Abstract:The Negishi cross-coupling is a powerful C-C bond-forming reaction widely utilised in many areas of organic synthesis. This review details the use of Negishi cross-couplings in the synthesis of unnatural amino acids. The application of this reaction in the preparation of aromatic, heteroaromatic, and, complex amino acid derivatives are reviewed and presented herein.
“…Negishi cross-coupling has been used to access a wide range of amino acids previously within the literature [ 26 , 27 ]. Therefore to begin with a halogenated amino acid precursor 4 was selected as one coupling partner for our Negishi strategy.…”
Graphical abstractHerein, a series of aromatic pentafluorosulfanyl (SF5) containing amino acids are reported. A Negishi cross-coupling strategy utilising a catalyst system of Pd(dba)2 and SPhos afforded the aforementioned SF5 amino acids in yields between 35% and 42%. Two dipeptides utilising both the amine and carboxylic functionalities of the synthesised SF5 containing amino acids were prepared, demonstrating their compatibility with common amide/peptide coupling reagents and strategies.
“…Negishi cross-coupling has been used to access a wide range of amino acids previously within the literature [ 26 , 27 ]. Therefore to begin with a halogenated amino acid precursor 4 was selected as one coupling partner for our Negishi strategy.…”
Graphical abstractHerein, a series of aromatic pentafluorosulfanyl (SF5) containing amino acids are reported. A Negishi cross-coupling strategy utilising a catalyst system of Pd(dba)2 and SPhos afforded the aforementioned SF5 amino acids in yields between 35% and 42%. Two dipeptides utilising both the amine and carboxylic functionalities of the synthesised SF5 containing amino acids were prepared, demonstrating their compatibility with common amide/peptide coupling reagents and strategies.
“…Chemical synthesis can access numerous ncAAs by employing intermediates such as serine-derived lactones, hydantoins, or aziridines (Scheme 4, blue). 19,20 A significant benefit of chemical synthesis approaches is their broad applicability, allowing a variety of ncAAs to be produced from a single synthetic pipeline. Limitations are also apparent: chemical synthesis can be labor-intensive, utilize hazardous reagents and produce significant waste products, or generate racemic products that require further purification.…”
The standard proteinogenic amino acids grant access to a myriad of chemistries that harmonize to create life. Outside of these twenty canonical protein building blocks are countless noncanonical amino acids (ncAAs), either found in nature or created by man. Interest in ncAAs has grown as research has unveiled their importance as precursors to natural products and pharmaceuticals, biological probes, and more. Despite their broad applications, synthesis of ncAAs remains a challenge, as poor stereoselectivity and low functional-group compatibility stymie effective preparative routes. The use of enzymes has emerged as a versatile approach to prepare ncAAs, and nature’s enzymes can be engineered to synthesize ncAAs more efficiently and expand the amino acid alphabet. In this tutorial review, we briefly outline different enzyme engineering strategies and then discuss examples where engineering has generated new ‘ncAA synthases’ for efficient, environmentally benign production of a wide and growing collection of valuable ncAAs.
“…The development of cross-coupling strategies to take advantage of halo-amino acid precursors has allowed access to a wide variety of fluorinated unnatural amino acids. Negishi cross-coupling of halo-serine derivatives is a mainstay in this area and was pioneered by the Jackson group [ [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] ]. The Negishi cross-coupling reaction allows two, often readily available, halogen containing building blocks to be coupled together through a halo-zinc intermediate in the presence of palladium.…”
“…The method employed a Negishi cross-coupling between the R or S isomer of halogenated amino acid precursor 226 and either pentafluorosulfanyl-aryl 227 or 228 in the presence of zinc, an SPhos ligand (10 mol%) and a palladium catalyst. This led to the successful isolation of desired enantiopure compounds 229 or 230, which could then undergo further selective deprotection at either the amine or carboxyl functionality for use in peptide coupling [ 31 ]. Scheme 45 Aromatic SF 5 amino acids, Cobb and co-workers [ 32 ].…”
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