Ortho-quinol

A full paper has appeared describing the oxidation of 6-hydroxylated tetrahy-drobenzylisoquinolines of type (38) with lead tetra-acetate, to furnish the corresponding ortho-quinol acetates (39), which can readily undergo cyclization to the corresponding aporphines in acid solution. Predicentrine (40), isodomesticine (41), boldine (42), and 2,10-dihydroxy-1,9-dimethoxyaporphine (43) were prepared by such a route, which is, therefore, a practical pathway for the synthesis of 2-hydroxylated aporphines.27... 

The oxidative activation of arenes is a powerful and versatile synthetic tactic that enables dearomatization to give useful synthons. Central to this chemistry are hydroxylated arenes or arenols, the phenolic functions of which can be exploited to facilitate the dearomatizing process by two-electron oxidation. Suitably substituted arenols can hence be converted, with the help of oxygen- or carbon-based nucleophiles, into ortho-quinone monoketals and ortho-quinols. These 6-oxocyclohexa-2,4-dienones are ideally functionalized for the construction of many complex and polyoxygenated natural product architectures. Today, the inherent and multiple reactivity of arenol-derived ortho-quinone monoketals and ortho-quinols species is finding numerous and, in many cases, biomimetic applications in modern organic synthesis. 

I 75 Oxidative Conversion ofArenols into ortho-Quinols and ortho-Quinone Monoketals... 

Many natural products display structural motifs biosynthetically derived from ortho-quinol precursors, and some even feature ortho-quinol moieties in their final structural arrangement [1, 6]. Asatone (7) and related neolignans can be put forward as classic examples of complex natural products derived from cyclodimerization of oxidatively activated simple phenol precursors (Figure 5) biomimetic syntheses of 7 have accordingly been accomplished by anodic oxidation (Section 15.2.1) and by Pelter oxidation (Section 15.2.2) of the naturally occurring phenol 9 [34, 36]. 

A series of new examples has recently emerged in the literature. Aquaticol (10), an unusual cuparane-type bis-sesquiterpene isolated from the medicinal plant Veronica anagailis-aquatica, can be derived from a Diels-Alder cyclodimerization of the ortfco-quinol 11, itself derived from an enantiospecific oxidative hydroxylation of (—)-d-cuparenol (12) (Figure 5) [37, 38]. Sorbicillinoid members of the vertinoid polyketide class of natural products also present the same chemical filiation inasmuch as they appear to originate biosynthetically from the sorbicillinol (13)-derived ortho-quinol 14 (Figure 6) (Section 15.3.3) [39, 40]. 

The humulones 23a-d have been known for many years, but they can still be considered as a topical family of natural products (Figure 8). Found in hop resins and brewing hops, these natural ortho-quinols aroused early interest because of their antibiotic and tuberculostatic properties. Oxidative dearomatizing hydroxylation of their phenolic parents 24a-d was used in their synthesis [1]. 

Study of the oxidation chemistry of exifone (25a) constitutes a perfect illustration of the above statement [59, 60]. This pyrogallol benzophenone (Adlone ) was commercialized in France for the treatment of cognitive disorders in the elderly, but it was withdrawn from the market because of its hepatotoxicity, which was attributed to its 3,4-quinone metabolite 26a. Fleury and co-workers found that blocking of 26 in the form of l,4-benzoxazin-8-one ortho-quinols such as 28 led to a twenty-fold decrease in toxicity, together with a five-fold activity enhancement (Figure 9) [59, 60]. 

Metal-based reagents are often used to promote one- and two-electron oxidations of arenols. Radical-mediated C-0 coupling reactions of aryloxy radicals can, of course, lead to ortho-quinol derivatives, but the preparative value of such an approach is poor and essentially limited to intramolecular cases. For example, certain bis-phenols such as 36a-c have been spiroannulated in good yields by diradical C-0 coupling under favorable one-electron oxidation regimes (Figure 12) [65-67]. 

The ability of the cydohexa-2,4-dienone unit of ortbo-quinone monoketals and other ortho-quinol derivatives to react as either a diene or a dienophile component in [An+2n cydoadditions is arguably their prindpal virtue in organic synthesis, and paradoxically it is also the prindpal reason why it is often difficult to exploit them in synthesis they often dimerize faster than they can combine with another -system partner. Adler, Andersson, and coworkers have extensively studied the behavior of ortbo-quinols in Diels-Alder cydoadditions,... 

The convenient generation of bicyclo[2.2.2]octenones through the use of ortho-quinol derivatives in Diels-Alder reactions recently inspired Wood and co-workers in their studies toward the total synthesis of CP-263,114 (110) [148]. They relied on the Wessely-Yates tandem oxidative acetoxylation/intramolecular Diels-Alder sequence to build bicyclo[2.2.2]octenones such as 114 en route to advanced isotwistane intermediates such as 111b, which could eventually be fragmented to furnish the carbocyclic core of 110 (i.e. 111a —> 110, Figure 29) [149-153],... 

The last example of this section serves to demonstrate that the oxidative conversion of arenols into ortho-quinol derivatives is not only a useful tactic to activate the aromatic nucleus toward further structural elaboration, but that it can also constitute the key reaction enabling the formation of strategic bonds. Cox and Danishefsky provided us with a glowing illustration of such synthetic applications in their recent report on the synthesis of lactona-mycin (161) [179]. A tetracyclic model 164 of this natural antibiotic was constructed by a Wessely oxidation applied in an intramolecular fashion to the phenolic acid 162 (Figure 41). 

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