Asymmetric oxidative dearomatization

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. ... 

SCHEME 15.21 lodinane-catalyzed asymmetric oxidative dearomatization. 

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. 

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 15.35 Enzymatic and oxidative dearomatization in the asymmetric synthesis of morphinan derivatives. 

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. 

Scheme 9.1 Catalytic asymmetric conjugate addition/oxidative dearomatization.

Rudolph, A., Bos, P H., Meetsma, A., Minnaard, A. J., Feringa, B. (2011). Catalytic asymmetric conjugate addition/oxidative dearomatization towards multifunctional spirocyclic compounds. Angewandte Chemie International Edition, 50, 5834-5838. 

The oxidation of ort/to-alkylphenols 49 with iodine(V) derivatives of type 42 containing chiral oxazoline moieties led to asymmetric [4+2] Diels-Alder dimerizations. The <9ri/io-alkylphenols 49 were transformed into ort/io-quinol dimers 50 with significant levels of asymmetric induction (up to 77% ee) (Scheme 21) [71], Similar substrates 51 were subjected to hydroxylative phenol dearomatization to give ort/io-quinol products 53 (Scheme 22) [72], The protocol was devised making use of the chiral iodoarene 52 in combination with mCPBA however, an... 

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... 

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