Direct asymmetric reductive amination of α-keto acetals: a platform for synthesizing diverse α-functionalized amines

Shi, Yongjie; Wang, Jingxin; Yang, Feifan; Wang, Chenhan; Zhang, Xumu; Chiu, Pauline; Yin, Qin

doi:10.1039/d1cc06601c

Cited by 16 publications

(12 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although all tested complexes displayed good reactivity (86–93 % yield), the enantioselectivities of 2 a varied (Table 1, entries 3–9). Overall, Ru‐complexes ligated with a sterically bulky ligand, including Ru[( R )‐DTBM‐SegPhos](OAc) 2 , Ru[( S , S , R )‐DTBM‐C 3 ‐TunePhos](OAc) 2 and Ru[( R )‐DTBM‐MeOBIPHEP](OAc) 2 , offered better enantiocontrol (Table 1, entries 6–8), with Ru[( R )‐DTBM‐SegPhos](OAc) 2 giving the best result (82 % ee, Table 1, entry 6) [16l] . Next, an optimization of the ammonium salts was conducted, and ammonium salicylate (NH 4 SA), the optimal nitrogen source used in the direct ARA of β‐keto amides, [16b] was found to further improve the ee of 2 a to 96 % (Table 1, entry 10, also see Table S3).…”

Section: Resultsmentioning

confidence: 99%

Highly Enantioselective Synthesis of N‐Unprotected Unnatural α‐Amino Acid Derivatives by Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination

Wang

et al. 2022

Angewandte Chemie

Self Cite

View full text Add to dashboard Cite

An unprecedented highly enantioselective Ru‐catalyzed direct asymmetric reductive amination of α‐keto amides with ammonium salts has been disclosed, efficiently offering valuable enantioenriched N‐unprotected unnatural α‐amino acid derivatives bearing a broad range of aryl or alkyl α‐substituents. This protocol features easily accessible substrates, good functional‐group tolerance and excellent enantiocontrol, making it a good complementary approach to the known methods. Moreover, this method is also applicable to the preparation of N‐unprotected unnatural α‐amino acid derivatives containing an additional stereogenic center at the β‐position through a dynamic kinetic resolution (DKR) process. Convenient transformations of the obtained products into chiral N‐unprotected unnatural α‐amino acids, drug intermediates, peptides, and organocatalysts/ligands further showcase the utility of this method.

show abstract

Section: Resultsmentioning

confidence: 99%

Highly Enantioselective Synthesis of N‐Unprotected Unnatural α‐Amino Acid Derivatives by Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination

Wang

et al. 2022

Angewandte Chemie

Self Cite

View full text Add to dashboard Cite

show abstract

“…-Ketoamides 21 underwent Ru(OAc) 2 (R)-DTBM-SegPhos catalyzed reaction in the presence of 1 equiv of Ti(Oi-Pr) 4 using NH 4 SA as the amine source to give various aryl-or alkyl-substituted primary aminoamides 22 (over 40 examples) (Scheme 15). 24 Treatment of (R)-2-amino-N,N-dimethyl-2-phenylacetamide (22a) with concentrated HCl gave phenylglycine hydrochloride (23) in high yield and with retention of the enantiopurity. Reduction of the amide group of 22i by LiAlH 4 and subsequent acylation resulted in the formation of chiral 1,2-diamine compound 24 with >99% ee, which is a chiral ligand used in asymmetric C-H bond functionalization.…”

Section: Enantioselective Reductive Amination Of -Functionalized Ket...mentioning

confidence: 99%

“…After evaluating a series of -functionalized ketones, in 2022, our group reported an ERA of -keto acetals 22 which afforded diverse -amino acetals with up to >99% ee (Scheme 14). 23 As the precursor of an aldehyde, the product primary -amino acetals could be transformed into various synthetic valuable molecules such as 1,2-amino alcohol 19b and -amino acid 19c or be modified to the secondary amine 19a. Deprotection of 18g-Bz gave the -amino aldehyde 20, an intermediate in the synthesis of (-)-cytoxazone.…”

Section: Enantioselective Reductive Amination Of -Functionalized Ket...mentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…二芳基酮的直接不对称还原胺化具有巨大的挑战性, 除了之前提到的还原胺化反应共同的难点, 其它难点还包括: [24] . 最终, 通过条件优化, 芳基取代的产物可以取得良好的收率以及最高大于 99% ee [25] . 有趣的是, 对于 β 酮酯底物, 反应也能顺利地进行, 当甲醇作溶剂时, 产物 19d 能得到 83%收率和 98% ee.…”

Section: 简单芳基酮不对称还原胺化unclassified

Advances on Asymmetric Reductive Amination with Ammonium Salts as Amine Sources

Dai¹,

Zhang²,

Yin³

2022

Chinese Journal of Organic Chemistry

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Direct asymmetric reductive amination of α-keto acetals: a platform for synthesizing diverse α-functionalized amines

Abstract: We report an efficient and straightforward method to synthesize enantio-enriched N-unprotected α-amino acetals via ruthenium-catalyzed direct asymmetric reductive amination. The α-amino acetal products are versatile and valuable platform molecules that...

Cited by 16 publications

References 54 publications

Highly Enantioselective Synthesis of N‐Unprotected Unnatural α‐Amino Acid Derivatives by Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination

Highly Enantioselective Synthesis of N‐Unprotected Unnatural α‐Amino Acid Derivatives by Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination

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

Advances on Asymmetric Reductive Amination with Ammonium Salts as Amine Sources

Contact Info

Product

Resources

About