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Organic Chemistry Highlights

Total Synthesis

Monday, May 6, 2019
Douglass F. Taber
University of Delaware

The Li Synthesis of Aplysiasecosterol A

Aplyiasecosterol A (3) features an array of ten stereogenic centers, eight of them contiguous. Ang Li of the Shanghai Institute of Organic Chemistry envisioned assembling the last three of those stereogenic centers by the cyclization of the diene 1 to 2 (J. Am. Chem. Soc. 2018, 140, 9211. DOI: 10.1021/jacs.8b05070).

The diene 1 was assembled by adding the bromoketone 18 to the aldehyde 11. The adjacent ternary stereogenic centers of 11 were assembled following the Aggarwal protocol. To this end, commercial citronellol (4) was dihydroxylated and protected to give acetonide 5, that was then dehydrated by way of the primary selenide and ozonized. The corresponding alcohol was coupled with the acid 6 to give the ester 7. Deprotonation of 7 in the presence of (+)-sparteine followed by the addition of the primary borane 8 led to the secondary borane, that was coupled with the alkenyl lithium 9, leading, after oxidation, to the desired alkene 10. Deprotection followed by oxidation completed the synthesis of the aldehyde 11.

The starting point for the preparation of the bromoketone 18 was the prochiral 2-methyl cyclopentanedione (12). Addition to acrolein (13) gave an aldehyde, that was coupled with the reagent 14 to give a secondary alcohol that spontaneously cyclized to 15, setting overall three new stereogenic centers. Protection followed by oxidation delivered the enone 16, that was cyclized under reductive free radical conditions to 17. Bromination followed by ozonolysis completed the assembly of 18, that was coupled with 11 and dehydrated to give 1.

There were two challenges in the key metal-mediated hydrogen atom transfer (HAT) cyclization of the diene 1, maximizing the yield of cyclopentane, and control of the three newly-formed stereogenic centers. While eight possible diastereomers could have been formed, only the four with the pendant cyclopentane exo on the tricyclic framework were observed. Of those, the desired 2 dominated, and was readily separated. Deprotection then completed the synthesis of aplysiasecosterol A (3).

D. F. Taber, Org. Chem. Highlights 2019, May 6.