Asymmetric dearomatization

Buchwald reported a Pd-catalyzed aryl-Heck asymmetric dearomatization of diaryl amines (Scheme 3, equation 1) [28]. Chianese described an interesting dealkylation en route to a carbazole synthesis (equation 2) [29]. Although the corresponding 2,6-diethyl analogue does not undergo deethylation, the labile cyclized intermediate cannot be isolated, and it undergoes dimerization (60%). 

During the past years. You et al. have published different examples of intramolecular asymmetric dearomatizing allylation reactions. As substrates they used indoles 143 [155c,d], phenols 145 [158], and pyrroles 147 [159]. The aromatic carbon... 

Scheme 12.67 Iridium-catalyzed asymmetric dearomatizing allylation reactions...

SCHEME 15.4 Asymmetric dearomatization of a phloroglucinol-based substrate. 

Organotransition metal reagents have been used in both catalytic and stoichiometric dearomatization reaction sequences and provide mechanistically distinct pathways to alicyclic products. Additionally, metal-catalyzed asymmetric dearomatization is an attractive strategy for enantioselective synthesis [75],... 

SCHEME 15.28 Pd- and Ir-catalyzed asymmetric dearomatization via (allyl)metal intermediates. 

Phenolic oxidations are pivotal steps frequently involved in the biosynthesis of natural products, which possess a variety of important biological activities. Therefore, a continuing interest exists in such transformations, in particular in asymmetric oxidative protocols. Kita et al. performed asymmetric dearomatization of naphthols 43 mediated by chiral hypervalent iodine(III) reagents, 33 and 45 having a rigid spirobiindane backbone (Scheme 20) [66, 67]. A series of other ortho-functionalized spirobiindane reagents of type 46 were synthesized. Intramolecular oxidative substitution of 43 afforded five-membered spirolactone 44 with good levels of enantioselectivity (up to 92% ee). Conformationally flexible iodoarenes employed in this study produced almost racemic products. Catalytic use of these chiral catalysts with wCPBA as cooxidant afforded the chiral spirolactones without detrimental effects on the ee values. 

Enzymatic asymmetric dearomatization Sharpless masamune Asymmetric... 

In 2008 Kita developed a procedure for the asymmetric dearomatization of naph-thols via the formation of ortho-spirolactones using a C2-symmetrical chiral precatalyst 36 (Figure 19.11) and co-oxidant mCPBA with acetic acid [115] (Scheme 19.16). This reaction proceeds via the mCPBA/acetic acid-mediated oxidation of precatalyst 36 to the hypervalent iodine(III) active catalytic species 37. Ishihara has taken this work further with the development of the conformationally more flexible chiral organo-iodine precatalyst 38 [116], offering increased enantioselectivity at... 

Figure 19.11 Chiral organo-iodine catalysts for asymmetric dearomatization of naphthols.

Scheme 19.16 Asymmetric dearomatization of naphthols using hypervalent iodine catalysts.

Anisole and its derivatives have thus far demonstrated the widest variety of [Os]-mediated dearomatization reactions. These transformations have included substitutions, asymmetric tandem addition sequences, and a variety of cyclizations. 

Keywords Arene-chromium complexes Arene-manganese complexes Dearomatization Cyclohexadiene Organo lithium reagents Asymmetric arene transformations... 

What follows is a description of the trials and tribulations we experienced during our development of a short synthetic route to sorbicillactone a target that Porco has described as a deceptively simple molecule. To be clear, this work led to the synthesis of racemic material. Our group does have a strong interest in developing aryl iodide catalysts for asymmetric oxidative dearomatization reactions, and we have made some progress in this area. However, this has proved to be a very challenging area of research and still requires a fair amount of development. ... 

On the basis of the above mechanistic studies, the You group designed an Ir-catalyzed tandem dearomatization/migration protocol for asymmetric synthesis of enantioenriched tetrahydro-p-carboline derivatives 190 (Table 6.16). The migratory group in this reaction is methylene adjacent... 

Scheme 6.84 Asymmetric synthesis of six-membered aza-spiroindolenines by Ir-catalyzed intramolecular allylic dearomatization of indoles reported by You.

Recently, an oxidative dearomatization of substituted phenols followed by a desymmetrizing asymmetric intramolecular Michael addition catalyzed by the pro-linol derivative 27 has been described towards the synthesis of highly functionalized polycyclic molecules with excellent enantioselectivities [40]. As shown in Scheme 2.15, the reaction starts with an oxidation of the phenol moiety to the corresponding mera-cyclohexadienones employing PhlCOAc), mild oxidant that does not react with the aldehyde nor with the catalyst. In the presence of different nucleophiles such as, methanol, cyanide, or fluoride, intermediates 26 are formed, which suffer intramolecular Michael addition of the aldehyde moiety to afford the desired chiral products 28 with excellent diastereo- and enantioselectivities. 

In 2009, Buchwald and co-workers reported the first asymmetric palladium-catalyzed intramolecular dearomatization reaction. Benzo-carbazole derivatives were obtained in high yields and enantioselectivities from naphthalene derivatives (Scheme 2.122). Here, it is important to note that dearomatization of arenes is recognized as a fundamental chemical transformation for organic chemists which allows efficient access to alicyclic frameworks present in many biologically active compounds. 

In this chapter, an overview of dearomatization tactics employed in organic synthesis is presented. The material is organized according to mechanistic considerations and includes discussion of conventional as well as transition metal-mediated dearomatization reactions, with particular emphasis accorded to asymmetric processes. This chapter highlights the most common dearomatization reactions encountered in synthesis (with the exclusion of the Birch reduction—the topic of another chapter in this volume) and is not meant to provide a comprehensive treatise on the subject. Only dearomatization reactions of carbocyclic arenes are discussed. 

Substrate-controlled routes to optically enriched materials via diastereoselective oxidative dearomatizations constitute a second strategy for harnessing this process in asymmetric synthesis. Best results are obtained in intramolecular dearomatizations in which a preexisting stereogenic center is present on the side-chain nucleophile of a prochiral arene substrate [50]. For example, intramolecular oxidative dearomatization of 54 proceeds diastereoselectively as a consequence of conformational effects operative in the course of acetal formation (Scheme 15.20) [51]. 

SCHEME 15.21 lodinane-catalyzed asymmetric oxidative dearomatization. 

Arenes suffer dearomatization via cyclopropanation upon reaction with a-diazocarbonyl compounds (Btlchner reaction) [76]. Initially formed norcaradiene products are usually present in equilibrium with cycloheptatrienes formed via electrocyclic cyclopropane ring opening. The reaction is dramatically promoted by transition metal catalysts (usually Cu(I) or Rh(II) complexes) that give metal-stabilized carbenoids upon reaction with diazo compounds. Inter- and intramolecular manifolds are known, and asymmetric variants employing substrate control and chiral transition metal catalysts have been developed [77]. Effective chiral catalysts for intramolecular Buchner reactions include Rh Cmandelate), rhodium carboxamidates, and Cu(I)-bis(oxazolines). While enantioselectivities as high as 95% have been reported, more modest levels of asymmetric induction are typically observed. 

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