Anionic Dearomatization

SCHEME 15.5 (a) Synthesis of podophyllotoxin (13) via anionic oxidative dearomatization, (b) Anionic dearomatization-alkylation of a simple oxazolinyl arene en route to carbocychc sugar analogues. 

Intramolecular anionic dearomatization reactions have been developed starting from substituted naphthalenes and benzenes. Carbanions generated from deprotonation of A-benzyl aryl amides 

SCHEME 15.6 Anionic dearomatization in the presence of bulky Lewis acids. 

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Complex 267 with methyl or phenyl lithium results in the opening of one of the chelate rings in bis-chelate 267 and the formation of anionic dearomatized 268 (R = Me, Ph) (08OM2627). The products are readily... 

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. 

Maron and coworkers reported in 2010 that bis(T -allyl)calcium reacts with pyridine to regioselectively afford a species with two anionic, dearomatized 1,4-dihydropyridide ligands, each resulting from the addition of an aUyl group to a coordinated pyridine.In excess pyridine, an octahedral complex could be isolated and structurally characterized by X-ray diffraction, which contains four intact pyridine Hgands, and the two anionic hgands in trans positions. Its reaction with E-Cl electrophiles generates the neutral N-protected 1,4-dihydropyridines and calcium chloride. 

TOTAL SYNTHESIS OF KAINOIDS BY DEAROMATIZING ANIONIC CYCLIZATION... 

The range of nucleophiles that add to (arene)Cr(CO)3 complexes to give anionic cyclohexadienyl complexes has been detailed in the previous chapter. For successful dearomatization, the forward reaction, leading ultimately to a cyclohex-adiene needs to be much faster than the back reaction that regenerates the starting complex (Scheme 1). 

Reversibility, even at low temperatures, has been shown to be fast for stabilized carbanions (e.g., nitrile stabilized carbanions, ester enolates) whereas (most) sulfur stabilized carbanions and simple organo lithium compounds add irreversibly. Nevertheless protonation is more rapid than anion dissociation even for the first category of anions mentioned and nucleophile addition/proto-nation reactions allows efficient conversion to a dearomatized product. 

The sequential nucleophile/electrophile addition can also be applied to the dearomatization of naphthalene and derivatives. Treatment of [Cr(CO)3(l,4-dimethoxynaphthalene)] with 2-methyl-2-litihiodithiane affords a single regio-isomeric dihydronaphthalene (Scheme 24) [35, 40]. In the second example in Scheme 26, an a-nitrile anion is used. HMPA is essential in this case to favor alkylation of the metal as opposed to anion dissociation [40]. 

Conventional nucleophilic substitution of halogens and other nucleofugal groups X in electron-deficient arenes, particularly nitroarenes, proceeds via addition of nucleophiles at positions occupied by X to form o -adducts. The addition is coimected with dearomatization—thus, the adducts, which are in fact nitronate anions of nitro cyclohexadienes, undergo rapid rearomatization via spontaneous departure of X" to form products of nucleophilic aromatic substitution (Sj Ar) reaction. Detailed discussion of these processes is presented in Chapter 6. 

Phenols can be viewed as stable forms of enol tautomers, and phenolate anions display ambident nucleophilicity at oxygen as weU as C2/C6 and C4 (ortholpara positions). Consequently, phenolate anions are susceptible to C—C bond formation upon reaction with appropriate organic electrophiles (e.g., alkyl halides and sulfonates). When bond formation occurs at a substituted arene carbon, a quatonaty centCT is generated, which may lead to isolation of stable cyclohexadienone products and complete a net alkylative dearomatization (Scheme 15.1) [2]. 

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. 

Many alkylative dearomatizations proceed with complete stereoselectivity due to conformational rigidity of the cyclization substrates. Diastereoselective dearomatization of more flexible substrates is possible provided nonbonding interactions encountered in the Sj.j2-like transition states are sufficient to differentiate prochiral faces of the phenolate anions. For example, benzoate... 

Dearomatization of r -benzylpalladium complexes represents an electronically reversed variation on the reactions described earlier. Initial examples utilized allyl and allenyl stan-nanes as nucleophilic components in combination with benzyl halides and invoked mechanisms involving aryl-alkyl Pd(II) intermediates [84]. Subsequently, direct addition of stabilized nucleophiles (e.g., malonate anions) to q -naphthylpalladium complexes has been achieved [85]. 

In 2013, Liao reported the first asymmetric total syntheses of the sesquiterpenoid lactones (+)-eudesmadiene-12,6-olide and (+)-fruUanolide, which were based oti an initial dearomatization of 4-bromo-2-methoxyphenol 240 into the corresprMidmg MOB 241 (Fig. 58) [129]. An asymmetric Diels-Alder reaction wifli the chiral furan R)-2A2 furnished the bicyclo[2.2.2]octenone 243 in good yield with high chemo-, regio-, and stereoselectivities. This compound was further transformed in a few steps to reach (+)-eudesmadiene-12,6-olide, whose m-decalin core was elaborated by a high-yielding anionic oxy-Cope rearrangement of the allylic alcohol 244 (Fig. 58) [129]. 

Treatment of 3-allyloxyphenyl oxazolines with organolithium gives allyllithiums that undergo dearomatizing cyclization. The resulting anions react with electrophiles to form benzopyrans (Scheme 188). ... 

The dearomatizing anionic cyclization of r-naphthamides bearing chiral fV-substitu-ents occurs with >99% retention of configuration. Apparently anion translocation following ortho lithiation occurs for only one of the two atropisomers at —78 °C the resulting a-lithiated species can cyclize to only one diastereoisomer of the product. 

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