Wessely oxidation reaction

Our initial approach centered on the use of a strategic Wessely oxidation reaction to transform an appropriately decorated resorcinol precursor into a tricyclic cage architecture formed by an in situ intramolecular Diels-Alder cycloaddition reaction (Scheme 1). From there we envisioned a 6-exo-type cyclization to form the tetracyclic core, which in the best case scenario would also set the C9-methyl stereocenter. Manipulation of the functional groups on the tetracyclic core would then be followed by a late-stage C—C bond fragmentation reaction to access the vinigrol core. Conversion of the exocyclic methyl ketone group was expected to afford the desired isopropyl moiety. 

Scheme 3)10. Indeed, independent photolysis of 2,4-cyclohexadien-l-ones 12 and 13 afforded the macrolides 15. These reactions likely proceed via a common intermediate, in this case dienylketene 14, which is trapped intramolecularly by the pendant hydroxyl group. Adjustment of the oxidation level and functional group interconversion then led efficiently to the desired macrolide 17. The sulfonyl group was used for two reasons first, to easily transform lactones 15 into dienyl lactones 16 needed for 17, and secondly, to control the regiochemistry of the Wessely oxidation of phenolic precursor needed to produce the photolysis substrates 12 and 13. 

Oxidative nucleophilic substitution is, however, a more versatile technique and a much better choice for target-oriented synthesis (Sections 15.1.1 and 15.1.2.2). In 1950, Wessely and co-workers examined the use of lead tetraacetate (LTA) in acetic acid to determine the structure of phenols and, in doing so, they developed their oxidative acetoxylation reaction, referred to herein as Wessely oxidation (Figure 13) [68-76]. If both an ortho- and a para-position are available to accommodate the entry of the acetoxy nucleophile, ortho products often predominate even when the ortho position is already occupied by a resident alkyl (e.g. 40 —> 41a/b) or allcoxy group (Figure 13) [69, 74]. 

The last example of this section serves to demonstrate that the oxidative conversion of arenols into ortho-quinol derivatives is not only a useful tactic to activate the aromatic nucleus toward further structural elaboration, but that it can also constitute the key reaction enabling the formation of strategic bonds. Cox and Danishefsky provided us with a glowing illustration of such synthetic applications in their recent report on the synthesis of lactona-mycin (161) [179]. A tetracyclic model 164 of this natural antibiotic was constructed by a Wessely oxidation applied in an intramolecular fashion to the phenolic acid 162 (Figure 41). 

The reaction is general for ortAo-substituted phenols and for a, -unsaturatcd acids, but yields are somewhat low (ca. 207 ) in the case of cresol. One useful result of this route is that the bicyclo[2.2.2]octenones are regioisomers of the adducts formed by intermolecular Diels-Alder reactions of the 2,4-dienones obtained by usual Wessely oxidation. ... 

Our first specific Wessely oxidation approach is outlined in Scheme 2. Following an aldol-type reaction between an appropriately protected resorcinol fragment and an aldehyde, we expected the Wessely oxidation to selectively dearomatize at the ortho position of both phenols. The intramolecular Diels-Alder cycloaddition reaction was then expected to form the tricyclic core, which could then be converted to the critical tetracyclic cage via a samarium diiodide(II)-type 6-exo-trig ketyl radical cyclization reaction. 

Fig. 1.15 Tandem Wessely oxidative dearomatization/DVIDA reaction (Reprinted with the...

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]. 

It is obviously seen in Fig. 1.16, the synthetic strategy of tandem Wessely oxidative dearomatization/IMDA reaction can effectively avoid the flaws of oxidative coupling/IMDA strategy in synthesizing the core structure of Maoecrystal V... 

After careful consideration and primary exploration, we decided to utilize tandem Wessely oxidative dearomatization/IMDA strategy to construct core structure of Maoecrystal V. Figure 1.19 shows the route of model synthesis. The main purpose of the model research is to look for efficient method to construct two continuous chiral centers in the molecule and quickly synthesize the [2.2.2] ring system on the right side of the molecule stmcture. Pb(lV) mediated coupling reaction was utilized to construct chiral quaternary carbon center on the right side, and Pb(OAc)4 was added to realize tandem oxidative dearomatization/... 

When we published our model study of natural product Maoecrystal V, Prof. Baran from Scripps Research Institute also pubhshed their synthetic strategy at the same time (Fig. 1.20) [31]. In their model, the Wessely oxidative dearomatization/ IMDA reaction is also employed as the key reaction. 

