A general strategy for the synthesis of indoloquinolizine alkaloids via a cyanide-catalyzed imino-Stetter reaction

Abstract

A new strategy applicable to the synthesis of indoloquinolizine natural products has been developed. A cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines, derived from 2-aminocinnamic acid derivatives and 2-pyridinecarboxaldehydes, provided indole-3-acetic acid derivatives bearing a pyridyl ring at the 2-position. Reduction of the carboxylic acid moiety to an alcohol followed by activation of the resulting alcohol with TfO or TsCl generated indoloquinolizinium salts, which were utilized as precursors for indoloquinolizine natural products. The advantage of this protocol was successfully demonstrated in the total syntheses of arborescidine A and nauclefidine.

Direct Access to (±)‐10‐Desbromoarborescidine A from Tryptamine and Pentane‐1,5‐diol

“…Other syntheses of (±)‐10‐desbromoarborescidine A involving Pictet‐Spengler condensation have been reported . Alternative approaches involve, amongst others, imino‐Stetter and Polonovski type reactions . Several enantioselective syntheses have also been reported .…”

Cyanide Anions as Nucleophilic Catalysts in Organic Synthesis

“…The latter result from the conversion of amino-cinnamates with pyridinecarbaldehydes via imines 87 (Scheme 23). The products could be further processed to arborescidine A (89 in four steps from 88 with X = Br and Y, Z = H) 92 and nauclefidine (90 in six steps from 88 with X, Z = H and Y = OMe). 92 When starting from 4-bromopyridine-2carbaldehyde (X, Y = H, Z = Br), the alkaloid antirhine (91) as well as an epimer and dihydrocongeners were accessed.…”

Recent Advances in Stetter Reaction and Related Chemistry: An update

“…An efficient methodology for the synthesis of these natural indoloquinolizines has been established by Cheon and co‐worker in 2017 [142] . Total synthesis of arborescidine A 290 was commenced by Knoevenagel condensation of picolinaldehyde 286 and ethyl ( E )‐3‐(2‐amino‐4‐bromophenyl)acrylate 287 .…”

“…Several important scaffolds present in natural products can easily be provided via Stetter reaction. They are quinazolinone 239 , [87f] 5,8‐methanobenzo[7]annulen‐9‐one 240 [94] indoloquinolizine 241 , [87c] indolo[3,2‐ j ]phenanthridine 242 , indolocarbazole 244 [87d] and ketosuccinimide 243 [32] (Figure 2).…”