Astruc D. - Modern arene chemistry (2002)(en)

15.2 Oxidative Dearomatization of ortho-Substituted Arenols 553

Fig. 19

19). It is not necessary to add acetic acid to the reaction medium; the PIDA reagent su ces for regioselective delivery of the acetate group [112].

The above oxidative nucleophilic substitutions are primarily used to introduce an oxygenbased nucleophile in order to convert arenols into ortho-quinone dialkyl monoketals and ortho-quinol acetates. Our own investigations into the synthetic utility of arenol dearomatization [113] led us to contemplate the possibility of introducing a carbon-based nucleophile. We ventured to find reagents that would promote the oxidative activation of 2-alkoxynaph- thols such as 64a/b in the presence of masked nucleophiles (Figure 20). Conditions needed to be found that would unveil their nucleophilic power in situ, and in a timely fashion to ensure chemoand regioselective carbon–carbon bond formation at the 2-position. This goal

Fig. 20

55415 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

was achieved by using PIFA as a non-nucleophilic oxidizing agent in the presence of oxida- tion-sensitive allylsilane or 1-trimethylsilyloxybuta-1,3-diene as soft carbon nucleophiles [113, 114]. The trifluoroacetic acid (TFA) released during the oxidation step generates an acidic medium that is certainly propitious to the requisite cleavage of the SiaC and SiaO bonds. The naphthalenone 68a had previously been synthesized by Adler oxidation of 2-allylnaph- thol in a pitiful yield of 0.53 % [115]. In the present case, the 2-methoxy group acts as a powerful regioselector aiding in the elaboration of the carbon–carbon bond; no C-4 adduct 69a is observed. An unfortunate loss of selectivity is observed with the 2-benzyloxynaphthol 64b, however, probably because of the greater steric demand of the phenyl group. There exist a few other approaches for the preparation of ortho-quinol derivatives besides those that can be grouped within the aforementioned three main categories. Our recent review on this topic constitutes a source of leading references for these subsidiary methods [6].

15.3

Synthetic Applications of ortho-Quinols and ortho-Quinone Monoketals

The predisposition of ortho-quinols and ortho-quinone monoketals toward aromatizing rearrangement and dimerization is at the origin of the di culties that surround their manipulations in organic synthesis (Section 15.1.2.1) [1, 2]. Aromatization through a methyl 1,2- shift was, for example, the cause of failure of the ortho-quinol-based route initially adopted by Wood and co-workers in their recent synthesis of epoxysorbicillinol (17; Figure 6) [116]. We have already noted that ortho-quinol acetates are less inclined to undergo dimerization than ortho-quinone dialkyl ketals, as well as free ortho-quinols, but that they are quite sensitive to rearomatizing acetate shifts [117–119]. We experienced this rearrangement chemistry ourselves when submitting certain ortho-quinol acetates such as 62 to silica gel chromatography (vide supra). Pericyclic [3,3]- and ‘‘pseudopericyclic’’ [3,5]sigmatropic acetate shifts furnished the phenols 63a and 63b, respectively (Figure 19) [6, 80].

It is nevertheless possible to bridle the reactivity of ortho-quinols and ortho-quinone monoketals for rapid elaboration of structural complexity and diversity in a pertinent manner for target-oriented synthesis. Some remarkable accomplishments have been highlighted in several review articles [3, 5, 6, 120]. Among the most significant ones, one can cite rearrangements of bicyclo[2.2.2]octenone cycloadducts into decalins, ring-contractions to polyquinanes, ring-expansions to tropolones, intramolecular cycloadditions to isotwistanes, cationic annulations to benzofurans, and nucleophilic additions to biaryls, enediyne units, and benzannulated heterocycles of various sizes.

15.3.1

Diels–Alder Cycloadditions

The ability of the cyclohexa-2,4-dienone unit of ortho-quinone monoketals and other orthoquinol derivatives to react as either a diene or a dienophile component in [4pþ2p] cycloadditions is arguably their principal virtue in organic synthesis, and paradoxically it is also the principal reason why it is often di cult to exploit them in synthesis; they often dimerize faster than they can combine with another p-system partner. Adler, Andersson, and coworkers have extensively studied the behavior of ortho-quinols in Diels–Alder cycloadditions,

