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Organic Chemistry Highlights

Total Synthesis

Monday, May 5, 2014
Douglass F. Taber
University of Delaware

The Gin Synthesis of Neofinaconitine

The hexacyclic norditerpenoid alkaloids, including Neofinaconitine (4), isolated from traditional Chinese and Japanese antiarrhythmics and analgesics, have long offered a challenge to organic synthesis. The late David Y. Gin of the Memorial Sloan-Kettering Cancer Center envisioned (J. Am. Chem. Soc. 2013, 135, 14313. DOI: 10.1021/ja4064958) an approach to 4 by way of the Diels-Alder coupling of 1 and 2. This project was completed under the supervision of his colleague Derek S. Tan.

The cyclopropene 6 was prepared from the ester 5. Addition of 6 to the diene derived from 7 proceeded with modest regioselectivity to give, after enol ether hydrolysis, the ketone 8. After two-carbon extension of the ketone to the ester 10, ionization with HBr led to 11, that was carried on the diene 1.

Opening of caprolactam (12) with ethylamine followed by oxidation delivered the aldehyde 13. Acid-mediated cyclization to the enamide followed by bromination gave 14. Carbomethoxylation followed by selenylation and oxidation completed the preparation of the dienophile 2.

With the sterically-demanding Br blocking one face of the diene, Diels-Alder cycloaddition of 2 to 1 proceeded with high diastereocontrol, leading after hydrolysis of the intermediate silyl enol ether to the ketone 15. Oxidative cleavage of the more accesible alkene followed by elimination led to the ketone 16, that on exposure to acid underwent Mannich cyclization. Oxidation followed by elimination completed the preparation of 17. Reductive cyclization established the sixth and last ring of 4, but the tertiary alcohol was lacking. This was installed by selenylation followed by oxidation, presumably by way of the transient anti-Bredt enone.

There are two classes of the norditerpenoid alkaloids, having 18 and 19 carbons respectively. The ester 19 could be a versatile precusor to both classes. For 4, the carbon had to be removed. Reduction and protection followed by oxidative cleavage gave 20, that was carried on to Neofinaconitine (4).

D. F. Taber, Org. Chem. Highlights 2014, May 5.