DOI: 10.1002/chem.201500823
Communication
& Asymmetric Catalysis
Triply Hydrogen-Bond-Directed Enantioselective Assembly of Pyrrolobenzo-1,4-diazine Skeletons with Quaternary Stereocenters Xiaoming Shen, Yongtao Wang, Tiandi Wu, Zhenjun Mao, and Xufeng Lin*[a] action.[11] Chiral phosphoric acids have been recognized as efficient organocatalysts for a variety of enantioselective transformations[12] and hydrogen-bonding (or ion-pairing) interactions play a crucial functional role in these asymmetric catalytic reactions. Theoretical studies of the chiral phosphoric acid-catalyzed reaction mechanisms have revealed that double hydrogen-bonding interactions play a key role in activating the substrate and determining the stereoselectivity,[13] but triple hydrogen-bonding interactions have, to our knowledge, not been disclosed to date in chiral phosphoric acid catalysis. In continuation of our efforts in exploring the application of spirocyclic phosphoric acids (SPAs) in asymmetric catalysis,[14, 15] we report herein the results of experimental and computational studies of the chiral SPA-catalyzed asymmetric Pictet–Spengler reaction of 2-(1H-pyrrol-1-yl)anilines with a-ketoamides to provide pyrrolobenzo-1,4-diazine skeletons with quaternary stereocenters, which possess a broad spectrum of physiologi-
Abstract: Highly efficient synthesis of optically enriched pyrrolobenzo-1,4-diazines bearing quaternary stereocenters has been realized through the chiral Brønsted acidcatalyzed Pictet–Spengler reaction of 2-(1H-pyrrol-1-yl)anilines and a-ketoamides in good to excellent yields and enantioselectivities. Computational studies suggest an unprecedented phenomenon whereby the chiral phosphoric acid catalyst employs attractive arene C H···N hydrogen bonding to activate the substrate and induce chirality through a triple hydrogen-bonding interaction.
Quaternary stereocenters are a common structural motif in a variety of bioactive natural products and chiral drugs.[1] However, the efficient and enantioselective formation of these stereocenters is a crucial challenge in chemical synthesis, since they cannot be constructed by asymmetric catalytic hydrogenation. In this context, development of catalytic enantioselective methods for construction of nitrogen-containing quaternary stereocenters in cyclic systems, which is a prevalent structure in natural alkaloids,[2] is a particular compelling objective. Consequently, significant efforts have been devoted to this field, such as Trost’s allylic alkylation,[3] Jørgensen’s conjugate addition,[4] Steglich rearrangement,[5] 1,3-dipolar cycloaddition,[6] Mannich reaction,[7] Friedel–Crafts reaction,[8] and Henry reaction of cyclic ketimines.[9] Despite these impressive advances, further exploration of novel methods and strategies for the catalytic asymmetric construction of nitrogen-containing quaternary stereocenters in cyclic systems is still challenging and highly desirable. In the meantime, the enantioselective Pictet–Spengler reaction represents an efficient approach to construct chiral nitrogen-containing heterocycles and has witnessed great progress.[10] However, there is still no general solution for the creation of nitrogen-containing quaternary stereocenters in cyclic systems by using the catalytic asymmetric Pictet–Spengler re-
Table 1. Optimization of reaction parameters.[a]
Entry 1 2 3 4 5 6 7 8 9 10 11[d]
[a] X. Shen, Y. Wang, T. Wu, Z. Mao, Prof. X. Lin Laboratory of Asymmetric Catalysis and Synthesis Department of Chemistry, Zhejiang University Hangzhou 310027 (P.R. China) Fax: (+ 86) 571-87952759 E-mail: [email protected]
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(S)-1 a (S)-1 b (S)-1 c (S)-1 d (S)-1 e (S)-1 d (S)-1 d (S)-1 d (S)-1 d (S)-1 d (S)-1 d
Solvent toluene toluene toluene toluene toluene xylene benzene CHCl3 CH3CN THF toluene
Yield [%][b] 88 95 trace 90 85 87 85 91 trace trace 80
ee [%][c] 9 32 n/d 96 91 91 96 70 n.d. n.d. 95
[a] Reactions were performed with 2 a (0.1 mmol), 3 a (0.12 mmol), 1 (10 mol %), and 4 M. S. (100 mg) in 1 mL solvent at 40 8C for 72 h; [b] yields of isolated product; [c] determined by chiral HPLC analysis; [d] catalyzed by 2 mol % 1. n.d. = not determined.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500823. Chem. Eur. J. 2015, 21, 1 – 6