15.3 Synthetic Applications of ortho-Quinols and ortho-Quinone Monoketals 555

Fig. 21

and observed that systems bearing substituents at their 5-position do not dimerize as readily [85–93, 95, 121]. A substituent at this locus can apparently interfere with the geminal C-6 groups of the other unit in their endo-selective ‘‘back-to-back’’ mutual approach, which is observed in all reported cases [1, 6]. Thus, for example, 6-hydroxy-5,6-dimethyl- (70a) and 6- hydroxy-3,5,6-trimethylcyclohexa-2,4-dienone (70b) do not dimerize, whereas 6-hydroxy-4,6- dimethyl- (72a) and 6-hydroxy-2,4,6-trimethylcyclohexa-2,4-dienone (72b) do (Figure 21) [85, 94, 95]. An explanation for the exclusive and regioselective participation of the 4,5-double bond as the 2p partner in these dimerizations can be found in a report by Houk [122], who calculated that both the HOMO and the LUMO of 1-substituted electron-deficient dienes possess slightly higher atomic coe cients at the sp2-carbon center remote from the carbonyl group, that is C-5 in the dimerizing cyclohexa-2,4-dienone units [79]. Other calculations made on 1-substituted and 1,4-disubstituted dienes did not allow any clear-cut interpretation and hence brought the debate round to the influence of secondary orbital interactions [122– 124]. The regioselectivity in Diels–Alder dimerizations of ortho-quinol derivatives still awaits theoretical clarification.

This tendency toward spontaneous dimerization was further elaborated for ortho-quinone monoketals by Liao, who concluded that electron-withdrawing and/or small groups at the 4-position of 6,6-dimethoxycyclohexa-2,4-dienones tend to facilitate self-dimerization, whereas electron-releasing and/or large groups at their 2- and/or 4-positions, as well as small electron-releasing groups at their 5-position, have the reverse e ect [125]. A bromide in the 4-position is particularly e cient at retarding self-dimerization [126]. Liao and co-workers also suggested that one methoxy group in ortho-quinone dimethyl ketals participates in sec-

55615 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

ondary interactions in endo-selective transition states and thus enhances the propensity of these cyclohexa-2,4-dienone derivatives to self-dimerize (e.g. 60 ! endo-61, Figures 19 and

21)[125]. A downward modulation of this orbital control with 6-acetoxy analogues (e.g. 62, Figure 21) could be the cause of their resistance toward dimerization. Furthermore, the 6- acetate carbonyl must be critical to this protecting e ect, since many ortho-quinol acetates tend to dimerize upon deacetylation [93, 94, 127, 128]. This acetoxy group e ect still remains to be clarified, notwithstanding it constitutes a useful control that can be exerted in carefully planned synthesis, as exemplified in the recent synthetic studies towards ‘‘bisorbicillinoid’’ natural products (Section 15.3.3).

Liao and his co-workers have spent the last twenty years investigating [4þ2] cycloaddition reactions with ‘‘masked’’ o-benzoquinones, or ‘‘MOBs’’ as they named them, and they remain today the frontrunners in unveiling the possibilities of using ortho-quinone monoketals in Diels–Alder reactions [6]. Their investigations demonstrated that numerous dienophiles, inter alia methyl vinyl ketone, acrylates, allyl, homoallyl crotyl, and cinnamyl alcohols, cyclopentadiene, acyclic dienes, and, more recently, even [60]fullerenes can react interor intramolecularly with ortho-quinone dimethyl monoketals such as 76 to furnish bicyclo[2.2.2]octenones [125, 129–133]. In all cases, the cycloadditions are regiospecific and proceed with high diastereoselectivity, irrespective of the electronic demand and position of substituents on the 6,6-dimethoxycyclohexa-2,4-dienone core; only the chemical yields are a ected [6]. Furans behave in a somewhat unusual manner as electron-rich dienophiles with these quinone monoketals [134, 135]. Cintas and collaborators have also investigated the cycloaddition of furans with the ortho-quinone monoketal 76a [136]. Acceleration of the reaction was achieved under ultrasonic irradiation, and the same stereochemical and regiochemical selectivities as those of the thermally-induced reaction were observed (Figure 22).

Here again, the cycloaddition is endo-selective, with only regioisomers 79 being formed, and, when using 2- and/or 3-substituted furans, only the unsubstituted furan double-bond reacts in these inverse electron-demand Diels–Alder processes [134–136]. Indoles, pyrroles, and thiophenes can also be made to react as dienophiles with ortho-quinone monoketals

Fig. 22

15.3 Synthetic Applications of ortho-Quinols and ortho-Quinone Monoketals 557

Fig. 23

76a–c bearing an electron-withdrawing group at their 4-position [136, 137]. The same regioand stereochemical outcomes as those of reactions with furans are observed with these other aromatic species (Figure 23). Supporting evidence for these selectivities was also provided by calculations performed at the ab initio RHF/3-21G* level, which indicated asynchronous but still concerted low-energy transition states featuring shorter distances between a heteroatombearing sp2 center of the aromatic units and the C-5 carbon center of cyclohexadienone unit (e.g. 81b þ 76c, Figure 23) [137, 138].

