Synthetic and Structural Studies on Phomalide
The cyclic pentadepsipeptide phomalide [cyclo(Val-('E')-Aba-Hpp-Hmp-(' R')-Leu); Aba = 2-amino-2-butenoic acid, Hpp = (2'S')-2-hydroxy-3-phenylpropanoic acid, Hmp =(2'S')-2-hydroxy-4-methylpentanoic acid] is the host-selective phytotoxin produced by the fungus [Leptosphaeria maculans (Desm.) Ces. et de Not, asexual stage Phoma lingam (Tode ex Fr.) Desm.] which causes blackleg disease (a devastating disease of several economically important brassica crops). Efficient total syntheses of phomalide (1), its ('Z')-isomer isophomalide (2), methylphomalide (3), desmethylphomalide ( 4) and the two dihydro analogues [R-dihydrophomalide (5) and S-dihydrophomalide (6)] are described.* A [2+3] fragment coupling of Cbz-Val-('Z')-Aba with Hpp-Hmp-(' D')-Leu-OBn followed by deprotection and cyclization gave isophomalide (2). The success of the synthesis relied on the PhSeH mediated isomerization of isophomalide (2) into phomalide (1). Isophomalide was selectively isomerized, to phomalide by conjugate addition of PhSeH to give predominantly diastereomeric selenides of 'like' relative stereochemistry (i.e. 'syn' PhSe and NHR). Oxidation-elimination of selenides of 'like' relative stereochemistry produced phomalide in excellent yields. This methodology to selectively isomerize á, â-unsaturated amino acids of ('Z')-configuration into the corresponding (' E') isomers would appear to has considerable generality and constitute an attractive alternative to access the otherwise elusive á,â-unsaturated amino acids of ('E')-configuration.* The dihydro analogues (5 and 6) and methylphomalide (3) were prepared similarly using Cbz-Val-('R')-Abu, Cbz-Val-('S')-Abu (Abu = 2-aminobutanoic acid), and Cbz-Val-Amb (Amb = 2-amino-3-methyl-2-butanoic acid), respectively in place of Cbz-Val-(' Z')-Aba. For desmethylphomalide (4), Boc-Val-(3-PhSe)Ala was used as the precursor of the dipeptide Boc-Val-[Delta]Ala ([Delta]Ala = 2-aminopropenoic acid) thus required. Biological evaluations of phomalide, isophomalide, methylphomalide, desmethylphomalide and the dihydrophornalides revealed that only phomalide (10-5 M) caused necrotic, chlorotic, and reddish lesions on canola ('Brassica napus' and 'B. rapa'; susceptible to blackleg) leaves whereas no damage was observed on brown mustard ('B. juncea'; resistant to blackleg) or white mustard ('Sinapis alba'; resistant to blackleg) leaves, even at significantly higher concentrations (10-4 M). Thus, both the presence and configuration of the double bond is crucial for selective phytotoxicity.* The original synthetic strategy was modified to prepare isotopically labelled phomalide (14C-phomalide) required for biological studies. Two approaches were used to prepare 14C-phomalide; the first approach consisted of coupling the dipeptide Cbz-Val-Aba (as a ' Z'/'E'-isomer mixture) with the tripeptide Hpp-Hmp-OBn, followed by stereoselective addition of PhSeH, incorporation of 14 C-1 ('R')-Leu, cyclization and oxidation-elimination. In the second approach, the selective isomerization of the tetrapetide Boc-Val-(' Z')-Aba-Hpp-Hmp-OCH2CH2-OTMS to the (' E')-isomer, via addition elimination of PhSeH was followed by incorporation of 14C-1 ('R')-Leu and cyclization. This is the first reported synthesis of an ('E')-Aba containing natural product and, importantly, the ('Z') [right arrow] (' E') isomerization approach should be applicable to other (depsi)peptide targets thereby allowing investigation of the effect of the double bond configuration on various properties. *Please refer to dissertation for diagrams.
Advisor:Ward, Dale E.
School:University of Saskatchewan
School Location:Canada - Saskatchewan
Source Type:Master's Thesis
Keywords:no keywords supplied
Date of Publication:01/01/1999