Proline-catalyzed cascade

Ramachary and his co-workers reported a proline-catalyzed cascade [3h-2]-cycloaddition/hydrolysis reactions for the synthesis of highly functionalized ATH-1,2,3-triazoles, Scheme 3.76 [94],... 

Ma et al. developed a sequentially craitroUed Cul/L-proline-catalyzed cascade C-S and C-N bond formation process for assembly substituted phenothiazines 207 (Scheme 72) [117]. In this case using substituted 2-iodoanilines 205 and 2-bromoben-zenethiols 206 as the coupling partners are essential for craitroUing regioselectivity. 

Scheme 72 Synthesis of phenothiazines via a Cul/L-proline-catalyzed cascade C-S and C-N bond framation process...

SCHEME 2.74 Double cascade proline-catalyzed five-component O-DA-E-O-H reaction. 

Shi and coworkers established a highly efficient cascade reaction for the synthesis of dihydrofurans 106, which was developed through a diastereo but not enantiose-lective, proline-catalyzed, one-pot, three-component condensation of nitro alkenes, aldehydes, and 1,3-diketone/p-ketoesters (Scheme 2.27) [42],... 

Use of proline-catalyzed five-component cascade olefmation/Diels-Alder/ epimerization/olefination/hydrogenation reactions of enones, aryl aldehydes, alkyl cyanoacetates, and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99% de) with excellent yields (70 to 75%) was also reported (Scheme 1.20) [23]. 

The enamine (/dienamine)-iminium cycle-specific cascade catalysis is an important constituent of amine-catalyzed cascade reactions [10]. This strategy has been explored extensively and also applied to natural product synthesis. One such example is the total synthesis of dihydrocorynantheol, which was first isolated from the bark of Aspidosperma marcgravianum in 1967 [29]. This indole alkaloid is a member of the corynantheine and was found to exhibit antiparasitic, antiviral, or analgetic activities, which have attracted considerable attention from the synthetic community. Among those reported total syntheses, Itoh et al. developed a Mannich-Michael cascade reaction catalyzed by L-proline 52 for the total synthesis of ent-dihydrocorynantheol 54 (Scheme 3.8) [30], The cascade reaction of 3-ethyl-3-buten-2-one 51 with dihydro-P-carboline 50 catalyzed by 30mol% of (S)-proline afforded the tetracyclic core structure 53 in 85% yield. Excellent stereoselectivity was achieved in this cascade reaction (99% enantiomeric excess and almost complete diastereomeric control). Therefore, this organocascade reaction could lead expeditiously to construction of the core structure, which enabled the authors to accomplish the total synthesis of enl-dihydrocorynantheol 54 in just five steps. 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

These findings were extended to a set of very useful cascade reactions by the MacMiUan group [111]. In a first series 1,4-hydride additions were combined with aminations, oxidations, or Mannich reactions (Scheme 4.30). The hydride transfer was catalyzed by imidazoHdinone 9, whereas subsequent functionalization was realized by enamine catalysis through the deployment of proline. Depending on the chirality of proline used, optically pure anti- or syu-configured products 84-86 were isolated. 

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