Oxidative phenolic coupling natural products

In the first of these, the key step in the synthetic sequence involves an oxidative phenol coupling reaction patterned after the biosynthesis of the natural product. Preparation of the moiety that is to become the aromatic ring starts by methyla-tion of phloroglucinol (5) with methanolic hydrogen chloride to give the dimethyl ether (6). Treatment of that intermediate with sulfuryl chloride introduces the chlorine atom needed in the final product (7). 

Organic syntheses based on biosynthetic proposals are often extremely concise and elegant.6 Although the constitution and stereochemical complexity of carpanone may seem formidable, the sequential application of the Diels-Alder and oxidative phenolic coupling transforms7 to the natural product provides an exceedingly efficient solution. Chapman s striking synthesis of carpanone typi-... 

Natural Products by Oxidative Phenolic Coupling Phytochemistry, Biosynthesis and Synthesis... 

NATURAL PRODUCTS BIOSYNTHESIS OF WHICH MAY INVOLVE OXIDATIVE PHENOLIC COUPLING ... 

Compounds are mentioned by their trivial names and respective codes of the Dictionary of Natural Products [2] are given in parentheses. When no trivial names were coined, only the codes are given. The bonds which may have been formed by oxidative phenolic coupling are indicated by heavy lines. 

As mentioned in Section 3, oxidative phenolic coupling plays an important role in the biosynthesis of a wide range of natural products. This stimulated the application of this reaction to the biomimetic synthesis of natural biaryls. Unlike the in vivo processes, very probably following a radical dimerization pathway [91] yields of in vitro syntheses are generally moderate or low. Classical work in this field has been extensively reviewed [92], and important developments after the 70s will therefore be summarised here. 

Codes in Dictionary of Natural Products for Natural Products Involving in Their Biosynthesis Oxidative Phenolic Coupling Footnote. 

Other isoquinoline alkaloids are derived from the biogenetic key compound 81 by further transformations, mainly by oxidative phenol coupling of the isoquinoline ring and on the benzyl residue. A number of structural types of isoquinoline alkaloids are known, e.g. the systems 82-87 (for individual examples and further details, see textbooks of natural products). 

The key step in the biosynthesis of morphine involves the oxidative phenolic coupling of reticuline (31) to salutaridine (32). This step can be viewed mechanistically as (1) oxidation of the two aromatic rings to phenoxy radicals followed by an intramolecular radical-radical coupling or (2) oxidation of one ring to a radical cation or cation, followed by an intramolecular electrophilic aromatic reaction. This process is very important in the biosynthesis of a number of natural products, and is a process that nature has used to crosslink peptides containing aromatic residues. The biosynthesis of morphine continues with reduction of salutaridine (32) to salutaridinol (33) followed by an intramolecular Sn2 reaction to give thebaine (34). Dienol ether hydrolysis to codeinone (35), reduction of the ketone to codeine (3) and 0-demethylation completes the biosynthesis of morphine (1). 

Show the structural relationship between the following natural products and oxidative phenolic coupling precursors. (Morphine-5)... 

All major pathways toward tyrosine-derived secondary metabolites discussed within the biosynthetic section of this chapter are summarized in Scheme 12.16. The great structural diversity of this important class of natural products arises from a very limited set of chemical transformations. Except for the extremely simple catecholamines and phenyl-ethylamines, tyrosine-derived alkaloids are generally formed via condensation of two aromatic substrates, facultatively followed by a Pictet-Spengler-type ring closing reaction. Next, the key oxidative phenolic coupling reaction then introduces stractural complexity and serves as convenient tool for the elaboration of different alkaloid frameworks. 

Mulzer s elegant synthesis of morphine is characterized by a stepwise elaboration of the ring motives in the natural product. While the biosynthetic pathway comprises an oxidative phenolic coupling, Mulzer employed a highly efficient Friedel-Crafts acylation to estabhsh the C12—C13 bond. Additionally, the implementation of observations from degradation studies represents an interesting alternative strategy to the exploitation of biomimetic pathways for natural product synthesis. 

In recent years, numerous applications of such peroxidase-catalyzed oxidative coupling of phenols and aromatic amines have been reported (Table 7). These peroxidase-catalyzed biotransformations lead to modified natural products with high biological activities [110-118]. Several examples have also been described for the oxidative coupling of phenols with peroxidases and other oxidative enzymes from a variety of fungal and plant sources as whole cell systems... 

The phenolic oxidation in the intra-molecular mode has been widely exploited as a synthetic tool for the construction of a spirodienone fragment. Kita and coworkers applied the oxidative coupling of various phenolic derivatives towards the synthesis of several pharmacologically interesting natural products [21,23,24]. In a recent example, spirodienone compounds 19, which are intermediates for the synthesis of an amaryllidaceae alkaloid, (+)-maritidine, were selectively obtained by the reaction of 18 and [bis(trifluoroacetoxy)iodo]ben-zene (Scheme 8) [24]. 

Some natural products have been synthesized by means of oxidative coupling promoted by iron reagents. In 1995, Herbert and co-workers reported the formation of the alkaloid kreysigine (84) by intermolecular oxidative coupling of diaryl substrates 83a/b with iron(III) chloride followed by methanol work-up [67]. The yield for the free phenolic compound 83a was 53 %, whereas the benzyl-protected analogue 83b presumably cydizes and then de-benzylates, in an overall yield of 71 % (Scheme 19). 

Barton and Cohen 10) and Erdtman and Wachtmeister 11) have related the concept of free radical coupling of phenols to the biogenesis of natural products, and suggested that bisbenzylisoquinoline alkaloids are formed by this reaction from benzylisoquinoline units. The mechanism of the reaction consists of generation of the resonance-stabilized phenoxy free radical by one-electron oxidation of the phenoxy anion, followed by coupling and tautomerization to form hydroxylated diphenyls or diphenyl ethers. Intermolecular coupling may involve any... 

---