Recent Advances in Phenol Dearomatization and Its Application in Complex Syntheses

Abstract

As a powerful tool, the dearomatization of phenols has been explored extensively and utilized by organic chemists during the course of complex syntheses. This review highlights recent advances in phenol dearomatizations, especially those accomplished in an enantioselective manner, and the application of dearomatization strategies in complex syntheses.

1 Introduction

2 New Developments in Phenol Dearomatization

3 Enantioselective Phenol Dearomatization

3.1 Controlled by Chiral Substrate

3.2 Controlled by Chiral Catalyst

3.3 Controlled by Chiral Hypervalent Iodine

4 Enantioselective Phenol Dearomatization Strategies in Complex Syntheses

4.1 With the Formation of a Carbon–Oxygen Bond

4.2 With the Formation of a Carbon–Carbon Bond

4.3 With the Formation of a Carbon–Nitrogen Bond

5 Conclusion

Key words

dearomatization - enantioselectivity - oxidation - phenols - tandem reaction

Biographical Sketches

Qiuping Ding was born in Jiangxi, China, in 1975. He received his Ph.D. from Fudan University under the supervision of Professor Jie Wu in 2009. He is currently an associate professor at Jiangxi­ Normal University, China. His research interest is focused on cascade reactions.

Yang Ye was born in Hunan, China, in 1985. In 2012, he received his Ph.D. from Fudan University under the supervision of Professor Renhua Fan. He is currently a technician in Pharmaron Beijing Co., Ltd.

Renhua Fan was born in Jiangxi, China, in 1976. He received his Ph.D. from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the supervision of Professor Xuelong Hou in 2003. After postdoctoral studies (2003–2006) at Purdue University, USA with Professor Alexander Wei, he moved to Fudan University, China. He is currently a full professor of organic chemistry at the Department of Chemistry of Fudan University. His research interest is focused on hypervalent iodine chemistry.

1

Introduction

Organic synthesis has reached a considerable level of maturity. Nowadays, almost any complex molecule can be synthesized, and selective functionalizations achieved. However, with ever-tighter resources, efficiency in organic synthesis is becoming more and more important. An ideal synthesis demands simplicity, safety, brevity, environmental friendliness, as well as high selectivity, yield and diversity.[ ¹ ]

Phenols are the most frequently utilized substrates for dearomatization to access complex molecules. A number of dearomatization strategies have been used by organic chemists to construct fused, bridged and spiro structures. Owing to the high efficiency of these tactics, more and more investigations have focused on this field.[ ² ]

The oxidation of o- and p-hydroquinones generally proceeds in methanol solution at room temperature, and the yield of benzoquinones is almost quantitative.[ ³ ] Dearomatization of 4- or 2-substituted phenols in the presence of an appropriate nucleophile (Nu) leading to the respective 4,4- or 2,2-disubstituted cyclohexadienones is especially interesting and synthetically useful (Scheme [1]). Various nucleophiles, such as water,[ ⁴ ] alcohols,[3] [5] fluoride ion,[ ⁶ ] carboxylic acids,[5d,7] amides,[ ⁸ ] oximes,[ ⁹ ] and electron-rich aromatic rings[10] [11] have been used successfully in dearomatization in either an inter- or an intramolecular mode. Besides, the resulting cyclohexadienones are good electrophilic substrates for various reactions, such as the Diels–Alder reaction, 1,4-addition, reduction and [3+2] cyclization. The following section of this report highlights some recent investigations on phenol dearomatizations, especially those accomplished in an enantioselective manner, and their application in complex syntheses.

Scheme 1 Dearomatization of 4- or 2-substituted phenols

2

New Developments in Phenol Dearomatization

Besides electron-rich aromatic rings, other carbon resources can be introduced into the cyclohexa-2,5-dienone structure through an oxidative dearomatization process. Canesi and co-workers developed an iodine(III)-mediated oxidative Wagner–Meerwein transposition involving different functionalities (Scheme [2]).[ ¹² ] The reaction occurred rapidly in hexafluoroisopropanol (HFIP) using iodobenzene diacetate as oxidant. This transformation provides new strategic opportunities to prepare highly functionalized compounds containing a prochiral dienone and a quaternary carbon center connected to several sp² carbons.

