Highly Diastereo- and Enantioselective Access to <i>syn</i>-α-Amido β-Hydroxy Esters via Ruthenium-Catalyzed Dynamic Kinetic Resolution-Asymmetric Hydrogenation

Lü, Bin; Wu, Xiaoyu; Li, Chengyang; Ding, Guo-Hui; Li, Wanfang; Xie, Xiaomin; Zhang, Zhaoguo

doi:10.1021/acs.joc.8b03106

Cited by 15 publications

(4 citation statements)

References 70 publications

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“…Asymmetric reduction via dynamic kinetic resolution (DKR) is regarded as a powerful synthetic method to simultaneously set up two adjacent stereogenic centers in a single transformation from racemic substrates. , Recently, we developed an efficient asymmetric synthesis of enantiomeric pure syn -aryl β-hydroxy-α-dibenzylamino esters via a DKR asymmetric transfer hydrogenation (DKR-ATH) in high yields . Excellent diastereoselectivity and enantioselectivity were obtained using an oxo-tethered Ru(II) catalyst that could be applied to a wide range of substrates.…”

Section: Introductionmentioning

confidence: 64%

Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Sun

Jian

Luo

et al. 2019

Org. Process Res. Dev.

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An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available 1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient ruthenium-catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr and 99.7% ee on a 100 g scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to scale-up. This process not only gives a desirable total yield but also avoids hazardous conditions and chromatographic purification. The robustness of this synthesis was successfully performed on a multigram scale to afford 1 with >99.9% de and >99.9% ee in 56.8% overall yield in nine steps.

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Section: Introductionmentioning

confidence: 64%

Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Sun

Jian

Luo

et al. 2019

Org. Process Res. Dev.

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“…Zhang and co-workers described the synthesis of syn-amido--hydroxy esters through AH/DKR of the corresponding -amido--keto esters using the preformed complex [RuCl(p-cymene)(S)-SunPhos]Cl obtained from [Ru-Cl 2 (p-cymene)] 2 and (S)-SunPhos [(S)-L6] (Scheme 9). 16 This study revealed the importance of the steric and electronic effects of the substituents on the aryl moiety and that the stereoselectivities were also deeply influenced by the nature of the amino protecting group. The hydrogenation proceeded in 66-96% yields with high reactivity (TON up to 940), 58:42 to >99:1 dr, and 51 to >99% ee.…”

Section: Methodsmentioning

confidence: 88%

Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

et al. 2020

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Based on the ever-increasing demand for enantiomerically pure compounds, the development of efficient, atom-economical, and sustainable methods to produce chiral alcohols and amines is a major concern. Homogeneous asymmetric catalysis with transition-metal complexes including asymmetric hydrogenation (AH) and transfer hydrogenation (ATH) of ketones and imines through dynamic kinetic resolution (DKR) allowing the construction of up to three stereogenic centers is the main focus of the present short review, emphasizing the development of new catalytic systems combined to new classes of substrates and their applications as well.1 Introduction2 Asymmetric Hydrogenation via Dynamic Kinetic Resolution2.1 α-Substituted Ketones2.2 α-Substituted β-Keto Esters and Amides2.3 α-Substituted Esters2.4 Imine Derivatives3 Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution3.1 α-Substituted Ketones3.2 α-Substituted β-Keto Esters, Amides, and Sulfonamides3.3 α,β-Disubstituted Cyclic Ketones3.4 β-Substituted Ketones3.5 Imine Derivatives4. Conclusion

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“…Successively, the organic phases were combined, washed with a saturated sodium bicarbonate aqueous solution (50 mL), filtered, and concentrated in vacuo . The crude product was purified by flash column chromatography (33% EtOAc in petrol) and triturated with Et 2 O to give the carbonyl derivative S7 as a white solid (2.55 g, 14.7 mmol, 40%). R f : 0.36 (90:10 EtOAc:petrol).…”

Section: Experimental Sectionmentioning

confidence: 99%

“…13 Methyl 2-Acetamido-3-oxobutanoate (S7). According to a procedure, 43 a solution of sodium nitrite (3.30 g, 48.0 mmol) in water (4 mL) was added dropwise to a solution of methyl acetoacetate (4.00 mL, 36.8 mmol) in acetic acid (10 mL). After stirring the solution at room temperature for 2 h, water (25 mL) was added and stirred for further 30 min.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients

Acebrón-García-de-Eulate

Mayol-Llinàs

Holland

et al. 2022

J. Med. Chem.

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Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of K d = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with K d = 3.57 μM (LE 0.35).

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Highly Diastereo- and Enantioselective Access to syn-α-Amido β-Hydroxy Esters via Ruthenium-Catalyzed Dynamic Kinetic Resolution-Asymmetric Hydrogenation

Cited by 15 publications

References 70 publications

Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients

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