OD) δ 1.00‒1.10 (m, 1H, H-
11

7), 1.13‒1.23 (m, 1H, H-7), 1.29 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.50 (s,
3H, CH3), 1.57‒1.67 (m, 3H, H-4, 2 × H-5), 2.31‒2.40 (m, 1H, H-3), 2.93‒3.05 (m, 3H, 2 ×
H-6, H-2), 3.26‒3.33 (m, 1H, H-8), 3.34‒3.36 (m, 2H, H-9, H-2), 3.94‒4.05 (m, 5H, OCH3,
H-4'', H-6''), 4.06‒4.12 (m, 1H, H-6''), 4.45 (dd, J = 11.9, 6.1 Hz, 1H, H-5''), 5.02‒5.16 (m,
3H, H-2'', H-8'', H-CH2), 5.17‒5.28 (m, 2H, H-8'', H-CH2), 5.78 (s, 1H, H-1''), 5.88‒6.00 (m,
2H, H-7'', CH), 6.24 (br s, 1H, NH), 7.43 (d, J = 9.2 Hz, 1H, H-7'), 7.48 (d, J = 4.6 Hz, 1H, H-
3'), 7.93 (d, J = 9.2 Hz, 1H, H-8'), 7.99 (s, 1H, H-5'), 8.67 (d, J = 4.6 Hz, 1H, H-2'); NH not
seen; 13C NMR (101 MHz, CD3OD) δ 25.6 (CH3), 26.5 (C-7), 26.6 (CH3), 26.9 (2 × CH3),
27.4 (C-5), 28.8 (C-4), 40.3 (C-3), 49.0 (C-2), 49.9 (C-9), 50.2 (C-6), 56.6 (OCH3), 61.2 (C-
8), 68.0 (C-6''), 71.0 (C-3''), 74.2 (C-5''), 83.2 (C-4''), 86.5 (C-2''), 104.0 (C-5'), 105.4 (C-1''),
111.2 (Cq), 113.6 (Cq), 115.2 (CH2), 119.3 (C-8''), 120.9 (C-3'), 124.0 (C-7'), 130.1 (C-4a'),
131.2 (C-8'), 132.9 (C-7''), 141.8 (CH), 145.2 (C-8a'), 148.2 (C-2', C-4'), 159.6 (C-6'), 183.7
(C=S); HSQC correlation: H-2/C-2, HMBC correlation: CH/C-2. ESI-HRMS: m/z calcd for
C35H47N4O6S [M + H]+ 651.3211, found 651.3243.
4.1.5. Preparation of catalyst 6
According to the same procedure described for the preparation of 5, 9-amino-(9-deoxy)-epi-
quinine trihydrochloride 10.3 HCl (0.12 g, 0.277 mmol), Et3N (0.12 mL, 0.831 mmol) and
isothiocyanate 17 (0.10 g, 0.305 mmol) provided after chromatography on silica
21
(CH2Cl2/MeOH, 98:2) 0.176 g (98%) of compound 6 as a white amorphous solid; [α]D
‒
1
52.6 (c 0.34, CHCl3). IR (neat) ν 3332, 2930, 2360, 1723, 1525 cm-1; H NMR (400 MHz,
CD3OD) δ 0.88 (dd, J = 13.1, 6.6 Hz, 1H, H-7), 1.29 (s, 6H, 2 × CH3), 1.35‒1.42 (m, 4H,
CH3, H-7), 1.50 (s, 3H, CH3), 1.57‒1.74 (m, 3H, H-4, 2 × H-5), 2.28‒2.38 (m, 1H, H-3),
2.69‒2.82 (m, 2H, H-2, H-6), 3.20‒3.32 (m, 3H, H-2, H-8, H-9), 3.35‒3.52 (m, 1H, H-6),
3.96 (dd, J = 8.5, 5.8 Hz, 1H, H-6''), 4.01 (s, 3H, OCH3), 4.02‒4.12 (m, 2H, H-4'', H-6''), 4.36
(dd, J = 11.5, 6.2 Hz, 1H, H-5''), 4.92‒5.04 (m, 2H, CH2), 5.13 (s, 1H, H-2''), 5.33-5.47 (m,
2H, 2 × H-8''), 5.74 (d, J = 3.0 Hz, 1H, H-1''), 5.82 (dd, J = 16.3, 8.9 Hz, 1H, CH), 6.01‒6.16
(m, 2H, H-7'', NH), 7.44 (d, J = 9.2 Hz, 1H, H-7'), 7.49 (d, J = 4.6 Hz, 1H, H-3'), 7.93 (d, J =
9.2 Hz, 1H, H-8'), 8.01 (s, 1H, H-5'), 8.66 (d, J = 4.6 Hz, 1H, H-2'); NH not shown; 13C NMR
(101 MHz, CD3OD) δ 25.5 (CH3), 26.6 (C-7), 26.7 (CH3), 26.9 (CH3), 27.0 (CH3), 28.7 (C-5),
28.9 (C-4), 40.9 (C-3), 42.5 (C-6), 49.1 (C-9), 56.5 (OCH3), 56.9 (C-2), 62.1 (C-8), 67.8 (C-
6''), 71.1 (C-3''), 74.2 (C-5''), 82.9 (C-4''), 86.3 (C-2''), 104.3 (C-5'), 105.4 (C-1''),111.2 (Cq),
113.7 (Cq), 115.0 (CH2), 120.2 (C-8''), 121.0 (C-3'), 123.6 (C-7'), 130.2 (C-4a'), 131.2 (C-8'),
132.8 (C-7''), 142.6 (CH), 145.0 (C-8a'), 148.3 (C-2', C-4'), 159.5 (C-6'), 182.5 (C=S); HSQC
12

