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Organocatalytic Asymmetric Michael Addition of Ketones to Α, Β-Unsaturated Nitro Compounds

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catalysts Article Organocatalytic Asymmetric Michael Addition of Ketones to α, β-Unsaturated Nitro Compounds Jae Ho Shim 1 , Si Hun Nam 1, Byeong-Seon Kim 2,* and Deok-Chan Ha 1,* 1 Department of Chemistry, Research Institute for Natural Sciences, Korea University, 145 Anam-ro Seongbuk-gu, Seoul 02841, Korea; [email protected] (J.H.S.); [email protected] (S.H.N.) 2 Department of Chemistry Education and Research Institute of Natural Science, Gyeongsang National University, Jinju 52828, Korea * Correspondence: [email protected] (B.-S.K.); [email protected] (D.-C.H.); Tel.: +82-2-3290-3131 (D.-C.H.) Received: 6 May 2020; Accepted: 28 May 2020; Published: 2 June 2020 Abstract: An organic catalyst “(R, R)-1,2-diphenylethylenediamine(DPEN) derivative” was devel-oped as a chiral bifunctional organocatalyst and applied for asymmetric Michael additions of aromatic ketones to trans-β-nitroalkene compounds under neutral conditions. The isopropyl-subs-tituted thiourea catalyst in neutral condition provides high chemical yield and enantioselectivities (ee) (up to 96% yield, 98% ee). Keywords: organocatalyst; enantioselectivity; yield; thiourea catalyst; asymmetric 1. Introduction Metal catalysts have been used for asymmetric synthesis; however, recent research, excluding the metal catalysts, has attracted interest because of the high cost of metal catalysts and the instability of metal ions in moist air, which limits the reaction conditions [1]. In addition, metal catalysts can leave metal residues in the product. To identify alternatives to metal catalysts, asymmetric reactions using organocatalysts have been developed [2–12]. The Michael reaction is widely used as one of the most general methods for the formation of C–C bonds in organic synthesis. Owing to the easy conversion of the electron-deficient nitro group to various functional groups, such as keto, amino, cyano, and carboxylic acid groups, research on asymmetric Michael reactions using the nitro group as the Michael acceptor has been conducted [13–21]. Jacobsen and Ma utilized catalysts with substituents on the thiourea of (R, R)-1,2-cyclohexyldiamine. In the Michael addition of aromatic ketones and trans-β-nitroalkenes, the stereoselectivity was high, but the yield was low [22,23]. In 2009, Lao et al. reported the Michael reaction of acetone and trans-β-unsaturated nitroalkene using (R, R)-1,2-cyclohexyldiamine derivatives as the catalyst and compared the reactivity according to the acidity of amine in the catalyst. For catalysts with electron-withdrawing groups, the stereoselectivity was lower than for catalysts with electron-donating groups. In addition, the reactivity increased when the electrophile was activated via double hydrogen bonding of the catalyst. The effects of the N–H bond and hydrogen bond acidity on catalyst activity and the stereotactic properties of functional primary amino catalysts influenced the Michael C–C reaction (Scheme1)[24–26]. Shao and Kokotos [27,28] used (R, R)-1,2-diphenylethylenediamine thiourea derivatives as the catalyst and benzoic acid as the additive. During the reaction, aromatic ketones were activated by acid additives, leading to accelerated enamine formation of the catalyst. Asymmetric reactions of aromatic ketones and α, β-unsaturated nitroalkenes led to a high selectivity and high yield. Nevertheless, it is necessary to develop catalysts for simple synthesis. Therefore, in this study, (R, R)-1,2-diphenylethylene-diamines were introduced into the basic framework of a chiral catalyst. Catalysts 2020, 10, 618; doi:10.3390/catal10060618 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 618 2 of 11 We used ketones and trans-β-nitrostyrene, which has a powerful electro-withdrawing group, to conduct an enantioselective Michael reaction. Scheme 1. Chiral primary amine organocatalysts. 2. Results and Discussion 2.1. Asymmetric Michael Addition of α, β-Unsaturated Nitroolefins and Ketones 2.1.1. Catalyst Screening The Michael addition was performed using acetophenone and nitrostyrene to examine the catalytic effects of enantioselective Michael addition on ketones and α, β-unsaturated nitroalkenes. The catalysts used in the reaction are listed in (Figure1.) First, N-mono-alkylated thiourea with 3-pentyl-substituted amine was used with benzoic acid as an additive. Figure 1. DPEN-thiourea based catalysts. The reaction carried out in the toluene solvent at room temperature (Table1, entries 1 and 2) did not proceed, likely because the steric hindrance of secondary amine thiourea with 3-pentyl-substituted amine hindered enamine formation, making the catalyst ineffective. Therefore, the reaction was carried out with N-mono-thiourea as the primary amine catalyst prior to amine alkylation. The amine was preserved from alkylation to promote enamine formation, which was activated through dehydration condensation between ketones and amines. The other amine was allowed to react with