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Organic Chemistry Highlights

Total Synthesis

Monday, May 7, 2012
Douglass F. Taber
University of Delaware

The Tan/Chen/Yang Synthesis of Schindilactone A

Schindilactone A (3) is one of a closely-related family of polycyclic lactones that have been used in China for the treatment of rheumatic disease. The synthesis of 3 reported (Angew. Chem. Int. Ed. 2011, 50, 7373. DOI: 10.1002/anie.201103088) by Ye-Feng Tang of Tsinghua University, and Jia-Hua Chen and Zhen Yang of Peking University is an elegant tour of metal-mediated bond construction, as exemplified by the cyclization of 1 to 2.

The preparation of 1 began with the Diels-Alder reaction of 4 with the butadiene 5. Addition of methyl magnesium chloride converted 6 to the crystalline lactone 7. Angular hydroxylation followed by ring expansion gave the bromo enone 8, that was homologated to the lactone 11. Apparently, the bulky silyloxy group directed the addition of the butenyl Grignard reagent 10 to the top face of the ketone carbonyl. Hydroxylation of the lactone followed by the addition of 12 then gave 1 as a mixture of diastereomers.

Only one of the two diastereomers of 1 could undergo ring-closing metathesis, to form the second of the three carbocyclic rings of 3. The two lactol diastereomers were in equilibrium with each other by way of the open-chain enone. When MgBr2 was added to encourage equilibration, the metathesis proceeded to completion, to give 2.

The tertiary alcohol of 2 was esterified with 2-butynoic acid, to give 13. Intramolecular Pauson-Khand cyclization, using the optimized protocol developed by the authors, then delivered the enone 13, completing the last carbocyclic ring of 3.

The last remarkable metal-mediated reaction in the synthesis was the oxidative carbonylation of 14 to 15. It is not clear if the post-carbonylation event is direct Pd-mediated C-O bond formation, or intramolecular addition of alkoxide to a transient butenolide.

To complete the synthesis, 15 was methylated, then deprotonated and kinetically quenched to set the proper relative configuration of the last methyl group. Remarkably, despite the presence in the molecule of three other acidic protons, including the one that had just been removed and kinetically reset, exposure of the acetate 16 to a large excess of base, followed by oxidation, gave clean conversion to Schindilactone A (3).

D. F. Taber, Org. Chem. Highlights 2012, May 7.