Strategy for Accessing 2,5‐Diketopiperazines to Elucidate the Absolute Configuration at the α‐Position of α‐Amino Acid Derivatives via 1H‐NMR Spectroscopy
Year: 2025
Type: article
Abstract: We present a novel and convenient strategy for accessing 2,5‐diketopiperazine (DKPs) derivatives to determine the absolute configuration at the α‐position of α‐amino acids using NMR. This approach stemmed from insights gained during solid‐phase peptide synthesis (SPPS) studies for cyclic peptide‐based drug discovery. Contrary to the traditional view of DKP formation as an undesired side reaction in SPPS, we developed a novel strategy that deliberately promotes this reaction to selectively obtain DKPs for absolute configuration analysis without the need for purification and isolation. Using commercially available Fmoc‐protected amino acids and deuterated solvents (DMF‐d7 or DMSO‐d6), our method allows direct NMR analysis of the released DKPs without complex purification procedures. The method shows broad substrate scope for various amino acids, including β‐branched, N‐methylated, and cyclic derivatives, offering significant time and resource savings compared to conventional approaches. However, limitations exist as the method is not applicable to N‐ethylated amino acids or α,α‐dialkyl amino acids, where cyclization reactions fail to proceed. This streamlined approach provides a practical solution for determining the absolute configuration at the α‐position of α‐amino acid derivatives.
Institution: Chugai Pharmaceutical Co., Ltd. (Japan)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4409706200