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Article

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

by
Samson Lalhmangaihzuala
1,2,
Vanlalngaihawma Khiangte
1,2,
Zathang Laldinpuii
1,2,
Lal Nunnemi
1,2,
Joute Malsawmsanga
1,2,
Gospel Lallawmzuali
1,3,
Thanhming Liana
1,
Chhakchhuak Lalhriatpuia
1,
Zodinpuia Pachuau
2 and
Khiangte Vanlaldinpuia
1,*
1
Department of Chemistry, Pachhunga University College, Mizoram University, Aizawl 796001, Mizoram, India
2
Department of Chemistry, Mizoram University, Tanhril, Aizawl 796004, Mizoram, India
3
Department of Environmental Science, Mizoram University, Tanhril, Aizawl 796004, Mizoram, India
*
Author to whom correspondence should be addressed.
Chemistry 2023, 5(4), 2362-2375; https://doi.org/10.3390/chemistry5040156
Submission received: 11 September 2023 / Revised: 10 October 2023 / Accepted: 16 October 2023 / Published: 23 October 2023
(This article belongs to the Topic Catalysis: Homogeneous and Heterogeneous)
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Abstract

:
The preparation of a new class of six bifunctional thiourea organocatalysts having a d-fructose scaffold and a primary amino group was demonstrated. In the present study, the novel organocatalysts exhibited excellent enantio- and moderate diastereoselectivities in the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to substituted nitroolefins at room temperature. In addition, the direct asymmetric aldol reaction between cyclic aliphatic ketone and aromatic aldehydes was also studied in the presence of the saccharide-thiourea organocatalysts giving excellent yield with moderate enantioselectivity.

Graphical Abstract

1. Introduction

The development of cost-effective and highly efficient synthetic techniques for the formation of carbon–carbon bonds remains an active field of research in organic chemistry [1,2]. Among the variants of these reactions, asymmetric Michael addition and Aldol reactions represent one of the most powerful and attractive transformations, mainly due to their widespread applications in the synthesis of several important biological and pharmaceutical compounds [3,4,5]. Significant efforts have been made in recent years to produce metal-free organocatalysts that are capable of promoting these asymmetric processes with exceptionally high yields and stereoselectivity [6,7,8]. In this context, the applications of chiral bifunctional amine-thioureas have emerged as a promising prospect and they have been successfully employed for a number of asymmetric transformations [9,10,11,12,13,14]. Their high efficacy in stereoselective synthesis is mainly attributed to their unique capability of multiple hydrogen-bonding donors as well as the readily accessible chiral diamines [15]. Some prominent examples include Jacobsen’s thioureas [16,17,18,19,20,21,22] and Takemoto’s amino thioureas [23,24,25,26,27,28], which were employed as catalysts in various asymmetric syntheses. Recently, with the aim of enhancing reactivity, widening substrate scope and improving the stereoselectivity of the organocatalytic reactions, the development of a bifunctional amine-thiourea-bearing saccharide moiety has also drawn the attention of various research groups [29,30].
Despite the variety of Michael acceptors employed in asymmetric Michael reactions, nitroalkenes have garnered particular interest due to their high reactivity and suitability as reaction partners for various aldehydes and ketones [31,32,33]. In addition, the generated functionalized nitroalkane adducts have a wide range of synthetic applications and can be converted into diverse functionalities, earning them the title of “synthetic chameleon” [34,35]. With a rise in the number of studies conducted in this field, several highly tuned and effective organocatalysts have been designed and developed. And, the potential of carbohydrate-based amine thioureas as a catalyst for the enantioselective Michael addition of ketones [36,37,38,39] and 1,3-dicarbonyl compound [40,41,42,43,44] to electron-poor nitroalkenes has also been extensively evaluated. In most of the cases, the resultant products obtained are in moderate to excellent yields and enantioselectivities.
Aside from the outstanding progress made with saccharide-based tertiary amine thiourea [36,45,46,47,48,49], laboratory efforts were also directed towards the creation of chiral thiourea, which contains a primary amino group and a carbohydrate scaffold. These chiral organic molecules, which were initially developed by Ma and co-workers in 2007 [36], were demonstrated to successfully facilitate reaction between ketone and nitroalkenes with high yields and excellent stereochemical results. In light of these important precedents, as well as our ongoing interest in asymmetric synthesis [50,51], we explored the asymmetric Michael addition reaction of aliphatic ketones and acetylacetone to substituted β-nitrostyrene using a new class of d-fructose-derived bifunctional primary amine-thiourea catalysts.
d-Fructose, a compound characterized by its abundant availability, cost-effectiveness, and well-defined stereogenic centers, has been explored for a number of asymmetric organic transformations. However, there has been no previous report on the utilization of d-Fructose as a saccharide scaffold in the synthesis of carbohydrate-based thiourea organocatalysts. Furthermore, there are only limited reports of the application of saccharide-based thioureas for the direct asymmetric Aldol reaction between ketones and aldehydes [52]. And the utilization of thiourea compounds containing carbohydrate scaffolds as organocatalysts continues to pose a significant challenge for the said transformation. So, the effectiveness of the newly synthesized compounds was further extrapolated for the asymmetric aldol reaction between cyclohexanone and aromatic aldehydes.

2. Materials and Methods

2.1. General

All reagents and solvents were commercial grade and purified prior to use when necessary. Optical rotations were measured with an Autopol IV, Rudolph Research Analytical Polarimeter (Rudolph Research Analytical, Hackettstown, NJ, USA) in chloroform, and described as follows: [α]D25 (c in mg per 10 mL, solvent). FT-IR spectra were recorded on an Agilent Cary 630 FT-IR spectrometer (Agilent, Santa Clara, CA, USA), with absorptions in cm−1. NMR spectra were recorded on a Bruker Avance II spectrophotometers. Chemical shifts for 1H NMR and 13C NMR spectra are reported (in parts per million) with reference to internal tetramethylsilane (Me4Si = 0.0 ppm) using CDCl3 and DMSO-d6 as solvents. ESI-MS was carried out on an Agilent 6520 Q-TOF Mass spectrometer (Agilent, Santa Clara, CA, USA) with an Agilent 1200 HPLC system (Agilent, Santa Clara, CA, USA). HRMS was recorded on XEVO G2-XS QTOF instrument (Waters, Milford, MA, USA) using CH3CN as a solvent. The elemental analyses of the catalyst were carried out on a Perkin–Elmer-2400 CHN/S analyzer (Perkin Elmer, Waltham, MA, USA). Using a Chiralpak OD-H or AD-H column (Diacel Corporation, Konan, Tokyo, Japan) with n-hexane and iso-propanol as the eluent, the enantioselectivity of the adducts was examined using a Waters 1525 binary pump (Waters, Milford, MA, USA) and a Waters UV detector 2489 (Waters, Milford, MA, USA).

