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Journal ArticleDOI: 10.1002/ANIE.202100363

Catalytic and Enantioselective Control of the C–N Stereogenic Axis via the Pictet–Spengler Reaction

02 Mar 2021-Angewandte Chemie (Wiley)-Vol. 60, Iss: 22, pp 12279-12283
Abstract: An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-β-carbolines with C-N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron-withdrawing group-substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.

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Topics: Axial chirality (60%), Enantioselective synthesis (53%), Kinetic resolution (52%) ... show more
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5 results found


Open accessJournal ArticleDOI: 10.1039/D1SC05161J
Wen-Lei Xu1, Wei-Ming Zhao1, Ru-Xia Zhang1, Jie Chen1  +1 moreInstitutions (1)
30 Oct 2021-Chemical Science
Abstract: The first chiral phosphoric acid (CPA) catalyzed cycloaddition-elimination cascade reaction of 2-naphthol- and phenol-derived enecarbamates with azonaphthalenes has been established, providing the highly atroposelective route to an array of axially chiral aryl-C3-benzoindoles in excellent yields with excellent enantioselectivities. The success of this strategy derives from stepwise process involving CPA-catalyzed asymmetric formal [3+2] cycloaddition and subsequent central-to-axial chirality conversion by elimination of a carbamate. In addition, the practicality of this reaction had been verified by varieties of transformations towards functionalized atropisomers.

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Topics: Cascade reaction (55%), Cycloaddition (54%)

1 Citations


Journal ArticleDOI: 10.1002/CCTC.202100539
Xiao-Long He1, Cheng Wang1, You-Wu Wen1, Zhouyu Wang1  +1 moreInstitutions (1)
20 Aug 2021-Chemcatchem
Abstract: Pentatomic heterobiaryl performs as a key structural motif in various natural products and bioactive compounds. With the rapid growth of asymmetric catalysis, five‐membered heterobiaryl‐based catalysts and ligands have emerged as an efficient complementary toolbox for asymmetric catalysis. Therefore, the development of enantioselective construction of such pentatomic atropisomers has received significant attention in recent decade. Various catalytic asymmetric strategies have been established, including central to axial chirality conversion, direct generation of heteroaryl, direct assembly of aryl‐heteroaryls, functionalization of racemic or prochiral biaryls, and chirality transfer from atropisomeric alkenes. Hundreds of unprecedented pentatomic atropisomers have proliferated. Importantly, a few promising axially chiral catalysts and ligands have been obtained from the prepared heterobiaryls after simple transformations. Hence, recent advances of catalytic asymmetric construction of axially chiral pentatomic heterobiaryls through asymmetric catalysis are summarized in this review, involving their scope, mechanism, transformations, and applications.

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1 Citations


Journal ArticleDOI: 10.1002/ANIE.202108747
Peng Zhang1, Xiao-Mei Wang1, Qi Xu1, Chang-Qiu Guo1  +3 moreInstitutions (1)
27 Sep 2021-Angewandte Chemie
Abstract: N-C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the enantioselective synthesis of N-C biaryl atropisomers by stereoselective metal-catalyzed aryl amination remains unprecedented. Herein, a Pd-catalyzed cross-coupling strategy is presented for the synthesis of N-C axially chiral biaryl molecules. A broad spectrum of N-C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 % ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules.

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Topics: Buchwald–Hartwig amination (55%), Enantioselective synthesis (55%), Amination (53%) ... show more

1 Citations



Journal ArticleDOI: 10.1016/J.CHEMPR.2021.07.013
Guang-Jian Mei1, Guang-Jian Mei2, Jonathan J. Wong3, Wenrui Zheng1  +3 moreInstitutions (3)
14 Oct 2021-Chem
Abstract: Summary 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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Journal ArticleDOI: 10.1021/JA0491533
Daisuke Uraguchi1, Masahiro Terada1Institutions (1)
Abstract: It was found that the phosphoric acid derivatives of general structure 1 serve as highly effective catalysts for the direct addition of acetyl acetone to N-Boc-protected arylimines. The beneficial effects of the 3,3‘-bisaryl substituents of the catalysts on the enantioselectivity are greatly appreciated, and thus 1d functions as an excellent catalyst. The Bronsted acid-catalyzed direct Mannich reactions presented herein provide an attractive way to construct β-aminoketones under extremely mild conditions. The stereochemical course of this reaction was established through the synthesis of Boc-(S)-phenylglycine methylester. The transformation thus demonstrated is applicable to a useful method for the synthesis of various phenylglycine derivatives.

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Topics: Mannich reaction (61%), Catalysis (51%)

1,056 Citations


Journal ArticleDOI: 10.1021/CR100155E
09 Feb 2011-Chemical Reviews
Abstract: Intellectual curiosity has always been one of the major driving forces leading to new advances in chemistry. At the onset of the 20th century, the fact that biaryls could be optically active even if lacking asymmetrically substituted carbon atoms arose interest, hinting at a novel type of stereomerism. It took quite a while (and some bizarre explanations)1 until in 1922 Christie and Kenner2 first correctly recognized that the phenomenon was the consequence of a hindered rotation about the aryl-aryl single bondshence termed atropisomerism by Kuhn. Still, no particular attention was initially paid to this class of stereoisomers until enantiomerically pure biaryls, such as BINAP (1),3 were found to be excellent ligands in asymmetric catalysis and until the chiral biaryl unit was recognized as the decisive structural element of many natural products (Figure 1).4,5 With the modern screening techniques and the bioassayguided search for novel compounds, the number of isolated axially chiral natural biaryls is steadily increasing.4 This class of secondary metabolites is characterized by a broad structural diversity, reaching from relatively simple molecules like the C2-symmetric biphenyl 2, which solely contains the element of axial chirality,6 to more complex compounds, like, e.g., the dimeric naphthylisoquinoline alkaloids michellamine A [(P,P)-3] and its axial epimer (i.e., its atropodiastereomer), michellamine B [(P,M)-3],7,8 which possess even three biaryl axes, of which the two outer ones are stereogenic, while * To whom correspondence should be addressed. E-mail: bringmann@ chemie.uni-wuerzburg.de; breuning@chemie.uni-wuerzburg.de. † These authors contributed equally to this work. ‡ Present address: Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany. § Present address: Kekulé Institute of Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk Str. 1, 53121 Bonn, Germany. Gerhard Bringmann was born in 1951 and studied chemistry in Gie en and Münster, Germany. After his Ph.D. with Prof. B. Franck in 1978 and postdoctoral studies with Prof. Sir D. H. R. Barton in Gif-sur-Yvette (France), he passed his habilitation at the University of Münster in 1984. In 1986, he received offers for full professorships of Organic Chemistry at the Universities of Vienna and Würzburg, of which he accepted the latter in 1987. In 1998, he was offered the position of director at the Leibniz Institute of Plant Biochemistry in Halle, which he declined. His research interests focus on the field of analytical, synthetic, and computational natural product chemistry, i.e., on axially chiral biaryls. He received several prizes and awards, among them the Otto-Klung Award in chemistry (1988), the Prize for Good Teaching of the Free State of Bavaria (1999), the Adolf-Windaus Medal (2006), the Honorary Doctorate of the University of Kinshasa (2006), the Paul-J.-Scheuer Award (2007), and the Honorary Guest Professorship of Peking University (2008). Chem. Rev. 2011, 111, 563–639 563

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Topics: Total synthesis (54%)

730 Citations