Probing host-selective phytotoxicity: Synthesis and biological activity ofphomalide, isophomalide, and dihydrophomalide

The cyclic depsipeptide phomalide [cyclo(Val-(E)-Aba-Hpp-Hmp-(R)-Leu); Aba = 2-amino-2-butenoic acid, Hpp = (2S)-2-hydroxy-3-phenylpropanoic acid, Hmp = (2S)-2-hydroxy-4-methylpentanoic acid] is the host-selective phytotoxin produced by the fungus [Leptosphaeria maculans (Desm.) Ces. et de Not., ase xual stage Phoma Lingam (Tode ex Fr.) Desm.] which causes blackleg disease (a devastating disease of several economically important brassica crops). E fficient total syntheses of phomalide, its (Z)-isomer isophomalide, and the two dihydro analogues [(R)-dihydrophomalide and (S)-dihydrophomalide] are described. A [2 + 3] fragment coupling of Cbz-Val-(Z)-Aba with Hpp-Hmp-D-Le u-OBn followed by deprotection and cyclization gave isophomalide which was diastereoselectively isomerized to phomalide by conjugate addition of PhSeH followed by elimination of the corresponding selenoxide. The dihydro analo gues were prepared similarly using Cbz-Val-(R)-Abu or Cbz-Val-(S)-Abu (Abu = 2-aminobutanoic acid) in place of Cbz-Val-(Z)-Aba. Biological evaluations of phomalide, isophomalide, and the dihydrophomalides revealed that only p homalide (10(-5) M) caused necrotic, chlorotic, and reddish lesions on cano la (Brassica napus and Brassica rapa; susceptible to blackleg) leaves where as no damage was observed on brown mustard (Brassica juncea; resistant to b lackleg) or white mustard (Sinapis alba; resistant to blackleg) leaves, eve n at significantly higher concentrations (10(-4) M). Thus, both the presenc e and configuration of the double bond is crucial for selective phytotoxici ty. This is the first reported synthesis of an (E)-Aba-containing natural p roduct, and importantly, the (Z) --> (E) isomerization approach should be a pplicable to other (depsi)peptide targets thereby allowing investigation of the effect of the double-bond configuration on Various properties.