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

Abstract

Indole dearomatization of tryptophan represents a key approach in the synthesis of indole containing alkaloids. Although the reactivity of C-3a-bromo-, 3a-iodo-, and 3a-chloro­pyrroloindolines has been explored, the utility and reactivity of C-3a-fluoro­pyrroloindolines has remained untapped. Here we induce the C–F bond to undergo a Sn1-like reaction. We demonstrate the utility of 3a-fluoropyrroloindoline to access C-2-thiol-substituted tryptophans and C-3a-substituted pyrroloindolines under mild conditions in high yield. A range of N α-protecting groups and free -COOH are well-tolerated.

Design, Synthesis, and Biochemical Evaluation of Alpha‐Amanitin Derivatives Containing Analogs of thetrans‐Hydroxyproline Residue for Potential Use in Antibody‐Drug Conjugates

“…Cmpd. separately loaded on 2-chlorotrityl chloride (CTC) resin, followed by the coupling of Fmoc-Asn(Trt)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Gly-OH and Boc-Fpi-OH (30), where Fpi = 3a-fluoro-hexahydropyrrolo-[2,3-b]indoline, [33] to afford the linear heptapeptide. Treating the resin with TFA/DCM (1 : 1) resulted in the global deprotection of the acid-labile protecting groups and tryptathionine formation via the Savige-Fontana reaction [34] to yield monocyclic heptapeptides of various amanitin analogs ( To synthesize analog 5 (mercapto-proline), the Acmprotected intermediate 8 was treated with a large excess of PdCl 2 in 6 M aq.…”

“…Following a solid phase strategy similar to our reported total synthesis, we incorporated the three aforementioned monomers into the corresponding dideoxy‐amanitins (Figure 5). To summarize, Hyp along with the synthetic Hyp analogs were separately loaded on 2‐chlorotrityl chloride (CTC) resin, followed by the coupling of Fmoc‐Asn(Trt)‐OH, Fmoc‐Cys(Trt)‐OH, Fmoc‐Gly‐OH, Fmoc‐Ile‐OH, Fmoc‐Gly‐OH and Boc‐Fpi‐OH ( 30 ), where Fpi=3a‐fluoro‐hexahydropyrrolo‐[2,3‐ b ]indoline, [33] to afford the linear heptapeptide. Treating the resin with TFA/DCM (1 : 1) resulted in the global deprotection of the acid‐labile protecting groups and tryptathionine formation via the Savige‐Fontana reaction [34] to yield monocyclic heptapeptides of various amanitin analogs ( 27 c , 28 c , 29 c ).…”

Meeting key synthetic challenges in amanitin synthesis with a new cytotoxic analog: 5′-hydroxy-6′-deoxy-amanitin

“…Following the approach used in the rst total synthesis of aamanitin 13a and supported by more recent work on the oxidative uorocyclization of tryptophan to give uoropyrroloindoline (FPI) for Savige-Fontana tryptathionylation, 17 we started with commercially available 5-OH-tryptophan. Following Fmocprotection, oxidative uorocyclization with N-uoro-2,4,6trimethylpyridinium triate (FP-T300) gave a diastereomeric pair of uoropyrroloindolines (syn-cis/anti-cis).…”

Alkali Metal Fluorides in Fluorinated Alcohols: Fundamental Properties and Applications to Electrochemical Fluorination

“…It is noteworthy that 2 was obtained in quantitative yield even in the presence of HFIP since it was reported that an additive amount of HFIP can activate the benzylic fluorine group via hydrogen bonding. − We attributed this to the hydrogen bonding interaction between the fluoride ion of CsF with HFIP, which decreased the interaction of HFIP with the benzylic fluoride.…”