One year later, the same research group reported a bimolecular oxidative process occurring with carbon–carbon bond formation that has been extended to allylsilanes (Scheme [3]).[ ¹³ ] In this reaction, different 4-alkyl-2-6-disubstituted phenols 19 were successfully oxidized leading to an oxidative variant of the famous Hosomi–Sakurai allylation.[ ¹¹ ] It is noteworthy that the first approach to this reaction was developed by Quideau and co-workers in aprotic solvents with phenyliodine(III) bis(trifluoroacetate) (PIFA), which provided some examples of oxidative allylation on substituted 1-naphthol.[ ¹⁴ ]

Canesi and co-workers also reported a dearomatization of phenol derivatives that promotes the formation of bicyclic and tricyclic products via a cationic cyclization process.[ ¹⁵ ] First, an oxidative vicinal-fused carbocycle formation was performed with a terminal alkyne on a lateral chain at the meta-position of phenol 21. The authors speculated that a strained half-chair intermediate 22 was generated, and that this strongly favored nucleophile capture, leading to the unsaturated decalin system 24 (Scheme [4]). Vicinal-fused carbocycles were produced in good yields (43–91%). This new process could have application in asymmetric synthesis governed by the benzylic stereogenic center at the meta position (Scheme [5]). Such scaffolds are present in numerous natural products such as anominine,[ ¹⁶ ] andrographolide,[ ¹⁷ ] or the decalin core of azadirachtin.[ ¹⁸ ] The cyclization reaction occurred with total stereocontrol in agreement with the configuration of the starting olefin, since a 2:1 mixture of diastereomers was obtained. To verify the high diastereoselectivity of this process, cis-25 was prepared, and led exclusively to the tricyclic core 28 in a 43% yield. Recently, Canesi’s research group also reported an oxidative ipso-rearrangement mediated by a hypervalent iodine reagent. A functionalized dienone system containing a quaternary carbon center connected to several sp² centers was constructed. This transformation was used in the total synthesis of sceletenone, a small alkaloid.[ ¹⁹ ]

Scheme 2 Wagner–Meerwein transposition by dearomatization of phenols

Scheme 3 Bimolecular oxidative process between phenols and allylsilanes

Scheme 4 Oxidative formation of fused carbocycles

Scheme 5 Asymmetric synthesis of a tricyclic scaffold

The substituted alkynyl group in 29, where R2 ≠ H, also performed as a nucleophile in the carbon–carbon bond formation. Kita and colleagues developed a very effective spirocyclization procedure for installing nucleophiles (Nu = N₃, NO₂, SCN, SO₂Tol, and Br) induced by iodonium(III) salts (Scheme [6]).[ ²⁰ ] The in situ generated cationic iodonium(III) species activates the alkynyl group and induces the ipso-cyclization of compound 29, thereby leading to a spirocyclized iodonium(III) salt. The latter undergoes a reductive coupling[ ²¹ ] with nucleophiles to afford the functionalized spirocyclic compounds 30.

Scheme 6 Synthesis of spirocycles

Zhang and co-workers reported a condition-controlled oxidative dearomatization of phenolic amides (Scheme [7]).[ ²² ] In the presence of copper(II) sulfate pentahydrate and 4-dimethylaminopyridine (DMAP), the oxidation of phenolic amides with iodobenzene diacetate as oxidant gave rise to highly functionalized spiro β-lactams. In the absence of copper salts and DMAP, the oxidation provided 4-meth­oxycyclohexadienones in nearly quantitative yields. After base-catalyzed intramolecular Michael addition and acid-catalyzed rearomatization, oxindoles were formed.

Scheme 7 Synthesis of spirolactams and oxindoles via oxidative dearomatization

In addition to oxidative dearomatization, a high-valent-palladium-mediated intramolecular cyclization cascade reaction developed by Stephenson and co-workers has been used to prepare spirocyclic cyclohexadienone structures from phenols (Scheme [8]).[ ²³ ] The resulting spirocyclic cyclohexadienone could be a precursor for a radical conjugate addition to efficiently provide the bicyclic fragment of platensimycin.[ ²⁴ ] A plausible catalytic cycle is outlined in Scheme [9]. In path A, palladium(II) coordinates to the olefin of the substrate and induces an oxypalladation to form a Wacker intermediate.[ ²⁵ ] Metallation of the carbon–hydrogen bond and subsequent oxidation by iodobenzene diacetate provides a palladacycle, which undergoes reductive elimination to produce the C–H insertion product 36. For phenols, the catalytic cycle proceeds through a dearomatization pathway (path B). The resulting Wacker intermediate undergoes oxidation to form a highly electrophilic alkylpalladium(IV) intermediate. After reductive nucleophilic substitution by the phenol ring, spirocyclohexadienone product 37 is formed.

