Rational design and atroposelective synthesis of N–N axially chiral compounds

•N–N axial chirality construction•Catalytic asymmetric N-allylic alkylation reaction•Facile access to enantioenriched 1-aminopyrroles and 3-aminoquinazolinones•Broad scope, good yields, and excellent enantioselectivities Stereoisomers could vary significantly in their biological activities and functions. As a type of stereoisomerism, atropisomerism involves stable isomers interconvertible by rotation about a single bond. Any forces imposing a high enough energy barrier to rotation may create atropisomers. The N–N bonds are widely present in natural products, pharmaceutical agents, and organic materials. Few examples of atropisomers involving rotation about N–N bonds exist. We present the catalytic asymmetric synthesis of N–N axially chiral 1-aminopyrroles and 3-aminoquinazolinones. Density functional theory calculations elucidate the origins of enantioselectivity and demonstrate remote enantiomeric control. N–N atropisomers are attractive compounds for further investigation as pharmaceuticals. The first catalytic asymmetric synthesis of N–N axially chiral compounds has been accomplished via a quinidine catalyzed N-allylic alkylation reaction. These N–N axially chiral frameworks are a new addition to the families of axially chiral molecules and to the atropisomerism involving heteroatom(s), e.g., N, O, and S. The reaction takes place smoothly under mild conditions and displays excellent functional group tolerance, allowing facile access to a variety of N–N axially chiral 1-aminopyrroles and 3-aminoquinazolinones in high yields and excellent enantioselectivities. DFT calculations have been applied to understand the origin of enantioselectivity and provide guidance for the design of additional molecules of this type. The investigation of N–N axis atropisomerism holds promise for new discoveries in medicinal chemistry and asymmetric catalysis. The first catalytic asymmetric synthesis of N–N axially chiral compounds has been accomplished via a quinidine catalyzed N-allylic alkylation reaction. These N–N axially chiral frameworks are a new addition to the families of axially chiral molecules and to the atropisomerism involving heteroatom(s), e.g., N, O, and S. The reaction takes place smoothly under mild conditions and displays excellent functional group tolerance, allowing facile access to a variety of N–N axially chiral 1-aminopyrroles and 3-aminoquinazolinones in high yields and excellent enantioselectivities. DFT calculations have been applied to understand the origin of enantioselectivity and provide guidance for the design of additional molecules of this type. The investigation of N–N axis atropisomerism holds promise for new discoveries in medicinal chemistry and asymmetric catalysis. 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The other nitrogen atom can be part of an aryl ring, ideally, an aryl moiety forming structure with potential biological significance. Therefore, 1-aminopyrroles and 3-aminoquinazolinones were chosen to be the core structures, since N–N axial bond, pyrrole, and quinazolinone rings were present in biologically active molecules (compounds II–IV in Figure 2). Since both classes of compounds contain configurationally labile N–N bond axes, we reasoned that they would be ideal substrates for evaluating potential N–N atropisomer formation via synthetic manipulations. Simple N-allylic alkylations were anticipated to introduce a significant rotational barrier to the existing N–N axis, thus allowing for derivatization of configurationally stable N–N atropisomers (Figure 3). We report the first example of an enantioselective preparation of N–N axial atropisomers and describe the asymmetric synthesis of two distinct classes of axially chiral 1-aminopyrroles 3 and 3-aminoquinazolinones 5. 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The Morita–Baylis–Hillman (MBH) adduct 2a was selected as the alkylating agent, and various commercially available chiral amine catalysts were tested,70Iwabuchi Y. Nakatani M. Yokoyama N. Hatakeyama S. Chiral amine-catalyzed asymmetric Baylis-Hillman reaction: a reliable route to highly enantiomerically enriched (α-methylene-β-hydroxy)esters.J. Am. Chem. Soc. 1999; 121: 10219-10220Crossref Scopus (488) Google Scholar and the results are summarized in Table 1. The rotation about the N–N bond in 1a is facile and no atropisomers were observed. 4-(Dimethylamino)pyridine (DMAP) efficiently catalyzed the reaction between 1a and 2a, and the desired N-alkylation product 1-aminopyrrole 3a was formed in excellent yield (entry 1). We were pleased to discover that such N-alkylation introduced sufficient N–N bond rotation constraint, leading to the formation of a pair of atropisomers (see the supplemental information for HPLC analysis on a chiral stationary phase). Importantly, the two atropisomers were sufficiently stable and not interconvertible at room temperature. Consequently, we turned our attention to the catalytic asymmetric formation of such atropisomers. When cinchonine (A) was employed as the catalyst, alkylation product 3a was obtained with 70% ee (entry 2). The subsequent solvent screening identified chloroform as the solvent of choice (entries 3–6). The reaction was further examined with different bases, and among a few readily available cinchona alkaloids, quinidine (D) was found to be best (entries 7–11). Under the catalysis of quinidine, the atropselective N-allylic alkylation reaction occurred smoothly at room temperature in chloroform, affording the N–N axially chiral 1-aminopyrrole 3a in 96% yield and 94% ee.Table 1Optimization of the reaction conditionsEntryCat.SolventYield (%)aIsolated yield.ee (%)bThe ee value was determined by HPLC.1DMAPCH3CN9802ACH3CN95703ACH2Cl288904Atoluene90855Adichloroethane88866ACHCl393917BCHCl395928CCHCl390909DCHCl3969410ECHCl3964611FCHCl39490Reaction conditions: unless indicated otherwise, the reaction was carried out at 0.1 mmol scale with 10 mol % of catalyst in a solvent (1 mL) at room temperature for 12 h, and the molar ratio of 1a:2a was 1:1.8.a Isolated yield.b The ee value was determined by HPLC. Open table in a new tab Next, with the optimal reaction conditions in hand, substrate scope was examined (Figure 4). The projected reaction was applicable to a wide range of 1-aminopyrroles 1 and MBH adducts 2. The ester group of MBH adducts 2 can be varied, from tBu (3a), Me (3b), Et (3c), Bn (3d), and benzhydryl (3e), to anthracene-9-ylmethyl (3f), with consistently excellent ee values and high yields. Moreover, the ester moiety of the carbamate was also well tolerated (3g, 3h). The neighboring substituent of 1-aminopyrroles appeared to be inconsequential to the reaction results, and excellent enantioselectivity was retained (3i, 3j). The electron-withdrawing substituents on the pyrrole ring were also evaluated, and the reaction worked equally well for different types of substituents, regardless of their positions (3k–3o).Figure 4Substrate scopeShow full captionReaction conditions: 1 (0.1 mmol), 2 (0.18 mmol), quinidine (10 mol %), in 1.0 mL of CHCl3, at 25°C, for 12 h. The absolute configuration of 3o was determined to be R via X-ray analysis (CCDC: 2009439).View Large Image Figure ViewerDownload Hi-res image