On 3 April 2017, the webpage http://www.organic-chemistry.org/Highlights/2017/03April.shtm described the total synthesis of the alkaloid sespenine by Ang Li of the Shanghai Institute of Organic Chemistry:

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. 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).

IIRC, many alkaloids have been synthesised before. What makes this one difficult?

mollwollfumble said:

IIRC, many alkaloids have been synthesised before. What makes this one difficult?

I don’t know that the total synthesis of this alkaloid is particularly difficult. It was just the latest of a list of alkaloids whose total synthesis was described by http://www.organic-chemistry.org/Highlights/totalsynthesis.shtm. I am actually making a point here, as mentioned in the other thread.

KJW said:

mollwollfumble said:

IIRC, many alkaloids have been synthesised before. What makes this one difficult?

I don’t know that the total synthesis of this alkaloid is particularly difficult. It was just the latest of a list of alkaloids whose total synthesis was described by http://www.organic-chemistry.org/Highlights/totalsynthesis.shtm. I am actually making a point here, as mentioned in the other thread.

This is an eye-opener to me. I had sort of written off alkaloids as pre-1960 wet chemistry, but the web link contains 150 or so new syntheses in the past thirteen years. eg. Strychnine was first synthesised in 1954.

Still, I will stick to the store bought stuff.