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A Step-Economic and One-Pot Access to Chiral Cα-Tetrasubstituted Α

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A Step-Economic and One-Pot Access to Chiral Cα-Tetrasubstituted Α Chemical Science EDGE ARTICLE View Article Online View Journal | View Issue A step-economic and one-pot access to chiral Ca- tetrasubstituted a-amino acid derivatives via Cite this: Chem. Sci., 2020, 11, 4801 a bicyclic imidazole-catalyzed direct All publication charges for this article have been paid for by the Royal Society enantioselective C-acylation† of Chemistry Mo Wang,ab Muxing Zhou,b Lu Zhang,b Zhenfeng Zhang *b and Wanbin Zhang *ab Ca-Tetrasubstituted a-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four- step acylation reaction for the efficient synthesis of chiral Ca-tetrasubstituted a-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords Creative Commons Attribution 3.0 Unported Licence. Received 11th February 2020 a the corresponding C -tetrasubstituted a-amino acid derivatives with excellent enantioselectivities (up to Accepted 24th April 2020 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important DOI: 10.1039/d0sc00808g chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and rsc.li/chemical-science synthetic chemistry. Introduction asymmetric Steglich rearrangement have been reported by many other research groups.5b–k Our group has also developed a C -Tetrasubstituted a-amino acids are ubiquitous and unique an efficient bicyclic imidazole organocatalyst for this reaction, This article is licensed under a structural units in many natural products and synthetic which can be easily synthesized from imidazole in only three f compounds, many of which exhibit signicant biological steps.5 However, the efficiency of this transformation is activities and physiological effects (Fig. 1).1 Several feasible hindered by the prefabrication of unstable azlactones and Open Access Article. Published on 24 April 2020. Downloaded 9/26/2021 12:22:57 PM. a methodologies have been developed for the synthesis of C - relatively inert O-acylated azlactones. Such inefficiencies are tetrasubstituted a-amino acids, ranging from the use of chiral present in many other transformations which lead to poor b auxiliaries to the presently reported catalytic models.2 These practical applicability.5 ,6 include: (1) the enantioselective addition of alkyl, aryl, or even In order to improve the synthetic efficiency, minimizing the acyl precursors (Strecker reaction followed by hydrolysis) to number of steps of the synthetic sequence is important. This ketimines,3 and; (2) the asymmetric a-alkylation, arylation, or strategy, termed step-economy, has frequently been employed acylation of a-substituted amino acid derivatives.4,5 However, in advanced total syntheses by utilizing new reactions.7 Herein, a due to the challenges imposed by C -tetrasubstituted a-amino we would like to put forward a more general approach in which acids, efficient methods are still lacking, especially for the a two-step rearrangement process (AB + C / AB–C / C–AB) is a synthesis of a-acyl-substituted C -tetrasubstituted a-amino acid replaced by a direct reaction (AB + C / C–AB) by altering che- derivatives.5 The most commonly used approach relies on the O- moselectivity. As the rst example, we recently developed acylation of azlactones followed by a Lewis base-catalyzed asymmetric O-toC-acyl transfer (well-known as Steglich rear- rangement, red arrows in Scheme 1). Aer the initial work developed by Fu et al.,5a several improvements on the aShanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China. E-mail: [email protected]; [email protected] bSchool of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China a † Electronic supplementary information (ESI) available. See DOI: Fig. 1 Examples of C -tetrasubstituted a-amino acid derivatives with 10.1039/d0sc00808g biological activities and physiological effects. This journal is © The Royal Society of Chemistry 2020 Chem. Sci.,2020,11,4801–4807 | 4801 View Article Online Chemical Science Edge Article that achieves excellent enantioselectivity has not been reported previously. Results and discussion We initially focused on screening the reaction conditions for the rst three steps in the sequence in one pot. (4-Methoxybenzoyl) alanine 1a was selected as the starting material and benzyl- amine was used as the nucleophilic reagent to derivatize the produced 4-carboxyazlactone shown in the square brackets in Table 1. Over the past decade, we have developed a series of bicyclic imidazole nucleophilic catalysts which have been successfully applied in a number of different reactions by our group5f,8,9,14 and other groups.15 We envisaged that the bicyclic imidazole would be able to catalyze all the steps in the acylation sequence. Several bicyclic imidazole catalysts were