Scheme 8 Synthesis of spirocyclic cyclohexadienones and tricyclic scaffolds

Scheme 9 Mechanism of Pd-mediated cyclization reactions leading to spirocyclic cyclohexadienones and tricyclic scaffolds

3

Enantioselective Phenol Dearomatization

3.1

Controlled by Chiral Substrate

Quideau and co-workers reported a convenient and enantioselective route to access spiroketals through dearomatization of phenols (Scheme [10]).[5a] [26] Phenolic alcohols 39a,b,e,f,h, with a tert-butyl substituent on the carbon atom attached to the hydroxy group in the side chain, underwent a highly diastereoselective transformation, in contrast to 39c,d,g, which have an ethyl or n-decyl group at this position. The stereoselectivity is controlled by the chiral alkyl branch, and a density–functional theory (DFT) calculation was done to explain the stereoselectivity. The authors hypothesized that the spiroketals were formed via a tandem ligand-exchange and ligand-coupling­ reaction (Scheme [11]). The ability of these chiral spiroketals to promote asymmetric induction was demonstrated during the synthesis of (+)-biscarvacrol,[ ²⁷ ] a naturally occurring bridge-ring system (Scheme [12]).

Scheme 10 Dearomatization of phenolic alcohols 39 into orthoquinone monoketals 40 and 41

Pettus and co-workers developed a diastereoselective dearomatization reaction and utilized it in the enantioselective synthesis of 4,6-dihydroxy-4-alkylcyclohexenone core structure with anticancer properties (Scheme [13]).[ ²⁸ ] This transformation was presumed to involve (1) in situ generation of PhI(OTf)OTMS, (2) oxidation of the phenol ring, (3) cyclization with the amide carbonyl, and finally (4) hydrolysis of the iminium species. The other diastereomer was not observed in the ¹H NMR spectrum of the crude product mixture. The modified conditions used here have significantly improved the versatility of this dearomatization process compared to their previous conditions, which used iodobenzene di(trifluoroacetate) as the oxidant­.[ ²⁹ ] Compound (–)-45 is the precursor of syn-diol (–)-46, a structure with anticancer properties.

Scheme 11 Plausible mechanism of the iodobenzene diacetate mediated spiroketalization of phenolic alcohols 39

Scheme 12 Enantioselective synthesis of (+)-biscarvacrol

Scheme 13 Dearomatization and diastereoselective synthesis of resorcinol-derived cyclohexadienone 45

3.2

Controlled by Chiral Catalyst

Gaunt and co-workers reported a process that directly converts para-substituted phenol 47 into the highly functionalized chiral molecule 48 via oxidative dearomatization and a desymmetrizing secondary-amine-catalyzed asymmetric intramolecular Michael addition (Scheme [14]).[ ³⁰ ] This one-step transformation constructs a complex structure with exquisite control of three new stereogenic centers. The corresponding decalin derivatives were formed with superb control of stereochemistry (up to >20:1 dr and 99% ee)

Scheme 14 Catalytic enantioselective dearomatization

You and Gu developed an intramolecular aza-Michael reaction catalyzed by a cinchonine-derived thiourea (Scheme [15]).[ ³¹ ] With 5 mol% of the thiourea in dichloromethane at room temperature, cyclohexadienones 50 reacted smoothly to provide compounds 51 in excellent yields and enantiomeric excess. With this methodology, asymmetric total synthesis of (–)-mesembrine[ ³² ] was accomplished with high enantioselectivity (98% ee). The same catalyst was also used in the dearomatization of phenols 52 bearing a bis(phenylsulfonyl)methylene group (Scheme [16]).[ ³³ ] Various highly enantioenriched polycyclic cyclohexenones 54 were prepared.

Scheme 15 Synthesis of pyrrolidine derivatives via enantioselective intramolecular aza-Michael reaction

Scheme 16 Asymmetric intramolecular Michael reaction

In an alternative to oxidation, the enantioselective dearomatization of phenols can also proceed in another way. Recently, Hamada and colleagues reported a palladium-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of phenols 55 to afford spiro[4.5]cyclohexadi­enones 56 (Scheme [17]).[ ³⁴ ] The method was thus applied to the catalytic enantioselective construction of an all-carbon­ quaternary spirocenter.

