Total Synthesis of Lamellarins U and A3 by Interrupting Halogen Dance

Abstract

A total synthesis of lamellarins U and A3 is described. The synthesis features interruption of a halogen dance reaction of a metalated α,β-dibromopyrrole. The pyrrolylmagnesium reagent, generated by deprotonative metalation using (TMP)MgCl·LiCl (TMP: 2,2,6,6-tetramethylpiperidide) as base, was transmetalated to the corresponding organozinc species without causing the halogen dance reaction, which underwent a Negishi coupling to incorporate an aryl group onto the pyrrole ring. The arylated α,β-dibromopyrrole was then converted into lamellarins U and A3 through an α-selective halogen–magnesium exchange followed by carboxylation and subsequent palladium-mediated cyclization. The late-stage introduction of another aryl group was performed using a Kosugi–Migita–Stille coupling to provide lamellarins U and A3.

Amidative Cyclization of Alkynyl Esters to Access Pyrazin-1(2H)-ones: Application to the Synthesis of Peramine and Dibromophakellin

“…As shown in Scheme , our synthesis was initiated by dibromination of commercially available ethyl 1 H -pyrrole-2-carboxylate 15 to obtain pivotal dibromo intermediate 15a with a reported protocol . On the other hand, the THP-protected propargyl bromo derivative 14 was obtained in good overall yield from propargyl alcohol 11 in three steps following a reported procedure .…”

Recent advances in the synthesis of chromenone fused pyrrolo[2,1-a]isoquinoline derivatives

“…In another report, Okano et al 80 described the synthesis of lamellarins starting from easily available pyrrole carboxylate by interrupting halogen dance by the construction of coumarin as well as pyrrolo[2,1- a ]isoquinoline rings in the key intermediates (Scheme 22). The main precursor pyrrolylzinc reagent was achieved by deprotonative metalation by using (TMP)MgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidide) as the base and followed by transmetalation with ZnCl 2 ·TMEDA without causing the halogen dance reaction.…”

Formal Synthesis of Dictyodendrin B

“…This synthetic strategy involves functionalization of the readily available α,β-dibromopyrrole and reductive formation of the benzene ring involved in the tetracyclic pyrrolo­[2,3- c ]­carbazole skeleton (Scheme ). We recently achieved the total synthesis of pyrrole alkaloids, lamellarins U and A3, by developing the C–H arylation of the α,β-dibromopyrrole through deprotonative magnesiation, transmetalation to the corresponding pyrrolylzinc species, and Negishi coupling, while the two bromo groups remained untouched . This reaction makes it possible to install the anisyl group onto pyrrole 1 and provide fully substituted dibromopyrrole 2 .…”

“…We recently achieved the total synthesis of pyrrole alkaloids, lamellarins U and A3, by developing the C−H arylation of the α,β-dibromopyrrole through deprotonative magnesiation, transmetalation to the corresponding pyrrolylzinc species, and Negishi coupling, while the two bromo groups remained untouched. 15 This reaction makes it possible to install the anisyl group onto pyrrole 1 and provide fully substituted dibromopyrrole 2. The distinct reactivity of the two bromo groups allows the We synthesized indolylboronic acid pinacol ester 8 and fully substituted bromopyrrole 3, which were assembled to provide iodolylpyrrole 9 for the construction of the benzene nucleus (Scheme 2).…”

“…After the regioselective dibromination of the pyrrole-2-carboxylic acid ethyl ester, the obtained dibromopyrrole was subjected to Mitsunobu conditions using 4-methoxyphenylethyl alcohol to provide 1 in 98% yield. According to our previous work, deprotonative magnesiation was performed using (TMP)­MgCl·LiCl at −40 °C. The resulting pyrrolyl­magnesium reagent was transmetalated to the corresponding organozinc species, which underwent Negishi cross coupling with p -iodoanisole in the presence of 10 mol % Pd­(PPh 3 ) 4 to give arylated dibromopyrrole 2 in 92% yield.…”