A Synthesis of Theopederin D and a Formal Synthesis of Pederin

Abstract

Theopederin D, a cytotoxic metabolite from a sponge of the genus Theonella, was synthesised in 14 steps (11.1% overall yield) from two advanced intermediates previously used in a synthesis of mycalamide B. A formal synthesis of pederin from similar intermediates is also reported.Pederin (1) was the first and simplest member of a family of secondary metabolites which comprises the mycalamides, onnamides and theopederins. Though pederin was isolated from an insect (Paederus fuscipes), 1,2 all the subsequent structures were isolated from sponges of the genus Mycale or Theonella. [3][4][5][6][7] The potent antitumour and antiviral activities of the marine compounds has stimulated interest in their synthesis because they are only available in minute amounts from natural sources. Total syntheses have been reported for pederin itself, 8-11 mycalamides A 12-14 and B 14,15 , and onnamide A. 16 Progress towards theopederin derivatives has been recorded 17,18 but no total syntheses have yet appeared. We recently devised a general approach to all known members of the pederin family based on the metallated dihydropyran 2 (Scheme 1), which is a precursor to the 'left-half' common to all members of the pederin family, and the dihydropyranone 3, a platform designed for side-chain variation (Note 1). Our strategy was exemplified in a synthesis of mycalamide B (4) 15 in which the trioxadecalin intermediate 5 was fabricated from the dihydropyranone 3, and we now Scheme 1Downloaded by: University at Buffalo (SUNY). Copyrighted material. December 1998SYNLETT 1433 disclose the first synthesis of a member of theopederin family, theopederin D (6) which likewise uses trioxadecalin intermediate 5.To further underscore the flexibility of our general strategy, we also report the conversion of dihydropyranone 3 to the amide 7, a key pederin intermediate. Theopederin DOur synthesis of theopederin D began with the reductive cleavage of the pivalate ester in 5 (Scheme 2) using Red-Al followed by oxidation of the primary alcohol with pyridinium dichromate to give the carboxylic acid 8. A crucial step of the synthesis, introduction of the aminal centre at C10, was performed using a Curtius rearrangement as described by Roush 19 in order to secure the stereochemistry at the aminal centre unambiguously. The sequence entailed preparation of the acyl azide by reaction of carboxylic acid 8 with diphenylphosphoryl azide followed by thermolysis in the presence of 2-(trimethylsilyl)ethanol to trap the intermediate isocyanate as its 2-(trimethylsilyl)ethyl carbamate 9. No epimerisation of the aminal centre was observed. Acylation of the carbamate 9 with methyl oxalyl chloride in the presence of DMAP occurred slowly but cleanly to give the N-acyl oxalamide 10 in 70% yield. The crucial oxalamide ester 11 (Note 2) was then released by fluoride-induced cleavage of the 2-(trimethylsilyl)ethyl carbamate 10. 20The bridge linking the two ring systems was created by reaction of the oxalamide ester 11 with 3 equivalents of the lithiated dihydropyran 2 in the prese...

Marine natural products

“…190,191 Both mycalamide B 254, which is a potent antitumor agent from Mycale sp., 192 and theopederin D 255, a cytotoxin from a Theonella sp., 193 have been synthesized in an economical and efficient manner. 194,195 Two total syntheses of (+)-callystatin A 256, which is a potent cytotoxin from the Japanese sponge Callyspongia truncata, 196 follow somewhat similar strategies. 197,198 An additional total synthesis of (+)-discodermolide 257, which is a potent cytotoxic and immunosuppressive agent from Discodermia dissoluta, 199 has been reported.…”

Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

“…13 Progress towards the synthesis of the theopederins has been disclosed by Fukumoto and co-workers 38,73 but only one total synthesis has been reported. 45 We now give full details of our synthesis of theopederin D (5D) and its C17 epimer in which we simply divert the course of the mycalamide synthesis described above at intermediate 8. As before, our principal concerns were first, the creation of the N-acyl aminal at C10, and then elaboration of the butyrolactone side chain at C15.…”

“…[35][36][37][38][39][40][41][42][43][44] Previous publications from our laboratory have traced the evolution of a general approach to the pederin family including pederin itself, 26 mycalamide B, 32 18-O-methylmycalamide B 32 and theopederin D (5D). 45 Our aim was to devise a synthesis which was robust enough to secure sufficient quantities of most members of the family for biological evaluation together with their analogues. We now give full details of our syntheses of mycalamide B and theopederin D together with substantial tactical improvements to our previous synthesis of pederin.…”

Isolation, biological activity, synthesis, and medicinal chemistry of the pederin/mycalamide family of natural products

“…3). 77 The lactone-containing side chain was prepared (Scheme 11) by the dihydroxylation and periodate-mediated cleavage of alkene 75 (with concurrent selenoxide elimination in the pederic acid unit) to form aldehyde 76. The addition of the Grignard reagent derived from 3-chloro-1-propanol followed by oxidation provided a mixture of diastereomeric lactones that could be separated to yield 77.…”