isothiocyanate to ensure that thiourea could create conditions suitable for double activation, thus, inducing hydrogen-bond formation at the nitro group. The reaction was carried out in toluene with benzoic acid as the additive at room temperature. The use of the isopropyl-substituted primary amine thiourea Catalysts 2020, 10, 618 3 of 11 catalyst led to the highest product yields and enantioselectivities (Table1, entry 4). This finding indicates that the enantioselectivity and yield of the reaction are improved by the appropriate steric hindrance impaired on the substituent rather than the hydrogen acidity of thiourea. Therefore, less steric hindrance leads to higher yields and enantioselectivity. Table 1. Catalyst screening. Entry Cat. Yield [a] ee [b] 1 1a N.R. [c] - 2 1b N.R. [c] - 3 1c 73 98 4 1d 85 98 5 1e 76 90 6 1f 58 92 7 1g 46 90 8 1h 78 94 9 1i 60 94 10 1j 51 92 11 1k 53 90 [a] Isolated yield. [b] The ee values were decided by chiral phase HPLC using an AD-H column. [c] N.R. = No Reaction. 2.1.2. Solvent Effects The previous experiment reported in Section 2.1.1 confirms that the use of an isopropyl-substituted catalyst leads to the highest yield and enantioselectivity. Using this catalyst, reactivity and enantioselectivity in different solvents were investigated. The reaction proceeded smoothly in all solvents; high enantioselectivity was obtained regardless of the solvent polarity, although differences in the yield were observed. It is predicted that polar solvents would obstruct hydrogen bond formation between the reactant and the catalyst, thereby decelerating the reaction (Table2, entry 1). In addition, when the reaction was performed without a solvent, the enantioselectivity decreased despite the high yield (Table2, entry 2). Among the non-polar solvents tested, toluene generated the highest enantioselectivity and yield (Table2, entry 3); hence, it was selected as the reaction solvent for subsequent experiments. Table 2. Solvent effects. Entry Solvent Yield [a] ee [b] 1 H2O 63 88 2 neat 91 92 3 toluene 85 98 4 ether 80 98 5 CH2Cl2 79 98 6 Tetrahydrofuran 74 94 7 methanol 60 94 8 CH3CN 54 94 [a] Isolated yield [b] The ee values were decided by chiral phase HPLC using an AD-H column. Catalysts 2020, 10, 618 4 of 11 2.1.3. Additive Effect The catalyst used in the previous experiment catalyst (1d) and toluene (solvent) were applied to the reaction to investigate the reactivity and stereoselectivity in the presence of different additives (Table3). The reaction carried out without an additive did not proceed (Table3, entry 1); therefore, an acid additive was employed to facilitate enamine formation. Nonetheless, certain acid additives prevented the progress of the reaction (Table3, entries 2 and 3), presumably because binding between highly acidic additives and the catalyst degraded the catalytic activity. In addition, water as an additive was conducive to the reaction progress (Table3, entries 8 and 9). These results confirm that the use of benzoic acid as additive leads to improved yields and enantioselectivities (Table3, entry 6). Table 3. Additive effects. Entry Additive Yield [a] ee [b] 1 - N.R. [c] - 2 Trifluoroacetic acid N.R. [c] - 3 Oxalic acid N.R. [c] - 4 Salicylic acid 80 90 5 Terephthalic acid 73 86 6 Benzoic acid 85 98 7 Acetic acid 68 94 8 H2O 74 98 9 H2O (1 eq.) 70 98 [a] Isolated yield. [b] The ee values were decided by chiral phase HPLC using an AD-H column. [c] N.R. = No Reaction. 2.1.4. Equivalence Effect The acetophenone equivalent (eq.) did not cause any differences in the yield and enanti-oselectivity of the reaction (Table4, entries 1 and 2). The use of 5 mol% of the catalyst resulted in a decreased yield, and 20 mol% of the catalyst produced a yield and enantioselectivity similar to those obtained with 10 mol% of the catalyst (entries 1, 3, and 4). The results obtained with 5–15 mol% of benzoic acid were similar (Table4, entries 1, 5, and 6). Thus, the use of 2 eq. acetophenone, 10 mol% catalyst, and 5 mol% benzoic acid additives produced the optimal results (Table4, entry 5). Table 4. Equivalence effect. Entry X (equiv) Y (mol%) Z (mol%) Yield (%) [a] ee (%) [b] 1 2 10 15 85 98 2 5 10 15 86 96 3 2 5 15 51 98 4 2 20 15 88 96 5 2 10 5 87 98 6 2 10 10 85 98 [a] Isolated yield. [b] The ee values were determined by chiral phase HPLC u-sing an AD-H column. Catalysts 2020, 10, 618 5 of 11 2.1.5. Temperature and Time Effects The yield varied substantially when the reaction time ranged between 24 and 48 h (Table5, entries 1 and 2). However, a slight difference in the yield and enantioselectivity was observed between the reaction times of 48 and 72 h (Table5, entries 2 and 3). Thus, the optimal reaction time was determined as 48 h. Furthermore, when the temperature was increased, the rate constant increased with the reactivity, but the enantioselectivity decreased, indicating that the optimal result can be obtained when the reaction is carried out at room temperature (Table5, entries 2, 4, and 5).
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  • Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of Α,Β-Unsaturated Aldehydes

