Copper-Catalyzed Asymmetric Hydroamination: A Unified Strategy for the Synthesis of Chiral β-Amino Acid and Its Derivatives

Open AccessCCS ChemistryCOMMUNICATION1 Jul 2021Copper-Catalyzed Asymmetric Hydroamination: A Unified Strategy for the Synthesis of Chiral β-Amino Acid and Its Derivatives Ge Zhang†, Yujie Liang†, Tao Qin, Tao Xiong, Shuyu Liu, Wei Guan and Qian Zhang Ge Zhang† Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal University, Changchun 130024 , Yujie Liang† Department of Chemistry, Institute of Functional Material Chemistry, Northeast Normal University, Changchun 130024 , Tao Qin Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal University, Changchun 130024 , Tao Xiong *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal University, Changchun 130024 , Shuyu Liu Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal University, Changchun 130024 , Wei Guan *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Institute of Functional Material Chemistry, Northeast Normal University, Changchun 130024 and Qian Zhang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Northeast Normal University, Changchun 130024 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 https://doi.org/10.31635/ccschem.020.202000434 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Catalytic asymmetric aza-Michael represents one of the most convenient and atom-economical approaches for the rapid construction of biologically active chiral β-amino acid frameworks. However, the direct enantioselective addition of nitrogen-based nucleophiles to intrinsically low reactivity of α,β-unsaturated carboxylic acid, ester, and amide, as well as simple α,β-unsaturated nitrile, remains a long-standing challenge. Herein, we report a unified Cu-catalyzed asymmetric reversal hydroamination, capable of direct preparation of a series of β-amino acid, ester, amide, and nitrile in a highly regio- and enantioselective manner, without the requirement of traditional preinstallation of stoichiometric quantities of auxiliaries. Download figure Download PowerPoint Introduction Catalytic asymmetric 1,4-addition of nitrogen-based nucleophiles to the Michael acceptors, namely aza-Michael addition reaction, has attracted continuous attention in recent decades,1–6 owing to its furnishing one of the most convenient and atom-economical approaches for the rapid construction of biologically and synthetically important chiral β-amino acid frameworks from readily accessible feedstocks.7,8 In this regard, impressive advances have been made for the chemo- and enantioselective addition of nitrogen-based nucleophiles to highly reactive Michael acceptors,1–6 such as α,β-unsaturated aldehydes, ketones, nitroolefins, and vinyl sulfones. However, the corresponding addition to intrinsically less reactive α,β-unsaturated acid, ester, and amide has been far less well established.1–6,9,10 Inspired by enzymatic systems activation of unreactive carboxylic acids to form corresponding activated ester surrogates,11 the preponderant strategy up to now has typically relied on the preinstallation of an activating functional group on the carbonyl to enhance the reactivity and increase the enantioselectiivty (Scheme 1a, top).11–26 Nevertheless, the requirement of preinstallation and subsequent deprotection of stoichiometric quantities of activating auxiliaries involves time-consuming multistep sequences and sometimes leads to chiral product racemization and/or incompatibility with delicate molecular architectures during removal of these auxiliaries. To the best of our knowledge, only some sporadic examples described the direct addition to α,β-unsaturated acid27 and α,β-unsaturated ester28,29 as well as enzyme-catalyzed transformations so far.30,31 Furthermore, the simple α,β-unsaturated nitriles (β-substituted acrylonitrile), another typical kind of Michael acceptor and versatile building block in synthetic chemistry,32 the enantioselective addition with nitrogen-based nucleophiles to form a chiral center at the β-position of the nitrile group is only up to 22% enantiomeric excess (ee) value (Scheme 1a, bottom).33–35 More importantly, up to now, there remains no unified strategy that is suitable for all of these challenging Michael acceptors. Therefore, exploitation of a general and alternative approach that is capable of rapid preparation of chiral β-amino acid derivatives from