Enantioselective Ruthenium(II)/Xyl-SunPhos/Daipen-Catalyzed Hydrogenation of γ-Ketoamides

Zhao, Mengmeng; Li, Wanfang; Li, Xiaoming; Ren, Kai; Tao, Xiaoming; Xie, Xiaomin; Ayad, Tahar; Ratovelomanana‐Vidal, Virginie; Zhang, Zhaoguo

doi:10.1021/jo5008916

Cited by 15 publications

(6 citation statements)

References 74 publications

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“…For the variation of the northern side chain several nonaromatic heterocyclic acids 6 – 8 were synthesized by acylating piperidine, morpholine, and N -methylpiperazine, respectively, with succinic anhydride at room temperature. , The aromatic heterocyclic acids 9 , 10 were obtained by a Friedel–Crafts acylation of furan and thiophene with succinic anhydride as well , (Scheme ). The remaining carboxylic acids were commercially available.…”

Section: Resultsmentioning

confidence: 99%

“…The crude mixture was purified by flash column chromatography (DCM/MeOH: 99/1) to afford compound 1 (2.37 g, 4.24 mmol, 80%) as a colorless solid. 1 (24), 263 (10), 218 (15), 180 (35), 174 (13), 167 (29), 108 (10), 91 (100), 84 (19), 79 (13), 59 (12), 57 (43.4), 56 (14), 44 (12), 41 (31), 39 (12), 30 (26), 28 (11) (18), 181 (11), 180 (25), 173 (14), 167 (27), 165 (18), 145 (13), 139 (15), 129 (12), 84 (100), 82 (18), 57 (50), 56 (18), 41 (26), 30 (36) Benzyl (S)-3-{[(S)-5-((tert-Butoxycarbonyl)amino)-6-((2,2diphenylethyl)amino)-6-oxohexyl]carbamoyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate (4). Compound 4 was prepared according to general procedure 1 (GP1).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…13 4-Oxo-4-(thiophen-2-yl)butanoic Acid (9). 29 Compound 9 was prepared according to general procedure 9 (GP6). The crude product was purified by recrystallization (H 2 O) to afford compound 9 (1.38 mg, 7.5 mmol, 63%) as a light yellow solid.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

et al. 2016

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In this work we report a design, synthesis, and detailed functional characterization of unique strongly biased allosteric agonists of CXCR3 that contain tetrahydroisoquinoline carboxamide cores. Compound 11 (FAUC1036) is the first strongly biased allosteric agonist of CXCR3 that selectively induces weak chemotaxis and leads to receptor internalization and the β-arrestin 2 recruitment with potency comparable to that of the chemokine CXCL11 without any activation of G proteins. A subtle structural change (addition of a methoxy group, 14 (FAUC1104)) led to a contrasting biased allosteric partial agonist that activated solely G proteins, induced chemotaxis, but failed to induce receptor internalization or β-arrestin 2 recruitment. Concomitant structure-activity relationship studies indicated very steep structure-activity relationships, which steer the ligand bias between the β-arrestin 2 and G protein pathway. Overall, the information presented provides a powerful platform for further development and rational design of strongly biased allosteric agonists of CXCR3.

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Section: Resultsmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

et al. 2016

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“…Higher reaction temperature led to as light drop of the ee value (entries 7,8), whereas al ower temperature dramatically reduced the reaction rate and moderately decreased the enantiomeric excess (entry 6). Performing the reaction at al ower pressure resulted in slightly lower yields of the desired product 2a,t houghh igh enantioselectivities remained (entry 1v s. entries 10,11). On the basis of the above results, the optimized reaction conditions were using 0.5 mol %o f[ RuCl(benzene)(S)-SunPhos]Cla st he catalyst and MeOH as the solvent with as ubstrate concentration of 0.5 m under 40 atm of H 2 at 50 8Cfor 12 h.…”

