A New Strategy for Solid-Phase Depsipeptide Synthesis Using Recoverable Building Blocks

Abstract

The technique of choice for synthesis of small-scale depsipeptides is on a solid support. However, if expensive monomers have to be incorporated, solid-phase synthesis can quickly turn out to be unattractive because of its low atom economy. Herein, we describe a new type of recoverable and reuseable alpha-hydroxy acid building block for solid-phase synthesis and its application in the synthesis of a number of small cyclic depsipeptides. [structure: see text]

Amide‐to‐Ester Substitution Allows Fine‐Tuning of the Cyclopeptide Conformational Ensemble

“…[8] Modulation of the internal H-bond pattern of nonmethylated CIL precursors-achieved by changing the flexibility or the chirality of the backbone-was found to influence the antagonist activity on the vitronectin (VN) and fibrinogen (FB) receptors, and has been proposed to control laminin P1 vs. vitronectin receptor specificity. For the introduction of the a-hydroxy acid residues onto the growing peptide chain, their HFA-activated/protected derivatives were used [10] (Scheme 1). For the introduction of the a-hydroxy acid residues onto the growing peptide chain, their HFA-activated/protected derivatives were used [10] (Scheme 1).…”

Application of hexafluoroacetone as protecting and activating reagent in solid phase peptide and depsipeptide synthesis

“…8 These findings encouraged us to explore the synthetic utility of other HFA building blocks such as α-branched HFA-hydroxy acids and HFA-amino acids for solid phase synthesis. Citramalic acid is a C α -hydroxy-C α -methyldicarboxylic acid.…”

“…DMSO was chosen as the solvent because it is non-volatile and it slightly accelerated aminolytic cleavage in previous experiments as compared to THF, although it can induce some racemization. 8 After 18 h the resins were washed with DMSO and DCM and the products were cleaved from the resin with 95% TFA and lyophilized. 11 HPLC-MS and 1 H-NMR showed a complex mixture of products, in which the presence of H-Phe-Tyr-NH 2 (4a) and H-Leu-Tyr-NH 2 (4b) could be detected by HPLC-MS. 12 These experiments show that in the case of HFA-amino acids 3a and 3b, side reactions compete with nucleophilic ring opening at the free terminal amines of solid-phase bound amino acids.…”

Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry

“…The operational simplicity of solid phase peptide synthesis (SPPS) has led to it becoming widely regarded as the method of choice for peptide synthesis, however one of the major limitations of SPPS is its fundamental lack of atom economy. SPPS typically employs a four‐ to tenfold excess of building blocks to force reactions to completion, which is significant with costly monomer units, such as d ‐Hiv and the related hydroxyester components needed to synthesise depsipeptides . Solid phase depsipeptide synthesis is also known to be problematic, with approaches often relying on using depsipeptide building blocks rather than forming the depsipeptide linkages on resin…”

“…[19] The operational simplicity of solid phase peptide synthesis [20] (SPPS) has led to it becoming widely regarded as the methodo fc hoice for peptides ynthesis, [21] however one of the major limitations of SPPS is its fundamental lack of atom econ-omy.S PPS typically employs af our-to tenfolde xcess of building blockst of orce reactions to completion, which is significant with costly monomer units,s uch as d-Hiv and the relatedh ydroxyester components neededt os ynthesise depsipeptides. [22] Solid phase depsipeptide synthesis is also known to be problematic,w ith approaches often relying on using depsipeptide building blocks rather than forming the depsipeptide linkages on resin. [23] After our group'sp reviousw ork on peptide couplings in flow, [24] cyclooligomeric depsipeptides were chosen as the targets for the current work as they exhibit highly desirable biological activity, [1] contain challenging N-methylated amide bonds, [25] and could be built-upiteratively as they consist of repeatedd ipeptidol monomer units.…”