2.2. Synthesis of Saccharide-Based Isothiocyanates 3 and 4

To a stirred solution of sugar amines (1.5 g, 5.8 mmol), 1 or 2, in absolute ethanol (5 mL) were added CS2 (3.50 mL, 58 mmol) and NEt3 (0.806 mL, 5.8 mmol) [53] The reaction mixture was stirred for 2 h at room temperature and then cooled on an ice bath. Next, Boc2O (6.38 mmol) and 3 mol% of DMAP were added to the reaction mixture and allowed to reach room temperature. After stirring for another three hours, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (5:95, ethyl acetate: hexane) to afford the desired product. (see Supplementary Materials Figures S1, S2, S9 and S10 for the 1H NMR, 13C NMR, and mass spectra data of compounds 3 and 4).
1,2:4,5-Di-O-isopropylidene-3-(isothiocyanato)-3-deoxy-α-d-fructopyranose (3): yield: 82% as white solid; mp: 64–66 °C. [α]D25 −198.00° (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3): δ 4.46–4.44 (m, 1H), 4.27–4.19 (m, 2H), 4.04–3.94 (m, 2H), 3.84–3.77 (m, 2H), 1.46 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.29 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 136.54, 111.54, 110.77, 104.35, 73.31, 72.50, 72.42, 62.76, 58.79, 27.02, 26.52, 26.04, 25.35 ppm. IR (KBr): 2937, 2344, 2067, 1698, 1460, 1378, 1198, 1077, 854, 742 cm−1. ESI-MS (m/z): 324.0 (M+ + Na). HRMS: calculated for [C13H19NO5S+H]: 302.1062, found 302.1064. Elemental Analysis for C13H19NO5S: calculated C 51.67, H 6.66, N 5.25, O 26.04, S 10.38; found C 51.88, H 6.75, N 5.11, O 26.08, S 10.18.
1,2:4,5-Di-O-isopropylidene-3-(isothiocyanato)-3-deoxy-β-d-fructopyranose (4): yield: 77% as white solid; mp: 68–70 °C. [α]D25 −248.83° (c 0.002, CHCl3). 1H NMR (400 MHz, CDCl3): δ 4.35–4.33 (m, 1H), 4.20–4.02 (m, 5H), 3.59 (d, 1H, J = 4 Hz), 1.52 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 135.04, 113.08, 109.57, 103.08, 75.95, 72.35, 72.32, 60.06, 60.01, 27.96, 26.08, 25.94, 25.75 ppm. IR (KBr): 2927, 2106, 1684, 1364, 1208, 1087, 863 cm−1. ESI-MS (m/z): 324.0 (M+ + Na). HRMS: calculated for [C13H19NO5S+H]: 302.1062, found 302.1063. Elemental Analysis for C13H19NO5S: calculated C 51.81, H 6.36, N 4.65, O 26.54, S 10.64; found C 51.72, H 6.29, N 4.91, O, 26.52, S 10.56.

2.3. Synthesis of Saccharide-Derived Amine Thiourea 5a–d and 6a–b

To a stirred solution of sugar isothiocyanate 3 or 4 (0.3 g, 1 mmol) in anhydrous dichloromethane (2 mL) were added the corresponding chiral diamines (1 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed under vacuum and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (100:5) as an eluent to obtain the desired product (see Supplementary Materials Figures S3–S8 and S11–S16 for the 1H NMR, 13C NMR, and mass spectra data of compounds 5 and 6).
1,2:4,5-Di-O-isopropylidene-3-[(1S,2S)-2-aminocyclohexyl-1-thioureido]-3-deoxy-α-d-fructopyranose (5a): yield: 68% as pale-yellow solid; mp: 58–60 °C. [α]D25 −117.00° (c 0.002, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 6.27 (s, 1H), 4.88 (d, 1H, J = 4 Hz), 4.46–3.76 (m, 8H), 2.04 (s, 1H), 1.84 (s, 1H), 1.63–1.25 (m, 20H). 13C NMR (100 MHz, CDCl3): δ 181.81, 110.26, 110.11, 105.56, 74.50, 73.90, 72.30, 62.76, 60.26, 60.24, 54.50, 31.79, 31.77, 27.17, 26.82, 26.20, 26.16, 24.92, 24.74 ppm. IR (KBr): 3282.52, 3067.99, 2925.76, 2869.35, 2344.94, 1533.49, 1360.49, 1212.71, 1045.06, 855.95, 728.83. ESI-MS (m/z): 416.3 (M+ + H). HRMS: calculated for [C19H33N3O5S+H]: 416.2219, found 416.2222. Elemental Analysis for C19H33N3O5S: calculated C 54.92, H 8.00, N 10.11, O 19.25, S 7.72; found C 54.88, H 7.85, N 10.22, O 19.39, S 7.65.
1,2:4,5-Di-O-isopropylidene-3-[(1R,2R)-2-aminocyclohexyl-1-thioureido]-3-deoxy-α-d-fructopyranose (5b): yield: 72% as pale-yellow solid; mp: 63–65 °C. [α]D25 −65.00° (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.58 (s, 1H), 4.94 (s, 1H), 4.58–4.56 (m, 1H), 4.32–3.85 (m, 8H), 1.77 (s, 2H), 1.48–1.17 (m, 20H). 13C NMR (100 MHz, CDCl3): δ 183.93, 110.46, 109.60, 104.77, 72.93, 72.71, 62.24, 62.17, 61.07, 55.86, 55.45, 34.21, 32.27, 31.59, 26.63, 25.66, 24.90, 24.78, 24.66 ppm. IR (KBr): 3278.32, 2926.35, 2342.06, 1540.11, 1455.98, 1361.81, 1233.65, 1054.62, 851.62. ESI-MS (m/z): 416.3 (M+ + H). HRMS: calculated for [C19H33N3O5S+H]: 416.2219, found 416.2221. Elemental Analysis for C19H33N3O5S: calculated C 55.12, H 8.09, N 10.20, O 18.95, S 7.63; found C 54.99, H 8.27, N 10.35, O 19.01, S 7.37.
1,2:4,5-Di-O-isopropylidene-3-[(1R,2R)-2-amino-1,2-diphenylethyl-1-thioureido]-3-deoxy-α-d-fructopyranose (5c): yield: 68% as white solid; mp: 61–64 °C. [α]D25 −80.50° (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.40–7.26 (m, 10H), 6.04 (d, 1H, J = 8 Hz), 5.16 (s, 1H), 4.44–3.78 (m, 9H), 1.69 (s, 2H), 1.44 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 182.65, 141.83, 129.17, 129.09, 129.04, 128.81, 128.07, 128.06, 127.97, 126.83, 126.64, 104.55, 104.47, 102.48, 73.03, 71.87, 64.26, 61.89, 60.33, 55.28, 55.26, 26.65, 26.12, 25.96, 25.02 ppm. IR (KBr): 3308.63, 3055.27, 2955.48, 2919.75, 2342.90, 2085.47, 1670.42, 1521.56, 1369.01, 1220.54, 1063.22, 857.54, 765.60, 683.20. ESI-MS (m/z): 514.3 (M+ + H). HRMS: calculated for [C27H35N3O5S+H]: 514.2376, found 514.2386. Elemental Analysis for C27H35N3O5S: calculated C 62.72, H 7.02, N 7.88, O 16.04, S 6.34; found C 62.56, H 7.16, N 7.64, O 16.28, S 6.36.
1,2:4,5-Di-O-isopropylidene-3-[(1S,2S)-2-amino-1,2-diphenylethyl-1-thioureido]-3-deoxy-α-d-fructopyranose (5d): yield: 74% as white solid; mp: 88–91 °C. [α]D25 −61.67° (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.37–7.25 (m, 10H), 6.58 (s, 1H), 4.80 (s, 1H), 4.47–3.72 (m, 9H), 1.65 (s, 2H), 1.43 (s, 3H), 1.40 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 183.26, 141.79, 139.24, 136.97, 136.87, 129.26, 128.78, 128.51, 128.36, 128.03, 126.91, 126.81, 111.64, 109.48, 104.50, 73.04, 71.95, 71.88, 64.65, 61.63, 61.49, 55.58, 26.47, 26.40, 25.74, 25.23 ppm. IR (KBr): 3299.65, 3050.39, 2989.10, 2923.72, 2342.79, 2080.59, 1674.68, 1530.30, 1372.98, 1215.66, 1058.34, 1009.98, 852.66, 760.72, 691.52. ESI-MS (m/z): 514.3 (M+ + H). HRMS: calculated for [C27H35N3O5S+H]: 514.2376, found 514.2384. Elemental Analysis for C27H35N3O5S: calculated C 65.44, H 6.34, N 7.68, O 14.24, S 6.30; found C 65.34, H 6.49, N 7.89, O 14.07, S 6.21.
1,2:4,5-Di-O-isopropylidene-3-[(1R,2R)-2-amino-1,2-diphenylethyl-1-thioureido]-3-deoxy-β-d-fructopyranose (6a): yield: 61% as white solid; mp: 130–134 °C. [α]D25 −197.33° (c 0.001, CHCl3). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H, J = 8 Hz), 7.96 (d, 1H, J = 8 Hz), 7.43–7.18 (m, 10), 5.44 (s, 1H), 4.62–3.56 (m, 10H), 1.44 (s, 3H), 1.40 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 183.11, 140.64, 126.45, 125.80, 125.39, 125.14, 109.19, 106.69, 103.95, 72.80, 72.69, 70.79, 69.52, 62.06, 58.08, 53.13, 26.38, 25.14, 25.06, 24.72 ppm. IR (KBr): 3267.08, 3070.26, 2959.88, 2341.63, 1529.65, 1376.04, 1207.78, 1068.85, 880.52, 687.55. ESI-MS (m/z): 514.3 (M+ + H). HRMS: calculated for [C27H35N3O5S+H]: 514.2376, found 514.2387. Elemental Analysis for C27H35N3O5S: calculated C 62.94, H 6.91, N 8.51, O 15.23, S 6.40; found C 62.78, H 6.86, N 8.33, O 15.47, S 6.55.
1,2:4,5-Di-O-isopropylidene-3-[(1S,2S)-2-amino-1,2-diphenylethyl-1-thioureido]-3-deoxy-β-d-fructopyranose (6b): yield: 59% as white solid; mp: 102–105 °C. [α]D25 −155.67° (c 0.002, CHCl3). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, 1H, J = 8 Hz), 7.96 (d, 1H, J = 12 Hz), 7.43–7.20 (m, 10H), 5.18 (s, 1H), 4.63–3.57 (m, 10H), 1.44 (s, 3H), 1.39 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 184.93, 143.74, 142.52, 128.34, 127.71, 127.29, 127.07, 127.02, 111.09, 108.59, 105.86, 74.71, 72.70, 71.44, 63.93, 59.99, 59.87, 55.04, 28.29, 26.97, 26.90, 26.67 ppm. IR (KBr): 3281.74, 3059.45, 2979.95, 2930.55, 2351.66, 2093.87, 1538.91, 1376.04, 1227.08, 1078.88, 989.53, 880.52, 767.06, 692.19. ESI-MS (m/z): 514.3 (M+ + H). HRMS: calculated for [C27H35N3O5S+H]: 514.2376, found 514.2389. Elemental Analysis for C27H35N3O5S: calculated C 63.14, H 6.87, N 8.18, O 15.57, S 6.24; found C 63.04, H 6.66, N 8.09, O 15.77, S 6.44.

