Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit. Heterointermediate reaction sequences toward the asperparalines and stephacidins

Abstract

A novel approach to the diazabicyclo[2.2.2]octane core of prenylated bridged diketopiperazine alkaloids is described by direct oxidative cyclizations of functionalized diketopiperazines mediated by ferrocenium hexafluorophosphate or the Mn(OAc) 3 2H 2 O/Cu(OTf) 2 system. Divergent reaction pathways take place depending on the substitution pattern of the substrates and the oxidation conditions such as temperature or the presence or absence of persistent radical TEMPO. For ester-substituted diketopiperazines, the ester group exerts a significant influence on the reaction outcome and stereochemistry of the radical cyclizations.ARTICLE HISTORY

Radicals in natural product synthesis

“…In particular, they sought to develop a method to access the diazabicyclo[2.2.2]octane core of the asperparaline and stephacidin alkaloid families. 45 They envisioned that single electron oxidation of enolate 132 would afford a radical capable of undergoing a 6- exo-trig cyclization. Unfortunately, oxidation of 132 with ferrocenium hexafluorophosphate (Cp 2 FePF 6 ) at 0 °C only afforded the dimeric product 131 ; furthermore, running the reaction at room temperature afforded only trace amounts of the desired product (Scheme 16A).…”

Unique Stereoselective Homolytic C−O Bond Activation in Diketopiperazine‐Derived Alkoxyamines by Adjacent Amide Pyramidalization

“…However, this principle may lay out new avenues for the design of catalytic and thermal reactions for the selective functionalization of amide‐containing natural products and feedstock materials. We recently introduced alkoxyamines IX as diketopiperazine (DKP)‐radical surrogates and applied them in the synthesis of diverse bridged DKP motifs that are present in numerous biologically active alkaloids . This transformation is controlled by the persistent radical effect (PRE), a powerful principle that governs the selective radical coupling between transient and persistent radical species X and XI .…”

“…We recently introduced alkoxyamines IX as diketopiperazine (DKP)-radicals urrogates and applied them in the synthesis of diverse bridged DKP motifs that are present in numerous biologically active alkaloids. [25][26][27] This transformation is controlled by the persistent radicale ffect (PRE), [28][29][30][31] ap owerful principle that governs the selectiver adical coupling between transient and persistent radicals pecies X and XI.T he homolysis of alkoxyamines is a well-appreciated phenomenon that is applied in nitroxidemediated polymerization (NMP), [32][33][34] tin-free radical transformations, [35] and in materialsr esearch, which is at estament to the power of PRE. However,t he vast majority of these transformations require temperatures beyond1 00 8Ct op roceed, which prohibits their application under milder conditions.…”

COST Action CM1201 “Biomimetic Radical Chemistry”: free radical chemistry successfully meets many disciplines

“…Antiviral cyclopentane derivatives became easily accessible by new complex tandem reactions consisting of polar organometallic additions coupled with radical cyclizations and oxygenations [128,129] and a new approach toward the total synthesis of bridged diketopiperazine alkaloids using the persistent radical effect emerged [130]. Alternatively, the central diazabicyclo[2.2.2]octane core of several alkaloids can be approached by reaction sequences proceeding through single electron transfer (SET) oxidation steps, thus switching among multiple intermediate types of different oxidation state in one pot [131].…”