Homochiral 4-azalysine building blocks: Syntheses and applications in solid-phase chemistry

Chhabra, Siri Ram; Mahajan, Anju; Chan, Weng C.

Abstract

Anomalous amino acids not only play central roles as mimics of natural amino acids but also offer opportunities as unique building blocks for combinatorial chemistry. This paper describes the chiral syntheses and solid-phase applications of a versatile atypical amino acid, 4-azalysine (2,6-diamino-4-azahexanoic acid) 1. The syntheses of differentially protected 4-azalysine derivatives 28a-e have been developed by two efficient and inexpensive routes that start either from Garner's aldehyde 16 or the chiron (S)-Nα-Cbz-2,3-diaminopropionic acid 23. Both approaches employ the convergent modular concept and exploit reductive amination of aldehydes with amines as the key step for the fusion of the two segments. In the first route, the overall process inverts the chirality of the starting material, L-serine, and thus provides an excellent route to the unnatural D-isomers. The alternative route starting from L-asparagine provides a shorter and high-yielding route to orthogonally protected 4-azalysine derivatives. The corresponding N2-Fmoc-4-azalysines 31a-e, readily derived from the key intermediate 27, are compatible with the Fmoc-based solid-phase peptide synthesis (SPPS) and solid-phase organic chemistry (SPOC) protocols. Furthermore, the utility and versatility of another key structure, tris-Boc-4-azalysine 2 in the engineering of novel high-loading dendrimeric polystyrene resins 33 and 36, have been demonstrated. Following derivatization with the Rink amide linker 34, the stability and robustness of these resin-bound dendrimers 35 and 37 in the synthesis of small molecules using a range of reaction conditions (e.g., Mitsunobu and Suzuki reactions) have been effectively illustrated.

Citation

Chhabra, S. R., Mahajan, A., & Chan, W. C. (2002). Homochiral 4-azalysine building blocks: Syntheses and applications in solid-phase chemistry. Journal of Organic Chemistry, 67(12), 4017-4029. https://doi.org/10.1021/jo010456e

• Journal Article Type: Article
• Online Publication Date: May 8, 2002
• Publication Date: Jun 14, 2002
• Deposit Date: May 12, 2023
• Journal: Journal of Organic Chemistry
• Print ISSN: 0022-3263
• Electronic ISSN: 1520-6904
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 12
• Pages: 4017-4029
• DOI: https://doi.org/10.1021/jo010456e
• Public URL: https://nottingham-repository.worktribe.com/output/3137787
• Publisher URL: https://pubs.acs.org/doi/10.1021/jo010456e