An intriguing dichotomy was revealed in the reactivity of indole (85) with ketals 76a–c (Figure 24). At room temperature, only the Diels–Alder adducts 86a–c are obtained in good yields, but at reflux temperature, only rearomatized Michael-type 1,6-adducts 87a–c are observed [139].

Arjona and Plumet recently contributed to the study of the use of non-aromatic enol and thioenol ethers as dienophiles with inverse electronic demand [140]. Cycloadditions using 76a also proved to be endo-selective and regiospecific (Figure 25). The regioisomers obtained were those having the heteroatom of the dienophile component adjacent (ortho) and anti to the carbonyl function, rather than ortho and anti to the dimethyl ketal function, as in the

Fig. 24

558 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 25

furan-, pyrrole-, thiophene-, and indole-derived bicyclo[2.2.2]octenones (Figures 22–24). These regiochemical observations are corroborated by those reported in Liao’s series of papers on the Diels–Alder reactivity between electron-rich dienophiles, such as benzyl vinyl ether 88b, dihydrofuran 89a, dihydropyran 89b, phenyl vinyl sulfide 88d, and styrene 88e, and ortho-quinone monoketals derived from eight di erent 2-methoxyphenols (Figure 25) [141, 142].

Calculations performed at the HF/3-21G level indicated smaller energy gaps between the HOMOs of the aforementioned electron-rich dienophiles and the LUMOs of the quinone ketals, as can be expected for inverse electron-demand Diels–Alder reactions under FMO control [141]. Regiochemical controls observed with quinone ketals such as 76a were well corroborated by the relative magnitudes of the atomic coe cients of the frontier orbitals. The highest coe cients at C-5 of the quinone ketal LUMO and at C-2 of the electron-rich alkenes would indeed promote bond formation between these centers. The results of calculations on other quinone ketals were, however, rather vague [141].

Numerous applications of the Diels–Alder reaction of ortho-quinone monoketals and ortho-quinols in natural products synthesis have been reported over the years [6]. The following few recent examples have been selected with the aim of illustrating the usefulness of the cycloaddition of ortho-quinol derivatives to give bicyclo[2.2.2]octenones, for these formidable strategic synthons can be further transformed in many ways to give various polycyclic architectures. Liao’s group has added a couple of notches to its already remarkable record in the field. They described a total synthesis of the norsesquiterpenoid (G)-eremopetasidione 97 [143], the key steps of which were the Diels–Alder reaction of the quinone ketal 93 with ethyl vinyl ketone, followed by a Cope rearrangement of the resulting bicyclo[2.2.2]octenone system 94 (Figure 26).

The first total synthesis of (G)-pallescensin 103 was also reported by Liao’s group [144] and features an intramolecular Diels–Alder reaction initiated by a regioselective oxidative alkoxylation of 2-methoxy-4-methylphenol 98 using the allylic alcohol 99 in the presence of PIDA. Vinylation of the resulting bicyclo[2.2.2]octenone 100, followed by ring-expansion through an ionic 1,3-allylic shift gave the bicyclo[4.2.2]decenone 102, which was further transformed into (G)-103 (Figure 27).

15.3 Synthetic Applications of ortho-Quinols and ortho-Quinone Monoketals 559

Fig. 26

Rodrigo and co-workers have made some progress towards viridin (109) [145]. After suffering a few setbacks due to a capricious installation of the C-10 methyl group, they managed to build the pentacyclic core of 109 from the tricyclic ortho-quinone monoketal 105 (Figure 28). This unit behaved both as a diene to furnish the desired pentacyclic fused system 106, and as a dienophile to furnish 107. The latter could be converted to the target 108 by a Cope rearrangement. A similar approach was used in their synthesis of (G)- xestoquinone and derivatives [146, 147].

The convenient generation of bicyclo[2.2.2]octenones through the use of ortho-quinol derivatives in Diels–Alder reactions recently inspired Wood and co-workers in their studies toward the total synthesis of CP-263,114 (110) [148]. They relied on the Wessely–Yates tandem oxidative acetoxylation/intramolecular Diels–Alder sequence to build bicyclo[2.2.2]octenones such as 114 en route to advanced isotwistane intermediates such as 111b, which could eventually be fragmented to furnish the carbocyclic core of 110 (i.e. 111a ! 110, Figure 29) [149–153].

