Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, August 3, 2020
Douglass F. Taber
University of Delaware

The Reisman Synthesis of Perseanol

Perseanol (3), isolated from the tropical shrub Persea indica found in the Azores, Madeira, and Canary islands, shows potent anti-feedant activity against lepidopteran pests. Sarah E. Reisman of Caltech envisioned assembling 3 via the Pd-mediated cyclization of 1 to 2 (Nature 2019, 573, 563. DOI: 10.1038/s41586-019-1580-x).

The aldehyde component of 1 was prepared from pulegone (4). Bromination followed by Favorskii rearrangement and oxygenation led to 5, the epoxide of which was eliminated with strong base to give 6. Protection followed by reduction and oxidation completed the assembly of 7.

Starting from 8, alkylation followed by iodination led to 9. Saponification of the vinylogous ester followed by bromination gave racemic 10. The Itsuno-Corey protocol selectively reduced one of the two enantiomers, leading after protection to the iodide 12.

The alcohol 1 was prepared by the transmetalation of 12 followed by the addition of 7. Exposure to stoichiometric Pd(0) followed by CO delivered the desired 2. Presumably the addition of the initial organopalladium intermediate to the target alkene is reversible, since only diastereomer 12 can go on to 2. Slow delivery of CO from N-formylsaccharin allowed the use of catalytic Pd.

Oxidation of 2 gave a keto benzoate, that was combined with methyl magnesium chloride to give the diol 14. Exposure to trifluoroacetic acid led to smooth formation of the orthoester 15. Epoxidation gave 16, that was reductively cyclized to 17. Pd-mediated hydrogenation completed the synthesis of perseanol (3).

Faced with assigning the absolute configuration of a natural product, Scott D. Rychnovsy of the University of California, Irvine used TMEDA and OsO4 to convert it into the corresponding chromatographically-stable osmate ester. This readily yielded an X-ray quality crystal, with the incorporated heavy element enabling the assignment of absolute configuration (Org. Lett. 2019, 21, 10125. DOI: 10.1021/acs.orglett.9b04133).

We note with sorrow the passing of our colleague Robert M. Williams of Colorado State.

D. F. Taber, Org. Chem. Highlights 2020, August 3.