2.4. Typical Procedure for Asymmetric Michael Addition Reaction

To a stirred solution of β-nitrostyrene (0.2 mmol) and ketone (3 equiv.) in dry dichloromethane (0.25 mL), 15 mol% saccharide-based amine-thiourea organocatalyst and benzoic acid were added. The reaction mixture was then stirred at room temperature for an appropriate reaction time, followed by concentration under vacuum. The reaction mixture was then subjected to purification by column chromatography using silica gel (60–120 mesh) with a hexane:EtOAc mixture as an eluent to obtain the desired product. The enantiomeric excess values of the product were determined by HPLC analysis on a chiral column using a mixture of n-hexane and iso-propanol as the mobile phase (see Supplementary Materials Figures S17–S46 for the 1H NMR, 13C NMR, and HPLC data for Michael adducts).

2.5. Typical Procedure for the Asymmetric Aldol Reaction

A solution of 20 mol% of the saccharide-based amine-thiourea organocatalyst 6a, 20 mol% of benzoic acid, aldehydes (0.2 mmol) and ketone (4 equiv.) in water (0.5 mL) was stirred at 0 °C. The reaction mixture was then concentrated under vacuum, followed by purification with column chromatography using silica gel with hexane:EtOAc mixture. The enantiomeric excess values of the products were identified by HPLC analysis on a chiral column using a mixture of n-hexane and iso-propanol as the mobile phase (see Supplementary Materials Figures S47–S56 for the 1H NMR, 13C NMR, and HPLC data for Aldol products).