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Communication cal and biological activities and attract the interest of Table 2. Substrate scope.[a] organic and medicinal chemists.[16] Theoretical calculations disclose the existence of triple hydrogen bonds between the catalyst and the substrate, including an unexpected arene C H···N hydrogenbonding interaction, and suggest that triple hydrogen-bonding interactions are crucial for activating substrates and inducing chirality. We began our study by examining the reaction of 2-(1H-pyrrol-1-yl)aniline (2 a) and a-ketoamide (3 a) using 10 mol % chiral phosphoric acid (1 a) as the catalyst in toluene in the presence of powdered 4 mo90 % yield, 96 % ee 94 % yield, 91 % ee 85 % yield, 91 % ee lecular sieves. The desired product 4 a was obtained in 88 % yield but with very low enantioselectivity (Table 1, entry 1). We next evaluated chiral SPAs with different substituents at the 6- and 6’-positions (Table 1, entries 1–5). The sterically congested phosphoric acid catalysts were found to be important for enantioselective control. Catalyst 1 b provided prod87 % yield, 95 % ee 89 % yield, 98 % ee 88 % yield, 98 % ee uct 4 a with slightly improved enantioselectivity and the absolute configuration opposite to that induced by catalyst 1 a, albeit in the highest yield (Table 1, entry 2), whereas catalyst 1 c, with 6,6’-bis(4-biphenyl) moieties, exhibited no catalytic activity (Table 1, entry 3). To our delight, catalyst 1 d, with 6,6’-bis(9phenanthryl) moieties, gave excellent yield and the highest enantioselectivity (90 % yield and 96 % ee; 87 % yield, 99 % ee 90 % yield, 96 % ee 90 % yield, 81 % ee Table 1, entry 4). The desired product 4 a was obtained in 85 % yield with 91 % ee when catalyst 1 e, with 6,6’-bis(9-anthracenyl) moieties, was employed (Table 1, entry 5). Screening of solvents was next carried out. The reaction could also run in benzene and chloroform to give the corresponding product 4 a in good yields and enantioselectivities (Table 1, entries 7 92 % yield, 86 % ee 85 % yield, 83 % ee[b] 85 % yield, 75 % ee and 8), whereas the reaction hardly occurred in coordinating solvents, such as acetonitrile or tetrahydrofuran (Table 1, entries 9 and 10). In addition, the reaction with 2 mol % catalyst 1 d also proceeded well to afford the corresponding product in slightly reduced yield without compromising the enantioselectivity (Table 1, entry 11). With the optimized reaction conditions in hand (Table 1, entry 4), we next turned our attention to assessing the substrate scope of the asymmetric Pictet–Spengler reaction (Table 2). Firstly, the effect of the substituents on the N-aryl ring (Ar2) of a-phenyl86 % yield, 94 % ee[c] X-ray crystal structure of 4 b ketoamide 3 was investigated by examining their reaction with 2-(1H-pyrrol-1-yl)aniline 2 a. The corre[a] Reactions were performed with 2 a (0.1 mmol), 3 a (0.12 mmol), 1 (10 mol %), and 4 M. S. (100 mg) in toluene (1 mL) at 40 8C for 72 h. Yields are of Isolated product. sponding products were obtained in good yields and Enantioselectivity was determined by chiral HPLC; [b] heated at 80 8C; [c] heated at excellent enantioselectivities (4 a–d, 85–94 % yield, reflux. 91–96 % ee), irrespective of the electronic and steric properties of the substituents on Ar2. The investigation of the substituent effect of the Ar1 moiety exhibduction in the enantioselectivity was found in the reaction of ited that different halide groups, such as F, Cl, or Br, with 12-(1H-pyrrol-1-yl)aniline 2 a with a halide substituent at Ar1 and naphthyl as Ar2 moiety were all well tolerated, and the corresponding products were obtained in excellent yields and enan2,6-difluorophenyl as Ar2 (4 i–k, 85–92 % yield, 81–86 % ee). tioselectivities (4 e–h, 87–90 % yield, 96–99 % ee). A slight reMoreover, the substituent on the aromatic ring of the 2-(1H&
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Communication pyrrol-1-yl)anilines has a marked effect on the stereoselectivity. Introduction of an electron-donating group (CH3) resulted in a noticeable decrease in the enantioselectivity, albeit with good yield (4 l, 85 % yield, 75 % ee), whereas introduction of bromide at the same position gave the product 4 m with no erosion of yield or enantioselectivity (86 % yield, 94 % ee). The absolute configuration (R) of the quaternary stereogenic center in product 4 was determined by X-ray crystallographic analysis of a single crystal of 4 b.[17] To establish whether this process is readily scalable, we next carried out a scale-up experiment with 3.0 mmol of 2 a (Scheme 1). This reaction proceeded without compromising
Scheme 1. Gram-scale preparation of 4 b.
