Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

Jain, Pankaj; Verma, Pritha; Xia, Guoqin; Yu, Jin‐Quan

doi:10.1038/nchem.2619

Cited by 304 publications

(138 citation statements)

References 37 publications

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“…However, the most straightforward way to synthesize these amino acid derivatives would be to directly employ the N -protected amino acid as the starting material. Inspired by recent developments in ligand-accelerated or ligand-enabled C–H activation reactions545556, we speculated that carboxylate-assisted β-C( sp 3 )-H activation might be achieved by employing a congruous ligand. Thus, we investigated whether synthetically important phenylalanine derivatives14545758596061 could be directly synthesized from phthaloylalanine through arylation of the β-C( sp 3 )–H bond with a carboxyl group as a coordination centre and the assistance of a ligand.…”

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Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

et al. 2017

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α-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various β-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N-protected amino acids as starting materials remain rare. Herein, we report an N-acetylglycine-enabled Pd-catalysed carboxylate-directed β-C(sp3)-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording β-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct β-C(sp3)-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method.

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Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

et al. 2017

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“…[3] While major progress was predominantly realized with precious transition metals,r ecent focus has shifted to less expensive,e arth abundant 3d metals. [11] However,inthe scenario of enantioselective CÀHactivation, progress was thus far primarily limited to noble 4d and 5d transition metals,s uch as palladium, [12] rhodium, [13] and iridium. [6][7][8][9][10] Thef ull control of selectivity is paramount to achieving synthetically meaningful CÀHf unctionalization.…”

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confidence: 99%

“…[4] In this context, highvalent pentamethylcyclopentadienyl cobalt(III) complexes [5] were identified as particularly powerful C À Ha ctivation catalysts. [11] However,inthe scenario of enantioselective CÀHactivation, progress was thus far primarily limited to noble 4d and 5d transition metals,s uch as palladium, [12] rhodium, [13] and iridium. [11] However,inthe scenario of enantioselective CÀHactivation, progress was thus far primarily limited to noble 4d and 5d transition metals,s uch as palladium, [12] rhodium, [13] and iridium.…”

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confidence: 99%

Enantioselective Cobalt(III)‐Catalyzed C−H Activation Enabled by Chiral Carboxylic Acid Cooperation

Pesciaioli,

Dhawa,

Oliveira

et al. 2018

Angewandte Chemie

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The enantioselective cobalt(III)-catalyzed C À H alkylation was achieved through the design of an ovel chiral acid. The cobalt(III)-catalyzed enantioselective CÀHa ctivation was characterized by high position-, regio-and enantiocontrol under exceedingly mild reaction conditions.T hereby, the robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups,i ncluding hydroxyl, bromo,a nd iodo substituents.M echanistic studies revealed ac onsiderable additive effect on kinetics and on an egative non-linear-effect.The activation of otherwise inert C À Hbonds has emerged as at ransformative tool in molecular sciences, [1] with notable applications to material sciences [2] and pharmaceutical industries. [3] While major progress was predominantly realized with precious transition metals,r ecent focus has shifted to less expensive,e arth abundant 3d metals. [4] In this context, highvalent pentamethylcyclopentadienyl cobalt(III) complexes [5] were identified as particularly powerful C À Ha ctivation catalysts. [6][7][8][9][10] Thef ull control of selectivity is paramount to achieving synthetically meaningful CÀHf unctionalization. [11] However,inthe scenario of enantioselective CÀHactivation, progress was thus far primarily limited to noble 4d and 5d transition metals,s uch as palladium, [12] rhodium, [13] and iridium. [14] In sharp contrast, enantioselective C À Ht ransformations by late 3d transition metals have largely been accomplished with superstoichiometric amounts of reactive Grignard reagents, [15,16] which leads to undesired byproducts, and, more importantly,l imits considerably the robustness in terms of functional group tolerance.B ased on our recent mechanistic findings on base-assisted internal electrophilic substitution (BIES)-C À Hm etalations, [17] we became intrigued to the development of unprecedented enantioselective cobalt(III)-catalyzed CÀHa ctivation, on which we wish to report herein ( Figure 1). Salient features of our findings include (a) first asymmetric Cp*Co III -catalyzed C À H activation, (b) robust functional group tolerance,(c) detailed mechanistic insights into cooperative catalysis by experiment and computation and (d) the de-novo design of ah ighly selective chiral carboxylic acid scaffold.We initiated our studies by probing various Brønsted acids for the envisioned asymmetric C À Ha lkylation of indole 1a (Table 1, and Table S-1 in the Supporting Information). [18] Thus,N -protected amino acids L1-L4 (entries 3-6) provided the product 3aa with only poor levels of enantiocontrol. Decreasing the L2 loading led to al ower efficacya nd only as light improvement of the enantioselectivity (entry 7). Interestingly,t he well-established BINOL-based Brønsted acids L5-L7 failed entirely in the enantioselective C À H alkylations (entry 8), reflecting the challenging nature of the asymmetric cobalt catalysis.Gratefully, [19] the newly designed C 2 -symmetric carboxylic acid L8 delivered the desired product 3aa with an enantiomeric ratio of 93:7, [20] albeit w...

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“…[4–6] The former generates a metalated intermediate that can react with a variety of electrophiles while the latter result in the formation carbocation [4] , iminium [5] and α-amino radical [6] intermediates from pyrrolidines that can be intercepted by suitable coupling partners. Direct C–H arylation catalyzed by various transition metal have also been developed [7,8] . In the realm of direct C–H alkylation and related transformations, examples include transition metal-catalyzed C–H activation in the absence (Ta [9] , Ti [10] , Ru [11] catalysts) or presence of directing groups on nitrogen (Ru [12] , Ir [13] and Rh [14] catalysts) had been reported.…”

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“…Previously, our group disclosed the development of thioamides as competent directing groups for Pd(II)-catalyzed racemic and enanantioselective α-arylation of azacycles with aryl boronic acid coupling partners (Scheme 1B) [8] . While these thioamides were competent in directing α-C–H cleavage, deprotection was often problematic.…”

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Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)‐Catalyzed C−H Alkylation of Azacycles

Trần

2017

Angew Chem Int Ed

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The development of new and practical 3-pentoxythiocarbonyl auxiliaries for Ir(I)-catalyzed C–H alkylation of azacycles is described. This method allows for the α-C–H alkylation of a variety of substituted pyrrolidines, piperidine and tetrahydroisoquinoline through alkylation with alkenes. While the practicality of these simiple carbamate type auxiliaries is underscored in the ease of installation and removal, the method’s novel reactivity is demonstrated in its ability to functionalize biologically relevant (L)-proline and (L)-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogues that are not accessible by other C–H functionalization methods.

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Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

Cited by 304 publications

References 37 publications

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids

Enantioselective Cobalt(III)‐Catalyzed C−H Activation Enabled by Chiral Carboxylic Acid Cooperation

Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)‐Catalyzed C−H Alkylation of Azacycles

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