Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, July 5, 2021
Douglass F. Taber
University of Delaware

The Wong/Peng Synthesis of Cryptotrione

Cryptotrione (3), isolated from the Japanese cedar Cryptomeria japonica, showed activity against human oral epidermoid carcinoma KB cells. Henry N. C. Wong and Xiao-Shui Peng of the Chinese University of Hong Kong assembled the tetracyclic core 2 of 3 by the diastereoselective cyclization of the alkyne 1 (Angew. Chem. Int. Ed. 2020, 59, 19929. DOI: 10.1002/anie.202009255).

The diazo ester 6 was prepared by coupling the malonate monoester 5 with the commercial acid 4. Rh-catalyzed cyclization led to 7, that was alkylated with 8, then reduced and protected to give 9. The derived aldehyde was carried on to the ester 10. Reduction and protection then completed the assembly of the pivalate 1.

The cyclization of 1 via the Pt carbene 11 proceeded with high diastereoselectivity. As discussed in the Supporting Information for this article, varying the protecting group and the diastereomer of the secondary alcohol starting material directed the cyclization toward several alternative outcomes.

The secondary alcohol of 2 was deprotected, hydrogenated and oxidized to give the ketone 12, that was alkylated with geranyl bromide to give the expected 1:1 mixture of diastereomers. The desired diastereomer was carried on to 13, and the other was recycled. The cyclization of 13 was best carried out at low temperature, to give 14, that was then brominated and coupled with 15, leading to 16. Diastereoselective side chain construction followed by oxidation then completed the synthesis of cryptotrione 3.

This synthesis leads to racemic cryptotrione. Enantioselective reduction of the ketone 7 should be straightforward. Fráter alkylation followed by silylation would then deliver the key intermediate 9, and thus cryptotrione 3, in high ee.

We note the passing of Professor Ei-ichi Negishi, whose work with transition metal-mediated carbon-carbon bond formation laid the foundation for much of what we do today.

D. F. Taber, Org. Chem. Highlights 2021, July 5.