the yield or enantioselectivity and the desired product 4 b was isolated in 92 % yield and 91 % ee, alongside 95 % recovery of catalyst 1 d. Moreover, the enantioselectivity could be easily increased to 98 % ee with 80 % yield by a single recrystallization. To gain mechanistic insight into this asymmetric Pictet– Spengler reaction, N-methyl-2-oxo-N,2-diphenylacetamide 3 b’ was investigated by examining its reaction with 2-(1H-pyrrol-1yl)aniline 2 a under optimized conditions (Scheme 2), but no desired product was observed, even after heating to reflux. We suspect that the N H bond of a-ketoamides 3 is crucial for the activation of substrates by the SPA catalyst in this Pictet–Spengler reaction (see below).
Figure 1. Optimized transition states: a) TS-R: Re face, DDG (toluene) = 0.0 kcal mol 1; b) TS-S: Si face, DDG (toluene) = +1.6 kcal mol 1. Distances are given in .
Figure 2. Proposed mechanistic model.
Scheme 2. SPA-catalyzed Pictet–Spengler reaction.
3 b’ is a poor substrate for this reaction (Scheme 2). Moreover, the chiral phosphoric acid concurrently activates both the nucleophilic group and the electrophilic group of the substrate through a two-point catalyst–substrate hydrogen-bonding interaction. The triple hydrogen bonds hold the transition structure rigidly and allow the catalyst’s 9-phenanthryl groups to influence the enantioselectivity. Thus, computational studies of the present catalytic reaction have shown that the directing effect of the triple hydrogen-bonding interaction is crucial in the catalyst activating the reaction and inducing chirality. In conclusion, we have developed a chiral phosphoric acidcatalyzed highly asymmetric Pictet–Spengler reaction of 2-(1Hpyrrol-1-yl)anilines and a-ketoamides. This protocol provides a facile and highly efficient access to functionalized pyrrolo-
To further understand the mechanism and the origin of enantioselectivity, we performed computational studies for the transition-state structure leading to the major product (R)-4 b. The transition states TS-R and TS-S are represented in Figure 1. The Re face attack TS-R is predicted to be more favored than the Si face attack TS-S by 1.6 kcal mol 1 after adding the solvent free energy (see the Supporting Information). This is in agreement with the experimental results, and the proposed mechanistic model is also shown in Figure 2. In addition, an unexpected attractive non-classical arene C H···N hydrogen bond is evident in the calculated complex, and consistent with the observation that N-methyl-2-oxo-N,2-diphenylacetamide Chem. Eur. J. 2015, 21, 1 – 6
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Communication benzo-1,4-diazine compounds with an amide-containing quaternary stereocenter in good to excellent yields and enantioselectivities by a simple scalable experimental procedure. More importantly, computational studies support the belief that the chiral phosphoric acid catalyst employs attractive arene C H···N hydrogen bonding to activate the substrate and induce chirality through triple hydrogen-bonding interactions. This is an exceptionally rare example in asymmetric Brønsted acid catalysis. Development of novel catalytic asymmetric reactions through triply hydrogen-bond-directed enantioselective assembly is currently underway.
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Acknowledgements We thank the National Natural Science Foundation of China (21272202 and J1210042) and the Fundamental Research Funds for the Central Universities. [13]
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COMMUNICATION & Asymmetric Catalysis
Tales of the unexpected: An efficient triply hydrogen-bond-directed enantioselective assembly of pyrrolobenzo-1,4diazine skeletons with quaternary stereocenters by chiral Brønsted acid-catalyzed Pictet–Spengler reaction has been developed. Theoretical calculations reveal that the chiral phosphoric acid catalyst employs unexpected arene C H···N hydrogen bonding for activation and stereoinduction. SPA = spirocyclic phosphoric acid.
