6a-Epipretazettine

Thus, in line with earlier observation, the use of dimethylsulfoxide and trifluoroacetic anhydride led, by preferential oxidation of the secondary alcohol, to the hemiketal ( )-tazettine (400). On the other hand, application of the Dess-Martin method furnished, by selective oxidation of the primary alcohol group, ( )-11-epipretazettine (412) (also known as ( )-6a-epipretazettine), in 73% yield, previously converted into ( )-tazettine [100]. 

Other applications of iodine(III)-mediated reactions toward total syntheses of bioactive alkaloids such as salutaridine (123), (-)-codeine (124), and 6a-epipretazettine (125) were reported by White et al. and Szantay et al. in the early 1980s [46-48] (Schemes 2-4). 

At this point the synthesis of the pretazettine nucleus with the inverted (cis) B-D ring fusion seemed possible starting from 11-epi-haemanthidine (262). Indeed, 262 easily undergoes rearrangement to N-demethyl-6a-epipretazettine (263) which cannot be converted back to the 5,10b-ethanophenanthridine form. Since 6a-epipretazettine... 

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]. 

Scheme 6-6 Geometry of the insertion step in a cyclization leading to ( )-6a-epipretazettine.

Enzymatic oxidation 1216-1224 Enzyme-glutathione binary complexes 105 Epi-deoxyschizandrins, formation of 1278 6a-Epipretazettine, synthesis of 1244, 1248 Epoxidation,... 

Carbopalladation has also been employed in the construction of six-membered rings. Most examples are 6-exo cyclizations as is the pyran ring synthesis (107—>108) used in the construction of ( )-6a-epipretazettine 109 and ( )-tazettine (Scheme 17). The Heck cyclization formed a quaternary center with a diastereoselectivity in excess of 20 1. The selectivity of the reaction is of particular interest in this case as it provides information about the orientation of the carbon-palladium a bond and the reacting aUcene in the carbopalladation transition state. Two limiting transition state geometries for the closure are intermediate 110, which leads to the observed product, and intermediate 111, which would lead to a diastereomer. In the preferred transition state 110, the carbon-palladium (7 bond and alkene are eclipsed, which is a lower energy state than the corresponding twisted orientation 111. 

There are also examples citing snbstructure F in the total synthesis of natural products containing 0-heterocycles, namely in a synthetic approach to (205 )-camptothecin [106] or in the synthesis of the Amaryllidaceae alkaloids ( )-tazettine and ( )-6a-epipretazettine (Scheme 6.39) [107]. 

Abelman, M.M., Overman, L.E. and Tran, V.D. (1990) Construction of quaternary carbon centers by paUadium-catalyzed intramolecular alkene insertions. Total s3uithesis of the Amarylh-dacea alkaloids ( )-tazettine and ( )-6a-epipretazettine. J. Am. Chem. Soc., 112, 6959 4. 

Other early applications of hypervalent iodine reagents in natural products are the total syntheses of bioactive alkaloids, by Szantay s and White s groups in early 1980s, such as salutaridine (Scheme 6), (-)-codeine, and 6a-epipretazettine [35-37]. Although these involved pioneering studies on phenolic coupling reactions, they had not received much attention because of their low yields of the chemical processes (up to 32% yield). 

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]. 

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