Peptides Containing meso‐Oxa‐Diaminopimelic Acid as Substrates for the Cell‐Shape‐Determining Proteases Csd6 and Pgp2

Abstract

Scheme1.The structure of peptidoglycan showing both crosslinkeda nd non-crosslinkedpeptide side chains.T he inset shows the structure of meso-diaminopimelica cid (meso-Dap).Scheme2.Catalytic activities of the enzymesC sd6 and Pgp2. A) Trimming of the non-crosslinkedPGt etrapeptide to give non-crosslinkedPGtripeptide. B) Trimmingo ft he crosslinkedP Gtetrapeptide to give crosslinkedPGt ripeptide.

Synthesis of a meso-Oxa-Diaminopimelic Acid Containing Peptidoglycan Pentapeptide and Coupling to the GlcNAc-anhydro-MurNAc Disaccharide

“…The Heine rearrangement byproduct 20 was also obtained in an 37% yield. These yields are similar to those obtained previously in the preparation of tripeptide substrates of the cell-shape-determining proteases . Since compound 18 can readily be prepared on a gram scale, this methodology can be used to rapidly prepare meso -oxa-Dap containing tripeptides on a multihundred milligram scale.…”

“…The synthesis relies on the ring opening of a peptide-embedded aziridine. The opening of peptide-embedded aziridines has been reported with more reactive nucleophiles such as amines, azides, and thiolates; however, our previous paper is the first that reports utilizing alcohols. ,− This is likely because of the intramolecular Heine rearrangement that competes with attack by the alcohol. − In this work, the Heine rearrangement product was formed in similar amounts as the desired product; however, the savings in reducing the number of overall steps still makes this an attractive route. Syntheses of the PG pentapeptide containing the natural meso -Dap residue are typically quite lengthy and not readily amenable to scale-up. − Preparing an isosteric analog to the PG pentapeptide therefore presents an attractive alternative to researchers in this field.…”

“…These syntheses are typically very lengthy or involve low yielding steps that are not amenable to scale-up. − An attractive alternative is to replace meso -Dap with the isosteric analog, meso -oxa-Dap, in which the central methylene has been replaced by an oxygen. This was first utilized by Vederas and co-workers who prepared a version of meso -oxa-Dap that was orthogonally protected and could be used in solid phase peptide synthesis. , More recently, we reported the synthesis of the tripeptide N -Ac- iso - d -Glu- meso -oxa-Dap- l -Ala, which was shown to serve as a substrate for the cell-shape-determining proteases of Helicobacter pylori and Camplobacter jejuni (Figure a) . The meso -oxa-Dap residue was generated from an aziridine embedded within a tripeptide precursor by an attack with a suitably protected serine derivative.…”

“…Such interactions presumably decrease the nucleophilicity of the hydroxyl group and result in poorer yields. The ring opening was performed under previously optimized conditions that involve 2.5 equiv of BF 3 etherate in CH 2 Cl 2 at −78 °C. , While pentapeptide 12 could be formed in this manner, the yield was only 9%. The major product in this reaction was oxazoline 13 (30%) which is formed from an intramolecular Heine rearrangement of starting material 10 . − The Heine rearrangement product was also seen in our previous work with a tripeptide aziridine; however, in that study both the desired meso -oxa-Dap and the oxazoline were obtained in comparable yields .…”

“…The ring opening was performed under previously optimized conditions that involve 2.5 equiv of BF 3 etherate in CH 2 Cl 2 at −78 °C. , While pentapeptide 12 could be formed in this manner, the yield was only 9%. The major product in this reaction was oxazoline 13 (30%) which is formed from an intramolecular Heine rearrangement of starting material 10 . − The Heine rearrangement product was also seen in our previous work with a tripeptide aziridine; however, in that study both the desired meso -oxa-Dap and the oxazoline were obtained in comparable yields . An additional byproduct in this reaction was a serine-containing pentapeptide (10%) formed from an attack on the aziridine by water (despite the presence of activated molecular sieves).…”