1. Sequential Reactions Initiated by Oxidative Dearomatization. Biomimicry or Artifact? Stephen K. Jackson, Kun-Liang Wu, and Thomas R. R. Pettusa a Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106- 9510 1.1 Overview Robert Robinson first introduced the concept of biomimetic synthesis in 1917 with a one-pot preparation of tropinone [1]. This remarkable transformation joins three reactants together capitalizing upon the reactive proclivities of polyketides. Because aromatic compounds themselves are the end point of polyketide biosynthetic sequences, which are followed by the action of a few specific tailoring decarboxylative and oxidative enzymes, it is hard to conclude that sequences commencing with dearomatization are indeed ‘biomimetic’ [2]. However, sequential reactions initiated by oxidative phenol dearomatization can often appear as ‘biomimetic’, reaching very complex molecular architectures in short order because the functionality and the stereo- and regio- chemical tendencies that are programmed into the polyketide intermediates are still efficacious in the corresponding phenol derivatives and in the reactions stemming from these compounds. In this chapter, we examine some of the sequential one-pot reactions initiated by oxidative dearomatization. This discussion is by no means a comprehensive treaty on this topic. However, we attempt to untangle this subject for the benefit of interested chemists by focusing on one-pot oxidative dearomatization sequences commencing from phenols that result in the formation or cleavage of three or more C–C, C–O or C–N bonds. In all of the following schemes, the intermediate formed by the initial oxidative dearomatization undergoes further chemical reactions involving the formation and breakage of two or more bonds. Thus, the examples presented are different from most rudimentary oxidative dearomatization reactions that most often result in the usual quinol and ketal adducts [3]. 1.2 Oxidative Dearomatization Sequences and the Initial Intermediate The processes that we will describe involve some type of phenoxonium cation [4], a p-quinone methide [5], an o-quinone methide [6], or their corresponding p- and o-quinones (Scheme 1.2.1, reactive intermediates A–E). These species can lead to a lengthy sequence of reactions, just so long as the subsequent intermediates are themselves compatible with the initial oxidative conditions. The reactivity of each species can be further expanded by an attached π-framework of conjugated sp2 R- substituents so as to augment the availability of reaction manifolds. 1 O O R δ+ δ+ R O R δ+ R R A B C phenoxonium p-quinone methide o-quinone methide oxidation cation two or more phenol products O bonds formed O or broken O R O R D E p-quinone o-quinone Scheme 1.2.1 The initial species formed by phenol oxidation that can lead to further events In the following sections, we will discuss some sequences leading from the above five species that follow oxidative dearomatization. These subsequent transformations include intermolecular dimerizations, as well as successive intermolecular [4+2], [3+2] and [5+2] cycloadditions (Sections 1.3–1.4). In addition, there are numerous examples of intramolecular cascade sequences including 1,4-additions, [5+2], [4+2], [3+2] cycloadditions and subsequent aldol like processes (Sections 1.5– 1.6). There are also several examples where oxidative dearomatization to one of the above species is then followed by a series of tautomerizations, sigmatropic shifts (Section 1.7) and further reaction. We will also present examples where oxidation is followed by ring rupture, resulting in either smaller rings or larger rings (Sections 1.8–1.9), which can even incorporate additional intramolecular and intermolecular events (Section 1.10). Finally, we present some natural products presumed to form through phenol oxidative pathways (Section 1.11). Our concluding opinions on the biomimetic authenticity of presented schemes and future of this area of research are provided in the last section. 1.3 Intermolecular Dimerizations The most memorable example of a phenol oxidative cascade is likely Chapman’s 1971 synthesis of carpanone (4) [7]. The cascade sequence can be viewed as commencing with a palladium promoted oxidation of the starting vinyl phenol 2 to its corresponding resonance stabilized phenoxonium cation 1, which succumbs to a vinylogous diastereoselective aldol-like process with the original phenol 2 (Scheme 1.3.1). This reaction affords the dimeric o-quinone methide intermediate 3, which undergoes a subsequent diastereoselective intramolecular Diels-Alder reaction to produce carpanone (4). The cascade is somewhat unusual in that it involves both inter- and intra- molecular components; a phenoxonium undergoing remote addition and subsequently, the 2 dimerization of two o-quinone