Intramolecular alkylative dearomatization

Intramolecular alkylative dearomatization offers a convenient means of constructing spirocyclo-hexadienone ring systems (Scheme 15.1). This reaction has been utilized in a number of total syntheses targeting construction of terpenoid ring systems found in natural products such as cedrene, hinesol, kaurene, p-vetivone, and isolongifolene [5], Subsequently, alkylative dearomatizations have been employed as key steps in approaches toward more complex natural products such as inter alia duocarmycin SA [6], cortistatin A [7], and platensimycin (Scheme 15.2) [8], This last example is notable as it illustrates the ability to employ silyl-protected phenols as masked phenolate anions in high-yielding alkylations. 

Fernandez, I. Forcen-Acebal, A. Garcia-Granda, S. Lopez-Ortiz, F. Synthesis of functionalized 1,4-cyclohexadienes through intramolecular anionic dearomatization of N-alkyl-N-benzyldiphenylphosphinamides. Insight into the reaction mechanism. /. Org. Chem. 2003, 68, 4472-4485. 

Early examples of this reaction involved cyclizations of 4-substituted phenols tethered to alkyl sulfonates and halides [3]. CycMzalions involving carbonyl electrophiles (aldehydes, ketones) and imines have been reported as well, but esters are not sufiSciently electrophilic to react [2]. Subsequent studies established that the facility of these so-called Ai-n cyclizations was strongly affected by the size of the newly formed ring in the order 3>5>6 >4. Since the vast majority of alkylative dearomatizations involve intramolecular cyclizations (thereby avoiding competitive 0-aDcylation reactions), stereoelectronic effects operative in the transition states (resembling the TS of an Sjj2 reaction) are crucially important. These sometimes subtle effects can result in differential reactivity of structurally similar substrates [4]. 

Several other mechanistically distinct metal-catalyzed dearomatization procedures have been reported, and almost all involve phenol or naphthol derivatives undergoing dearomatization via intramolecular transformations. Intramolecular Pd- and Rh-catalyzed C4-arylation and alkylation of /)ara-substituted phenols has been used to construct compounds of general structure 82 (Fig. 15.1) [86]. These reactions rely on generation of electrophilic aryl or alkyl o-metal complex intermediates that participate in tandem C4 metalation-reductive elimination with an attached phenol. Ruthenium- and Pt-catalyzed reactions of naphthalenes and alkynes deliver spirocyclic products such as 83 [87, 88]. An asymmetric intramolecular naphthalene dearomatization catalyzed by Pd(0)-phosphine complexes has been used to prepare carbazole derivatives 84 in good enantiomeric excess from l-(AI-2-bromophenyl)aminonaphthalene precursors [89]. 

In principle, cyclohexadienones can be accessed through tautomerization of the corresponding phenol. However, the loss of aromatic stabilization makes this impractical in all but the most specialized of cases. In order to access an isolable cyclohexadienone, the aromaticity of the phenol must be destroyed. One way to do this is through C-alkylation, but this is mostly limited to intramolecular electrophiles. Oxidative dearomatization of the phenol is by far the most conunon method used to prepare both 2,4- and 2,5-cyclohexadienones. A variety of oxidants can be used for this transforma-tiOTi, but iodine(III)- and iodine(V)-based oxidants" have emerged as the reagents of choice in many cases. An attractive feature of these oxidants, especially those based on iodine(III), is that they can be used with a variety of different nucleophiles, thereby providing access to cyclohexadienones with different substitutents. 

We decided to investigate one final substrate that contained our desired side chain for the intramolecular Diels-Alder cycloaddition as well as a small and removable cyano group. Our synthesis is outlined in Scheme 11. Phenol 53 was alkylated with chloroacetonitrile, then condensed to form 2-cyano benzo-furan 54. Subsequent quatemarization to 56 was accomplished with sodium hydride and a bromocrotcMiate (55) electrophile. Following phenol ether deprotection and reduction of the benzylic ketone with sodium borohydride, we were in a position to evaluate the dearomatization step. Unfortunately, all attempts to access the quinone epoxide 58 under classic or modified Adler-Becker reaction conditions failed. With these results, we closed the book on the second chapter in our vinigrol saga and went back to the drawing board. 

A trispirobisdienone has been obtained by double intramolecular C-alkylation with phenol-dearomatization . 

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