Highly Enantioselective Zirconium-Catalyzed Cyclization of Aminoalkenes

Manna, Kuntal; Everett, William C.; Schoendorff, George; Ellern, Arkady; Windus, Theresa L.; Sadow, Aaron D.

doi:10.1021/ja4000189

Cited by 81 publications

(63 citation statements)

References 118 publications

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“…20 In particular, substrate N-deuteration increases the % ee of the pyrrolidine product, as does lower reaction temperatures. However, the reaction concentration does not affect the enantiomeric ratio of the products.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…20 The pyrrolidine products are formed as a mixture of two diastereomers containing stereocenters at the C2 position resulting from C− N bond formation and at the C4 position generated by desymmetrization of the prochiral tetrahedral center. Four isomers are possible in total as enantiomeric pairs of two diastereomers.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…This sharp drop had been previously observed in the {S-1}Zr(NMe 2 ) 2 -catalyzed cyclization of aminoalkenes, and we suggested a change in mechanism occurs when the substrate/catalyst ratio drops below 2. 20 In contrast, the cis:trans ratio improves in a near-linear fashion as conversion increases (plotted on the left y-axis in Figure 7). This trend is likely related directly to the effect of substrate concentration on diastereoselectivity; as the reaction proceeds, the concentration of the primary aminodialkene decreases and the cis:trans ratio increases.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

“…Previously, we reported that the catalyst generated from {S-1}Zr(NMe 2 ) 2 is less enantioselective and less active for the formation of 2-methyl-5,5-disubstituted-piperidines than 2-methyl-4,4-disubstituted-pyrrolidines. 20 Despite this limitation which means that both 2S and 2R stereocenters are abundant in the product 7b, dilute conditions provide a d.r. of 6.6:1.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

“…20 In previous studies of this zirconium catalyst, we have established the experimental parameters that affect the enantioselectivity of the hydroamination/cyclization reactions. Namely, N-deuterated amine substrates are cyclized with higher enantioselectivity than perproteo analogues, the concentration of the reaction mixture does not significantly affect the enantioselectivity, and the products' % ee is highest up to ∼80% conversion.…”

Section: ■ Introductionmentioning

confidence: 99%

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Zirconium-Catalyzed Desymmetrization of Aminodialkenes and Aminodialkynes through Enantioselective Hydroamination

2015

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The catalytic addition of alkenes and amines (hydroamination) typically provides α-or β-amino stereocenters directly through C-N or C-H bond formation. Alternatively, desymmetrization reactions of symmetrical aminodialkenes or aminodialkynes provide access to stereogenic centers with the position controlled by the substrate's structure. In the present study of an enantioselective zirconium-catalyzed hydroamination, stereocenters resulting from C-N bond formation and desymmetrization of a prochiral quaternary center are independently controlled by the catalyst and reaction conditions. Using a single catalyst, the method provides selective access to either diastereomer of optically enriched five-, six-, and seven-membered cyclic amines from aminodialkenes and enantioselective synthesis of five-, six-, and seven-membered cyclic imines from aminodialkynes. Experiments on hydroamination of aminodialkenes testing the effects of the catalyst:substrate ratio, the absolute concentration of the catalyst, and the absolute initial concentration of the primary amine substrate show that the latter parameter strongly influences the stereoselectivity of the desymmetrization process, whereas the absolute configuration of the α-amino stereocenter generated by C-N bond formation is not affected by these parameters. Interestingly, isotopic substitution (H2NR vs D2NR) of the substrate enhances the stereoselectivity of the enantioselective and diastereoselective processes in aminodialkene cyclization and the peripheral stereocenter in aminodialkyne desymmetrization/cyclization. ABSTRACT: The catalytic addition of alkenes and amines (hydroamination) typically provides α-or β-amino stereocenters directly through C−N or C−H bond formation. Alternatively, desymmetrization reactions of symmetrical aminodialkenes or aminodialkynes provide access to stereogenic centers with the position controlled by the substrate's structure. In the present study of an enantioselective zirconium-catalyzed hydroamination, stereocenters resulting from C−N bond formation and desymmetrization of a prochiral quaternary center are independently controlled by the catalyst and reaction conditions. Using a single catalyst, the method provides selective access to either diastereomer of optically enriched five-, six-, and seven-membered cyclic amines from aminodialkenes and enantioselective synthesis of five-, six-, and seven-membered cyclic imines from aminodialkynes. Experiments on hydroamination of aminodialkenes testing the effects of the catalyst:substrate ratio, the absolute concentration of the catalyst, and the absolute initial concentration of the primary amine substrate show that the latter parameter strongly influences the stereoselectivity of the desymmetrization process, whereas the absolute configuration of the α-amino stereocenter generated by C−N bond formation is not affected by these parameters. Interestingly, isotopic substitution (H 2 NR vs D 2 NR) of the substrate enhances the stereoselectivity of the enantioselective and diastereoselecti...

