Amaryllidaceae alkaloids phenol oxidative coupling

Kita et al. found that phenolic oxidative coupling in case of 272 provides seven-membered N heterocyclic compounds 274 and 275 by bond shift of the initially formed spiro intermediate 273 under suitable conditions. Besides 274 and 275, piperidino-spiroquinone 276 is also formed in this oxidation (Scheme 68). Of particular interest is the recently developed synthesis of amaryllidaceae alkaloids such as (+)-maritidine (Scheme 69) (96JOC5857). 

The Amaryllidaceae alkaloids (e.g., lycorine) are derived from the phenol oxidative coupling of a C6C2NC6C1 unit. One unit (C6C2N) is derived from tyrosine, whereas the other (CsCi) is projected to be... 

Figure 3. Phenol oxidative coupling in Amaryllidaceae alkaloids.

The amaryllidaceae alkaloid maritidine was synthesized by a route which featured an improved method of achieving phenol oxidative coupling (24—>25). ... 

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]. 

The hypervalent iodine reagents PIFA and PIDA have also been used in the synthesis of naturally occurring structures, primarily the amaryllidaceae alkaloids and related species. Work by White s group showed the feasibility of this method for the synthesis of 6a-epipretazettine and (-)-codeine [45, 46]. In the early 1990s, Rama Krishna and co-workers demonstrated that PIDA can promote the oxidative phenolic coupling of diaryl substrates 38a-e to deliver cyclohexadienones 39a-e, respectively, in consistent 30 % yields for all of the substrates examined (Scheme 10) [47]. 

Development of intramolecular oxidative phenolic coupling reactions using hypervalent iodine(III) reagents and their application to the synthesis of Amaryllidaceae alkaloids 00YZ1061. 

Barton and Cohen (116) proposed that norbelladine (85) or related compounds could undergo oxidative coupling of phenols in Amaryllidaceae plants, once ring A had been suitably protected by methylation, resulting in the different skeletons of the Amaryllidaceae alkaloids (Fig. 4). 

Another domino application of an oxidative carbo-spirocyclization and an aza-Michael addition was developed by She and co-workers to construct the core skeleton of the Amaryllidaceae alkaloids tazettine and 6a-epipretazettine. In 2013, they disclosed their approach that requires the phenolic amide 185 as key precursor of the intended carbo-spirocyclization [112]. Both DIB and BTI were first used to mediate this oxidative para-para phenolic coupling reaction, but the more electrophilic Kita s p-oxoBTI reagent (see Fig. 4) in TFE gave higher yields. The addition of potassium hydroxide in the reaction mixture then promoted the aza-Michael addition to furnish the known tazettinone intermediate 187 in 72% yield as a single diastereomer (Fig. 46) [112]. 

Kita anployed a hypervalent iodine species for the oxidative cyclization of phenol 310 as shown in Equation 12.54-1, Scheme 12.54 [190]. When allowed to react with phenyliodinedll) bisftrifluoroacetate) (FIFA), 310 delivered the desired galantamine skeleton in 40% yield. The cyclization most likely proceeds via the initial reaction of the phenolic oxygen with the hypervalent iodine reagent and subsequent nucleophilic attack of the second electron-rich aromatic ring onto the intermediary formed cation radical intermediate. Kita and coworkers outlined the importance of the fluorinated solvent. When carried out in benzene or dichloromethane, the desired product was not formed. A similar oxidative coupling protocol has been successfully employed by the authors for other Amaryllidaceae alkaloids [191]. 

Another interesting example of an oxidative phenolic coupling reaction was reported by Koga and coworkers in 1977 (Eq. 12.54-2, Scheme 12.54) [192], Exposure of chiral ester 312 to three equivalents of Mn(acac)3 in acetonitrile allowed the isolation of adduct 313 in 49% isolated yield. Koga s efforts resulted in the first enantioselective total synthesis of the biologically highly interesting Amaryllidaceae alkaloid. 

Intramolecular oxidative phenol coupling has long been recognized as the key step biosynthesis of Amaryllidaceae alkaloids. Chemical simulation of this biogenetic process is expected to provide an exceedingly simple synthetic route to these alkaloids, and is illustrated in the synthesis of dZ-maritidine from 0-methylnorbelladine utilizing an efficient hew oxidative phenol coupling procedure. 

The manifold possibilities for the elaboration of structurally intriguing natural products via the aforementioned oxidative aryl-aryl coupling reactions emphasize the importance of phenolic coupling reactions in the biosynthesis of tyrosine-derived alkaloids. This important reaction not only plays a significant role in the biosynthesis of benzyltetrahydroisoquinoline alkaloids but also for the construction of phenethylisoquinoline alkaloids and Amaryllidaceae constituents, discussed in the following sections. 

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