Scheme 17 Enantioselective construction of an all-carbon quaternary spirocenter

3.3

Controlled by Chiral Hypervalent Iodine

Asymmetric dearomatization induced by chiral hypervalent iodine reagent is still a challenge in organic synthesis.[ ³⁵ ] In 2008, Kita and co-workers developed the symmetric chiral iodine(III) reagent 60 and applied it in the tandem enantioselective oxidative dearomatization and spirolactonization reaction of naphthols (Scheme [18]).[ ³⁶ ] The enantiomeric excess values for the products reached 86%. The reaction might proceed through an ‘associative’[14] [37] or ‘dissociative’[ ³⁸ ] pathway. The higher levels of asymmetric induction were observed in those reactions carried out in nonpolar and moderately polar solvents such as carbon tetrachloride, dichloromethane, and chloroform, in contrast to the polar solvents such as hexafluoroisopropanol, and with substrates carrying electron-withdrawing substituents, rather than those with electron-donating substituents. These observations support an associative mechanism. A catalytic version of the same reaction afforded inferior enantioselectivity (up to 69% ee; Scheme [19]).

Scheme 18 Enantioselective spirolactonization and plausible reaction mechanisms

Scheme 19 Catalytic application of the chiral hypervalent iodine(III) reagent (R)-62

Ishihara and colleagues reported a similar spirolactonization reaction mediated by chiral iodoarenes 65 with m-chloroperoxybenzoic acid as co-oxidant (Scheme [20]).[ ³⁹ ] In the presence of 10 mol% of 65, lactones 64 bearing an electron-donating or an electron-withdrawing group were formed in good to excellent yields (up to 92% ee). The active λ³-iodane catalyst may be stabilized by the electron donation from the carbonyl groups of the lactic amides to the electron-deficient iodine(III) center, as in 66, or may be activated by the hydrogen bonding between the mesityl-protected NH groups and the oxygen ligands connected to the iodine atom, as in 67.

In 2009, Quideau et al. developed an asymmetric iodoarene-mediated hydroxylative dearomatization reaction (Scheme [21]).[ ⁴⁰ ] In the presence of 10–200 mol% of the chiral iodoarene, the enantioselectivities of o-quinol 69 or epoxide 70 were up to 50% ee. Both λ³- and λ⁵-iodane- mediated mechanisms were proposed (Scheme [22]).

Scheme 20 Catalytic oxidative spirolactonization

Scheme 21 Enantioselective iodoarene-mediated hydroxylative dearomatization

Scheme 22 Proposed mechanism of hydroxylative dearomatization

In the same year, Birman and Boppisetti developed a new class of chiral iodine(V) derivatives such as 76 with a chiral oxazoline group at the ortho-position (Scheme [23]).[ ⁴¹ ] This kind of chiral polyvalent iodine reagent proved to be efficient in promoting the transformation of o-alkylphenols to o-quinol Diels–Alder dimers with significant asymmetric induction.

Scheme 23 Asymmetric oxidation of isomeric dimethylphenols with 76

4

Enantioselective Phenol Dearomatization Strategies in Complex Syntheses

4.1

With the Formation of a Carbon–Oxygen Bond

In the total synthesis of (–)-acutumine (81), which was originally isolated from the Asian vine Menispermum dauricum and possesses selective T-cell cytotoxicity and antiamnesic properties, the iodobenzene diacetate mediated oxidative dearomatization was used as the key step to construct masked o-benzoquinone derivative 78 (Scheme [24]).[ ⁴² ] This result highlighted the utility of iodine(III) reagents for the dearomatization of complex substrates.

Scheme 24 Total synthesis of (–)-acutumine

A cascade process involving a hypervalent iodine induced intramolecular oxidative dearomatization and an intramolecular dipolar cycloaddition[ ⁴³ ] was reported by Sorensen and co-workers[ ⁴⁴ ] for the construction of the pentacyclic core of cortistatin A (86; Scheme [25]). The exposure of compound 82 to iodobenzene diacetate[ ⁴⁵ ] in trifluoroethanol directly produced compound 85 as a single diastereomer through two oxidations and two ring formations.