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Zirconium-Catalyzed Desymmetrization of Aminodialkenes and Aminodialkynes through Enantioselective Hydroamination

2015

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Hydroamination of Alkenes

Reznichenko

Hultzsch

2015

Organic Reactions

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The addition of an amine NH‐functionality to alkenes (including vinyl arenes, conjugated dienes, allenes or ring‐strained alkenes), the so‐called hydroamination, represents a simple and highly atom‐economical approach for the synthesis of nitrogen‐containing products. A large variety of catalyst systems are available, ranging from alkali, alkaline earth, rare earth, Group 4 and Group 5 metals, to late transition metal catalysts, and, less prominent, Brønsted and Lewis acid‐based catalyst systems. The mode of operation of these catalyst systems can vary significantly and the different reaction mechanisms and the scope and limitations are discussed. While intramolecular hydroamination reactions can be readily achieved with a large number of catalyst systems, significantly fewer examples for the more challenging intermolecular hydroamination are known, especially for unactivated alkenes. The stereoselective hydroamination has also received significant attention due to the importance of chiral nitrogen‐containing molecules in pharmaceutical industry. A variety of highly selective chiral catalyst systems have been developed for intramolecular hydroaminations, while examples of intermolecular asymmetric hydroaminations are scarce. Hydroamination in the context of this review article is defined as the addition of HNR 2 across a non‐activated, unsaturated carbon‐carbon multiple bond. This review focuses on the hydroamination reaction of simple, non‐activated alkenes. The addition of amines to slightly activated alkenes, such as vinyl arenes, 1,3‐dienes, strained alkenes (norbornene derivatives, methylenecyclopropenes) and allenes is closely related and is covered as well. However, hydroamination reactions of alkynes and Aza‐Michael reactions involving the addition of an N‐H fragment across the conjugated or otherwise activated double bond of a Michael acceptor are not covered. The scope of amine types includes ammonia, primary and secondary aliphatic and aromatic amines, azoles, and hydrazines. N ‐Protected amines, such as ureas, carboxamides, and sulfonamides are covered as well, as they are important substrates for metal‐free and late transition metal‐based catalysts. The literature through January 2011 will be covered with two selected references from 2012 (comprising Table 3D). A supplemental reference list is provided for reports appearing February 2011 through April 2015. The chapter is organized by the nature of the carbon unsaturation to which the amine is added. Ranging from less reactive substrates such as ethylene and unactivated alkenes, to slightly activated substrates, such as vinyl arenes, and more activated substrates, including conjugated dienes, allenes and strained alkenes. Enantioselective hydroamination reactions, an area that has seen significant progress over the past decade, are discussed next. Finally, tandem hydroamination/carbocyclization reactions of aminodialkenes provide rapid access to complex alkaloidal skeletons. The tables at the end of the chapter are separated into five main sections: achiral intermolecular hydroamination, achiral intramolecular hydroamination, enantioselective intermolecular hydroamination, enantioselective intramolecular hydroamination, and tandem hydroamination/carbocyclization. Within the first four sections the tables are further divided into subsections based on the participating alkene, i.e. alkenes, vinyl arenes, dienes, allenes, and strained alkenes.

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Addition Reactions: Polar Addition

Kočovský¹

2016

Organic Reaction Mechanisms · 2013

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Highly Enantioselective Zirconium-Catalyzed Cyclization of Aminoalkenes

Cited by 81 publications

References 118 publications

Zirconium-Catalyzed Desymmetrization of Aminodialkenes and Aminodialkynes through Enantioselective Hydroamination

Zirconium-Catalyzed Desymmetrization of Aminodialkenes and Aminodialkynes through Enantioselective Hydroamination

Hydroamination of Alkenes

Addition Reactions: Polar Addition

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