Facile synthesis of orthogonally protected amino acid building blocks for combinatorial N‐backbone cyclic peptide chemistry

Abstract

Protected Nalpha-(aminoallyloxycarbonyl) and Nalpha-(carboxyallyl) derivatives of all natural amino acids (except proline), and their chiral inverters, were synthesized using facile and efficient methods and were then used in the synthesis of Nalpha-backbone cyclic peptides. Synthetic pathways for the preparation of the amino acid building units included alkylation, reductive amination and Michael addition using alkylhalides, aldehydes and alpha,beta-unsaturated carbonyl compounds, and the corresponding amino acids. The resulting amino acid prounits were then subjected to Fmoc protection affording optically pure amino acid building units. The appropriate synthetic pathway for each amino acid was chosen according to the nature of the side-chain, resulting in fully orthogonal trifunctional building units for the solid-phase peptide synthesis of small cyclic analogs of peptide loops (SCAPELs). Nalpha-amino groups of building units were protected by Fmoc, functional side-chains were protected by t-Bu/Boc/Trt and N-alkylamino or N-alkylcarboxyl were protected by Alloc or Allyl, respectively. This facile method allows easy production of a large variety of amino acid building units in a short time, and is successfully employed in combinatorial chemistry as well as in large-scale solid-phase peptide synthesis. These building units have significant advantage in the synthesis of peptido-related drugs.

The cyclization of peptides and depsipeptides

“…Some of the disadvantages of these lactamizations, e.g. the need for Lys and Glu to be specifically sited in the main chain, can be overcome by the approach based on the work of Gilon et al in which two backbone nitrogens can be connected via bridges as in (7) [56]. Suitable N -derivatized building blocks have to be prepared for prior insertion.…”

Improvement of drug-like properties of peptides: the somatostatin paradigm

“…Additionally, C-and N-termini are still free. The availability of building units derived from a large array of amino acids [76][77][78] and improvements in solid phase peptide synthesis methodologies [79] allow the preparation of conformational libraries of BC peptides (a concept called cycloscan) [80]. The diversity of the cycloscan libraries is a spatial diversity (also called conformational diversity), namely, all the members in the library maintain the original side-chain sequence of the parent linear peptide.…”

Targeting small-cell lung cancer with novel fluorescent analogs of somatostatin

“…Building units bearing carboxy functionalities were synthesized according to Gellerman et al [17]. Those bearing thiol functionalities were synthesized according to Gazal et al [20].…”

“…Backbone cyclization is a synthetic method that allows formation of rigid cyclic peptides, synthesized using building units consisting of N-alkylated amino acids bearing a variable-length alkyl arm [17][18][19][20][21].…”