screened for a a Scheme 1 Our new approach to enantiopure C -tetrasubstituted - the sequential acylation of 1a with benzyl chloroformate as the amino acid derivatives by a four-step acylation sequence using auto- acylating agent and di(isopropyl)ethylamine (DIPEA) as a base tandem catalysis. to afford product 2a (Table 1, entries 1–4). Catalysts bearing an alkoxy group gave better ee than those bearing an acyloxy group, and catalyst OBn-DPI was found to give the best result. a bicyclic imidazole-catalyzed direct enantioselective C-acyla- Replacing the acylating agent, benzyl chloroformate with allyl tion of benzofuran-2(3H)-ones and 2-oxindoles.8 For the most Creative Commons Attribution 3.0 Unported Licence. chloroformate or phenyl chloroformate, afforded the desired part, the starting material is directly converted to the C-acylated products in lower yield and ee (entries 5 and 6, respectively). Use product but not via the relatively inert O-acylated intermediate. of ethyl chloroformate only afforded a trace amount of the As a result, the efficiency for the synthesis of the desired prod- product (entry 7). The base triethylamine (TEA) was also applied ucts is dramatically improved compared to the corresponding in this reaction but no product was observed (entry 8). The effect Black rearrangement.9 Inspired by this, and in continuation of a our interest in the construction of C -tetrasubstituted a-amino acids,10 we propose a direct enantioselective C-acylation of Table 1 The effect of catalyst, acylating reagent, base, and solvent azlactones with the purpose of improving the synthetic effi- This article is licensed under a ciency for the preparation of 4-carboxyazlactones (pink arrow in Scheme 1).11 To further improve the synthetic efficiency, simplifying the operations via a sequential process in one pot is Open Access Article. Published on 24 April 2020. Downloaded 9/26/2021 12:22:57 PM. an applicable method. This strategy, termed pot-economy, has been widely used for the construction of multiple bonds in one pot.12 Generally, different catalysts are used for different reac- tion steps (tandem catalysis). Obviously, carrying out all the reaction steps with a single catalyst would be more benecial Entrya Catalyst Acylating reagent Solvent Yieldb (%) eec (%) (auto-tandem catalysis).13 This strategy, termed catalyst- economy, has oen been employed in two-step sequences but 1 OAc-DPI ClCOOBn Toluene 77 84 seldom in multi-step sequences.13c During the initial research 2 OMe-DPI ClCOOBn Toluene 62 87 concerning the direct enantioselective C-acylation of azlactones, 3 OEt-DPI ClCOOBn Toluene 65 88 4 OBn-DPI ClCOOBn Toluene 78 91 we found that the starting azlactones could be prepared via 5 OBn-DPI ClCOOallyl Toluene 71 91 intramolecular O-acylation of in situ generated anhydrides 6 OBn-DPI ClCOOPh Toluene 81 60 (shown in the square brackets in Scheme 1); the produced 4- 7 OBn-DPI ClCOOEt Toluene Trace — carboxyazlactones could be readily derivatized by another acyl- 8d OBn-DPI ClCOOBn Toluene —— a ation to produce various C -tetrasubstituted a-amino acid 9 OBn-DPI ClCOOBn THF 80 90 10 OBn-DPI ClCOOBn Dioxane 77 90 derivatives. Therefore, by combining the aforementioned step-, 11 OBn-DPI ClCOOBn Et2O 30 91 pot-, and catalyst-economy strategies, we aimed to design 12 OBn-DPI ClCOOBn MTBE 66 91 a four-step acylation sequence for the efficient synthesis of 13 OBn-DPI ClCOOBn DCM 45 88 a chiral C -tetrasubstituted a-amino acid derivatives and biolog- 14 OBn-DPI ClCOOBn t-AA 76 71 ically active dipeptides from simple N-acylated amino acids. The a Conditions: 1a (0.1 M), ClCOOR (3.5 eq.), catalyst (20 mol%), DIPEA reaction would proceed via auto-tandem catalysis using a single (4.0 eq.), solvent (2 mL), 20 C, 36 h, unless otherwise noted. b Yields 1 c bicyclic imidazole nucleophilic catalyst (blue part in Scheme 1). were calculated from H NMR spectra. The ee values were calculated from HPLC spectra. d TEA was used instead of DIPEA and only To the best of our knowledge, this type of sequential reaction azlactone without COOBn substituent was obtained together with some NEt2COOBn. 4802 | Chem. Sci.,2020,11,4801–4807 This journal is © The Royal Society of Chemistry 2020 View Article Online Edge Article Chemical Science of solvents was studied and toluene provided the product with the highest ee and satisfactory conversion (entries 4, 9–14). Aer preliminary screening, the catalyst OBn-DPI, acylating agent benzyl chloroformate, base DIPEA and solvent toluene were chosen as the optimal conditions for further study, affording the desired product in 78% yield and with 91% ee (entry 4). Next, the effect of reaction temperature was researched (Table 2). At a lower reaction temperature of 0 C for 36 h, product 2a was obtained with same yield and better ee compared to that of 20 C (entries 1 and 2).
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