Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and


Total Synthesis

Monday, August 1, 2016
Douglass F. Taber
University of Delaware

The Jia Synthesis of (-)-Pallavicinin

(-)-Pallavicinin (3), isolated from the Taiwanese liverwort Pallavicinia subciliata, presents an intriguing challenge, with seven contiguous stereogenic centers. Yanxing Jia of Peking University envisioned (Angew. Chem. Int. Ed. 2015, 54, 13599. ) that the carbabicyclic core 2 of 3 could be established by conjugate addition to the compact enone 1.

The enantioselective preparation of the enone 1 followed the Stoltz modification of the Stork-Danheiser protocol. Enantioselective Pd-catalyzed rearrangement of 4 led to 5, that was reduced and hydrolyzed to give the previously-reported (Tetrahedron 2011, 67, 10234. ) enone 6. The cyclization of 6 to 1, catalyzed by Pd under oxidative conditions, proceeded with remarkable facility. As anticipated, the Cu-mediated conjugate addition of 7 indeed delivered 2 with substantial (10:1) diasterocontrol. Exhaustive methylation then completed the assembly of the ketone 8.

With 8 in hand, the next challenge was the selective allylic oxygenation of the more nucleophilic disubstituted alkene. This was accomplished with SeO2, leading to 9. The intermediates at this stage were still about 86% ee, the selectivity of the initial Stoltz rearrangement. Selective epoxidation of 9 followed by oxidation delivered the crystalline diketone 10, that was readily recrystallized to > 99% ee.

The cyclohexanone of 10 is quite congested, so 11 could be added selectively, leading to 12. To reach the natural product, the epoxide then had to be reduced and its oxygenated quaternary center had to be inverted. The authors postulated that a Payne rearrangement followed by reduction would accomplish both objectives. In the event, however, reduction of 12 led to 13. The authors speculate that 13 was the product of a kinetic quench of the ketone enolate, itself the result of chelotropic elimination of formaldehyde from an intermediate alkoxy oxetane.

Unexpected though it was, the transformation of 12 to 13 allowed rapid progress toward 3. Oxidation followed by selective addition of CH3MgBr converted 13 into 14. Further oxidation unveiled the γ-lactone 15, that cyclized to 16 on exposure to DBU. Installation of the ethylidene group by condensation with acetaldehyde followed by dehydration then completed the synthesis of (-)-Pallavicinin (3).

It is particularly noteworthy that this synthesis was carried through successfully without any use of functional group protection.

D. F. Taber, Org. Chem. Highlights 2016, August 1.