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Organic Chemistry Highlights

Total Synthesis

Monday, April 3, 2017
Douglass F. Taber
University of Delaware

The Li Synthesis of Sespenine

The alkaloid sespenine (3) was isolated, along with several biogenetically-related indole sesquiterpenoids, from a Streptomyces species isolated from mangrove. Ang Li of the Shanghai Institute of Organic Chemistry described (Angew. Chem. Int. Ed. 2014, 53, 9012. DOI: 10.1002/anie.201404191) a total synthesis based on the elegant oxidation/acid-mediated rearrangement of the precursor 1 to 2. He has now reported (Org. Chem. Front. 2016, 3, 368. DOI: 10.1039/C5QO00416K) a new route to 1, making the overall synthesis much more efficient.

The indole component of 1 was prepared from the ester 4. Iodination gave 5, that was stannylated to give 6.

To establish the absolute configuration of 3, the authors took advantage of Sharpless asymmetric epoxidation. To this end, farnesyl acetate 7 was oxidized with SeO2 to the allylic alcohol 8. Epoxidation gave 9, that was oxidized directly to the acid using the Iwabuchi procedure. Alkylative esterification completed the preparation of 10. Pd-mediated coupling of 10 with 6 then led to 11.

The Ti(III)-mediated opening of an epoxide to the free radical, that could then add to a distal alkene, was originally described (J. Am. Chem. Soc. 1988, 110, 8561. DOI: 10.1021/ja00233a051) by William A. Nugent and T. V. RajanBabu, both then at DuPont Central Research. Further investigations by other research groups led to the Cuerva modification, catalytic Cp2TiCl2 with stoichiometric Mn metal. With that procedure, using diisopropylethyl amine, the cyclization of 11 to 1, by way of 12, proceeded with high diastereocontrol.

Following the procedure developed in their original publication, oxidation of 1 with in situ generated dimethyldioxirane delivered 13 as an inconsequential mixture of diastereomers. The presence of the ester deactivating the indole ring was critical for preventing over-oxidation. Acid-mediated rearrangement of 13 led to 2, that was converted by Krapcho decarbomethoxylation followed by saponification to sespenine (3).

D. F. Taber, Org. Chem. Highlights 2017, April 3.