Section: Entrymentioning

confidence: 99%

Ruthenium‐Catalyzed Enantioselective Hydrogenation/Lactonization of 2‐Acylarylcarboxylates: Direct Access to Chiral 3‐Substituted Phthalides

et al. 2017

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Highly enantioselective tandem hydrogenation/lactonization of various 2‐acylarylcarboxylates including 2‐aroylarylcarboxylates were realized by using [RuCl(benzene)(S)‐SunPhos]Cl as the catalyst under mild reaction conditions. Excellent enantioselectivities (up to 99.6 % ee) and activities (S/C=1000) were obtained. This convenient and practical method enables a direct access to a series of highly optically pure 3‐substituted phthalides that are very important molecules as valuable pharmacological compounds and diversified synthons for medicinal chemistry. Moreover, a gram‐scale reaction was performed to further demonstrate the practicality of this approach.

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“…This moderate ee implied that the amide group might be too far away to direct the enantioinduction of the hydrogenation. When γ‐ketoamides were hydrogenated as simple ketones, excellent ee values were obtained when R was an aryl or heteroaryl (Scheme ) 51. For alkyl substrates ( 34o and 34p ), the reactivity was lower and the ee values were less than 10%.…”

Section: γ‐ and δ‐Functionalized Ketones And Simple Ketonesmentioning

confidence: 99%

A Decennary Journey towards the Efficient Asymmetric Hydrogenation of Highly Functionalized Ketones

Lü

Zhang

2016

The Chemical Record

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Around 2006, our group launched a long-term project on the asymmetric hydrogenation of functionalized ketones by using ruthenium complexes with SunPhos ligands. In this review, we recount the burgeoning and blossoming of this project. At the outset, we attempted some benchmark reactions with an array of monofunctionalized ketones, including α- and β-keto esters/amides, β-keto sulfones, phosphonates, and α-hydroxy ketones. For α-keto esters and amides, we discovered that CeCl •7H O was an efficient additive for both activity and enantioselectivity. The element iodine was found to be a valid additive for β-keto sulfones. β,γ-Unsaturated α-keto acids and esters were also hydrogenated to the saturated chiral blocks with good enantioselectivity and a high turnover number. For the α-substituted β-keto esters and phosphonates, exceptionally high stereoselectivity was achieved through dynamic kinetic resolution. Based on these incipient successes, we diverted to bifunctionalized ketone substrates, such as γ-heteroatom-substituted β-keto esters and δ-ketal-β-keto esters. For the δ-ketal-β-keto esters, CaCO was added to stabilize the δ-ketal groups, which ensured the formation of δ-ketal-β-hydroxy esters in good yields and high ee values. More interestingly, γ-halo-γ,δ-unsaturated-β-keto esters were hydrogenated to afford highly enantiopure chiral allyl alcohols under mild and neutral conditions. The distance effect of the directing groups was investigated in β-, γ-, and δ-keto amides; the last two were hydrogenated with the Ru-SunPhos-diamine system. To implement the pinpoint recognition of two carbonyl groups in similar chemical propinquity, we compared the reaction rates of different β-keto acid derivatives. THF was found to be a helpful coordinative solvent to control the chemo- and enantioselectivity for more challenging polycarbonyl substrates, such as 3-oxo glutaric acid derivatives, β,δ-diketo carboxamides, and γ-heteroatom-substituted β-diketones. The effects of solvents and heteroatoms in these substrates were also studied. Applications of these hydrogenation reactions were also exemplified by the employment of the products for important pharmaceutical syntheses.

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Enantioselective Ruthenium(II)/Xyl-SunPhos/Daipen-Catalyzed Hydrogenation of γ-Ketoamides

Cited by 15 publications

References 74 publications

Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

Discovery and Characterization of Biased Allosteric Agonists of the Chemokine Receptor CXCR3

Ruthenium‐Catalyzed Enantioselective Hydrogenation/Lactonization of 2‐Acylarylcarboxylates: Direct Access to Chiral 3‐Substituted Phthalides

A Decennary Journey towards the Efficient Asymmetric Hydrogenation of Highly Functionalized Ketones

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