Side Chain Anchoring of Tryptophan to Solid Supports Using a Dihydropyranyl Handle: Synthesis of Brevianamide F

Peptides 2015, Proceedings of the 24th American Peptide Symposium

“…In trouble-shooting the chemistry, we found that the Zumach-Weiss-Kühle-type reaction that for other substrates is essentially instantaneous under normal conditions, now slowed down enough to allow us to isolate, characterize, and/or trap relevant intermediates. As revealed at this meeting [34], we found four structures, all of which could be solved at the atomic level by x-ray crystallography, and all of which model stages in the classic Zumach-Weiss-Kühle mechanism towards Dts-amines. In particular, we believe that delving into the molecular geometries will explain why bis(chlorocarbonyl)disulfane fails to give Dts when reacted with primary amines, but successfully gives Dts when reacted with bis(TMS)-amines.…”

Understanding Tetrahydropyranyl as a Protecting Group in Peptide Chemistry

“…The authors concluded that the α‐aminotetrahydropyran ring underwent rapid reversible ring‐opening in aqueous solution, as revealed in studies on N ‐glycosidic bond lability in aqueous media with N ‐glucosamines . More recently, Nicolás et al . used the dihydropyranyl linker to anchor the indolic nitrogen of the amino acid Trp to a solid support for the synthesis of Trp‐containing diketopiperazines.…”

“…Interestingly, the introduction of the Thp moiety at the indolic nitrogen of Trp was more successful and has a greater impact on SPPS. The protocol described by Nicolás et al . involved the reaction of Fmoc‐Trp‐OR (R=Allyl or Me) with DHP using pyridinium p ‐toluenesulfonate (PPTS) as catalyst and 1,2‐dichloroethane (DCE) as solvent at 70 °C for 8 h. A yield of 80 % was achieved for Fmoc‐Trp(Thp)‐OAllyl and 69 % for Fmoc‐Trp(Thp)‐OMe.…”

“…Furthermore, they also anchored a Trp derivative on Ellman resin through its side chain using PPTS as a catalyst in anhydrous DCE under microwave conditions for 2 h at 120 °C. The authors realized that, in order to attach Trp to a tetrahydropyran‐functionalized resin through its indole ring, the α‐amino and carboxyl functions had to be protected with groups compatible with the conditions necessary for the formation of the hemiaminal linkage and peptide chain elongation …”

Trends to Acid-Labile Cys Protecting Groups: Thp as an Efficient and Non-Aromatic Cys Protecting Group for Fmoc Chemistry

“…Apart of its recent application in Fmoc chemistry [26], Thp is extensively used as hydroxyl protecting group [27][28][29][30] as well as a linker [31][32][33][34], due to its chemical properties and its stability in strong bases, and acylating and alkylating agents among others. Accordingly, Thp is an excellent candidate for use in SPPS, but it is known that the main drawback should be the formation of a new stereocenter that leads to diastereomeric mixtures.…”