Scheme 25 Total synthesis of cortistatin A

As shown in Scheme [26, a] concise asymmetric synthesis of (+)-rishirilide B (92) was reported by Pettus and co-workers.[ ⁴⁶ ] Resorcinol 87 was coupled with lactate derivative 88 through a Mitsunobu reaction and a deprotection. Diastereoselective oxidative dearomatization of 89 presumably proceeds via chair-like transition state 90 and leads to chirality transfer from the chiral auxiliary to afford 1,4-dioxan-2-one 91 in high diastereoselectivity. Further transformations of 91 completed an efficient asymmetric total synthesis of (+)-rishirilide B (92) in 15 steps and a 12.5% overall yield.

Scheme 26 Total synthesis of (+)-rishirilide B

Recently, Pettus and colleagues also developed an oxidative dearomatization induced [5+2]-cascade reaction enabling the synthesis of α-cedrene, α-pipitzol, and sec-cedrenol (Scheme [27]).[ ⁴⁷ ] The benzylic stereocenter effectively guides the formation of the first two stereocenters during the intramolecular [5+2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin.[ ⁴⁶ ]

Scheme 27 Synthesis of α-cedrene, α-pipitzol, and sec-cedrenol

Baran and co-workers executed a sequential Barton arylation, Wessely oxidation and Diels–Alder strategy to create the core of the natural product, maoecrystal V (Scheme [28]).[ ⁴⁸ ] A similar process was reported by Mehta and Maity in the preparation of the complete carbon framework present in tashironin-type sesquiterpenoid natural products.[ ⁴⁹ ]

Scheme 28 Total synthesis of maoecrystal V

Porco and co-workers described the synthesis of (–)-mitorubrin (106) and related azaphilone natural products using copper-mediated enantioselective oxidative dearomatization of resorcinols (Scheme [29]).[ ⁵⁰ ] Dearomatization of the resorcinol aldehyde 101 using complex 102 was achieved in a regioselective manner with high enantioselectivity to afford vinylogous acid 103. Enyne 103 was subjected to copper(I) iodide catalyzed cycloisomerization to afford the mitorubrin core structure 104 (58% yield and 97% ee for two steps). Further esterification with acid 105 and final deprotection afforded the desired azaphilone (–)-mitorubrin (106). This convergent synthesis features the highly enantioselective oxidative dearomatization of resorcinol aldehyde using a readily accessible chiral bis-μ-oxodicopper complex.

Scheme 29 Total synthesis of (–)-mitorubrin

This oxidation system was also used in the enantioselective synthesis of (+)-chamaecypanone C, a novel microtubule inhibitor (Scheme [30]).[ ⁵¹ ] In the presence of copper bis(oxo) complex derived from (–)-sparteine, the chemoselective ortho-dearomatization of 2,4-disubstituted lithium phenolate led to o-quinol 108 which equilibrated by means of a [1,2]-ketol shift to isomer 109. The latter underwent a Diels–Alder dimerization to generate bicyclo[2.2.2]octenone 110 (>99% ee). After a retro-Diels–Alder­ reaction and a subsequent Diels–Alder cycloaddition with the in situ generated diarylcyclopentadienone, the desired enantiopure cycloadduct 113 was obtained in 61% yield.

Scheme 30 Total synthesis of (+)-chamaecypanone C

Dimethylketal 116, generated from the corresponding oxidative dearomatization of o-prenylphenol 115, underwent a transketalization with (2S,4S)-pentanediol to form chiral quinone monoketal 117. The latter is a key intermediate in the total synthesis of 118, the epoxyquinoid natural product (–)-jesterone (Scheme [31]).[ ⁵² ]

Scheme 31 Total synthesis of (–)-jesterone

4.2

With the Formation of a Carbon–Carbon Bond

As highlighted in the previous section, many oxidative dearomatizations involve soft carbon nucleophiles. The carbon–carbon bond formation during the oxidative dearomatization is of significant interest in complex natural product synthesis. Kita and co-workers reported the first versatile iodoarene-catalyzed carbon–carbon bond-forming reaction (Scheme [32]).[ ⁵³ ] With the in situ generated active catalytic iodine(III) species, the oxidative dearomatization of compound 119 produced the discrete carbocation intermediate 120, which was selectively trapped by the pendant aromatic ring to afford the desired spirocyclic amino ester 121. This reaction was used in the key synthetic process of producing biologically important amaryllidaceae alkaloids, such as (+)-maritidine (123).

