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21.11.7.2 Modern Methods for the Synthesis of Peptide Thioesters

DOI: 10.1055/sos-SD-121-00066

Malins, L. R.; Payne, R. J.Science of Synthesis Knowledge Updates, (20213205.

Reliable methods to access peptides functionalized as thioesters at the C-terminus have been crucial to the success of the native chemical ligation (NCL) methodology and related ligation methods that employ thioesters as the acyl donor. Early approaches to peptide thioesters included the use of tert-butoxycarbonyl-based solid-phase peptide synthesis (Boc-SPPS) to elongate a thioester-functionalized solid support, and through the (9-fluorenylmethoxy)carbonyl (Fmoc)-based SPPS strategy on sulfamylbutaryl resin (see Section 21.11.6.2.1). A number of synthetic strategies have since been developed that enable robust access to peptide thioesters. Many methods have sought to generate these molecules through the more popular Fmoc-SPPS protocols. The challenge of using Fmoc chemistry is the difficulty in preserving the thioester functionality in the presence of piperidine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which is used for Fmoc deprotection steps. To overcome the inherent base lability of the thioester linkage, modern methods for peptide thioester synthesis install or unmask this functionality at a late stage in the synthesis. The five most common general strategies used to access peptide thioesters by the community (not already discussed in the original chapter on peptides) are described in the following sections, together with representative protocols. It should be noted that this is by no means an exhaustive account of all methods available; other strategies for peptide thioester synthesis include the use of backbone amide linkages (see Section 21.11.5.3),[‌67‌‌69‌] backbone pyroglutamyl imides,[‌70‌] O→S acyl-shift chemistry,[‌71‌‌73‌] and cyclizing self-purifying linkers,[‌74‌,‌75‌] which are not discussed further here. A number of other less commonly employed methods can be found in several detailed reviews.[‌35‌,‌76‌,‌77‌]

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