unmasked α,β-unsaturated acid, ester, amide, even for simple α,β-unsaturated nitrile, is highly desirable. Scheme 1 | (a–c) Approaches for asymmetric aza-Michael addition reaction to α,β-unsaturated carboxylic acid and its derivatives and CuH-catalyzed transformations of Michael acceptors. Download figure Download PowerPoint Transition-metal-catalyzed asymmetric hydroamination of unsaturated hydrocarbons is a straightforward and powerful approach for rapid assembly of a variety of biologically active chiral amines.36–39 In this context, asymmetric hydroamination of various alkenes and alkynes40–56 with in situ generated CuH catalysts56–61 has attracted much attention since the pioneering reports by Buchwald62 and Hirano, and Miura in 2013.63 Besides, an array of electronically matched CuH-catalyzed asymmetric transformations of Michael acceptors, namely undergoing the 1,4-hydrocupration process, have also been disclosed in past decades (Scheme 1b).58,64–67 Given our continuing interest in Cu-catalyzed asymmetric hydrofunctionalization of unsaturated hydrocarbons,68–70 herein, we report a Cu-catalyzed asymmetric reversal hydroamination of α,β-unsaturated acid, ester, amide, and nitrile with hydroxylamine derivatives as aminating reagents (Scheme 1c).71,a We provide a unified and straightforward method to synthesize a series of chiral β-amino acid and its derivatives, without the traditional requirement of preinstallation of auxiliaries in aza-Michael addition reaction. Results and Discussion At the outset of our studies, we selected ethyl cinnamate 1a and O-benzoylhydroxylamine 4a as the model substrates in the presence of 5 mol % of Cu(OAc)2 and (S)-DTBM-SEGPHOS L1, the extremely powerful catalytic system of CuH-catalyzed asymmetric hydroamination pioneeringly developed by the Buchwald's group, with an excess of TMDS (1,1,3,3-tetramethyldisiloxane) at room temperature under N2 atmosphere in tetrahydrofuran (THF) for 48 h (Table 1). In line with the regioselectivity of previous CuH-catalyzed transformations of α,β-unsaturated ester,58,64–67 the α-alkylaminyl-substituted product 5a′ was obtained in 39% yield but without enantioinduction. Moreover, 5a′ was also observed in 46% and 63% yields with (R)-Tol-BINAP and (R,R)-DIPAMP as chiral ligands, respectively (see Supporting Information for details). During a thorough evaluation of various chiral ligands, we were surprised to discover that the regioreversal β-alkylaminyl-substituted ester 5a, namely formal aza-Michael addition product, could be obtained. (S,S)-Ph-BPE L2 showed the most efficiency in terms of reactivity, regio- and stereocontrol (77% yield and 97% ee). Moreover, we did not observe the regioisomer 5a′ with L2 as the ligand. Examination of other commercially available hydrosilanes and solvents was also performed, and slightly inferior yield or enantiocontrol under the otherwise optimal reaction conditions was observed (see Supplementary Information for details). Table 1. | Scope of Hydroamination of α,β-Unsaturated Ester, Acid, and Amidea,b aReaction conditions: α,β-unsaturated esters (0.2 mmol), 4 (0.3 mmol, 1.5 equiv), 1,1,3,3-tetramethyldisiloxane (TMDS) (3.0 equiv), Cu(OAc)2 (5 mol %), and chiral ligand L2 (5 mol %) in 2.0 mL dry THF at room temperature for 48 h. bYields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard and ee value determined by HPLC. c(R,R)-Ph-BPE was used. dα,β-unsaturated acids (0.3 mmol, 1.5 equiv), 4 (0.2 mmol), 6.0 equiv TMDS were used and the reactions were performed at 50 °C. eα,β-unsaturated amides (0.3 mmol, 1.5 equiv), 4 (0.2 mmol) were used and the reactions were performed at 50 °C. In assessing the scope of the catalytic reaction (Table 1), we found that an array of α,β-unsaturated esters 1 bearing different steric hindrance functional groups could be efficiently transformed to the corresponding chiral β-aminyl esters 5a–5e in generally high yields with excellent enantioselectivities. Various substituents including alkyl, methoxyl, phenyl, and methylthioyl at either ortho-, meta-, or para-position on the aromatic rings of the unsaturated esters 1 were also efficiently converted into chiral products 5f– 5k with high levels of enantiocontrol. An array of electronic-withdrawing groups, including –F, –Cl, –Br, –OCF3, –CF3, –C(O)OMe, and some privileged heteroaromatic ring motifs widespread in bioactive molecules and pharmaceuticals, such