An Iridium Catalytic System Compatible with Inorganic and Organic Nitrogen Sources for Dual Asymmetric Reductive Amination Reactions

Gao, Zhaofeng; Li, Jingwen; Huang, Hefei; Geng, Hua; Chang, Mingxin

doi:10.1002/anie.202112671

Cited by 22 publications

(10 citation statements)

References 68 publications

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“…In 2021, the Chang group developed an iridiumcatalyzed ERA of alkyl aryl ketones 41 with NH 4 OAc as the nitrogen source (Scheme 21). 30 Different from Ru-catalyzed ERA reactions, the initially generated primary amine could serve as an organic amine source that underwent further reductive amination, thus providing secondary amines 42 as the final product. The use of a monophosphine ligand L1 provided the highest ee values after optimization.…”

Section: Short Review Synthesismentioning

confidence: 99%

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

et al. 2022

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Chiral primary amines widely exist in drugs and are exceptionally important subunits or synthons toward the syntheses of chiral secondary and tertiary amines of medicinal interest. Metal-catalyzed enantioselective reductive amination (ERA) of ketones with ammonium salts or ammonia provides a direct method for the synthesis of them. Although very useful, progress in this field is very slow and important advance has just been achieved in the last few years. Several major challenges exist in this reaction, including 1) the reversible formation of unstable NH imine intermediates; 2) the strong coordination property of N-containing reagents toward metal species ; 3) the lack of efficient catalytic systems that enable high enantiocontrol. Generally, the efficiency and enantiocontrol of this reaction is dependent on substrate types, for instance, α-keto esters/amides or aryl alkyl ketones have been well established and even used in industrial production of chiral amine drugs. However, highly enantioselective control on dialkyl ketones, cyclic ketones and α-keto acids remains unsolved. Herein, the historical development of ERA reactions with ammonium salts or ammonia gas are summarized, and the novel synthetic applications toward useful synthons or drugs are presented. In addition, the bottlenecks of this method are also discussed in the review.

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Section: Short Review Synthesismentioning

confidence: 99%

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

et al. 2022

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“…虽然氢气作还原剂条件下, 铵盐参与的不对称还原胺化反应已得到一定程度的发展, 底物范围也有所拓宽, 但面临着催化体系单一的问题, 目前大部分报道均采用了同一种类型的催化剂, 即手性双膦-Ru(OAc) 2 络合物 [31] . 尽管手性双膦配体种类繁多, 但以目前的结果来看, 这类配体形成的催化剂很难解决一些挑战性底物, 如烷基-烷基酮、 α-酮酸(酯)等.…”

Section: 手性 Ir 络合物催化的不对称还原胺化unclassified

Advances on Asymmetric Reductive Amination with Ammonium Salts as Amine Sources

Dai¹,

Zhang²,

Yin³

2022

Chinese Journal of Organic Chemistry

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α-Chiral primary amine subunits are widespread structural units in a large number of pharmaceutical molecules and are key intermediates toward the preparation of numerous amine-containing drugs. Versatile functionalizations on the NH2 group also supply a quick way to construct molecular complexity. Additionally, chiral primary amines can serve as ligands or organocatalysts which can be applied in organic synthesis. Therefore, efficient synthetic routes toward chiral primary amines have attracted tremendous attention. Asymmetric chemo-catalytic reactions that are capable of directly preparing chiral primary amines remain scarce. Transition-metal-catalyzed asymmetric reductive amination (ARA), a reaction type that transforms easily available ketones and amines into chiral amines in the presence of a chiral metal-catalyst and reductant, is among the most straightforward methods to access chiral amines. However, studies on ARA are still limited compared to that on imine hydrogenation, probably due to the presence of competitive ketone reduction as the side reaction. ARA using ammonium salts as the amine sources can directly yield chiral primary amines from prochiral ketones and are thus highly attractive and of great significance. In addition to competition with ketone reduction process, this reaction also faces some other challenges, including: (1) NH3 or the produced primary amines can coordinate to the metal center which results in catalyst poisoning effect; (2) the coordination of amine ligand to the metal center may lead to ligand exchange that enhances the challenge on asymmetric control; (3) the produced primary amines may undergo further alkylation process via double reductive amination, thus providing more complicated outcome. The existing problems and challenges in ARA require urgent development of applicable catalytic systems. Aiming to solve some challenges in the field of ARA with ammonium salts, we have carried out systematic studies and will present the latest progress achieved from our team in this account.

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“…For the transition-metal-catalyzed DARA, as some progress has been made, the applicable scope of the amine coupling partners are still very limited. Apart from the intramolecular DARAs 16 – 23 , most reported N-sources of DARAs generally fall into three categories: inorganic ammonium salts 24 – 29 /ammonia 30 for the synthesis of primary amines; aryl amines 31 – 35 , the popularly applied N-sources, albeit often times the N -Ar group in the product is not desired and needs to be removed, which lead to secondary chiral amine products; and one example of secondary amine sources for the construction of tertiary chiral amine products 36 . Besides, there are some other sporadically reported special amines, including benzyl amines 37 , 38 , diphenylmethylamine 39 – 41 , hydrazine 42 , and hydrazides 43 , 44 .…”

Section: Introductionmentioning

confidence: 99%

Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources

Wang

Guo

et al. 2022

Nat Commun

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Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.

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An Iridium Catalytic System Compatible with Inorganic and Organic Nitrogen Sources for Dual Asymmetric Reductive Amination Reactions

Cited by 22 publications

References 68 publications

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

Advances on Asymmetric Reductive Amination with Ammonium Salts as Amine Sources

Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources

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