Catalytic N-modification of α-amino acids and small peptides with phenol under bio-compatible conditions

Abstract

The functionalization of α-amino acids and peptides provides the opportunity to tailor the properties of these biomolecules for diverse applications in chemistry and biology. Previous methods for N-modification involve the use of aliphatic alcohols, aldehydes, or halides. Alternatively, phenolic compounds are more desirable alkylating reagents as they constitute the backbone of lignin, making them an attractive bio-renewable resource. Here we report a method to N-modify 17 out of the 20 amino acids with phenol or derivatives, with water as the sole by-product. N-arylation is achieved using 2-cyclohexen-1-one and cyclohexanone as the coupling partners. Notably, phenol is successfully used to N-cyclohexylate α-amino acids and small peptides in excellent yields under bio-compatible conditions without racemization.

Exploration of new reaction tools for late-stage functionalization of complex chemicals

“…Amino acids are bio-renewable, C-chiral nitrogen sources with important applications in chemistry [87][88][89][90] and biology. [91][92][93] Our laboratory has developed novel methodologies through which these building blocks can be arylated or cylohexylated by using 2-cyclohexen-1-one or phenol, respectively. 94 By using a phenolic compound as the N-alkylating reagent, we can circumvent the need of halogen derivatives and protecting groups, while generating water as the sole by-product.…”

“…Glycine ethyl ester hydrochloride was employed as the model substrate for the N-arylation with 2-cyclohexen-1-one, since using amino acids in their free carboxylic form led to decomposition through decarboxylation. 93 The transformation was found to work best using 10 mol% of palladium on charcoal (5 wt%) and 20 mol% of calcium carbonate in toluene at 140 °C under an oxygen atmosphere (Scheme 13).…”

Transition Metal‐Free N‐Arylation of Amino Acid Esters with Diaryliodonium Salts

“…SFC and HPLC analyses were performed to determine the ee of the products, since previously reported methods for N ‐arylation of amino esters showed partial racemization [7c, 12a, 13, 25c] or had insufficient data to judge the enantiomeric purity [1c, 9–10, 12b] . As expected, the current methodology generally left the existing stereocenter intact and the majority of the products were isolated with 95 to >98 % ee .…”

Synthesis of Functional Chemicals from Lignin‐derived Monomers by Selective Organic Transformations

“…As an example, diphenyl ether was converted to N ‐cyclohexylaniline in 83% and benzene in 82% yield by using ammonia (Scheme 19C) [45] . An attractive method has also been developed for the selective amination of phenols with amino acids to obtain N ‐cyclohexylate α ‐amino acids in excellent yields by using commercial 10 wt% Pd/C catalyst (Scheme 19D) [46] . Under optimized conditions, various amino acids bearing functional groups such as alcohols, carboxylic acids, and amides were well tolerated for their N ‐modification without any racemization (Scheme 19D).…”