X. Shen, Y. Wang, T. Wu, Z. Mao, X. Lin* && – && Triply Hydrogen-Bond-Directed Enantioselective Assembly of Pyrrolobenzo-1,4-diazine Skeletons with Quaternary Stereocenters
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Communication
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Triply Hydrogen-Bond-Directed Enantioselective Assembly of Pyrrolobenzo-1,4-diazine Skeletons with Quaternary Stereocenters Xiaoming Shen, Yongtao Wang, Tiandi Wu, Zhenjun Mao, and Xufeng Lin*[a] action.[11] Chiral phosphoric acids have been recognized as efficient organocatalysts for a variety of enantioselective transformations[12] and hydrogen-bonding (or ion-pairing) interactions play a crucial functional role in these asymmetric catalytic reactions. Theoretical studies of the chiral phosphoric acid-catalyzed reaction mechanisms have revealed that double hydrogen-bonding interactions play a key role in activating the substrate and determining the stereoselectivity,[13] but triple hydrogen-bonding interactions have, to our knowledge, not been disclosed to date in chiral phosphoric acid catalysis. In continuation of our efforts in exploring the application of spirocyclic phosphoric acids (SPAs) in asymmetric catalysis,[14, 15] we report herein the results of experimental and computational studies of the chiral SPA-catalyzed asymmetric Pictet–Spengler reaction of 2-(1H-pyrrol-1-yl)anilines with a-ketoamides to provide pyrrolobenzo-1,4-diazine skeletons with quaternary stereocenters, which possess a broad spectrum of physiologi-
Abstract: Highly efficient synthesis of optically enriched pyrrolobenzo-1,4-diazines bearing quaternary stereocenters has been realized through the chiral Brønsted acidcatalyzed Pictet–Spengler reaction of 2-(1H-pyrrol-1-yl)anilines and a-ketoamides in good to excellent yields and enantioselectivities. Computational studies suggest an unprecedented phenomenon whereby the chiral phosphoric acid catalyst employs attractive arene C H···N hydrogen bonding to activate the substrate and induce chirality through a triple hydrogen-bonding interaction.
Quaternary stereocenters are a common structural motif in a variety of bioactive natural products and chiral drugs.[1] However, the efficient and enantioselective formation of these stereocenters is a crucial challenge in chemical synthesis, since they cannot be constructed by asymmetric catalytic hydrogenation. In this context, development of catalytic enantioselective methods for construction of nitrogen-containing quaternary stereocenters in cyclic systems, which is a prevalent structure in natural alkaloids,[2] is a particular compelling objective. Consequently, significant efforts have been devoted to this field, such as Trost’s allylic alkylation,[3] Jørgensen’s conjugate addition,[4] Steglich rearrangement,[5] 1,3-dipolar cycloaddition,[6] Mannich reaction,[7] Friedel–Crafts reaction,[8] and Henry reaction of cyclic ketimines.[9] Despite these impressive advances, further exploration of novel methods and strategies for the catalytic asymmetric construction of nitrogen-containing quaternary stereocenters in cyclic systems is still challenging and highly desirable. In the meantime, the enantioselective Pictet–Spengler reaction represents an efficient approach to construct chiral nitrogen-containing heterocycles and has witnessed great progress.[10] However, there is still no general solution for the creation of nitrogen-containing quaternary stereocenters in cyclic systems by using the catalytic asymmetric Pictet–Spengler re-
Table 1. Optimization of reaction parameters.[a]
Entry 1 2 3 4 5 6 7 8 9 10 11[d]
[a] X. Shen, Y. Wang, T. Wu, Z. Mao, Prof. X. Lin Laboratory of Asymmetric Catalysis and Synthesis Department of Chemistry, Zhejiang University Hangzhou 310027 (P.R. China) Fax: (+ 86) 571-87952759 E-mail: [email protected]
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(S)-1 a (S)-1 b (S)-1 c (S)-1 d (S)-1 e (S)-1 d (S)-1 d (S)-1 d (S)-1 d (S)-1 d (S)-1 d
Solvent toluene toluene toluene toluene toluene xylene benzene CHCl3 CH3CN THF toluene
Yield [%][b] 88 95 trace 90 85 87 85 91 trace trace 80
ee [%][c] 9 32 n/d 96 91 91 96 70 n.d. n.d. 95
[a] Reactions were performed with 2 a (0.1 mmol), 3 a (0.12 mmol), 1 (10 mol %), and 4 M. S. (100 mg) in 1 mL solvent at 40 8C for 72 h; [b] yields of isolated product; [c] determined by chiral HPLC analysis; [d] catalyzed by 2 mol % 1. n.d. = not determined.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500823. Chem. Eur. J. 2015, 21, 1 – 6
