9-Fluorenylmethoxycarbonyl (Fmoc) amino acids were first used for solid phase peptide synthesis a little more than a decade ago. Since that time, Fmoc solid phase peptide synthesis methodology has been greatly enhanced by the introduction of a variety of solid supports, linkages, and side chain protecting groups, as well as by increased understanding of solvation conditions. These advances have led to many impressive syntheses, such as those of biologically active and isotopically labeled peptides and small proteins. The great variety of conditions under which Fmoc solid phase peptide synthesis may be carried out represents a truly "orthogonal" scheme, and thus offers many unique opportunities for bioorganic chemistry.

Solid phase peptide synthesis utilizing 9‐fluorenylmethoxycarbonyl amino acids

The proteins, as the Greek root of their name implies, are of first rank in living systems, and their smaller relatives, the peptides, have now also been discovered to have important roles in biology. Among their members are many of the hormones, releasing factors, growth factors, ion carriers, antibiotics, toxins, and neuropeptides. My purpose today is to describe the chemical synthesis of peptides and proteins and to discuss the use of the synthetic approach to answer various biological questions. The story begins with Emil Fischer (1) at the turn of this century when he synthesized the first peptide and coined the name. The general chemical requirements were to block the carboxyl group of one amino acid and the amino group of the second amino acid. Then, by activation of the free carboxyl group the peptide bond could be formed, and selective removal of the two protecting groups would lead to the free dipeptide. Fischer himself was never able to find a suitable reversible blocking group for the amine function, but his former student Max Bergmann, with Zervas, was successful (2). Their design of the carbobenzoxy group ushered in a new era. When I began working on the synthesis of peptides many years later this same general scheme was universally in use and was very effective, having led, for example, to the first synthesis of a peptide hormone by Du Vigneaud in 1953 (3). It soon became clear to me, however, that such syntheses were difficult and time consuming and that a new approach was needed if large numbers of peptides were required or if larger and more complex peptides were to be made.

http://science.sciencemag.org/content/sci/232/4748/341.full.pdf

Solid phase synthesis

Quantitative monitoring of solid-phase peptide synthesis by the ninhydrin reaction.

Fluorescent labeling of biomolecules with organic probes.

http://www.sciencemadness.org/talk/files.php?pid=302583&aid=26587

Azole-based energetic salts.

http://chemistry-chemists.com/chemister/Warning/Explosives/ExplosiveAbstacts/review-energetic-materials.pdf

A review of energetic materials synthesis

A new synthetic route to tert-butyloxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethyl-resin, an improved support for solid-phase peptide synthesis

C-Terminal peptide thioesters are key intermediates in the synthesis/semisynthesis of proteins and of cyclic peptides by native chemical ligation. They are prepared by solid-phase peptide synthesis (SPPS) or biosynthetically by protein splicing techniques. Until recently, the chemical synthesis of C-terminal alpha-thioester peptides by SPPS was largely restricted to the use of Boc/Benzyl chemistry due to the poor stability of the thioester bond to the basic conditions required for the deprotection of the N(alpha)-Fmoc group. In the present work, we describe a new method for the SPPS of C-terminal thioesters using Fmoc/t-Bu chemistry. This method is based on the use of an aryl hydrazine linker, which is totally stable to conditions required for Fmoc-SPPS. When the peptide synthesis has been completed, activation of the linker is achieved by mild oxidation. This step converts the acyl hydrazine group into a highly reactive acyl diazene intermediate which reacts with an alpha-amino acid alkyl thioester (H-AA-SR) to yield the corresponding peptide alpha-thioester in good yield. This method has been successfully used to prepare a variety of peptide thioesters, cyclic peptides, and a fully functional Src homology 3 (SH3) protein domain.

Alexander R. Mitchell

Papers

A review of energetic materials synthesis

A new synthetic route to tert-butyloxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethyl-resin, an improved support for solid-phase peptide synthesis

Fmoc-Based Synthesis of Peptide α-Thioesters Using an Aryl Hydrazine Support†

Direct photometric or fluorometric assay of proteinases using substrates containing 7-amino-4-trifluoromethylcoumarin.

Synthesis of 4‐amino‐3,5‐dinitro‐1H‐pyrazole using vicarious nucleophilic substitution of hydrogen