TY - JOUR

T1 - Solid-phase route to Fmoc-protected cationic amino acid building blocks

AU - Clausen, Jacob Dahlqvist

AU - Linderoth, Lars

AU - Nielsen, Hanne Mørck

AU - Franzyk, Henrik

PY - 2012

Y1 - 2012

N2 - Diamino acids are commonly found in bioactive compounds, yet only few are commercially available as building blocks for solid-phase peptide synthesis. In the present work a convenient, inexpensive route to multiple-charged amino acid building blocks with varying degree of hydrophobicity was developed. A versatile solid-phase protocol leading to selectively protected amino alcohol intermediates was followed by oxidation to yield the desired di- or polycationic amino acid building blocks in gram-scale amounts. The synthetic sequence comprises loading of (S)-1-(p-nosyl)aziridine-2-methanol onto a freshly prepared trityl bromide resin, followed by ring opening with an appropriate primary amine, on-resin N(ß)-Boc protection of the resulting secondary amine, exchange of the N(a)-protecting group, cleavage from the resin, and finally oxidation in solution to yield the target ¿-aza substituted building blocks having an Fmoc/Boc protection scheme. This strategy facilitates incorporation of multiple positive charges into the building blocks provided that the corresponding partially protected di- or polyamines are available. An array of compounds covering a wide variety of ¿-aza substituted analogs of simple neutral amino acids as well as analogs displaying high bulkiness or polycationic side chains was prepared. Two building blocks were incorporated into peptide sequences using microwave-assisted solid-phase peptide synthesis confirming their general utility.

AB - Diamino acids are commonly found in bioactive compounds, yet only few are commercially available as building blocks for solid-phase peptide synthesis. In the present work a convenient, inexpensive route to multiple-charged amino acid building blocks with varying degree of hydrophobicity was developed. A versatile solid-phase protocol leading to selectively protected amino alcohol intermediates was followed by oxidation to yield the desired di- or polycationic amino acid building blocks in gram-scale amounts. The synthetic sequence comprises loading of (S)-1-(p-nosyl)aziridine-2-methanol onto a freshly prepared trityl bromide resin, followed by ring opening with an appropriate primary amine, on-resin N(ß)-Boc protection of the resulting secondary amine, exchange of the N(a)-protecting group, cleavage from the resin, and finally oxidation in solution to yield the target ¿-aza substituted building blocks having an Fmoc/Boc protection scheme. This strategy facilitates incorporation of multiple positive charges into the building blocks provided that the corresponding partially protected di- or polyamines are available. An array of compounds covering a wide variety of ¿-aza substituted analogs of simple neutral amino acids as well as analogs displaying high bulkiness or polycationic side chains was prepared. Two building blocks were incorporated into peptide sequences using microwave-assisted solid-phase peptide synthesis confirming their general utility.

U2 - 10.1007/s00726-012-1239-5

DO - 10.1007/s00726-012-1239-5

M3 - Journal article

C2 - 22358257

VL - 43

SP - 1633

EP - 1641

JO - Amino Acids

JF - Amino Acids

SN - 0939-4451

IS - 4

ER -