correlation: H-9/C-9. ESI-HRMS: m/z calcd for C35H47N4O6S [M + H]+ 651.3211, found
651.3220.
4.1.6. General procedure for the catalytic Michael addition
To a solution of the corresponding nitroolefin (50 mg, 12a-d) in dry CH2Cl2 (1.5 mL) was
added organocatalyst (20 mol%, 2-6) and 1,3-dicarbonyl compound (2 eq, 11, 14, 15). After
being stirred at room temperature, the resulting mixture was concentrated, and the residue was
subjected to flash chromatography on silica gel. The enantiomeric excess was determined by
HPLC analysis on chiral columns (Chiralpak-IA, Lux i-Amylose-1) using n-hexane/i-PrOH as
the mobile phase. The corresponding HPLC chromatograms are listed in ESI.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgement
Financial support from Slovak Grant Agency VEGA, grant no. 1/0375/19, and also from the
Slovak Research and Development Agency under contract no. APVV-14-0883 is gratefully
acknowledged. The present work was also supported by and Internal Scientific Grant System
of P. J. Šafárik University (Grant No. VVGS-PF-2019-1056) and the Operational Programme
Research and Development through the project: ITMS 26220120064.
Appendix A. Supplementary data
Supplementary data related to this article can be found at [it will be filed by the Editorial
office].
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15

Highlights
•
•
Novel cinchona derived glucofuranose-based thiourea catalysts were developed.
The Michael reaction provided the corresponding products in excellent yields with a
high degree of enantioselectivity (up to 94% ee).
•
The resulting stereochemistry of Michael adducts was controlled by the quinuclidine
part of the bifunctional catalyst.

Novel carbohydrate-based thioureas as organocatalysts for asymmetric
Michael addition of 1,3-dicarbonyl compounds to nitroolefins
Róbert Rončák a, Monika Tvrdoňová a, , Jozef Gonda a,†, Ján Elečko a
aInstitute of Chemical Sciences, Department of Organic Chemistry, P.J. Šafárik University, Moyzesova
11, 040 01 Košice, Slovak Republic
Conflicts of interest
The authors declare no conflicts of interest.
Corresponding author.
e-mail address: monika.tvrdonova@upjs.sk (M. Tvrdoňová).