Dearomatization-annulation reaction

Herein, three syntheses of morphine or related alkaloids are discussed in detail, which utilize completely different protocols for the coupling of the ring motifs of the alkaloid. Rice published a biomimetic approach with an acid-mediated electrophilic cyclization strategy as key step [144]. Mulzer employed a Friedel-Crafts acylation and a Robinson annulation to construct the phenanthrenone ring system [145]. The D ring of the alkaloid was elaborated with a 1,4-cuprate addition as key step. In his most recent contribution to morphine research, Hudlicky employed a Diels-Alder cycloaddition reaction to construct the ABCE ring system of the natural product. The requisite diene was obtained after oxidative dearomatization of the A ring precursor [146]. 

All the latter reactions lack practical utility. This is definitely not the case with the wealth of cyclization reactions that have emerged in the past decade. These enable the controlled dearomatization of benzenes and naphthalenes, which up to now have been the domain of Birch reductions. The new objective is to generate, mostly by metalation of an allylic or benzylic site, an organometallic species that is connected to an arene part by a carboxamide or sulfonamide type tether. Intramolecular attack on the arene ring followed by quenching of the enolate-like intermediate (e.g., 187 and 188) provides an annulated heterocycle for ftirther elaboration (Scheme 1-133). 

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