Natural products Pummerer rearrangement

Scheme 2.146. Synthesis of several natural products via Pummerer-type rearrangement/ 1,3-dipolar cycloaddition/ring-opening reactions.

Quartromicins are complex C2 symmetric macrocyclic natural products that have significant activity against a number of human viral targets.The diastereoselective synthesis of the endo- and exo-spirotetronate subunits of the quartromicins was accomplished by W.R. Roush and co-workers. The preparation of the exo-a-acetoxy aldehyde involved the Pummerer rearrangement oi a sulfoxide using acetic anhydride as the activating reagent and NaOAc as the co-catalyst. The yield of this transformation was modest and all attempts to improve its efficiency failed. 

The total synthesis of (+)-deethylibophyiiidine was achieved by J. Bonjoch et ai. using a tandem Pummerer rearrangement/thionium ion cyclization to generate the quaternary spiro center.The suifoxide was exposed to an equimoiar mixture of TFA/TFAA and heated for 2h to form the quaternary stereocenter at C7 with the desired stereochemistry, but at C6 a mixture of epimers were formed. Reductive desuifurization with Raney-Ni followed by photochemical rearrangement afforded the natural product. 

Reaction of thioethers with one equivalent of NF-reagent results in the formation of a-fluorothioethers via a fluoro-Pummerer rearrangement [199] (Scheme 2.90). With appropriate excesses a-fluorosulfoxides and sulfones are obtained [200]. The thiophenyl group can also be used as a subsequently removable directing function for site-selective fluorination of natural products [201]. 

The Pummerer rearrangement has been employed in tandem with other reactions to enable complex transformations to be carried out efficiently and in a one-pot manner. Studies of these have been reported mainly by Padwa who has utilized such transformations in the syntheses of natural products. A particularly intriguing cascade sequence involving the Pummerer rearrangement was employed in the synthesis of the alkaloid jamtine, 57. " Padwa et al. synthesized the bromo-enamide 55 in a 4 1 (Z/ ) mixture of isomers. Treatment of the isomeric mixture with camphorsulfonic acid caused the the sulfoxide to undergo a Pummerer/Mannich ion cyclization, which was then followed by a spontaneous Pictet-Spengler reaction to furnish the isoquinoline core. Although a 5 2 1 1 mixture of diastereoisomers was obtained, the desired diastereoisomer 56 was formed preferentially. This was attributed to a 4 r-Nazarov-type conrotatory electrocyclisation which controls the direction of closure from the a-acylthionium ion intermediate. 

The Pummerer rearrangement can also be carried in tandem with a Diels-Alder reaction. This sequence has been utilized in the syntheses of the arylnaphthalene lignan natural products. Sulphoxide 64 in acetic anhydride was slowly added to a solution of dimethyl maleate in acetic anhydride under reflux, resulting in cycloadduct 65 in 85% yield. 

An important variant is the allylic silane directed Pummerer rearrangement. Magnus et al. utilized this in their studies towards complex diterpenoid natural products. An added feature in this case was the formation of the bicyclo[1.2.1]octanone core. 

Aldehydes and alcohols can be generated by the Pummerer rearrangement and many examples exist. For example, Lee et al. employed this reaction in their synthesis of the natural product rolliniastatin 1, among others. The reaction requires the addition of base and proceeds in good yield. 

In their studies towards the synthesis of polycyclic natural products such as pseudolaric acid A, Bai et al. reported the tandem Pummerer rearrangement and intramolecular [4 + 3] cycloaddition of sulfoxide 104." The reaction constitutes the overall [4 + 3] cycloaddition of a fully... 

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