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Organic Chemistry Highlights

Total Synthesis

Monday, March 4, 2024
Douglass F. Taber
University of Delaware

The Baran Synthesis of Cyclopamine

Cyclopamine (4), a teratogenic alkaloid isolated from the California corn lily Veratrum californicum, has been shown to disrupt the hedgehog signalling pathway. Phil S. Baran of Scripps/La Jolla envisioned a convergent route to 4, assembling the triene 3 by the coupling of 1 and 2, with the skeleton to be completed by ring-closing metathesis (J. Am. Chem. Soc. 2023, 145, 21760. DOI: 10.1021/jacs.3c09085).

Following the recent precedent of Arseniyadis, the preparation of 2 began with the Pd-catalyzed addition of methyallyl acetate 6 to the silyloxyfuran 5 to give 7. Conjugate addition of the hydroxylamine derivative 8 slightly degraded the enantiomeric excess, but this could be restored by recrystallization after reduction, leading to 9 in high ee. Iodocyclization followed by reduction delivered the lactone 10, that was alkylated with high diastereocontrol to give 11. The addition of isopropenyl lithium followed by protection then completed the assembly of 2.

The tricyclic 1 was readily available from the commercial Wieland-Miescher ketone 12. Ketalization followed by deconjugation, reduction, protection and deketalization delivered the ketone 13. Alkylation with 14 followed by hydrolysis and intramolecular Horner-Wadsworth-Emmons cyclization led to the cyclopentenone 15. Alkylation with 16 followed by conjugate reduction gave the ester 17. Methylenation followed by reduction and Appel iodination then completed the preparation of 1, that was coupled with 2 to give 3.

The Pd-mediated closure of the tetrahydrofuran ring required some experimentation. The carbonate derived from 3 proved successful, leading to 18. Ring closing metathesis followed by reductive cleavage of the protecting groups then completed the synthesis of cyclopamine (4).

Nearly simultaneously, Shou-Fei Zhu of Nankai University and Shuanhu Gao of East China Normal University described a very different route to cyclopamine 4 (J. Am. Chem. Soc. 2023, 145, 25086. DOI: 10.1021/jacs.3c10362). The synthesis of the Veratrum alkaloid heilonine by Viresh H. Rawal of the University of Chicago, which addresses many of the same issues, is also worth studying (J. Am. Chem. Soc. 2021, 143, 16394; DOI: 10.1021/jacs.1c08756, The Rawal Synthesis of Heilonine 2022, August 1).

D. F. Taber, Org. Chem. Highlights 2024, March 4.
URL: https://www.organic-chemistry.org/Highlights/2024/04March.shtm