as pyridine and thiophene, were also readily accommodated. They provided expected hydroamination products 5l– 5u in good yields with excellent enantioselectivities. In addition to examining the scope of α,β-unsaturated esters, we also surveyed the substrate scope with respect to the hydroxylamine ester component. We found that electron-rich or electron-deficient hydroxylamine esters, nitrogen-containing heterocyclic hydroxylamine esters, as well as the enantiomeric hydroxylamine esters were all applicable to this hydroamination. They provided β-aminyl esters 5v– 5z with high efficiency and good-to-excellent enantiocontrol. Structurally more complicated diaceton-d-glucose and cholesterol-derivated α,β-unsaturated esters could also be transferred smoothly into corresponding β-amino ester 5aa and 5 ab in good yield with excellent diastereo- and enantiocontrol. The relatively low yields in some cases, such as 5e, 5t, and 5u, ascribed to the competitive reduction reaction of C–C double bond, and corresponding reduction products were obtained in 43%, 41%, and 38% yields. In addition, the β-alkyl-substituted α,β-unsaturated ester, such as ethyl (E)-but-2-enoate, was also assessed under the present conditions, whereas α-alkylaminyl-substituted product was obtained in 68% yield (see Supporting Information). The success of this asymmetric hydroamination strategy for α,β-unsaturated ester encouraged us to continue examining whether this approach could also be applied to synthesize chiral β-aminyl acids and amides. To our delight, by slightly improving the temperature and increasing the amount of silane, a diverse range of α,β-unsaturated acids with various electronic-withdrawing or -donating functional groups on the aromatic rings ( 2a– 2n), including methyl, ethoxyl, ester, phenyl, methylthioyl, halogens, trifluoromethoxyl and trifluoromethyl, and (E)-3-(quinolin-3-yl)acrylic acid ( 2o), were suitable coupling partners for this amination. They provided corresponding β-alkylaminyl-substituted acid 6a– 6o with high efficiency and generally excellent level of enantiocontrol. In addition, some representative hydroxylamine esters were also examined and could be readily converted into chiral β-aminyl acids 6p– 6r with over 90% ee. α,β-Unsaturated amides 3a–3f could also be converted into corresponding β-aminyl amides 7a–7f under this catalytic system with high efficiency, despite showing relatively low enantiocontrol in some cases compared with that of α,β-unsaturated ester and acid. Encouraged by these promising results, we were next particularly interested in whether this reversal hydroamination strategy could be applicable to α,β-unsaturated nitriles to form synthetically challenging chiral β-amino nitriles. We then began our investigation using (E)-cinnamonitrile 8 as the Michael acceptor. To our delight, the expected β-amino-substituted nitrile 9a was indeed generated in 91% yield and 92% ee without any further optimization reaction conditions. Encouraged by this result, we then commenced assessment of substrate scope and the functional group compatibility (Table 2). In general, this reaction also showed good functional group tolerance. For example, either electron-donating functional groups (–CH3, –OCH3, –SCH3, –C6H5, –OAc, and –OC6H5) or electron-withdrawing functional groups (–F, –Cl, –Br, –OCF3, and –CF3) on the aromatic rings of the α,β-unsaturated nitriles was tolerated well, and corresponding substrates converted smoothly into the desired chiral β-amino nitriles 9b–9r in good-to-excellent yields with more than 90% ee values in most cases. In addition, the reduction product for 8d was observed in 33% yield. Two representative aminating reagents were also examined and enabled the nitrogen-containing substructures to integrate into the expected chiral products 9s and 9t with high efficiency and good enantiocontrol. In addition, the absolute configuration of the product 9o was unequivocally determined by single-crystal X-ray diffraction. In addition, the success of the reversal hydroamination of α,β-unsaturated nitrile also suggested that the regioselectivity of this method was not dominated by the chelation effect of the carbonyls in Michael acceptors72 because the linear configuration of nitrile group was not favorable as a directing group in this transformation. In addition, other α,β-unsaturated carbonyls, such as