Synthesis of Nature-Inspired Medium-Sized Fused Heterocycles from Amino Acids.

Herein, we describe the synthesis of molecular scaffolds consisting of medium-sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid-phase peptide synthesis, and cyclization was carried out through acid-mediated tandem endocyclic N-acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven-, eight-, and nine-membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases.

From amino acids to nature-inspired molecular scaffolds: incorporation of medium-sized bridged heterocycles into a peptide backbone.

Novel molecular scaffolds comprising two to four bridged and fused heterocycles were synthesized from amino acids using seven-membered endocyclic N-acyliminium ions as key intermediates in acid-mediated tandem reactions with internal nucleophiles. This complexity-generating synthesis proceeds with high efficiency and with full stereocontrol of the newly generated stereogenic center. These results have extended the scope of medium-sized cyclic iminium ion chemistry, making it applicable as a regio- and stereoselective synthetic strategy for the generation of complex polycyclic structures.

Privileged structures as peptide backbone constraints: polymer-supported stereoselective synthesis of benzimidazolinopiperazinone peptides.

A molecular scaffold comprising a privileged structure was designed and synthesized to serve as a peptide backbone conformational constraint. The synthesis of highly functionalized 2,3,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-4(1H)-ones on a solid-phase support was performed via a tandem N-acyl-N-aryliminium ion cyclization-nucleophilic addition reaction. The synthesis proceeded with full stereocontrol of the newly formed stereogenic center.

Synthesis and cytotoxicity of some D-mannose click conjugates with aminobenzoic acid derivatives.

Two sets of new conjugates obtained from d-mannose derivatives and o-, m-, and p-substituted benzoic acid esters interconnected through a triazole ring were synthesized by Cu(I) catalyzed azide-alkyne cycloaddition. All synthesized compounds were tested for their in vitro cytotoxic activity against seven cancer cell lines with/without multidrug resistance phenotype as well as non-tumor MRC-5 and BJ fibroblasts. Butyl ester of 4-aminobenzoic acid 6c showed the highest activity among all tested compounds, however, it was active only against K562 myeloid leukemia cells.