Photochemical transformations of bicyclo[2.2.2]octenones derived from Diels–Alder reaction of spiroepoxycyclohexa-2,4-dienones 116 have been exploited by Singh’s group in their synthetic studies towards triquinane 119 and oxa-triquinane 121, protoilludane 120, and oxa-sterpurane 122 frameworks (Figure 30) [120, 154]. Spiroepoxycyclohexa-2,4-

Fig. 27

560 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 28

dienones 116 are cyclic ortho-quinol ethers that can easily be generated by Adler oxidation of 2-hydroxymethylphenols 115. Formal total syntheses of the triquinane (G)-coriolin have been achieved through 1,2-acyl shift as a result of oxa-di-p-methane rearrangement of bicyclo[2.2.2]octenones 117 upon triplet oxidation [155, 156]. Oxa-triquinanes 121 and oxasterpuranes 122 can be constructed in a stereoselective manner by modulation of the chemical reactivity of photochemically excited bicyclo[2.2.2]octenones [157]; triplet excitation of the b,g-enone system furnishes 121, whereas its singlet excitation induces a 1,3-acyl shift to give

122.

Fig. 29

15.3 Synthetic Applications of ortho-Quinols and ortho-Quinone Monoketals 561

Fig. 30

15.3.2

Photochemical Rearrangements

Cyclohexa-2,4-dienones are particularly sensitive to photochemically-induced transformations. Seminal investigations by Barton and co-workers [158, 159] have demonstrated the facile thermally reversible photoisomerization of these linearly conjugated cyclohexadienones into dienyl ketenes, which can evolve into hexadienoic acid derivatives in the presence of a protonic nucleophile (NuH) (e.g. 126, Figure 31) [160, 161]. Reaction conditions favoring the p ,n excitation state as the lowest excited state are best for initiating such a ring-opening event. Under certain conditions allowing the p ,p excitation path to be followed, bicyclo[3.1.0]hexenones can be produced directly (e.g. 134, Figure 33), as first observed by Hart and co-workers [160–162]. Early on, ortho-quinol acetates were used as substrates to study the photochemical behavior of cyclohexa-2,4-dienones [158, 159], and numerous examples have been described by Quinkert and co-workers [160, 163, 164]. In contrast to the photolytic ring-opening of cyclohexa-2,4-dienones bearing two carbon substituents at their 6-position, ortho-quinol acetates of type 123 only led to diene ketenes with the (5E )-configuration (Figure 31).

This stereochemical preference is attributed to a stereoelectronic promotion of the C6–C7 bond into a pseudoaxial orientation due to a stabilizing interaction between the corresponding s orbital and the antibonding p CbO orbital in the photoexcited cyclohexadienone 124 (Figure 31). Quinkert additionally invoked a through-space interaction between the two polar carbonyl groups to rationalize the conformational preference leading to the (5E )-geometry [160]. From a general viewpoint, di erent primary and several secondary photoproducts can be obtained under di erent reaction conditions from di erently substituted starting orthoquinol acetates. Of particular note is the possibility of building seven-membered rings from ortho-quinol acetates such as 127a–c bearing a side chain with a 2-oxo group at the 6-position (Figure 32). The presence of a bulky substituent at the 4-position increases the deviation from planarity of the nucleophilically-trapped primary photoproduct 128a–c. This deviation

562 15 Oxidative Conversion of Arenols into ortho-Quinols and ortho-Quinone Monoketals

Fig. 31

favors the intramolecular aldol-type reaction that produces the seven-membered rings 130a– c (Figure 32). Other interand intramolecular applications of this nucleophilic trapping of ketenes to the synthesis of macrolides and photochemically modifiable ionophores (e.g. 131 ! 132, Figure 32) have also been described by Quinkert and co-workers [160, 164].

Liao and Wei took advantage of the possibility of photochemically rearranging cyclohexa- 2,4-dienones into bicyclo[3.1.0]hexenones in their approach to synthetically useful cyclopentenones such as 135 [6, 160–162]. This approach was based on the acid-catalyzed cyclopropane ring-opening of bicyclo[3.1.0]hexenones such as 134, as generated photochemically from non-dimerizing ortho-quinone monoketals such as 133 (Figure 33) [165].

Fig. 32