Direct Asymmetric α‐C−H Addition of N‐unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

Ji, Pengwei; Liu, Xiaopei; Xu, Jiwei; Zhang, Xu; Guo, Jianhua; Chen, Wenwen; Zhao, Baoguo

doi:10.1002/anie.202206111

Cited by 23 publications

(21 citation statements)

References 76 publications

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“…However, inert primary amines with extremely low acidity of the -C-H bonds are still highly challenging in this transformation. In 2022, Zhao and co-workers 28 reported the successful chiral-pyridoxal-catalyzed asymmetric -C-H addition of propargylic amines 31 to trifluoromethyl ketones 22, which provided chiral alkynyl -amino alcohols 32 in good yields with excellent enantioselectivities and high diastereoselectivities (Scheme 14a). The computational studies revealed that the formation of a Schiff base leads to a dramatic increase in the acidity of the -C-H bonds of propargylic amines, from pK a 42.6 to pK a 20.1 (Scheme 14b), which is acidic enough to be deprotonated under the reaction conditions.…”

Section: Short Review Synthesismentioning

confidence: 99%

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

Wen¹,

Guo²

2022

Synthesis

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Asymmetric functionalization of amines and their derivatives is of great significance in synthetic chemistry and is widely used in the preparation of natural products and pharmaceuticals. In recent years, chiral aldehyde catalysis has emerged as a well-established and recognized tool, providing excellent catalytic activation and stereoselective control in asymmetric reactions of N-unprotected amino acid esters and amino acid ester analogs. In this Minireview, recent advances in enantioselective aldehyde catalysis, including chiral aldehydes as organocatalysts and co-catalysis combined with transition metals, will be summarized. Lastly, continued development of enantioselective aldehyde catalysis is prospected in the future.

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Section: Short Review Synthesismentioning

confidence: 99%

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

Wen¹,

Guo²

2022

Synthesis

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“…Our group has been devoted to the development of vitamin B 6 -based biomimetic asymmetric catalysis by using chiral pyridoxals/pyridoxamines as the catalysts (Figure ). We are particularly interested in biomimetic transamination ,− and α-C–H transformations of glycinates, − ,− respectively, imitating enzymatic transamination and aldol reaction of glycine promoted by threonine aldolase. With chiral pyridoxals/pyridoxamines 32 – 35 , we have developed the asymmetric biomimetic transamination of α-keto acids and α-keto amides.…”

Section: Introductionmentioning

confidence: 99%

“…By the bioinspired carbonyl catalysis strategy, ,, we have achieved asymmetric 1,4-addition of glycinates toward α,β-unsaturated esters and asymmetric α-allylation of glycinate with Morita–Baylis–Hillman acetates, respectively, using pyridoxals 38 and 39 . These studies encouraged us to broaden the scope to more challenging primary amines such as propargylamines and benzylamines, which bear inert α-C–H bonds. Both propargylamines (with pyridoxal 40 ) and benzylamines (with pyridoxal 41 ) were amenable to direct α-C–H transformations, i.e., asymmetric addition to trifluoromethyl ketones and aldehydes, respectively.…”

Section: Introductionmentioning

confidence: 99%

Vitamin B₆-Based Biomimetic Asymmetric Catalysis

Xiao

Zhao

2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: One of the fundamental goals of chemists is to develop highly efficient methods for producing optically active compounds, given their wide range of applications in chemistry, pharmaceutical industry, chemical biology, and material science. Biomimetic asymmetric catalysis, which imitates the structures and functions of enzymes, has emerged as an extremely attractive strategy for producing chiral compounds. This field has drawn tremendous research interest and has led to various protocols for constructing complex molecular scaffolds. The Vitamin B 6 family, including pyridoxal, pyridoxamine, pyridoxine, and the corresponding phosphorylated derivatives, serves as the cofactors to catalyze more than 200 enzymatic functions, accounting for ∼4% of all enzyme activities. Although significant progress has been made in simulating the biological roles of vitamin B 6 during the past several decades, its extraordinary catalytic power has not yet been successfully applied into asymmetric synthesis. In recent years, our group has been devoted to developing vitamin B 6 -based biomimetic asymmetric catalysis using chiral pyridoxals/pyridoxamines as catalysts. We are particularly interested in mimicking the processes of enzymatic transamination and biological aldol reaction of glycine, respectively, developing asymmetric biomimetic transamination and carbonyl catalysis enabled α-C−H transformation of primary amines. Using a chiral α,α-diarylprolinol-derived pyridoxal as the catalyst, we reported the first chiral pyridoxal catalyzed asymmetric transamination of α-keto acids in 2015. A significant breakthrough in biomimetic transamination was achieved by using an axially chiral biaryl pyridoxamine catalyst that bears a lateral amine side arm. The amine side arm acts as an intramolecular base, accelerating the transamination and proving highly effective for transamination of α-keto acids and α-keto amides. In addition, we discovered the catalytic power of chiral pyridoxals as carbonyl catalysts for asymmetric biomimetic Mannich/aldol reactions of glycinates. These chiral pyridoxals also enabled more α-C− H conversions of glycinates, such as asymmetric 1,4-addition toward α,β-unsaturated esters and asymmetric α-allylation with Morita−Baylis−Hillman acetates. Moreover, carbonyl catalysis can be further applied to highly challenging primary amines with inert α-C−H bonds, such as propargylamines and benzylamines, which represents a powerful strategy for direct asymmetric α-C−H functionalization of various primary amines without protection of the NH 2 group. These biomimetic/bioinspired transformations provide efficient new protocols for the synthesis of chiral amines. Herein, we summarize our recent efforts on the development of the vitamin B 6 -based biomimetic asymmetric catalysis.

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“…The unique property of chiral aldehyde catalysis, [21][22][23][24] directly promoting the asymmetric functionalization of Nunprotected amino acid esters, has been demonstrated in alkylation, 25 Michael addition, [26][27][28] Mannich, [29][30] aldol, [31][32][33] allylation, [34][35][36] benzylation, 37 and propargylation 38 reactions. We envisioned that this strategy may be promising for the direct asymmetric hydrocarbylation of amino acid esters with halohydrocarbons.…”

Section: Introductionmentioning

confidence: 99%

Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

Shen

Jiang

et al. 2023

Preprint

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The direct catalytic hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to disubstituted non-proteinogenic amino acid compounds. However, all the re-ported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric arylation, allylation, and benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing disubstituted amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.

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Direct Asymmetric α‐C−H Addition of N‐unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

Cited by 23 publications

References 76 publications

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

Vitamin B₆-Based Biomimetic Asymmetric Catalysis

Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

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Direct Asymmetric α‐C−H Addition of N‐unprotected Propargylic Amines to Trifluoromethyl Ketones by Carbonyl Catalysis

Cited by 23 publications

References 76 publications

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

Recent Advances in Chiral Aldehyde Catalysis for Asymmetric Functionalization of Amines

Vitamin B6-Based Biomimetic Asymmetric Catalysis

Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

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Vitamin B₆-Based Biomimetic Asymmetric Catalysis