3. Results and Discussions

As described in Scheme 1, sugar amines 1 (1,2:4,5-di-O-isopropylidene-3-amino-3-deoxy-α-d-fructopyranose) or 2 (1,2:4,5-di-O-isopropylidene-3-amino-3-deoxy-β-d-fructopyranose) prepared from d-fructose [50,51], were converted to the corresponding isothiocyanates (3 and 4) according to the reported procedure [53]. Subsequently, the newly prepared isothiocyanates were coupled with commercially available chiral 1,2-diamines to afford the desired bifunctional thiourea organocatalysts 5 and 6 (Figure 1) in good yields.
Our investigations started with the reaction of acetone with trans-4-bromo-β-nitrostyrene at room temperature using 10 mol% of amine-thiourea catalysts (5 and 6) in the presence of DCM as solvent. After completion of the reactions as shown by TLC, the products were separated using column chromatography. The enantiomeric excess (ee) of the final products was estimated using a chiral column and compared with the chromatograms of racemic mixtures, which were prepared by using dl-proline as a catalyst. Table 1 summarizes the results of these preliminary studies. The desired product was generated with a reasonable yield and enantioselectivity when a saccharide-derived amine catalyst with an S,S-configured 1,2-diaminocyclohexane moiety 5a was utilized (Table 1, entry 1). In order to improve the yield as well as stereoselectivity, several additives were subsequently examined, and they were found to play a crucial role in the outcome of the reactions (Table 1, entries 2–6). The potential function of the acidic co-catalyst appears to lie in its ability to facilitate the generation of an enamine intermediate, which arises from the interaction between the primary amine catalyst and ketones. Remarkably, the best result was obtained when the catalyst was employed in conjunction with benzoic acid, affording the Michael adduct 8a with an 89% yield and 96% ee. Other chiral primary-amine-thioureas (5b–d and 6a–b) were also explored for the reaction (Table 1, entries 7–11), and it was observed that all of the examined thioureas could promote the addition reaction, with yield and selectivity ranging from moderate to good. However, the thiourea catalyst 5a was found to be the most promising catalyst for the asymmetric process. Further, a primary amine-thiourea 7, which do not contain a saccharide scaffold was also evaluated for this asymmetric reaction. The catalyst afforded the desired product in 78% yield and 88% enantioselectivity (entry 12), which demonstrate that the carbohydrate moiety is essential for maintaining high level of enantioselectivity.
After identifying the principal catalyst and additive for the asymmetric transformation, we next examined the influence of their concentrations in the reaction medium. The reaction could only be completed after 72 h when the catalyst loading was reduced to 5 mol%, resulting in a 73% yield and 95% ee (Table 1, entry 13). However, when the catalyst loading was raised to 15 mol%, the reaction time was shortened to 52 h, and the yield (92%) and enantioselectivity (97% ee) of the product also improved significantly (Table 1, entry 14). Increasing the catalyst concentration to 20% resulted in a further reduction in reaction time but a slightly lower ee value (Table 1, entry 15); therefore, it was decided that 15 mol% was the optimal amount for the catalyst concentration. The observed initial rise in product formation as well as the increase in enantiomeric excess %, noticed after increasing the catalyst loading, can be attributed to the simultaneous increase in the number of actives within the reaction medium. On the other hand, the utilization of a lesser amount of catalyst causes the catalyst stereocontrol to erode, leading to a reduction in the ee of the resultant adducts [41,46]. Another variable that influenced the final result of the reaction was the amount of benzoic acid employed; decreasing the amount had a detrimental effect on the reaction, whereas raising the concentration improved the yield and ee of the products (Table 1, entries 16–18). Furthermore, a brief investigation of the solvents revealed that the reaction is substantially solvent-dependent, with DCM being the most reactive (Table 1, entries 19–22). Moreover, reducing the reaction temperature prolonged the reaction time while having no influence on the product’s yield or selectivity (Table 1, entry 23). Thus, the optimal reaction conditions for this reaction were determined to be 0.2 mmol of nitrostyrene, 15 mol% of 5a, 15 mol% of benzoic acid, and three equivalents of ketones in 0.25 mL of dichloromethane at room temperature.
After determining the optimal reaction conditions, the scope of the reaction was investigated using a range of nitrostyrenes and ketones. (Table 2). It was observed that all the addition processes between acetone and β-nitrostyrene derivatives (Table 2, entries 1–6) proceeded smoothly, furnishing high yields (81–95%) with excellent enantiomeric excess values (up to >99%). The findings also demonstrated that the reactions worked extremely well with both the electron-withdrawing and electron-donating substituted nitroolefins. However, when acetylacetone was employed as a substrate (Table 2, entries 7 and 8), thiourea 5a afforded the corresponding products 8g and 8h in good yield, albeit with poor stereoselectivity. Interestingly, even after prolonging the reaction period to 6 days, the conjugate addition of cyclohexanone to β-nitrostyrene failed entirely (Table 2, entry 9). The above findings are similar to those reported previously by Ma [39], Tvrdoňová [44] and Wu [37], that the thiourea derivatives having 1,2-diaminecyclohexane scaffolds perform well with acetone but abysmally with acetylacetone and cyclic ketones.
Therefore, additional investigation on thiourea organocatalysts 5b–d and 6a–b was conducted under the optimum conditions in order to identify the best catalyst for the asymmetric addition of ketones (other than acetone) to nitrostyrene, and the results are presented in Table 3, entries 1–5. The experimental results showed that by substituting the cyclohexane-1,2-diamine moiety with 1,2-diphenylethane-1,2-diamine scaffolds, the enantioselectivity of the products could be considerably enhanced (Table 3, entry 1 vs. entry 2–5). Amongst the tested catalysts, amine-thiourea 6a bearing the R,R-configured 1,2-diphenylethylenediamine scaffold delivered the best result (Table 3, entry 4) in terms of enantioselectivity (84% ee), and it was selected as the optimal catalyst. With the catalyst 6a at hand, the enantioselective addition of ketones to derivatives of nitroalkenes was conducted and the corresponding Michael adducts 8h–l were obtained in high yields (73–85%) with good enantioselectivities (between 71 and 81%) (Table 3, entries 5–9). Additionally, the reactions of substituted and electron-neutral nitroolefins with cyclohexanone could be completed, giving moderate yields (up to 55%) and stereoselectivities (up to 83% ee and 68:32% dr) (Table 3, entries 11–13).
The enantioselectivity of the adducts generated by the present saccharide-derived amine thioureas was compared to that described in the previous literature (Figure 2). So far, there is only one report available that discusses the application of an organocatalyst containing a primary-amine thiourea and saccharide scaffold for the asymmetric Michael addition reaction of acetone to nitroolefins. In this report, different saccharide moieties such as d-glucose, d-galactose, and d-mannose were employed. After a fine examination, the desired product could be obtained with a good yield (up to 94%) and enantioselectivity levels of 84% or higher. Accordingly, when the reported data are compared to our experimental findings, it can be concluded that the primary-amine thiourea organocatalyst, which incorporates a saccharide scaffold of d-glucose, d-galactose, d-mannose, or d-fructose, were all able to achieve comparable stereochemical results.
The saccharide-derived organocatalysts 5a–d and 6a–b were also examined for the asymmetric aldol addition of cyclohexanone to 4-nitro-benzaldehyde, and the results are summarized in Table 4. According to the experimental results (Table 4, entries 2–7), the bifunctional thioureas were able to promote the conjugate reaction when water was used as a reaction medium and benzoic acid (20 mol%) was added as an acidic co-catalyst. The amine-thiourea catalyst 6a has been shown to be the most effective for the transformation, producing the required product in moderate yield but with poor adduct stereocontrol. Additional testing of various additives and solvents failed to improve the catalyst’s stereoselectivity (entries 8–12). However, the enantioselectivity was slightly increased when the reaction temperature was lowered to 0 °C (entry 13). Even after establishing the optimized reaction condition, the corresponding aldol adducts 9a–e could only be obtained in modest yields with enantioselectivity up to 73% and dr up to 33:67 (syn:anti) (Table 5, entries 1–5).

4. Conclusions

In summary, we have successfully reported the synthesis of a new class of d-fructose-derived primary amine-thiourea organocatalysts. It is demonstrated that the chiral organic molecules are highly enantioselective for the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to a series of substituted nitroalkenes. The functionalized γ-nitro ketones could be obtained in good yield (up to 95%) with excellent enantioselectivities (>99%) and diastereomeric ratios up to 67:33 (syn:anti). Further investigation of the efficacy of the novel bifunctional organocatalysts in the asymmetric aldol reaction yielded the corresponding aldol products with low-to-moderate enantio- and diastereoselectivities.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry5040156/s1, 1H and 13C NMR data of the synthesized novel sugar-derived compounds, Michael and aldol products. Figures S1–S8: 1H and 13C NMR spectra of the catalysts. Figures S9–S16: HRMS data of the catalysts. Figure S17–S31: 1H and 13C NMR spectra of Michael adducts. Figures S32–S46: HPLC data of enantioenriched and racemic data of compound 7a–o. Figures S47–S51: 1H and 13C NMR spectra of Aldol adducts. Figures S52–S56: HPLC data of enantioenriched and racemic data of compound 8a–e.