Model compound 2.1.1 was designed to test key reactions, which may be applied to the total synthesis, such as intramolecular Diels-Alder reaction, Wessely oxidative dearomatization reaction, and Pinhey arylation. The synthetic strategy of model research is shown in Fig. 2.16 compound 2.1.1 could be constructed from the precursor 2.1.2 after IMDA. Compound 2.1.2 could be prepared from compound 2.1.3 through esterification. Compound 2.1.3 could be obtained from 2.1.4 by reduction. Compound 2.1.4 was designed to be obtained by Pinhey arylation between 1,3-keto ester compounds 2.1.5 and organic lead compound 2.1.6. The advantage of this model system is that it contains three key reactions in total synthesis design, which can effectively supply the synthetic information for the total synthesis. 

Though MOM deprivation product 2.2.21 was accidentally obtained, it was still useful to test two key reactions for total synthesis Wessely oxidative dearomatization reaction and intramolecular Diels-Alder reaction (Fig. 2.20). A pair of diethyl phthalate derivative 2.2.22 with the ratio of 2 1 and 95 % yield could be obtained from phenol 2.2.21 in acetic acid solvent with the presence of lead tetraacetate at room temperature after 5 min. Then, we tried intennolecular Diels-Alder reaction. Unfoitunately, both substrate 2.2.22 and dimethyl acetylene dicarboxylate were not producing Diels-Alder product 2.2.23 under toluene refluxing or sealing mbe heating conditions, only gave the results of raw material recovery. 

Although intermolecular Diels-Alder reaction was failed, Wessely oxidative dearomatization was satisfactorily successful. Thus, functionalizing the coupling product 2.2.20 with side chain and trying intramolecular Diels-Alder reaction were necessary. As shown in Fig. 2.21, intermediate 2.2.20 was dissolved in THF. 

Fig. 2.20 The first attempt of Wessely oxidative dearomatization and Diels-Alder reaction...

As shown in Fig. 2.26, the other IMDA precursor 2.2.32 also underwent Wessely oxidative dearomatization to create a pair of separable 2 1 products 2.2.37 and 2.2.38 with 92 % total yield. Unfortunately, the precursors could not be transformed into IMDA products under the same conditions. It was speculated that the steric hindrance of the bromine atom blocked the activity of the reaction. 

Yates P, Bhamare NK, Granger T et al (1993) Tandem Wessely oxidation and intramolecular Diels-Alder reactions. IV. The synthesis of (it)-coronafacic acid. Can J Chem 71 995-1001... 

With intramolecular oxa-Michael precursor 3.47, constructing the six-seven bicyclic structure directly through the oxygen Michael addition reaction was carried out under the alkaline condition. However, only the starting materials were recovered. Thus, MOM group was first removed to obtain the free phenol 3.50 under sulfuric acid. After Wessely oxidative dearomatization, we got a pair of diastereomeric isomers 3.51 with the ratio 3 1, which was considered as the Diels-Alder precursor. The expected IMDA reaction did not happen in a sealed tube. No desired 3.52 or IMDA product 3.53 was separated. Starting materials were partially recycled, but most of the precursors were decomposed (Fig. 3.23). 

With compound 3.60 in hand, the key Wessely oxidative dearomatization and IMDA reaction succeeded in the model study could be used to construct the real natural product Maoecrystal V (Fig. 3.30). After forming the o-Benzoquinone acetate through the oxidative dearomatization in Pb(OAc)4, the obtained product was directly dissolved in toluene and heated to 145 °C in a sealed tube for 24 h and generated three products. Fortunately, the target product 2 (yield 36 %) was the main product and the structure could be corroborated by single-crystal X-ray diffraction. Surprisingly, the diastereoisomer of product 2 was not generated on the... 

The next step then was to isolate and identify the four enzymatic components participating in this process. Here again, my training as a chemist was a big help. The intermediates in the oxidative reaction are ,/3-unsaturated-, / -hydroxy-, and jS-keto-carboxylic acids bound to coenzyme A. In order to learn something about their chemical properties, Luise Wessely and Werner Seubert synthesized simple models in which these carboxylic acids were bound, not to coenzyme A, but to iV-acetyl cysteamine (Fig. 2). 

Scheme 28. Lead(IV)-mediated oxidation (Wessely reaction) of a simple gallic acid derivative without biaryl formation.

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],... 

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