Highly Chemoselective Synthesis of Indolizidine Lactams by SmI₂‐Induced Umpolung of the Amide Bond via Aminoketyl Radicals: Efficient Entry to Alkaloid Scaffolds

Abstract

Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen-containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N-tethered olefins using SmI2 /H2 O. This new umpolung protocol leads to the rapid synthesis of nitrogen-containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond-forming reactions by umpolung radical processes. The reaction advances the SmI2 cyclization platform to the challenging unactivated N-tethered acyl-type radical precursors to access nitrogen-containing architectures.

Amide activation: an emerging tool for chemoselective synthesis

“…When treated with SmI 2 and H 2 O, glutarimide 248 forms a radical intermediate which can then attack a tethered alkene to form indolizidines of type 250 (Scheme 34b). 130 High regioselectivity is reported for this transformation through stabilisation of the reactive aminoketyl radical intermediate. A similar reaction with alkene-containing barbiturates has been shown to lead to the formation of highly complex ring systems.…”

“…Although the reduction of activated thioamides is generally possible (vide infra), this approach has become virtually obsolete due to the advances in modern amide activation: in 2008 Charette and Barbe discovered that amides that were activated with triflic anhydride were smoothly converted into the corresponding amines (126) by the action of Hantzsch ester (Scheme 19, left). 80 Later, the method was rendered more general, enabling the conversions of secondary amides (127) into imines (128), aldehydes (129) or amines (130), depending on the reaction conditions (Scheme 19, right). 81 In the same year it was found that sodium borohydride can also be used as a reducing agent.…”

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide‐Type Carbonyl Compounds

“…Ther adical heterocyclization cascade of 9a proceeds by reductive ET to generate the radical 10 (Scheme 4). [15,16] Such radicals bearing a-allylsubstituents typically undergo radical fragmentation and deallylation, [22] however,the choice of the cyclopentene moiety is likely to render such ap rocess reversible and ensures that radical 10 persists.D iastereoselective 5-exo-trig cyclization then gives rise to the secondary benzylic radical intermediate 12,w hich undergoes ah ighly selective 6-exo-trig cyclization via achair transition structure in which the phenyl substituent adopts ap seudoequatorial orientation.…”

“…[8i] Recently,w ed escribed how SmI 2 , when activated by H 2 O, can execute the challenging ET reduction of cyclic esters,a nd have exploited the unusual ketyl radicals in new radical carbocyclizations. [9] Theu biquitous amide moiety [10] is even more resistant to ET reduction and the development of new radical cyclization methods based on the reduction of amide derivatives presents as ignificant challenge.I nspired by the pioneering work of the groups of Reissig, [11] Skrydstrup, [12] Py, [13] and Huang [13a,14] on SmI 2 -mediated nitrogen heterocycle synthesis (Scheme 1a), [15,16] herein, we describe radical heterocyclizations, [16d-f] and the first radical heterocyclization cascades of amide-type substrates.T he SmI 2 /H 2 O-mediated radical processes involve the coupling of amide carbonyls and alkenes, tethered through an sp 2 -hybridized nitrogen center, and provide expedient access to important polycyclic heterocycles possessing bridgehead nitrogen atoms (Figure 1a nd Scheme 1b). Thes ubstrate 1a,p ossessing an alkene radical trap attached through the nitrogen center,was readily synthesized in one step from commercial barbituric acid and 4-phenylbut-3-en-1-ol.…”

“…Theradical heterocyclization of 1a proceeds by reductive ET to the amide-type carbonyl group to generate the radical 3 (Scheme 2). [15,16] The5 -exo-trig cyclization and dehydration via the acyl iminium ion intermediate 4 delivers 2a.T he 5exo-dig cyclization of the radical derived from 1m gives the vinyl radical intermediate 5,w hich upon further reduction and protonation gives the bicyclic hemiaminal 2m.…”