Synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer via fluorocyclisation of tryptophan-containing dipeptides

Abstract

Synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer was accomplished using fluorocyclisation of tryptophan-containing dipeptides with N-fluoro-2,4,6-trimethylpyridinium triflate to 3a-fluoropyrrolo[2,3-b]indoles as a key step. Acetylation of the indole nitrogen and the following diketopiperazine formation gave the 10b-fluorinated analogues of protubonine A and its 11a-epimer.

Synthesis of the Death-Cap Mushroom Toxin α-Amanitin

“…As a solution, we turned to halogenating agents since these react less readily with arylboronates and would selectively oxidize position 3. Given the relative stability of 3a-fluoro-indolines , compared to other 3a-halo-indolines, , we opted for electrophilic fluorocyclization of 4 (Figure ) to create 3a-fluoro-6-MIDA-boronyl-1,2,3,3a,8,8a-hexa-hydropyrrolo-[2,3- b ]­indolyl- N α -Boc-2-carboxylate ( 5 ). Although fluorocyclization of tryptophan derivatives is known, , the feasibility of converting a 3a-fluoro-indoline to a trypta­thionine cross-link is unprecedented .…”

“…Given the relative stability of 3a-fluoro-indolines , compared to other 3a-halo-indolines, , we opted for electrophilic fluorocyclization of 4 (Figure ) to create 3a-fluoro-6-MIDA-boronyl-1,2,3,3a,8,8a-hexa-hydropyrrolo-[2,3- b ]­indolyl- N α -Boc-2-carboxylate ( 5 ). Although fluorocyclization of tryptophan derivatives is known, , the feasibility of converting a 3a-fluoro-indoline to a trypta­thionine cross-link is unprecedented . Following desilylation and de-esterification, 1 was converted to MIDA-boronate ester 4 , which gratifyingly fluorocyclized cleanly in the presence of 1-fluoro-2,4,6-trimethyl­pyridinium triflate to afford 5 as an inseparable pair of diastereomers ( syn-cis and anti-cis ) in 85% yield (Scheme ).…”

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

“…A recent addition to the halopyrroloindoline series has been the incorporation of fluorine at position-3a to afford fluorinated analogs of gypsetin, brevianamide E, and protubonine, all of which naturally contain a 3a-hydroxy­pyrroloindoline that is mimicked by a 3a-fluoro­pyrroloindoline core (Figure a) . A case of enantioselective fluorocyclization was reported for tryptamine susbtrates .…”