Diastereoselective synthesis of fluoroisosteric analogues of antiparasitic pyrrolobenzoxazine alkaloids from tryptophan by successive fluorination–cyclization and a Meisenheimer-type rearrangement

Abstract

Fluoroisosteric analogues of an antiparasitic pyrrolobenzoxazine alkaloid CJ-12663 were designed and diastereoselectively synthesized.

Synthesis and Activation of Bench-Stable 3a-Fluoropyrroloindolines as Latent Electrophiles for the Synthesis of C-2-Thiol-Substituted Tryptophans and C-3a-Substituted Pyrroloindolines

“…This was unexpected given previous reports on preferential formation of the syn-cis diastereomer in the case of DMDO-mediated oxidative cyclization of N α -Tr-Trp-OMe to N α -Tr-3a-hydroxypyrroloindoline-COOMe . Furthermore, to the best of our knowledge, all previously reported 3a-fluoropyrroloindoline-containing compounds formed with only a slight-to-moderate diastereoselectivity in favor of the syn-cis diastereomer. , Consistent with other reports, we observed little diastereoselectivity with other substrates; compounds 3–8a,b were obtained generally as a mixture of two inseparable diastereomers, with syn-cis in a slight excess (∼1.2:1 syn-cis : anti-cis , as determined by 19 F-NMR spectroscopy of the crude reaction). (Note: As a previous report (ref ) has described the use of N ε -acetylation to assist in the separation of these two diastereomers, we did not address protection/separation here.)…”

“…A case of enantioselective fluorocyclization was reported for tryptamine susbtrates . A 3a-fluoropyrroloindoline was recently exploited as a key intermediate in the synthesis of fluorinated pyrrolobenzoxazine alkaloids . Moreover, in the total synthesis of α-amanitin, a 3a-fluoropyrroloindoline, produced from tryptophan-6-MIDA-boronate ester, facilitated production of the characteristic tryptathionine staple (Figure b,c) shared by amatoxins and phallotoxins …”

“…9 A 3a-fluoropyrroloindoline was recently exploited as a key intermediate in the synthesis of fluorinated pyrrolobenzoxazine alkaloids. 10 Moreover, in the total synthesis of α-amanitin, a 3a-fluoropyrroloindoline, produced from tryptophan-6-MIDA-boronate ester, facilitated production of the characteristic tryptathionine staple (Figure 2b,c) 11 shared by amatoxins and phallotoxins. 12 Notwithstanding these advances, most reports have focused on methodological developments toward the synthesis of 3afluoropyrroloindoline and its incorporation into natural product analogues, while little attention has been devoted to studying its reactivity as an electrophile.…”

Biosynthesis of Terpenoid–Pyrrolobenzoxazine Hybrid Natural Product CJ‐12662

“…First isolated by Pfizer in 1991, CJ‐12662 and the nonhalogenated derivative CJ‐12663 ( 2 ) are pyrrolobenzoxazine terpenoids [9] . The unique scaffold of 1 has led to several total synthesis efforts, and the pyrrolobenzoxazine core was constructed by consecutive oxidations of N ‐methyl‐tryptophan [9, 13–15] …”

“…[9] The unique scaffold of 1 has led to several total synthesis efforts, and the pyrrolobenzoxazine core was constructed by consecutive oxidations of N-methyltryptophan. [9,[13][14][15] The structure of 1 is exemplary of the aforementioned complexity generation strategies used by nature. First, 1 is a hybrid terpene-amino acid natural product, of which the sesquiterpene component is esterified to the carboxylate group of a modified tryptophan.…”