Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine

Abstract

Stereocontrolled Mn-mediated radical addition of alkyl iodides to chiral N-acylhydrazones enables strategic C–C bond disconnection of chiral amines. This strategy was examined in the context of a total synthesis of quinine, generating new findings of functional group compatibility leading to a revised strategy. Completion of a formal synthesis of quinine is presented, validating the application of Mn-mediated radical addition as a useful new C–C bond construction method for alkaloid synthesis. The Mn-mediated addition generates the chiral amine substructure of quinine with complete stereocontrol. Subsequent elaboration includes two successive ring closures to forge the azabicyclo [2.2.2] octane ring system of quincorine, linked to quinine through two known reactions.

Diastereoselective C-alkylation of aldimines, derived from chiral α-carbon heteroatom-substituted aldehydes, with triethylborane. Application to the synthesis of benzylisoquinolines

“…1 There are numerous methods for chiral amine synthesis, such as asymmetric reductive amination of carbonyl compounds, catalytic asymmetric reduction of ketimines, enamines or enamides, catalyzed direct reductive amination of alkyl aryl ketones, or the asymmetric addition reaction of organometallic reagents to imines. Most of the strategies use activated imines bearing electron-withdrawing groups on the nitrogen, for example, oxime ethers, 2 hydrazones, 3 and tosylimines. 4 The 1,2-radical addition of alkyl groups to the CN bond has also emerged as a valuable option for the preparation of a variety of both non-chiral and chiral amines.…”

The radical-polar crossover annulation approach to chiral substituted pyrrolidines and piperidines

“…The reaction was used in a synthetic scheme toward the formal synthesis of the antimalarial compound, quinine 1, to demonstrate synthetic utility. 26 The synthesis of γ-amino esters was also accomplished with the manganesemediated radical addition method ( Figure 16). 27 Starting with a γ-hydrazonoester 56, and adding functionalized 1° and 2° alkyl iodides, yields of 33->99% were observed with diastereomer ratios ranging from 85:15 to 97:3 in products 57 a-g. γ-Hydrazonoesters with substituents at the position α to the ester gave excellent yields when isopropyl iodide was added as well (96->99% yield, dr 90:10-99:1).…”

“…This approach was used in the total synthesis of the freshwater cyanobacterial heptatotoxin cylindrospermopsin. Our group has contributed much to the area of chiral amine synthesis through Mn-mediated radical additions to N-acylhydrazones, and we recognized the need for further development of this method [23][24][25][26][27]115,116 Towards this goal, research was completed on the topic of further testing the scope of the radical addition including optimization of an in situ subsequent cyclization which was discovered in the past 23 and which contributes to the field of RPC chemistry.…”

“…Hydrazones with R groups (Figure 64) consisting of hydrocarbon chains of multiple lengths (with or without α or β-branching), 23 or with ester, 27,116 halogen, 23,24,116 aromatic, 26,117 substituted cyclohexene, 116 and protected or free alcohol 116,117 functionality have been used. Likewise, alkyl iodides with R' groups consisting of hydrocarbon chains of multiple lengths (with or without α or β-branching), 23,27 or with halogen, 23,27,116 protected or free alcohol, 24,26,27,116,117 substituted cyclohexene, 116 or substituted cyclohexane 116 have successfully added to the imine carbon. This methodology has been applied to complex targets 310 a-g, in synthetic studies of tubulysins 117 ( Figure 65) and in a formal synthesis of quinine ( Figure 67, later in text).…”

“…This methodology has been applied to complex targets 310 a-g, in synthetic studies of tubulysins 117 ( Figure 65) and in a formal synthesis of quinine ( Figure 67, later in text). 25,26,116 N…”