Phenols oxidative dearomatization

A more recent report includes the biomimetic total syntheses of potent antiviral spirooliganones A and B utilizing the phenol oxidative dearomatization/ spirocyclization to buUd the spiro-fused cyclohexadienone/tetrahydrofuran moiety... 

Oxidation of a phenol to an acetoxy enone The key step in a recent synthesis of anthracyclinones is the oxidative dearomatization of the A ring of 1 to the enone 2 in 50-55% yield. The product was converted in several steps into the aglycone SM-173B (3). 

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]. 

New data on the chemistry of 4,5-dihydroisoxazole 2-oxides were reported. Oxidative dearomatization of phenol 51 with bis(trifluoroacetoxyiodo)benzene (PIFA) afforded spironitronate 52 in 74% yield. Lastly, spiroisoxazoline 53 was obtained in quantitative yield by reduction of 52 with refluxing trimethylphosphite <07OL3229>. 

An intramolecular Michael reaction (catalyzed by 2C) following the oxidative dearomatization of 4-substituted phenols provides valuable octalones. A method involving two consecutive Michael reactions to form optically active polysubstituted cyclopentanes should be highly rated. 

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. 

There were hints in the literature that certain silylated phenols were more efficient substrates than free phenols in hypervalent iodine-mediated oxidative dearomatization reactions." The mechanistic underpinnings for this observation are still murky. Nevertheless, when phenol 40 was first converted into the corresponding trimethylsilyl ether and then treated with PhI(OAc)2 in acetonitrile-water, the desired quinol (42) was formed with improved yields (77-95%) and on larger scale (>1 g) (Scheme 16B). The conditions used to... 

Of particular use are the reactions of oxidative dearomatization of 4- or 2-substituted phenols 222 and 225 with -iodanes in the presence of an external or internal nucleophile (Nu) leading to the respective... 

Oxidative dearomatization of 4-substituted phenols 222 with [bis(acyloxy)iodo]arenes in the presence of an external nucleophile provides a convenient approach to various 3,3-disubstituted cyclohexadienones 224 according to Scheme 3.92. Several examples of this reaction are provided below in Schemes 3.93-3.97. 

Synthetic application of the oxidative dearomatization of ort/io-substituted phenolic substrates in the intramolecular mode is exemplified by the preparation of azacarbocyclic spirodienones 274 from phenol derivatives 273 (Scheme 3.114) [322]. 

Hypervalent iodine induced oxidative dearomatization of orf/io-substituted phenolic substrates in the intramolecular mode has been realized as an enantioselective reaction. In particular, Kita and coworkers have developed the enantioselective spirocyclization reaction of the orfho-substituted phenolic substrates 275 using chiral aryliodine(III) diacetate 276 having a rigid spirobiindane backbone (Scheme 3.115) [346]. Similar enantioselective oxidative spirocyclization reactions of the ort/io-substituted phenolic substrates under catalytic conditions in the presence of chiral iodoarenes or chiral quaternary ammonium iodide catalysts are discussed in Sections 4.1.6 and 4.4. 

The oxidative dearomatization of ort/io-substituted phenols 225 leads to 6,6-disubstituted cyclohexa-2,4-dienones 226 (Scheme 3.92), which can be conveniently utilized in situ as dienes in the Diels-Alder cycloaddition reaction. When the oxidation of phenols is performed in the absence of an external dienophile, a dimerization via [4-f2] cycloaddition often occurs spontaneously at ambient temperature to afford the corresponding dimers with an extraordinary level of regio-, site- and stereoselectivity [348-350]. A detailed experimental and theoretical investigation of such hypervalent iodine induced Diels-Alder cyclodimerizations... 

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

Aniline derivatives can be oxidatively dearomatized analogously to the phenol derivatives. In particular, the oxidative //Ji o-tluorination of para-substituted tosylated anilines 286 using hypervalent iodine reagents... 

The oxidative dearomatization of appropriately substituted phenolic substrates resulting in intramolecular cyclization with the formation of spirocyclic products represents one of the most powerful synthetic tools in modern organic synthesis (Seetion 3.1.11). Kita and coworkers were the first to report a catalytic variant of the oxidative spirocyclization reaction based on the in situ regeneration of a [bis(trifluoroacetoxy)iodo]arene from iodoarene using mCPBA as a terminal oxidant [2]. In a representative example, the oxidation of... 

In the following example, a phenolic substrate was treated with PIFA to cause an oxidative dearomatization/spirocyclization reaction. Spirooliga-nones A and B were formed in 5-exo-trig cyclization manner exclusively (14OL3740). 

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. 

Intramolecular [4+2] cycloaddition can also be initiated via incorporation of a dienophile into the nucleophilic participant in an oxidative dearomatization sequence (e.g., an ally lie alcohol) [45]. Additionally, dienophilic alcohol moieties can be tethered to phenol substrates... 

Scheme 7 Hypervalent iodine-induced oxidative dearomatization of phenols leading to spirodienones...

Oxidative dearomatizations with introduction of nitrogen nucleophiles are rather rare in reports. Sorensen and co-workers describe the total synthesis of a powerful immunosuppressant (FR901483) by oxidative aza-spiroannulati(Hi with PIDA in HFIP followed by an intramolecular aldol addition (Scheme 12, top) [77]. Similar to Sorensen s procedure, Hrmda and co-workers completed the formal total synthesis of enantiopure (-)-TAN1251A by dearomatizing spirocyclization reaction of the enantiopure chiral phenol substrate with high stereocontrol at the diastereomeric spiro center [78]. 

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. 

Literature reported that phenolic compound would yield substituted ortho-quinone compound after Wessely oxidative dearomatization reaction. The obtained compound could act as a diene to trigger intramolecular or intermolecular Diels—Alder reaction and produce [2.2.2] bicyclic compound. This synthetic methodology has been extensively used in total synthesis [26]. 

Oxidative dearomatization reaction can start from ortho-substimted phenol and quickly construct dienes structure after oxidation. It is often used to design Diels-Alder reaction. 

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