Author Contributions

Conceptualization, K.V.; methodology, K.V.; formal analysis, S.L., V.K. and Z.L.; investigation S.L., V.K. and Z.L.; resources K.V., T.L. and C.L.; funding, T.L., C.L., J.M., G.L. and K.V.; software, V.K., S.L., J.M., and L.N.; data curation, L.N., J.M. and G.L.; writing—original draft preparation, K.V. and S.L.; writing—review and editing, L.N., J.M., G.L. and Z.P.; supervision, K.V. and Z.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Science and Engineering Research Board (SERB), New Delhi, India (File no. CRG/2022/000821, EEQ/2017/000505 and EEQ/2021/000101).

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank the Science and Engineering Board (SERB), New Delhi, India for their financial support. The authors also gratefully acknowledge IISc, Bangalore and IIT, Ropar for sample analysis.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Scheffler, U.; Mahrwald, R. Recent advances in organocatalytic methods for asymmetric C-C bond formation. Chem.-Eur. J. 2013, 19, 14346–14396. [Google Scholar] [CrossRef] [PubMed]
  2. Schmidt, N.G.; Eger, E.; Kroutil, W. Building Bridges: Biocatalytic C-C-Bond Formation toward Multifunctional Products. ACS Catal. 2016, 6, 4286–4311. [Google Scholar] [CrossRef] [PubMed]
  3. Wang, Y.; Du, D.M. Recent advances in organocatalytic asymmetric oxa-Michael addition triggered cascade reactions. Org. Chem. Front. 2020, 7, 3266–3283. [Google Scholar] [CrossRef]
  4. Gupta, V.; Singh, R.P. Enantioselective vinylogous Michael addition of β,γ-unsaturated butenolide to 2-iminochromenes. New J. Chem. 2019, 43, 9771–9775. [Google Scholar] [CrossRef]
  5. Ara, G.; Miran, M.S.; Islam, M.M.; Mollah, M.Y.A.; Rahman, M.M.; Susan, M.A.B.H. 1,8-Diazabicyclo[5.4.0]-undec-7-ene based protic ionic liquids and their binary systems with molecular solvents catalyzed Michael addition reaction. New J. Chem. 2020, 44, 13701–13706. [Google Scholar] [CrossRef]
  6. Serdyuk, O.V.; Heckel, C.M.; Tsogoeva, S.B. Bifunctional primary amine-thioureas in asymmetric organocatalysis. Org. Biomol. Chem. 2013, 11, 7051–7071. [Google Scholar] [CrossRef]
  7. Xiang, S.H.; Tan, B. Advances in asymmetric organocatalysis over the last 10 years. Nat. Commun. 2020, 11, 3786. [Google Scholar] [CrossRef] [PubMed]
  8. Aukland, M.H.; List, B. Organocatalysis emerging as a technology. Pure Appl. Chem. 2021, 93, 1371–1381. [Google Scholar] [CrossRef]
  9. Tsogoeva, S.B.; Yalalov, D.A.; Hateley, M.J.; Weckbecker, C.; Huthmacher, K. Asymmetric organocatalysis with novel chiral thiourea derivatives: Bifunctional catalysts for the Strecker and nitro-Michael reactions. Eur. J. Org. Chem. 2005, 19, 4995–5000. [Google Scholar] [CrossRef]
  10. Parvin, T.; Yadav, R.; Choudhury, L.H. Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs). Org. Biomol. Chem. 2020, 18, 5513–5532. [Google Scholar] [CrossRef] [PubMed]
  11. Rufino, V.C.; Pliego, J.R. Bifunctional Primary Amino-thiourea Asymmetric Catalysis: The Imine-Iminium Ion Mechanism in the Michael Addition of Nitromethane to Enone. Asian J. Org. Chem. 2021, 10, 1472–1485. [Google Scholar] [CrossRef]
  12. Joshi, H.; Singh, V.K. Cinchona Derivatives as Bifunctional H-bonding Organocatalysts in Asymmetric Vinylogous Conjugate Addition Reactions. Asian J. Org. Chem. 2022, 11, e202100053. [Google Scholar] [CrossRef]
  13. Zheng, Z.; Lin, J.; Sun, Y.; Zhang, S. Threonine-derived thioureas as bifunctional organocatalysts for enantioselective Michael addition. Tetrahedron Lett. 2020, 61, 151382. [Google Scholar] [CrossRef]
  14. Held, F.E.; Tsogoeva, S.B. Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: Recent advances. Catal. Sci. Technol. 2016, 6, 645–667. [Google Scholar] [CrossRef]
  15. Fang, X.; Wang, C.J. Recent advances in asymmetric organocatalysis mediated by bifunctional amine-thioureas bearing multiple hydrogen-bonding donors. Chem. Commun. 2015, 51, 1185–1197. [Google Scholar] [CrossRef]
  16. Sigman, M.S.; Jacobsen, E.N. Schiff base catalysts for the asymmetric strecker reaction identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 1998, 120, 4901–4902. [Google Scholar] [CrossRef]
  17. Sigman, M.S.; Vachal, P.; Jacobsen, E.N. A general catalyst for the asymmetric strecker reaction. Angew. Chem. Int. Ed. 2000, 39, 1279–1281. [Google Scholar] [CrossRef]
  18. Vachal, P.; Jacobsen, E.N. Structure-based analysis and optimization of a highly enantioselective catalyst for the strecker reaction. J. Am. Chem. Soc. 2002, 124, 10012–10014. [Google Scholar] [CrossRef]
  19. Taylor, M.S.; Jacobsen, E.N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558–10559. [Google Scholar] [CrossRef]
  20. Yoon, T.P.; Jacobsen, E.N. Highly Enantioselective Thiourea-Catalyzed Nitro-Mannich Reactions. Angew. Chem. 2005, 117, 470–472. [Google Scholar] [CrossRef]
  21. Huang, H.; Jacobsen, E.N. Highly enantioselective direct conjugate addition of ketones to nitroalkenes promoted by a chiral primary amine-thiourea catalyst. J. Am. Chem. Soc. 2006, 128, 7170–7171. [Google Scholar] [CrossRef]
  22. Lalonde, M.P.; Chen, Y.; Jacobsen, E.N. A Chiral Primary Amine Thiourea Catalyst for the Highly Enantioselective Direct Conjugate Addition of α,α-Disubstituted Aldehydes to Nitroalkenes. Angew. Chem. Int. Ed. 2006, 45, 6366–6370. [Google Scholar] [CrossRef] [PubMed]
  23. Okino, T.; Hoashi, Y.; Takemoto, Y. Thiourea-catalyzed nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes. Tetrahedron Lett. 2003, 44, 2817–2821. [Google Scholar] [CrossRef]