Scheme 32 Total synthesis of (+)-maritidine

An important example of the oxidative dearomatization of a phenolic substrate with concomitant carbon–carbon bond formation in the context of complex total synthesis was reported by Nicolaou and colleagues in their enantio­selective synthesis of (–)-platensimycin (Scheme [33]).[ ⁵⁴ ] The authors employed oxidative dearomatization with an intramolecular para-spiroannulation of a pendant allylsilane[13] [14] [37e] [55] using hypervalent iodine activation to assemble the first two rings of the natural product. Activation of the free phenol moiety by iodobenzene diacetate in a polar solvent (trifluoroethanol) afforded the activated intermediate 125 bearing a delocalized carbocation which reacted internally with the allylsilane to furnish the desired spirocyclic dienone. Subsequent removal of the ethylene acetal group led to the free aldehyde substrate 126, which was ready to undergo a radical-mediated cyclization and an acid-mediated etherification to efficiently produce the tetracyclic core of platensimycin (129). Danishefsky and Dai developed an alkylative para-dearomatization of compound 130 to synthesize 131, the core matrix of the steroidal alkaloid cortistatin A (Scheme [34]).[ ⁵⁶ ]

Scheme 33 Total synthesis of (–)-platensimycin

Scheme 34 Total synthesis of cortistatin

Porco and Wang made efforts toward the synthesis of the soybean lipoxygenase inhibitors, tetrapetalones A to D (Scheme [35]).[ ⁵⁷ ] Treatment of macrocyclic hydroquinone 132 with iodobenzene diacetate led to a diastereoselective transannular [4+3] cyclization and formed the tetracyclic core of the targeted molecules. The attack of the electron-rich diene unit at the oxidatively activated hydroquinone moiety generated an intermediate with an allylic cation, which could rotate to form a suitable conformation (134) for reaction with the amide nitrogen atom. The para-quinolic tetracycle 135 was obtained in 42% yield from 132 via this one-pot process.

Scheme 35 Synthesis of tetrapetalones A to D

In the first total synthesis of the amaryllidaceae alkaloid (+)-plicamine (139), Ley and co-workers used a solid-supported iodobenzene diacetate (PS-DIB) to mediate the spirocyclization of 136 (Scheme [36]).[ ⁵⁸ ] The resulting advanced intermediate 138 was also exploited for the synthesis of both (–)-obliquine (141) and (+)-plicane (142) via the common secondary amine precursor 140.[ ⁵⁹ ]

Scheme 36 Polymer-supported approach to the total synthesis of amaryllidaceae alkaloids

An iron(III)-mediated cascade oxidative dearomatization and intramolecular Diels–Alder reaction was developed by Mulzer and Heckrodt in their total synthesis of (+)-elisabethin A (Scheme [37]).[ ⁶⁰ ] Tricyclic compound 146 was formed via endo transition state 145. This cascade process relied on the Z-configuration of the terminal olefin to induce the desired stereochemistry. The facial selectivity of the diene–quinone cycloaddition is presumably dictated by the minimization of allylic strain between the substituents at C9 and the quinone carbonyl moiety in endo transition state 145 such that cycloadduct 146 is produced as a single diastereoisomer. The required chemoselective removal of the endocyclic alkene, epimerization at C2, and deprotection afforded (+)-elisabethin A (147).

Scheme 37 Total synthesis of (+)-elisabethin A

In the total synthesis of the antimitotic natural product (–)-diazonamide A (154), Harran and co-workers subjected the advanced phenolic–indolic amide intermediate 148 to reaction with iodobenzene diacetate in the presence of lithium acetate in trifluoroethanol at –20 °C (Scheme [38]).[ ⁶¹ ] This treatment led to the formation of an undesired dearomatized and spiroannulated cyclohexa-2,5-dienone product 150 in 15% yield (path a). Nevertheless, the two diastereomeric macrolactams 152 and 153 were fortunately also obtained in a 1:3 ratio (ca. 30% yield) according to the proposed path b, through which the transient intermediate 149 is trapped intramolecularly by the nucleophilic indolic moiety, followed by rearomatization of the resulting cyclohexa-2,4-dienone intermediate 151 with a concerted oxocyclization onto its iminium unit leading to the observed benzofurans. Finally, the major benzofuran product 153 was further transformed to afford (–)-diazonamide A (154) after 14 additional steps.

