Segment Solid‐Phase Total Synthesis of the Anthelmintic Cyclooctadepsipeptides PF1022A and Emodepside

Abstract

Cyclodepsipeptides of the enniation, PF1022 and verticilide families represent a diverse class of highly interesting natural products with respect to their manifold biological activities. However, until now, no practicable solid‐phase syntheses of these compounds have been accomplished, probably due to the problematic combination of N‐methyl amino acids and hydroxycarboxylic acids. We report herein an efficient synthesis of the anthelmintic PF1022A and its commercial analogue emodepside on Kaiser and Wang resins. Our protocol provides the basis for the solid‐phase synthesis of cyclodepsipeptide libraries with a high probability of anthelmintic, antibacterial or insecticidal activity.

Cyclodepsipeptides: A Rich Source of Biologically Active Compounds for Drug Research

“…A segment total synthesis based on couplings of the didepsipeptides prepared in solution developed by the same group worked well on both Wang- and Kaiser-resin (Scheme 17) [112]. The advantage of this procedure is, that in the coupling steps solely amide bonds are formed which succeeds in higher yields as ester formation.…”

Enantioselective Reduction of 3‐Aryl‐2‐oxo‐propanoic Acids: A Comparison of Enzymatic and Transition‐Metal‐Catalyzed Methods

“…[1] In particular, α-hydroxy acids are essential constituents of depsipeptides where they function as mimetics for the corresponding natural amino acids; thus causing a wide range of biological activities. [9,10] Despite there being different routes to α-hydroxy acids, no general methods are available that allow the synthesis of a broad variety of structurally diverse aryllactic acids. [9,10] Despite there being different routes to α-hydroxy acids, no general methods are available that allow the synthesis of a broad variety of structurally diverse aryllactic acids.…”

“…[2][3][4][5][6][7][8] During our studies on the solid-phase synthesis of the anthelmintic PF1022A and related biologically active cyclodepsipeptides, we required a set of enantiomerically pure d-aryllactic and dhetaryllactic acids. [9,10] Despite there being different routes to α-hydroxy acids, no general methods are available that allow the synthesis of a broad variety of structurally diverse aryllactic acids. The basic methods to enantiomerically pure, or at least enantiomerically enriched, phenyllactic acids can be attributed to four basic strategies ( Figure 1).…”

Reprogramming the Biosynthesis of Cyclodepsipeptide Synthetases to Obtain New Enniatins and Beauvericins

“…[27] Apart from the suitable protecting-group strategy,t echnical difficul- ties to be mastered by chemical synthesis comprise racemization and hindered couplingo fN -methyl amino acids. [43,44] Our approachp rovides ar obust in vivo system for the generation of structurally diverseC PDs, and we have significantly expandedt he possibilities for the design and engineering of CDP synthetasesw ith novel biosynthetic capabilities. The newly generated chimeric compounds point to af uture of rational engineering of CDP structures that might have beneficial pharmacological effects.…”