α,β-unsaturated ketone and imine, were also evaluated, and the complex mixture of α,β-unsaturated ketone and almost completely recovered α,β-unsaturated imine was observed under these catalytic conditions. Table 2 | Scope of Hydroamination of α,β-Unsaturated Nitrilea,b aReaction conditions: α,β-unsaturated nitrile 8 (0.2 mmol), 4 (0.3 mmol, 1.5 equiv), TMDS (3.0 equiv), Cu(OAc)2 (5 mol %), and chiral ligand L2 (5 mol %) in 2.0 mL dry THF at room temperature for 48 h. bYields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard and ee value determined by HPLC. A gram-scale synthesis was conducted to demonstrate the practicability of this method, the target chiral β-amino ester 5a was obtained in good yield without any erosion in enantioselectivity with 1 mol % Cu(OAc)2 and 1 mol % chiral ligand L2 (Scheme 2a). We also examined further applications of this chiral compound (Scheme 2b). For instance, chiral β-amino ester 5a underwent a selective monodebenzylation or reduction process, offering chiral β-amino ester 10 and important chiral γ-amino alcohol 11 in excellent yield with 95% and 92% ee, respectively. In addition, ester 5a also converted into the chiral cyclic β-amino ketone 12 smoothly in 68% yield with slight erosion of enantioselectivity. The chiral β-amino ester 5a was further functionalized at the α-position of the ester group and deliver more complex molecules. For example, 5a was efficiently allylated with allyl bromide in the presence of potassium bis(trimethylsilyl)amide (KHMDS), providing synthetically versatile compound 13 with 2∶1 diastereoselectivity. Moreover, without any racemization, the chiral center in 5a was observed under harsh conditions [e.g., in the presence of NaOH or trifluoroacetic acid (TFA)], indicating that these types of chiral compounds might have the capacity to transfer into more complicated chiral compounds while maintaining the enantioselectivity. According to previous reports,40–56,62,63 a mechanism involving a regio- and enantioselective insertion of CuH into C–C double bond in a Michael acceptor to form benzylcopper intermediate, followed by an amination process with hydroxylamine 4 to provide expected chiral β-amino carbonyls, might be possible. Other mechanisms cannot be excluded, and further studies need to be carried out to illuminate the origin of this unusual regio- and enantionselectivity. Scheme 2 | (a and b) Gram-scale synthesis and applications of chiral β-amino ester. Download figure Download PowerPoint Conclusion We have developed an efficient reversal hydroamination strategy of α,β-unsaturated carboxylic acid, ester, amide, and nitrile through precise choice of chiral ligand, providing a unified approach for the convenient and rapid synthesis of an array of important chiral β-amino acids and their derivatives with a high level of regio- and enantiocontrol. This approach not only provides an alternative route to traditional aza-Michael addition but also opens a new door to the challenging asymmetric addition of other nucleophiles to low reactivity of Michael acceptors. Mechanism studies are currently underway in our lab. Footnote a We note that during the preparation of this manuscript (the preprint version was submitted on July 3, 2020), with 1,2-benzisoxazole as the aminating reagent, Guo, Buchwald, and co-worker reported a reversal asymmetric hydroamination of mainly focusing on β-aryl-substituted acrylates. Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Preprint Acknowledgment Research presented in this article was posted on a preprint server prior to publication in CCS Chemistry. The corresponding preprint article can be found here: ( org/10.26434/chemrxiv.12606554.v1; Direct Link). 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Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentVolume 3Issue 7Page: 1737-1745Supporting Information Copyright & Permissions© 2020 Chinese Chemical SocietyKeywordscopper catalysisasymmetric catalysisMichael acceptorsreversal hydroaminationchiral β-amino acid and its derivativesAcknowledgmentsThe authors acknowledge the National Natural Science Foundation of China (grant nos. 21672033, 21801039, and 21831002), the Jilin Educational Committee (grant no. JJKH20190269KJ), the Fundamental Research Funds for the Central Universities, and the Ten Thousand Talents Program for generous financial support. Downloaded 2,577 times Loading ...