Much Improved Conditions for the Negishi Cross-Coupling of Iodoalanine Derived Zinc Reagents with Aryl Halides

Abstract

A combination of Pd(2)(dba)(3) and SPhos (1:2 molar ratio) is an excellent precatalyst for the Negishi cross-coupling of the serine-derived organozinc reagent 2 with aryl halides, including previously difficult ortho-substituted examples. In the case of meta- and para-substituted aryl halides, Pd-loadings of 0.5 mol % give satisfactory results. Use of 2-iodoaniline as substrate gives the lactam 12 in good yield.

Indole–Indole Ullmann Cross‐Coupling for CAr–N Bond Formation: Total Synthesis of (–)‐Aspergilazine A

“…The palladium‐mediated Negishi cross‐coupling reaction was performed next to construct the C6–N1′ bis‐tryptophan. Reaction of diiodide 21 with 2 equivalents of the alkylzinc reagent derived from N ‐Boc‐protected iodoalanine 22 (synthesized from l ‐serine) by using Pd(OAc) 2 and S‐PHOS ( 23 ) in DMF at ambient temperature afforded compound 24 in excellent yield (84 % from 22 ). Cleavage of the Boc protecting groups by using TMSI led quantitatively to the C6–N1′ bis‐tryptophan, which was not isolated.…”

Convenient synthesis of chiral tryptophan derivatives using Negishi cross-coupling

“…Recently, Jackson reported the improved synthesis of phenylalanine derivatives using Pd 2 (dba) 3 and S-PHOS. 19 We applied that system to our tryptophan synthesis; however the yield of 3d was not satisfactory (43% yield, entry 8). Since unreacted 1c was remained under the heating conditions, catalyst deactivation might be a main reason for the low yields in above both cases.…”

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…In contrast to these aromatic amino acids bearing (pseudo)halogenated moieties, amino acid-based alkyl halides are not used directly as substrates in the Suzuki-Miyaura reaction. To date, their use is limited to the Negishi reaction of β-iodoalanine, β-iodohomoalanine, and iodobishomoalanine with various aryl iodides, to gain access to non-proteinogenic phenylalanine analogues [66][67][68][69]. For peptides that are prepared by chemical methods, SPPS easily enables the replacement of an aromatic amino acid with a non-natural (pseudo)halogenated analogue.…”