Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, July 5, 2010
Douglass F. Taber
University of Delaware

The Nicolaou Synthesis of (+)-Hirsutellone B

(+)-Hirsutellone B (3), isolated from the insect pathogenic fungus Hirsutella nivea BCC 2594, shows good activity (MIC = 0.78 μg/mL) against Mycobacterium tuberculosis. Approaching the synthesis of 3, K. C. Nicolaou of Scripps/La Jolla envisioned and reduced to practice (Angew. Chem. Int. Ed. 2009, 49, 6870. DOI: 10.1002/anie.200903382) a spectacular tandem intramolecular epoxide opening - internal Diels-Alder cyclization (12) that established all three of the carbocyclic rings of 3 with the proper relative and absolute configuration.

The construction of 1 began with commercial (R)-(+)-citronellal (4). Wittig homologation established the (Z)-iodide 5. Selective ozonolysis followed by condensation with the phosphorane 7 set the stage for J°rgensen-Cˇrdova epoxidation (Tetrahedron Lett. 2006, 47, 99. DOI: 10.1016/j.tetlet.2005.10.128) with H2O2 and a catalytic amount of the Hayashi catalyst 9. Condensation of 10 with the phosphorane 11 followed by Cu-catalyzed coupling of 12 with the organostannane 13 completed the assembly of 1.

This approach underscores the strategic advantages the J°rgensen-Cˇrdova epoxidation has over the Sharpless protocol. It is not necessary to reduce the aldehyde to the allyic alcohol, then reoxidize. Further, the J°rgensen-Cˇrdova epoxidation, using catalytic 9, is operationally easier than the Sharpless procedure, that often uses stoichiometric amounts of tartrate ester.

The cyclization of 1 proceeded by way of 14, with the newly formed stereogenic center having the diene equatorial on the cyclohexane. Endo cycloaddition catalyzed by the Lewis acid in the solution then gave 2. The facility with which the cyclization of 14 set both the substituents and the stereogenic centers of 2 raises the possibility that the biosynthesis might also follow such an internal [4 + 2] cycloaddition.

To complete the synthesis of 3, it was necessary to construct the strained paracyclophane. The authors took advantage of the facile cyclization of the thiolate liberated from 19, then installed the ring-contracted alkene with a Ramberg-Bńcklund rearrangement. They completed the synthesis of (+)-Hirsutellone B (3) by exposing the ketone 22 to NH3 in CH3OH/H2O.

D. F. Taber, Org. Chem. Highlights 2010, July 5.