  24. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. Enantio- and diastereoselective michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc. 2005, 127, 119–125. [Google Scholar] [CrossRef] [PubMed]
  25. Hoashi, Y.; Okino, T.; Takemoto, Y. Enantioselective Michael Addition to α,β-Unsaturated Imides Catalyzed by a Bifunctional Organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 4032–4035. [Google Scholar] [CrossRef]
  26. Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Enantioselective Aza-Henry Reaction Catalyzed by a Bifunctional Organocatalyst. Org. Lett. 2004, 6, 625–627. [Google Scholar] [CrossRef]
  27. Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y. Enantioselective tandem Michael reaction to nitroalkene catalyzed by bifunctional thiourea: Total synthesis of (−)-epibatidine. Tetrahedron 2006, 62, 365–374. [Google Scholar] [CrossRef]
  28. Inokuma, T.; Hoashi, Y.; Takemoto, Y. Thiourea-catalyzed asymmetric michael addition of activated méthylene compounds to α,β-unsaturated imides: Dual activation of imide by intra- and intermolecular hydrogen bonding. J. Am. Chem. Soc. 2006, 128, 9413–9419. [Google Scholar] [CrossRef] [PubMed]
  29. Faísca Phillips, A.M. Applications of Carbohydrate-Based Organocatalysts in Enantioselective Synthesis. Eur. J. Org. Chem. 2014, 2014, 7291–7303. [Google Scholar] [CrossRef]
  30. Henderson, A.S.; Bower, J.F.; Galan, M.C. Carbohydrates as enantioinduction components in stereoselective catalysis. Org. Biomol. Chem. 2016, 14, 4008–4017. [Google Scholar] [CrossRef]
  31. Baslé, O.; Raimondi, W.; Duque, M.D.M.S.; Bonne, D.; Constantieux, T.; Rodriguez, J. Highly diastereo- and enantioselective organocatalytic michael addition of α-ketoamides to nitroalkenes. Org. Lett. 2010, 12, 5246–5249. [Google Scholar] [CrossRef] [PubMed]
  32. Palomo, C.; Vera, S.; Mielgo, A.; Gómez-Bengoa, E. Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes catalyzed by a simple trans-4-hydroxyprolylamide. Angew. Chem. Int. Ed. 2006, 45, 5984–5987. [Google Scholar] [CrossRef]
  33. Nguyen, K.D.; Kutzscher, C.; Drache, F.; Senkovska, I.; Kaskel, S. Chiral Functionalization of a Zirconium Metal-Organic Framework (DUT-67) as a Heterogeneous Catalyst in Asymmetric Michael Addition Reaction. Inorg. Chem. 2018, 57, 1483–1489. [Google Scholar] [CrossRef]
  34. Berner, O.M.; Tedeschi, L.; Enders, D. Asymmetric Michael additions to nitroalkenes. Eur. J. Org. Chem. 2002, 2002, 1877–1894. [Google Scholar] [CrossRef]
  35. Das, T.; Mohapatra, S.; Mishra, N.P.; Nayak, S.; Raiguru, B.P. Recent Advances in Organocatalytic Asymmetric Michael Addition Reactions to α, β-Unsaturated Nitroolefins. ChemistrySelect 2021, 6, 3745–3781. [Google Scholar] [CrossRef]
  36. Liu, K.; Cui, H.F.; Nie, J.; Dong, K.Y.; Li, X.J.; Ma, J.A. Highly enantioselective Michael addition of aromatic ketones to nitroolefins promoted by chiral bifunctional primary amine-thiourea catalysts based on saccharides. Org. Lett. 2007, 9, 923–925. [Google Scholar] [CrossRef]
  37. Gu, Q.; Guo, X.T.; Wu, X.Y. Highly enantioselective Michael addition of acetone to nitroolefins catalyzed by chiral bifunctional primary amine-thiourea catalysts with acetic acid. Tetrahedron 2009, 65, 5265–5270. [Google Scholar] [CrossRef]
  38. Lu, A.; Gao, P.; Wu, Y.; Wang, Y.; Zhou, Z.; Tang, C. Highly enantio- and diastereoselective Michael addition of cyclohexanone to nitroolefins catalyzed by a chiral glucose-based bifunctional secondary amine-thiourea catalyst. Org. Biomol. Chem. 2009, 7, 3141–3147. [Google Scholar] [CrossRef]
  39. Hai, M.; Liu, K.; Zhang, F.G.; Zhu, C.L.; Nie, J.; Jun-An, M. Chiral bifunctional thiourea-catalyzed enantioselective michael addition of ketones to nitrodienes. J. Org. Chem. 2010, 75, 1402–1409. [Google Scholar] [CrossRef]
  40. Li, X.J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.A. Highly enantioselective Michael addition of malonates to nitroolefins catalyzed by chiral bifunctional tertiary amine-thioureas based on saccharides. Synlett 2008, 20, 3242–3246. [Google Scholar] [CrossRef]
  41. Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C. Sugar-derived bifunctional thiourea organocatalyzed asymmetric Michael addition of acetylacetone to nitroolefins. Eur. J. Org. Chem. 2008, 2008, 4563–4566. [Google Scholar] [CrossRef]
  42. Pu, X.W.; Peng, F.Z.; Zhang, H.B.; Shao, Z.H. Doubly stereocontrolled asymmetric conjugate addition of acetylacetone to nitroolefins catalyzed by bifunctional tertiary amine-thiourea catalysts derived from both acyclic α-amino acids and carbohydrates. Tetrahedron 2010, 66, 3655–3661. [Google Scholar] [CrossRef]
  43. Puglisi, A.; Benaglia, M.; Raimondi, L.; Lay, L.; Poletti, L. Novel carbohydrate-based bifunctional organocatalysts for nucleophilic addition to nitroolefins and imines. Org. Biomol. Chem. 2011, 9, 3295–3302. [Google Scholar] [CrossRef] [PubMed]
  44. Rončák, R.; Tvrdoňová, M.; Gonda, J.; Elečko, J. Novel carbohydrate-based thioureas as organocatalysts for asymmetric michael addition of 1,3-dicarbonyl compounds to nitroolefins. Tetrahedron 2020, 76, 131339. [Google Scholar] [CrossRef]
  45. Reddy, B.V.S.; Reddy, S.M.; Swain, M. Sugar thiourea catalyzed highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinone to β-nitroalkenes. RSC Adv. 2013, 3, 930–936. [Google Scholar] [CrossRef]
  46. Zheng, W.; Zhang, J.; Liu, S.; Yu, C.; Miao, Z. Asymmetric synthesis of spiro[chroman-3,3′-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael-Michael cascade strategy with bifunctional amine-thiourea organocatalysts. RSC Adv. 2015, 5, 91108–91113. [Google Scholar] [CrossRef]