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Communication cal and biological activities and attract the interest of Table 2. Substrate scope.[a] organic and medicinal chemists.[16] Theoretical calculations disclose the existence of triple hydrogen bonds between the catalyst and the substrate, including an unexpected arene C H···N hydrogenbonding interaction, and suggest that triple hydrogen-bonding interactions are crucial for activating substrates and inducing chirality. We began our study by examining the reaction of 2-(1H-pyrrol-1-yl)aniline (2 a) and a-ketoamide (3 a) using 10 mol % chiral phosphoric acid (1 a) as the catalyst in toluene in the presence of powdered 4 mo90 % yield, 96 % ee 94 % yield, 91 % ee 85 % yield, 91 % ee lecular sieves. The desired product 4 a was obtained in 88 % yield but with very low enantioselectivity (Table 1, entry 1). We next evaluated chiral SPAs with different substituents at the 6- and 6’-positions (Table 1, entries 1–5). The sterically congested phosphoric acid catalysts were found to be important for enantioselective control. Catalyst 1 b provided prod87 % yield, 95 % ee 89 % yield, 98 % ee 88 % yield, 98 % ee uct 4 a with slightly improved enantioselectivity and the absolute configuration opposite to that induced by catalyst 1 a, albeit in the highest yield (Table 1, entry 2), whereas catalyst 1 c, with 6,6’-bis(4-biphenyl) moieties, exhibited no catalytic activity (Table 1, entry 3). To our delight, catalyst 1 d, with 6,6’-bis(9phenanthryl) moieties, gave excellent yield and the highest enantioselectivity (90 % yield and 96 % ee; 87 % yield, 99 % ee 90 % yield, 96 % ee 90 % yield, 81 % ee Table 1, entry 4). The desired product 4 a was obtained in 85 % yield with 91 % ee when catalyst 1 e, with 6,6’-bis(9-anthracenyl) moieties, was employed (Table 1, entry 5). Screening of solvents was next carried out. The reaction could also run in benzene and chloroform to give the corresponding product 4 a in good yields and enantioselectivities (Table 1, entries 7 92 % yield, 86 % ee 85 % yield, 83 % ee[b] 85 % yield, 75 % ee and 8), whereas the reaction hardly occurred in coordinating solvents, such as acetonitrile or tetrahydrofuran (Table 1, entries 9 and 10). In addition, the reaction with 2 mol % catalyst 1 d also proceeded well to afford the corresponding product in slightly reduced yield without compromising the enantioselectivity (Table 1, entry 11). With the optimized reaction conditions in hand (Table 1, entry 4), we next turned our attention to assessing the substrate scope of the asymmetric Pictet–Spengler reaction (Table 2). Firstly, the effect of the substituents on the N-aryl ring (Ar2) of a-phenyl86 % yield, 94 % ee[c] X-ray crystal structure of 4 b ketoamide 3 was investigated by examining their reaction with 2-(1H-pyrrol-1-yl)aniline 2 a. The corre[a] Reactions were performed with 2 a (0.1 mmol), 3 a (0.12 mmol), 1 (10 mol %), and 4 M. S. (100 mg) in toluene (1 mL) at 40 8C for 72 h. Yields are of Isolated product. sponding products were obtained in good yields and Enantioselectivity was determined by chiral HPLC; [b] heated at 80 8C; [c] heated at excellent enantioselectivities (4 a–d, 85–94 % yield, reflux. 91–96 % ee), irrespective of the electronic and steric properties of the substituents on Ar2. The investigation of the substituent effect of the Ar1 moiety exhibduction in the enantioselectivity was found in the reaction of ited that different halide groups, such as F, Cl, or Br, with 12-(1H-pyrrol-1-yl)aniline 2 a with a halide substituent at Ar1 and naphthyl as Ar2 moiety were all well tolerated, and the corresponding products were obtained in excellent yields and enan2,6-difluorophenyl as Ar2 (4 i–k, 85–92 % yield, 81–86 % ee). tioselectivities (4 e–h, 87–90 % yield, 96–99 % ee). A slight reMoreover, the substituent on the aromatic ring of the 2-(1H&
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Communication pyrrol-1-yl)anilines has a marked effect on the stereoselectivity. Introduction of an electron-donating group (CH3) resulted in a noticeable decrease in the enantioselectivity, albeit with good yield (4 l, 85 % yield, 75 % ee), whereas introduction of bromide at the same position gave the product 4 m with no erosion of yield or enantioselectivity (86 % yield, 94 % ee). The absolute configuration (R) of the quaternary stereogenic center in product 4 was determined by X-ray crystallographic analysis of a single crystal of 4 b.[17] To establish whether this process is readily scalable, we next carried out a scale-up experiment with 3.0 mmol of 2 a (Scheme 1). This reaction proceeded without compromising
Scheme 1. Gram-scale preparation of 4 b.