Scheme 38 Total synthesis of (–)-diazonamide A

4.3

With the Formation of a Carbon–Nitrogen Bond

Matsumoto and co-workers[ ⁶² ] relied on 6,6-dimethoxycyclohexa-2,4-dienone derivatives as key intermediates in the synthesis of the erythrinan skeleton, an indolo[7a,1-α]isoquinoline core common to alkaloids isolated from many plant species of the Erythrina family. These unique tetracyclic amino structures were shown to exhibit curare-like, sedative, hypotensive and central-nervous-system-depressant activities. The atropisomerically pure biphenylic phenol 155 was successfully dearomatized into the desired o-quinone monoketal 156 upon treatment with iodobenzene diacetate in methanol at room temperature (Scheme [39]).[ ⁶² ] Subsequent Lewis acid promoted aza-spirocyclization converted compound 156 into 157. Both cyclohexa-2,4-dienone and the spiro-isoquinoline product proved to be enantiomerically pure, thus demonstrating the efficacious transmission of the axial chirality of the biphenyl 155 to the sp³-center chirality of the spirocycle 157 during this focal S_N2′-type reaction of the synthesis.[ ^62a ] The total synthesis of (+)-O-methylerysodienone (158) was next completed through three additional steps.[ ^62b ] More recently, this strategy was followed by the same research group to achieve the total synthesis of (+)-11-hydroxyerythratidine (162), a C-11 oxygenated erythrinan alkaloid (Scheme [40]).[ ⁶³ ]

Scheme 39 Total synthesis of (+)-O-methylerysodienone

Scheme 40 Total synthesis of (+)-11-hydroxyerythratidine

Ciufolini and co-workers reported a synthesis of the cyclohexa-2,5-dienone spirolactam 164 by treating the l-tyrosine-derived oxazoline 163 with iodobenzene diacetate in trifluoroethanol, following immediately with an acetylation (Scheme [41]).[ ⁶⁴ ] This spirolactam then served as a common intermediate for the synthesis of (+)-FR901483 (165)[8a] [65] and (+)-TAN1251C (166).[ ⁶¹ ] Further investigations led them to work with phenolic sulfonamides that turned out to be much better substrates than oxazolines for aza-spirocyclization.[ ⁶⁶ ] For example, sulfonamide 167 was converted into the cyclohexa-2,5-dienone spirocycle 168, which is the key synthetic intermediate for the total synthesis of the ascidian Clavelina cylindrica metabolite (–)-cylindricine C (169) (Scheme [42]).[ ⁶⁷ ]

Scheme 41 Synthesis of (+)-FR901483 (165) and (+)-TAN1251C (166)

Scheme 42 Synthesis of (–)-cylindricine C (169)

Sorensen and co-workers also accomplished an enantiospecific synthesis of the potent immunosuppressant (+)-FR901483 (165) by relying on a λ³-iodane-mediated oxidative phenol dearomatization reaction to cast the azaspirane system (Scheme [43]).[ ⁶⁸ ] In this case, phenolic secondary amine 170 was used as substrate to afford azaspiro[4.5]decadienone 171. Eight additional transformations completed the synthesis of the targeted (+)-FR901483 (165).

Scheme 43 Synthesis of (+)-FR901483 (165)

A similar strategy was used by Honda and colleagues as the key step in the synthesis of (–)-TAN1251A (175), isolated from a culture of Penicillium thomii RA-89 (Scheme [44]).[ ⁶⁹ ]

Scheme 44 Synthesis of (–)-TAN1251A (175)

5

Conclusions

A large number of papers have been published since the beginning of the century on the investigation of phenol dearomatizations, both in natural product synthesis and methodology development. This review highlights some recent advances in the phenol dearomatization reactions, especially those carried out in an enantioselective manner, and the application of dearomatization strategies in complex syntheses. Future research in this area should lead to additional strategies and methods for the use of new and efficient chiral reagents and catalysts which should be of great value to the field of natural products total synthesis.

Acknowledgment

Financial supports from National Natural Science Foundation of China (21072033), and the Open Project Program of Key Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi Normal University (No. KLFS-KF-201201) is gratefully acknowledged.

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