  47. Yuan, H.-N.; Wang, S.; Nie, J.; Meng, W.; Yao, Q.; Ma, J.-A. Hydrogen-Bond-Directed Enantioselective Decarboxylative Mannich Reaction of β-Ketoacids with Ketimines: Application to the Synthesis of Anti-HIV Drug DPC 083. Angew. Chem. 2013, 125, 3961–3965. [Google Scholar] [CrossRef]
  48. Yuan, H.N.; Li, S.; Nie, J.; Zheng, Y.; Ma, J.A. Highly enantioselective decarboxylative Mannich reaction of malonic acid half oxyesters with cyclic trifluoromethyl ketimines: Synthesis of β-amino esters and anti-HIV drug DPC 083. Chem.-Eur. J. 2013, 19, 15856–15860. [Google Scholar] [CrossRef] [PubMed]
  49. Qiao, B.; Huang, Y.J.; Nie, J.; Ma, J.A. Highly Regio-, Diastereo-, and Enantioselective Mannich Reaction of Allylic Ketones and Cyclic Ketimines: Access to Chiral Benzosultam. Org. Lett. 2015, 17, 4608–4611. [Google Scholar] [CrossRef]
  50. Vanlaldinpuia, K.; Bora, P.; Basumatary, G.; Mohanta, R.; Bez, G. Enantioselective aminocatalysis: Michael addition of unactivated ketones to nitroolefins catalyzed by d-fructose derived monofunctional primary amine. J. Chem. Sci. 2017, 129, 1603–1610. [Google Scholar] [CrossRef]
  51. Vanlaldinpuia, K.; Bora, P.; Bez, G. Monofunctional primary amine: A new class of organocatalyst for asymmetric Aldol reaction. J. Chem. Sci. 2017, 129, 301–312. [Google Scholar] [CrossRef]
  52. Nie, J.; Li, X.J.; Zheng, D.H.; Zhang, F.G.; Cui, S.; Ma, J.A. Chiral bifunctional thiourea-catalyzed enantioselective aldol reaction of trifluoroacetaldehyde hemiacetal with aromatic ketones. J. Fluor. Chem. 2011, 132, 468–473. [Google Scholar] [CrossRef]
  53. Munch, H.; Hansen, J.S.; Pittelkow, M.; Christensen, J.B.; Boas, U. A new efficient synthesis of isothiocyanates from amines using di-tert-butyl dicarbonate. Tetrahedron Lett. 2008, 49, 3117–3119. [Google Scholar] [CrossRef]
  54. Vural, U.; Durmaz, M.; Sirit, A. A novel calix[4]arene-based bifunctional squaramide organocatalyst for enantioselective Michael addition of acetylacetone to nitroolefins. Org. Chem. Front. 2016, 3, 730–736. [Google Scholar] [CrossRef]
  55. Li, H.; Zhang, X.; Shi, X.; Ji, N.; He, W.; Zhang, S.; Zhang, B. Modular bifunctional chiral thioureas as versatile organocatalysts for highly enantioselective aza-Henry reaction and michael addition. Adv. Synth. Catal. 2012, 354, 2264–2274. [Google Scholar] [CrossRef]
  56. Ban, S.; Du, D.M.; Liu, H.; Yang, W. Synthesis of Binaphthyl Sulfonimides and Their Application in the Enantioselective Michael Addition of Ketones to Nitroalkenes. Eur. J. Org. Chem. 2010, 2010, 5160–5164. [Google Scholar] [CrossRef]
  57. Yang, Z.; Liu, J.; Liu, X.; Wang, Z.; Feng, X.; Su, Z.; Hua, C. Highly efficient amine organocatalysts based on bispidine for the asymmetric Michael addition of ketones to nitroolefins. Adv. Synth. Catal. 2008, 350, 2001–2006. [Google Scholar] [CrossRef]
  58. Shim, J.H.; Ahn, B.K.; Lee, J.Y.; Kim, H.S.; Ha, D.C. Organocatalysis for the asymmetric michael addition of cycloketones and α, β-unsaturated nitroalkenes. Catalysts 2021, 11, 1004. [Google Scholar] [CrossRef]
  59. Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong, M.W.; Lu, Y. Direct asymmetric aldol reactions between aldehydes and ketones catalyzed by l-tryptophan in the presence of water. Org. Biomol. Chem. 2010, 8, 1368–1377. [Google Scholar] [CrossRef]
  60. Huang, J.; Zhang, X.; Armstrong, D.W. Highly Efficient Asymmetric Direct Stoichiometric Aldol Reactions on/in Water. Angew. Chem. 2007, 119, 9231–9235. [Google Scholar] [CrossRef]
  61. Gao, J.; Bai, S.; Gao, Q.; Liu, Y.; Yang, Q. Acid controlled diastereoselectivity in asymmetric aldol reaction of cycloketones with aldehydes using enamine-based organocatalysts. Chem. Commun. 2011, 47, 6716–6718. [Google Scholar] [CrossRef] [PubMed]
Chemistry 05 00156 sch001
Scheme 1. Preparation of the saccharide-derived amine thiourea organocatalysts, (i) CS2, NEt3, Boc2O, EtOH, DMAP; (ii) 1,2-diamine, CH2Cl2, rt. * an optically active carbon center [51].
Scheme 1. Preparation of the saccharide-derived amine thiourea organocatalysts, (i) CS2, NEt3, Boc2O, EtOH, DMAP; (ii) 1,2-diamine, CH2Cl2, rt. * an optically active carbon center [51].
Chemistry 05 00156 sch001
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Figure 1. d-fructose-based bifunctional amine-thioureas.
Figure 1. d-fructose-based bifunctional amine-thioureas.
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Figure 2. Comparison of the catalytic activity of primary-amine thiourea organocatalysts containing different saccharide scaffold on the asymmetric Michael addition of acetone to nitroolefins [37].
Figure 2. Comparison of the catalytic activity of primary-amine thiourea organocatalysts containing different saccharide scaffold on the asymmetric Michael addition of acetone to nitroolefins [37].
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Table 1. Optimization of reaction condition for the asymmetric Michael addition of acetone to trans-4-bromo-β-nitrostyrene [a].
Table 1. Optimization of reaction condition for the asymmetric Michael addition of acetone to trans-4-bromo-β-nitrostyrene [a].
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EntrySolventCatalyst (mol%)Additives (mol%)Time (h)Yield (%) [b]ee (%) [c]
1CH2Cl25a (10)-964857
2CH2Cl25a (10)AcOH (10)567692
3CH2Cl25a (10)PhCO2H (10)548996
4CH2Cl25a (10)CF3CO2H (10)775476
5CH2Cl25a (10)4-NO2C6H4CO2H (10)488732
6CH2Cl25a (10)4-BrC6H4CO2H (10)528343
7CH2Cl25b (10)PhCO2H (10)528290
8CH2Cl25c (10)PhCO2H (10)667793
9CH2Cl25d (10)PhCO2H (10)968186
10CH2Cl26a (10)PhCO2H (10)498889
11CH2Cl26b (10)PhCO2H (10)728192
12CH2Cl27 (10)PhCO2H (10)247888
13CH2Cl25a (5)PhCO2H (10)727395