the yield or enantioselectivity and the desired product 4 b was isolated in 92 % yield and 91 % ee, alongside 95 % recovery of catalyst 1 d. Moreover, the enantioselectivity could be easily increased to 98 % ee with 80 % yield by a single recrystallization. To gain mechanistic insight into this asymmetric Pictet– Spengler reaction, N-methyl-2-oxo-N,2-diphenylacetamide 3 b’ was investigated by examining its reaction with 2-(1H-pyrrol-1yl)aniline 2 a under optimized conditions (Scheme 2), but no desired product was observed, even after heating to reflux. We suspect that the N H bond of a-ketoamides 3 is crucial for the activation of substrates by the SPA catalyst in this Pictet–Spengler reaction (see below).
Figure 1. Optimized transition states: a) TS-R: Re face, DDG (toluene) = 0.0 kcal mol 1; b) TS-S: Si face, DDG (toluene) = +1.6 kcal mol 1. Distances are given in .
Figure 2. Proposed mechanistic model.
Scheme 2. SPA-catalyzed Pictet–Spengler reaction.
3 b’ is a poor substrate for this reaction (Scheme 2). Moreover, the chiral phosphoric acid concurrently activates both the nucleophilic group and the electrophilic group of the substrate through a two-point catalyst–substrate hydrogen-bonding interaction. The triple hydrogen bonds hold the transition structure rigidly and allow the catalyst’s 9-phenanthryl groups to influence the enantioselectivity. Thus, computational studies of the present catalytic reaction have shown that the directing effect of the triple hydrogen-bonding interaction is crucial in the catalyst activating the reaction and inducing chirality. In conclusion, we have developed a chiral phosphoric acidcatalyzed highly asymmetric Pictet–Spengler reaction of 2-(1Hpyrrol-1-yl)anilines and a-ketoamides. This protocol provides a facile and highly efficient access to functionalized pyrrolo-
To further understand the mechanism and the origin of enantioselectivity, we performed computational studies for the transition-state structure leading to the major product (R)-4 b. The transition states TS-R and TS-S are represented in Figure 1. The Re face attack TS-R is predicted to be more favored than the Si face attack TS-S by 1.6 kcal mol 1 after adding the solvent free energy (see the Supporting Information). This is in agreement with the experimental results, and the proposed mechanistic model is also shown in Figure 2. In addition, an unexpected attractive non-classical arene C H···N hydrogen bond is evident in the calculated complex, and consistent with the observation that N-methyl-2-oxo-N,2-diphenylacetamide Chem. Eur. J. 2015, 21, 1 – 6
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Communication benzo-1,4-diazine compounds with an amide-containing quaternary stereocenter in good to excellent yields and enantioselectivities by a simple scalable experimental procedure. More importantly, computational studies support the belief that the chiral phosphoric acid catalyst employs attractive arene C H···N hydrogen bonding to activate the substrate and induce chirality through triple hydrogen-bonding interactions. This is an exceptionally rare example in asymmetric Brønsted acid catalysis. Development of novel catalytic asymmetric reactions through triply hydrogen-bond-directed enantioselective assembly is currently underway.
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Acknowledgements We thank the National Natural Science Foundation of China (21272202 and J1210042) and the Fundamental Research Funds for the Central Universities. [13]
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COMMUNICATION & Asymmetric Catalysis
Tales of the unexpected: An efficient triply hydrogen-bond-directed enantioselective assembly of pyrrolobenzo-1,4diazine skeletons with quaternary stereocenters by chiral Brønsted acid-catalyzed Pictet–Spengler reaction has been developed. Theoretical calculations reveal that the chiral phosphoric acid catalyst employs unexpected arene C H···N hydrogen bonding for activation and stereoinduction. SPA = spirocyclic phosphoric acid.
X. Shen, Y. Wang, T. Wu, Z. Mao, X. Lin* && – && Triply Hydrogen-Bond-Directed Enantioselective Assembly of Pyrrolobenzo-1,4-diazine Skeletons with Quaternary Stereocenters
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