Described herein is an imidazole ring formation strategy for the synthesis of axially chiral N-arylbenzimidazoles by means of chiral phosphoric acid catalysis. Two sets of conditions were developed to transform two classes of 2-naphthylamine derivatives into structurally diverse N-arylbenzimidazole atropisomers with excellent chemo- and regioselectivity as well as high levels of enantiocontrol. It is worth reflecting on the unique roles played by the nitroso group in this domino reaction. It functions as a linchpin by first offering an electrophilic site (N) for the initial C-N bond formation while the resulting amine performs the nucleophilic addition to form the second C-N bond. Additionally, it could facilitate the final oxidative aromatization as an oxidant. The atropisomeric products could be conveniently elaborated to a series of axially chiral derivatives, enabling the exploitation of N-arylbenzimidazoles for their potential utilities in asymmetric catalysis.

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C-H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C-N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C-N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.

Functionalization of arenes represents the most efficient approach for constructing a core backbone of important aryl compounds. Compared with the well-developed electrophilic aromatic substitution and transition-metal-catalyzed C-H activation, nucleophilic aromatic substitution remains challenging because of the lack of a convenient route for rapid conversion of the sigma(H) adduct to other stable and versatile intermediates in situ. Guided by computational design, we were able to realize asymmetric nucleophilic aromatic substitution by introducing a nitroso group on naphthalene via chiral phosphoric acid catalysis. This strategy enables efficient construction of atropisomeric indole-naphthalenes and indole-anilines with excellent stereocontrol. Density functional theory (DFT) calculations provide further insights into the origins of enantioselectivity and the reaction mechanisms. The successful application in the synthesis of NOBINs (2-amino-2'-hydroxy-1,1'-binaphthyl) extends the utility of this strategy.

An asymmetric domino reaction was developed utilizing readily available cyclic α-dehydroamino ketones and aldehydes, which when subjected a 2-iodoxybenzoic acid (IBX)-mediated oxidation gives pyrrolidinone-containing tricyclic derivatives. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 94% yield, 99% ee, and >20:1 dr). The product could be conveniently converted to synthetically useful intermediates via simple transformations. A possible stereocontrolled process has been suggested according to X-ray crystallography studies.

A highly enantioselective Pd-catalyzed asymmetric allylic substitution cascade of cyclic N-sulfonylimines with an accompanying asymmetric desymmetrization has been developed for the construction of fused tetrahydroindole derivatives bearing two chiral centers. Mechanistic studies confirmed that the cascade reaction proceeds by initial allylic alkylation and subsequent allylic amination. The first alkylation is a chirality-control step and represents an asymmetric desymmetrization of cis-cyclic allyl diacetates. The reaction has been performed on a gram scale, and the desired products can take part in several transformations.

A Pd-catalyzed asymmetric allylic alkylation of azlactones with 4-arylvinyl-1,3-dioxolan-2-ones was developed, providing "branched" chiral α-amino acids with vicinal tertiary and quaternary stereocenters, in high yields and with excellent selectivities. Mechanistic studies revealed that the formation of a hydrogen bond between the Pd-allylic complex and azlactone isomer is responsible for the excellent regioselectivities. This asymmetric alkylation can be carried out on a gram scale without a loss of catalytic efficiency, and the resulting product can be further transformed to a chiral azetidine in two simple steps.

An interesting temperature-controlled switchable o,o′-dilithiation of chiral bisoxazoline ferrocene was developed for the preparation of three kinds of ferrocene bis(oxazoline-phosphine) ligands with different planar chiralities. Diastereoselectivities of more than 4.5/1 were obtained. As a result of their different planar chiralities, the ligands 1∼3 exhibit different coordination behaviors with PdCl2(MeCN)2.

An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and α,β-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives.

ChemInformVolume 46, Issue 24 Heterocyclic Compounds ChemInform Abstract: Asymmetric Tandem Reactions of N-Sulfonylimines and α,β-Unsaturated Aldehydes: An Alternative Reaction Pathway to that of Using Saturated Aldehydes. Qianjin An, Qianjin An Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorJing Li, Jing Li Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorJiefeng Shen, Jiefeng Shen Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorNicholas Butt, Nicholas Butt Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorDelong Liu, Delong Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorYangang Liu, Yangang Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorWanbin Zhang, Wanbin Zhang Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this author Qianjin An, Qianjin An Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorJing Li, Jing Li Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorJiefeng Shen, Jiefeng Shen Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorNicholas Butt, Nicholas Butt Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorDelong Liu, Delong Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorYangang Liu, Yangang Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorWanbin Zhang, Wanbin Zhang Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this author First published: 27 May 2015 https://doi.org/10.1002/chin.201524180Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume46, Issue24June, 2015 RelatedInformation

