Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three‐Component Reaction

Abstract

The synthesis of pyrrolidine and indolizidine derivatives through radical carboazidation of alkenes with α-iodoketones, followed by reductive amination, is described. When properly substituted, further lactamization afforded pyrrolizidinones in good yield. This carboazidation/reductive amination sequence was efficiently applied to the total synthesis of three different simple alkaloids, including (±)-monomorine I.

Radical azidation reactions and their application in the synthesis of alkaloids

“…Recently, we reported a simple way to shorten this sequence by running the radical carboazidation with α-iodoketones. This extension allows, after reduction, direct access to the desired substituted pyrrolidines (Scheme 3) [18]. It is possible, by the careful choice of the reaction partners, to install functionalized side chains having protected hydroxyl group and esters.…”

“…Monomorine I [38,39], isolated from two species of ants [40,41] and from the dendrobate Melanophryniscus stelzneri [42] was synthesized using the α-iodoketone radical carboazidation (Scheme 10) [18]. The radical carboazidation between 2-iodohexan-2-one and hept-6-en-2-one proceeded in good yield, and bis-reductive amination of the azide afforded the natural product as a single diastereoisomer.…”

Asymmetric syntheses of functionalized pyrrolizidin-3-ones

“…One commonly encountered function of this skeleton is in the formation of rigid dipeptide mimics. 1 Moreover, these bicyclic systems are known to be effective intermediates in the preparation of alkaloids such as the polyhydroxylated pyrrolizidines or indolizidines, [2][3][4] and of more complex structures like lepadiformine 5 or furopyrrolizidinone. 6 The synthesis of pyrrolizidin-3-ones mono-or disubstituted at positions 1 or 7 was reviewed in 2000.…”

Diastereoselective synthesis of α,α,α′-trisubstituted pyrrolidines and piperidines by directed sequential lithiation/alkylation

“…3 Additionally, the versatility of substituted pyrrolidines and piperidines in the synthesis has been amply demonstrated. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In 1989, Beak disclosed that unsubstituted Boc-protected azaheterocycles may be effectively functionalized at the a-position through a lithiation/alkylation sequence. 19 Several researchers, [20][21][22][23][24][25][26] including one of us, 27,16 have since extended the Beak methodology to include sequential a-functionalizations en route to access a,a-and a,a 0 -disubstituted N-heterocycles, in both racemic and enantioenriched forms.…”