14CH2Cl25a (15)PhCO2H (10)529297
15CH2Cl25a (20)PhCO2H (10)449396
16CH2Cl25a (15)PhCO2H (5)589293
17CH2Cl25a (15)PhCO2H (15)4895>99
18CH2Cl25a (15)PhCO2H (20)449698
19Toluene5a (15)PhCO2H (15)726088
20THF5a (15)PhCO2H (15)964393
21CH3CN5a (15)PhCO2H (15)1205166
22Neat5a (15)PhCO2H (15)487882
23 [d]CH2Cl25a (15)PhCO2H (15)1206698
[a] Unless otherwise stated, the reactions were conducted with 0.2 mmol trans-4-bromo-β-nitrostyrene, three equivalents of acetone and 0.25 mL solvents. [b] Isolated yield of the product. [c] The enantiomeric excess values were determined by HPLC. [d] The reaction was performed at 0 °C.
Table 2. Asymmetric Michael addition of ketones to nitroolefins [a].
Table 2. Asymmetric Michael addition of ketones to nitroolefins [a].
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EntryR1R2R3Time (h)Yield (%) [b]ee (%) [c,d]
14-BromoMeH4895 (8a)>99 (S)
24-ChloroMeH4890 (8b)91 (S)
34-MethylMeH6881 (8c)85 (S)
42-ChloroMeH4895 (8d)83 (S)
52-MethoxyMeH9492 (8e)81 (S)
6HMeH3693 (8f)95 (S)
74-ChloroMeCOMe10088 (8g)32 (S)
84-MethylMeCOMe12091 (8h)22 (S)
9HR2 = R3 = (CH2)4-168Nr [e]Nd [f]
[a] The reaction was conducted with nitroolefins (0.2 mmol), ketone (3 equiv.), catalyst 5a (0.03 mmol), and benzoic acid (0.03 mmol) in 0.25 mL DCM at room temperature. [b] Isolated yield. [c] The ee values were determined by HPLC. [d] The configuration was assigned according to the reference [37]. [e] No reaction. [f] Not determined.
Table 3. Asymmetric Michael addition of ketones to various β-nitroolefins [a].
Table 3. Asymmetric Michael addition of ketones to various β-nitroolefins [a].
Chemistry 05 00156 i003
EntryCatalyst (mol%)R1KetoneTime (h)Yield (%) [b]dr (%) [c] syn/antiee (%) [d,e]
15b (15)4-ClChemistry 05 00156 i0049282 (8g)-12 (R)
25c (15)4-ClChemistry 05 00156 i0049681 (8g)-79 (S)
35d (15)4-ClChemistry 05 00156 i0047666 (8g)-43 (S)
46a (15)4-ClChemistry 05 00156 i0047280 (8g)-84 (S)
56b (15)4-ClChemistry 05 00156 i0048884 (8g)-72 (R)
66a (15)4-MeChemistry 05 00156 i0047273 (8h)-81 (S)
76a (15)4-BrChemistry 05 00156 i0048178 (8i)-81 (S)
86a (15)2-ClChemistry 05 00156 i0049685 (8j)-76 (S)
96a (15)2-MeOChemistry 05 00156 i00412077 (8k)-71 (S)
106a (15)HChemistry 05 00156 i0049681 (8l)-74 (S)
116a (15)4-MeChemistry 05 00156 i00516846 (8m)68/3278 [f] (R,S)
126a (15)4-BrChemistry 05 00156 i00516855 (8n)68/3220 [f] (S,R)
136a (15)HChemistry 05 00156 i00518042 (8o)67/3379 [f] (S,R)
[a] The addition reaction was performed with nitroolefins (0.2 mmol), ketone (3 equiv.), thiourea catalyst (0.03 mmol), and benzoic acid (0.03 mmol) in 0.25 mL DCM at room temperature. [b] Isolated yield. [c] The dr values were obtained from 1H NMR data. [d] The ee values were determined by HPLC. [e] The configuration was assigned according to the references [41,54,55,56,57,58]. [f] Enantioselectivity of the syn-diastereomer.
Table 4. Optimization of reaction condition for asymmetric Aldol reaction using catalysts 5 and 6.
Table 4. Optimization of reaction condition for asymmetric Aldol reaction using catalysts 5 and 6.
EntryCatalyst (mol%)TempAdditives (mol%)SolventTime
(h)		Yield
(%)		dr (%)
Syn:anti		er (%)
Syn:anti
15a (20)RT-Neat12 h8550:50Racemic
25a (20)RTPhCO2H (20)H2O24 h6348:5215:21
35b (20)RTPhCO2H (20)H2O36 h6556:448:16
45c (20)RTPhCO2H (20)H2O38 h5551:4914:24
55d (20)RTPhCO2H (20)H2O38 h3458:426:25
66a (20)RTPhCO2H (20)H2O58 h5443:5713:39
76b (20)RTPhCO2H (20)H2O48 h4448:5212:35
86a (20)RTCH3CO2H (20)H2O72 h6552:489:28
96a (20)RTDNP (20)H2O48 h7247:5311:3
106a (20)RTTFA (20)H2O56 h6643:5719:12
116a (20)RTPhCO2H (20)DMSO96 h4844:56Racemic
126a (20)RTPhCO2H (20)DCM126 htrace--
136a (20)0 °CPhCO2H (20)H2O144 h6247:5330:47
146a (20)0 °CPhCO2H (20)Neat110 h7245:559:38
Table 5. Asymmetric Aldol reaction of cyclohexanone with aldehydes [a].
Table 5. Asymmetric Aldol reaction of cyclohexanone with aldehydes [a].
Chemistry 05 00156 i006
EntryAldehydesReaction Time (h)Yield (%) [b]dr (%) [c] Syn:antiee (%) [d,e]
14-Nitro14458 (9a)47:5330 (R,R)
23-Nitro12052 (9b)46:5415 (R,R)
32-Nitro16846 (9c)55:4540 (R,R)
43-Chloro12854 (9d)54:4623 (R,R)
54-Bromo12050 (9e)33:6769 (R,R)
[a] The reaction was performed with aldehydes (0.2 mmol), cyclohexanone (4 equiv.), thiourea (0.04 mmol), and benzoic acid (0.04 mmol) in 0.5 mL of water at 0 °C. [b] Isolated yield. [c] The diastereoselectivity was obtained from 1H NMR data. [d] The enantioselectivity values of the adducts were determined by HPLC. [e] The configuration of the syn-adduct was assigned according to references [59,60,61].
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Lalhmangaihzuala, S.; Khiangte, V.; Laldinpuii, Z.; Nunnemi, L.; Malsawmsanga, J.; Lallawmzuali, G.; Liana, T.; Lalhriatpuia, C.; Pachuau, Z.; Vanlaldinpuia, K. Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions. Chemistry 2023, 5, 2362-2375. https://doi.org/10.3390/chemistry5040156

AMA Style

Lalhmangaihzuala S, Khiangte V, Laldinpuii Z, Nunnemi L, Malsawmsanga J, Lallawmzuali G, Liana T, Lalhriatpuia C, Pachuau Z, Vanlaldinpuia K. Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions. Chemistry. 2023; 5(4):2362-2375. https://doi.org/10.3390/chemistry5040156

Chicago/Turabian Style

Lalhmangaihzuala, Samson, Vanlalngaihawma Khiangte, Zathang Laldinpuii, Lal Nunnemi, Joute Malsawmsanga, Gospel Lallawmzuali, Thanhming Liana, Chhakchhuak Lalhriatpuia, Zodinpuia Pachuau, and Khiangte Vanlaldinpuia. 2023. "Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions" Chemistry 5, no. 4: 2362-2375. https://doi.org/10.3390/chemistry5040156

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