Fmoc-L-norleucine

Although few Fmoc-functionalized amino acids (Fmoc-AA) were capable of forming hydrogels, the exact levels of hydrophobicity, hydrogen bonding, and ionic nature of Fmoc-AA gelator required for hydrogel formation remains uncertain. Here, the role of hydrophobicity of amino acid side chain, particularly, in the formation of hydrogel was studied using Fmoc-Norleucine (Fmoc-Nle) and its simple sulfur analogue such as Fmoc-Methionine (Fmoc-M) where γCH2 of Fmoc-Nle is replaced by sulfur. Results indicate that Fmoc-M forms thermally reversible hydrogels in water (pH ~6.8) whereas Fmoc-Nle fails to display any gelation under similar conditions. The result suggests that substitution of sulfur atom likely reduces the hydrophobicity of the alkyl side chain in Fmoc-Nle to the optimum level, which is sufficient to induce supramolecular hydrogelation in Fmoc-M. The difference in the self-association behaviour of Fmoc-M and Fmoc-Nle emphasize the importance of weak non-covalent interaction between side chains (in addition to the hydrogen bond and aromatic interactions) to stabilize supramolecular self-assembly of Fmoc-functionalized compounds.

The sodium salts of amino acids with hydrophobic fluorenyl methyloxy carbonyl (FMOC) group and short alkyl side chains are found to have surfactant properties. This was ascertained first through visual observation of concentration dependent solution behavior and then confirmed by tensiometry measurements. The critical micelle concentrations (CMCs) for the sodium salts of FMOC-l-valine, FMOC-L-leucine, and FMOC-L-isoleucine have been determined to be ~0.1 M. The sodium salt of FMOC-l-norleucine forms a gel at >0.2 M. Powder X-ray diffraction measurements indicated that these surfactants adopt bilayer structures. Three different chiroptical spectroscopic properties, namely optical rotation, electronic circular dichroism, and vibrational circular dichroism, are presented for these surfactants. The specific rotation is found to exhibit an unprecedented increase with concentration beyond CMC. This observation opens up a new area of research relating the concentration dependent increase in specific rotation to the size and shape of aggregates formed by the surfactants.

Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to side-chain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of Cu(I)-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including epsilon-azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(epsilon-N3) or the incorporation of Fmoc-Nle(epsilon-N3)-OH during the stepwise build-up of the resin-bound peptide 1b.

In the present study, we describe in detail the synthesis of a relatively rare class of phosphorus compounds, α-carboxyphosphinopeptides. We prepared several norleucine-derived α-carboxyphosphinic pseudopeptides of the general formula Nle-Ψ[PO(OH)]-Gly. These compounds could have important applications as transition state-mimicking inhibitors for methionine or leucine aminopeptidases or other enzymes. For the preparation of the key α-carboxyphosphinate protected precursors, we investigated, compared and improved two different synthetic methods described in literature: the Arbuzov reaction of a silylated N-protected phosphinic acid with a bromoacetate ester and the nucleophilic addition of a mixed O-methyl S-phenyl N-protected phosphonic acid or a methyl N-protected phosphonochloridate with tert-butyl lithioacetate. We also prepared two N-Fmoc protected synthons, Fmoc-Nle-Ψ[PO(OH)]-Gly-COOH and Fmoc-Nle-Ψ[PO(OAd)]-Gly-COOH, and demonstrated that these precursors are suitable building blocks for the solid-phase synthesis of α-carboxyphosphinopeptides.