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    molecules Review Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes Zhonglei Wang 1,2 1 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; [email protected] 2 School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China Academic Editor: Ari Koskinen Received: 12 August 2019; Accepted: 19 September 2019; Published: 19 September 2019 Abstract: Chirality is one of the most important attributes for its presence in a vast majority of bioactive natural products and pharmaceuticals. Asymmetric organocatalysis methods have emerged as a powerful methodology for the construction of highly enantioenriched structural skeletons of the target molecules. Due to their extensive application of organocatalysis in the total synthesis of bioactive molecules and some of them have been used in the industrial synthesis of drugs have attracted increasing interests from chemists. Among the chiral organocatalysts, chiral secondary amines (MacMillan’s catalyst and Jorgensen’s catalyst) have been especially considered attractive strategies because of their impressive efficiency. Herein, we outline advances in the asymmetric total synthesis of natural products and relevant drugs by using the strategy of chiral secondary amine catalyzed reactions of α,β-unsaturated aldehydes in the last eighteen years. Keywords: bioactive natural products; pharmaceuticals; asymmetric total synthesis; chiral secondary amines; α,β-unsaturated aldehydes 1. Introduction In 2000, the MacMillan group [1] first described the fundamental concept of LUMO-lowering iminium-ion activation. In 2005, the Jørgensen group [2,3] reported diarylprolinol silyl ether catalysts, which have also been used in iminium-ion catalysis.
  • A Novel Aza-Nazarov Cyclization of Quinazolinonyl Enones: a Facile Access to C- Ring Substituted Vasicinones and Luotonins

    A Novel Aza-Nazarov Cyclization of Quinazolinonyl Enones: a Facile Access to C- Ring Substituted Vasicinones and Luotonins

    A Novel Aza-Nazarov Cyclization of Quinazolinonyl Enones: A Facile Access to C- Ring Substituted Vasicinones and Luotonins Sivappa Rasapalli,a* Vamshikrishna Reddy Sammeta,a Zachary F. Murphy,a Yanchang Huang,a Jeffrey A. Boertha, James A. Golena and Sergey N. Savinovb a Department of Chemistry and Biochemistry, University of Massachusetts, 287 Old Westport Rd, N. Dartmouth, MA-02747, USA. b Department of Biochemistry and Molecular Biology. UMass Amherst, Amherst, MA-01003, USA [email protected] Received Date (will be automatically inserted after manuscript is accepted) ABSTRACT: A facile four-step synthetic access to C-ring substituted luotonins and vasicinones has been realized via a novel super acid mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability and overall polarity of the reaction medium. Quinazolinone is one of the most privileged through inhibition of topoisomerase-I (topo-I), through pharmacophores in medicinal chemistry.1, 2 There are mechanism of action analogous to camptothecin (CPT) more than 20 drugs that are currently in market (3),8 which attracted the attention of medchem and containing thequinazolinone core.3 Additionally, synchem communities alike.9 This increased attention is pharmacologically important natural products harboring partly due to toxic side effects associated with CPT and the quinazolinone core are also abundant and are known its analogs, due to hydrolysis of the E-ring in basic pH to possess wide range of
  • The Abnormal Michael Reaction: Scope, Limitations, and Mechanism

    The Abnormal Michael Reaction: Scope, Limitations, and Mechanism

    Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 1971 The Abnormal Michael Reaction: Scope, Limitations, and Mechanism. William George Haag III Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Recommended Citation Haag, William George III, "The Abnormal Michael Reaction: Scope, Limitations, and Mechanism." (1971). LSU Historical Dissertations and Theses. 2126. https://digitalcommons.lsu.edu/gradschool_disstheses/2126 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Historical Dissertations and Theses by an authorized administrator of LSU Digital Commons. For more information, please contact [email protected]. 72-17,764 HAAG, 3rd., William George, 1946- THE ABNORMAL MICHAEL REACTION: SCOPE, LIMITATIONS, AND MECHANISM. The Louisiana State University and Agricultural and Mechanical College, Ph.D., 1971 Chemistry, organic University Microfilms, A XEROX Company, Ann Arbor, Michigan © 1972 WILLIAM GEORGE HAAG, 3rd. ALL RIGHTS RESERVED THE ABNORMAL MICHAEL REACTION: SCOPE, LIMITATIONS, AND MECHANISM A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Biochemistry by William George Haag, 3rd B.S., Louisiana State University, 1968 December 19JI PLEASE NOTE: Some pages may have indistinct print. Filmed as received. University Microfilms, A Xerox Education Company ACKNOWLEDGMENT The author would like to acknowledge Professor G.E. Risinger for his suggestions, discussion, and encouragement. His ever-present influence made completion of this paper possible.