Nickel-Catalyzed Cross-Coupling of Amino-Acid-Derived Alkylzinc Reagents with Alkyl Bromides/Chlorides: Access to Diverse Unnatural Amino Acids

Abstract

Unnatural α-amino acids are important synthetic targets in the field of peptide science. Herein we report an efficient, versatile, and straightforward strategy for the synthesis of homophenylalanine derivatives via the nickel-catalyzed Csp3–Csp3 cross-coupling of (fluoro)­benzyl bromides/chlorides with natural α-amino-acid-derived alkylzinc reagents. The current protocol features the advantages of a low-cost nickel catalyst system, synthetic convenience, and the tolerance of rich functionality and stereochemistry.

Synthesis of Alkylated Polyfluorobenzenes through Decarboxylative Giese Addition of Aliphatic N-Hydroxyphthalimide Esters with Polyfluorostyrene

“…However, their syntheses are time-consuming and remain a challenge. Through our method, we could obtain an UAA bearing a pentafluoroaryl motif at its α-side chain, offering a promising and efficient strategy for such demanding transformations ( 27 ) . Furthermore, we successfully modified complex bioactive molecules, such as indomethacin ( 28 ) and abietic acid ( 29 ), with a pentafluoroaryl motif using our method, highlighting the applicability of this approach to advanced chemical modifications.…”

“…To our delight, all these substrates underwent the reaction smoothly, resulting in successful product formation. Intriguingly, other functionalities including phenyl sulfide (15), phenol ether (16), and thiophene (17) were also well tolerated. and quaternary (20−21) NHPI esters all afforded the products in high yields, thus showcasing the superiority of our approach.…”

“…The product (50.3 mg, 79% yield) was purified with silica gel chromatography (PE) as a white solid, mp: 37−38 °C. 1 H NMR (400 MHz, CDCl 3 ) δ 7.36−7.35 (m, 2H), 7.31−7.25 (m, 2H), 7.22−7.18 (m, 1H), 2.93 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 1.93−1.86 (m, 2H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 144.9 (dm, J = 247.0 Hz), 139.6 (dm, J = 250.8 Hz), 137.4 (dm, J = 252.9 Hz), 135.6, 129.8, 128.9, 126.3, 114.1 (m), 33.2, 28.5, 21.3; 19 1,2,3,4,benzene (16). The product (46.9 mg, 78% yield) was purified with silica gel chromatography (PE) as a white solid, mp: 47−48 °C.…”

Recent advances in the synthesis of fluorinated amino acids and peptides

“…Using a similar strategy, He and coworkers prepared a series of polyfluoroaryl substituted α-amino acids through the nickel-catalyzed cross-coupling of 85 with polyfluorobenzyl halides (Scheme 20). 40 The synthetic convenience and structural diversity render these methods effective for obtaining diverse FAAs of medicinal and chemicobiological interest.…”

Synthesis of Secondary Trifluoromethyl Boronic Esters through Visible Light Induced Decarboxylative Alkylation Reactions

“…Of them, keto (7), -MeO (9), -Cl (10), -CF 2 (11), substituents were all well tolerated, as well as substrates derived from piperidine, tetrahydropyranyl and tetrahydrofuranyl (13)(14)(15). Moreover, no obvious bias toward reaction efficiency was observed in acyclic substrates which exhibited in either secondary (16, 17), primary (18,19) or benzyl (20) structures. To further study if the electronic nature of the substituents could affect the coupling yield, various kinds of aryl-substituted alkyl substrates were tested and unexpectedly they all exhibited good reactivity (21-33).…”