methides resulting in the formation of two carbon-carbon bonds and one carbon-oxygen bond. O O O HO O O O O O O O O H O O O 46 % O O H 1 2 O 3 carpanone (4) Scheme 1.3.1 Chapman’s synthesis of carpanone In a more recent related example, Antus has shown that oxidative dimerization of isoeugenol (5) leads to dehydrodiisoeugenol (9) in a single operation (Scheme 1.3.2) [8]. Treatment of 5 with phenyl iodinediacetate (PIDA) results in the formation of p-phenoxonium 6, the resonance structure (7) of which is intercepted by a second equivalent of isoeugenol (5). Nucleophilic ring closure then gives rise to the formal [3+2] addition product, dehydrodiisoeugenol (9). OMe OH O PIDA OH CH Cl , rt OMe 2 2 OMe 35 % isoeugenol (5) dehydrodiisoeugenol (9) OMe OH OMe OH O O OMe OMe 6 7 8 O OMe Scheme 1.3.2 Antus’ carpanone related net [3+2] sequence for dehydrodiisoeugenol The more common oxidative dimerization cascade processes involve subsequent Diels-Alder dimerization of an intermediate formed by addition of a nucleophile to the phenoxonium species. In particular, these products capitalize upon the inherent preference for the p-quinol and o-quinol intermediate to undergo subsequent dimerization of the same side as the polar C-O bond that is formed from dearomatization. This trait is likely imbued through asymmetric orbital development. Within this class, bisorbicillinol (15), a dimer of the oxidative dearomatization of sorbicillin (10), is perhaps the most recognized putative natural product involving this hypothetical oxidative dearomatization biomimicry (Scheme 1.3.3). In the Nicolaou synthesis, sorbicillin undergoes oxidation and saponification to form a tautomeric mixture of non-isolable o- and p-quinols (13 and 3 14), which then succumb to a regioselective Diels-Alder reaction on the same side of the quinol as the newly installed tertiary alcohol to afford bisorbicillinol (15) in a 16 % yield from sobicillin (10) [9]. Pettus, on the other hand, installs a glycolic acid derived disposable linker to produce 11 [10]. Oxidation and sequential treatment with aqueous base and acid affords the manageable spiroketal intermediate 12. Further saponification proceeds to the same tautomeric quinol mixture of 13 and 14, producing bisorbicillinol in a somewhat improved 33 % yield. OH O OH HO neither isolable HO oxidation Pb(OAc) OH 4 13 14 then saponification OH O O O O sorbicillin (10) diene: reacts from bottom dienophile: reacts from bottom o-quinol p-quinol saponification [4+2] O X O OH O R O O HO O O HO oxidation R O HO OH PhI(OCOCF3)2 O OH + O H3O R = O O 11 12 bisorbicillinol (15) Scheme 1.3.3 Nicolaou and Pettus’ syntheses of bisorbicillinol from sorbicillin Other examples of this kind of dearomatization and [4+2] dimerization can be found throughout the literature [11]. For example, Pettus has shown that ortho oxidation of xylenol 16 with the I(V) reagent 17, also known as o-iodoxybenzoic acid (IBX), results in the formation of the I(III) o-quinol derivative 18 (Scheme 1.3.4) [12]. This o-quinol intermediate undergoes [4+2] dimerization to afford the corresponding dione 19, which succumbs to further reduction to produce 20 in 51 % overall yield. O Me O O (V) Me I I Me Me O OR OH 17 HO O Me I(III) O Me O I Me OR Me O 16 O 19: R = C H IO reductant 7 4 2 20: R = H, 51 % overall 18 Scheme 1.3.4 Pettus’ oxidative dearomatization and dimerization of 2,6-xylenol with IBX 4 Although it remains debatable as to whether products of oxidative dimerization actually constitute legitimate natural products or are themselves merely artifacts of isolation, many examples exist in the literature. For instance, Takeya has shown that the o-quinone 22 generated from oxidation of the demethylsalvicanol (21) affords grandione (23) when heated in the solid state, through a [4+2] cycloaddition pathway (Scheme 1.3.5) [13]. O O O OH O OH HO OH H O O H OH [O] O solid state O H 74 % Δ HO HO H (+)-demethylsalvicanol (21) H H 22 (+)-grandione (23) Scheme 1.3.5 Takeya’s o-quinone dimerization 1.4 Successive Intermolecular Reactions Intermediates arising from oxidative dearomatization can also serve as reacting partners in intermolecular cycloadditions. For example, Singh has demonstrated that the Adler-Becker oxidation product 25 of 24 undergoes smooth cycloaddition with methyl acrylate to yield the Diels- Alder adduct 26 in 67 % yield in a regio- and diastereoselective fashion (Scheme 1.4.1) [14]. Further manipulation of the adduct resulted in assembly of the diquinane skeleton of ptychanolide. O Me Me OH OH O O CO2Me Me aq. NaIO O 4 O Me Me Me aq. MeCN [4+2] O Me Me 0 °C to rt H Me Me Me CO Me Me 67 % Me 2 ptychanolide 24 25 26 Scheme 1.4.1 Singh’s application of Adler-Becker oxidation and successive cycloaddition A novel oxidative cascade involving an o-quinone methide intermediate was recently reported by Sigman [15].