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Organic Chemistry Highlights

Total Synthesis

Monday, October 7, 2019
Douglass F. Taber
University of Delaware

The Ding Synthesis of Rhodomollein XX

Rhodomollein XX (3), isolated from the flowering shrub Rhododendron molle, is a congener of the toxic grayanotoxins isolated from the same source. Hanfeng Ding of Zhejiang University envisioned elaborating the [3.3.1] skeleton of 3 by the reductive rearrangement to 2 of the more readily prepared [2.2.2] skeleton of 1 (Angew. Chem. Int. Ed. 2019, 58, 8556. DOI: 10.1002/anie.201903349).

The starting material for the preparation of 1 was the commercial aldehyde 4. Protection followed by reduction led to the bromide 5, that was converted to the Grignard reagent and added to 6 to give 7. Claisen rearrangement followed by Rosenkamp homologation led to 10, that was cyclized to 11.

The anticipated SN2 opening of 11 with an oxygen nucleophile having failed, the fragmented ketal 13 was prepared by the exposure of 11 to 12 and TMSOTf. Epoxide formation by way of the bromohydrin proceeded with high diastereoselectivity, allowing reduction to the desired alcohol 14. Addition of dimethyl methyl phosphonate 15 followed by paraformaldehyde generated the enone 16, that on oxidation cyclized via the expected intramolecular Diels-Alder reaction to 17. Reduction followed by epoxidation across the more accessible face of the alkene completed the preparation of 1.

The reductive rearangement of 1 worked best with the free alcohol, leading to 2. Methylenation followed by hydrolysis of the ketal and exposure to PhSeCl led directly to the oxidized product 18. Mukaiyama hydration followed by enol ether formation then delivered 19, that was carried on to the tertiary alcohol. After some experimentation, it was found that Rubottom oxidation could be effected with catalytic MeReO3, leading, after desilylation, to rhodomollein XX (3).

D. F. Taber, Org. Chem. Highlights 2019, October 7.