ChemInformVolume 46, Issue 10 Heterocyclic Compounds ChemInform Abstract: Asymmetric Domino Reaction of Cyclic N-Sulfonylimines and Simple Aldehydes with trans-Perhydroindolic Acid as an Organocatalyst. Qianjin An, Qianjin An Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorJiefeng Shen, Jiefeng Shen Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorNicholas Butt, Nicholas Butt Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorDelong Liu, Delong Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorYangang Liu, Yangang Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorWanbin Zhang, Wanbin Zhang Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this author Qianjin An, Qianjin An Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorJiefeng Shen, Jiefeng Shen Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorNicholas Butt, Nicholas Butt Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorDelong Liu, Delong Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorYangang Liu, Yangang Liu Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this authorWanbin Zhang, Wanbin Zhang Sch. Pharm., Shanghai Jiaotong Univ., Shanghai 200240, Peop. Rep. ChinaSearch for more papers by this author First published: 19 February 2015 https://doi.org/10.1002/chin.201510210Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume46, Issue10March, 2015 RelatedInformation

An efficient trans-perhydroindolic acid-catalyzed asymmetric aza-Diels-Alder reaction of cyclic 1-azadienes and propanal was developed for the synthesis of chiral 3-methyl-4-aryldehydropiperidine derivatives (up to 98% yield and 99% ee). Such scaffolds are often found in bioactive compounds and medicines. A gram scale reaction was carried out with a low catalyst loading to give the desired product in high yield and with excellent enantioselectivity. The resulting dehydropiperidine derivatives can be further transformed to chiral 3-methyl-4-aryl-substituted piperidines with high efficiency.

An asymmetric domino reaction was developed utilizing readily available cyclic N-sulfonylimines and simple aldehydes to construct biologically important and synthetically challenging piperidine derivatives consisting of three contiguous stereocenters. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 89% yield, 80:20 dr, and 99% ee). The absolute configuration of the catalytic product was determined by X-ray crystallography studies. The product could be conveniently converted to synthetically useful intermediates, such as (3R,4S)-4-ethyl-3-methyl-6-phenylpiperidinyridin-2-one (8), via a simple transformation.

AbstractA synthetic route towards trans‐perhydroindolic acid (VI), a key intermediate for preparation of trandolapril, as a mixture of four isomers is developed.

The key intermediate of antihypertensive drugs trandolapril, (25,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate, was synthesized by improvement of synthetic route and optimation of synthetic technology with satisfactory results (99% ee and 13.2% overall yield). The structure and absolute configuration of the product were characterized by NMR. and HPLC analysis, which are completely consistent with the reported data of the literature. It was obvious that the current methodology provided an efficient pathway for the synthesis of trandolapril.

An asymmetric domino double Michael addition reaction was developed using accessible substrates to construct biologically important and synthetically challenging cyclopentanes with four contiguous stereocenters. The proline-like molecules, trans-perhydroindolic acids, proved to be efficient organocatalysts in this reaction. Under the optimal reaction conditions, the asymmetric domino double Michael addition provided good yields (up to 98%), and excellent diastereoselectivities (up to 100% dr) and enantioselectivities (up to 99% ee). The obtained polysubstituted aliphatic cyclopentanes not only exist in biologically active natural products and medicines, but can also be converted into many other useful scaffolds via a simple transformation, such as cis-fused bicyclic lactams. Our current methodology is suitable for the synthesis of polysubstituted aliphatic cyclopentanes with contiguous multiple stereocenters.

(2S,3aR,7aS)-Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans-isomers, were readily prepared. These proline-like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with β,γ-unsaturated α-keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi-substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of β,γ-unsaturated α-keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyrano[2,3-b]pyrans (possessing a multi-substituted bicyclic backbone).

An efficient asymmetric domino reaction of amino aldehyde to beta,gamma-unsaturated alpha-keto esters was achieved by using trans-perhydroindolic acid 1d as a chiral organocatalyst with excellent asymmetric behavior. Under the optimal reaction conditions, products with more than 99% de and up to 93% ee were obtained in high chemical yield (up to 98%) for a series of beta,gamma-unsaturated a-keto esters. The methodology provided an efficient route to dihydropyran derivatives containing many substituent groups (including amino groups).