Solution-Phase Automated Synthesis of Tripeptide Derivatives.

Abstract

An improved general method for automated synthesis of tripeptides was developed, in which methanesulfonic acid (MSA) was used in place of trifluoroacetic acid (TFA), thus making it possible to avoid, 1) corrosion of the apparatus by strong acid vapor, 2) formation of emulsions, and 3) use of the restricted solvent, dichloromethane. As an application of the automated synthesis apparatus, 216 fragment tripeptide derivatives were synthesized systematically using the MSA method, in excellent yield and with increased efficiency.

An Efficient Synthesis of a Cyclic Ether Key Intermediate for 9-Membered Masked Enediyne Using an Automated Synthesizer

“…The synthetic route for the masked 9-membered enediyne 3 is illustrated in Scheme 1. The transannular [2,3]-Wittig rearrangement 30 of the 12-membered cyclic ether 7 is the most crucial step in the construction of the highly strained 9-membered diyne, in which the newly formed secondary alcohol can be used to introduce a phthalic acid. A β-elimination of the phthalate "triggers" biradical formation.…”

“…1 Recently, automated synthesizers have been used for two to four steps of the solution-phase synthesis of condensed-azoles, tripeptides, quinazolinones, and spirooxazolinoisoxazolines. [2][3][4][5][6] We previously reported a formal total synthesis of taxol using an automated synthesizer that was developed in our laboratory. Use of the ChemKonzert 7 enabled production of a key synthetic intermediate in a 36-step, solution-phase synthesis.…”

“…Automation of synthetic operations, such as mixing of compounds, temperature control of reaction mixtures, quenching of reactions, filtration, liquid−liquid extraction, and washing and drying, effectively improves both the reproducibility and reliability of the syntheses because automated synthesizers minimize the variability of the experimental manipulations . Recently, automated synthesizers have been used for two to four steps of the solution-phase synthesis of condensed-azoles, tripeptides, quinazolinones, and spirooxazolinoisoxazolines. − We previously reported a formal total synthesis of taxol using an automated synthesizer that was developed in our laboratory. Use of the ChemKonzert enabled production of a key synthetic intermediate in a 36-step, solution-phase synthesis .…”

“…In particular, automation of liquid−liquid extractions is not simple . Moreover, it is sometimes necessary to modify reaction conditions and/or experimental operations to utilize an automated synthesizer. ,, Therefore, in general, application of an automated process to solution-phase synthesis is challenging. Nevertheless, it is important to apply various solution-phase reactions to an automated synthesizer.…”

Peptide Synthesis and Applications

“…An automated system for solution phase synthesis was described by Japanese authors and applied to the synthesis of only short peptides (112)(113)(114). Multiple solution synthesis is even more rare.…”