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Organic Chemistry Highlights

Total Synthesis

Monday, June 1, 2015
Douglass F. Taber
University of Delaware

The Morken Synthesis of (+)-Discodermolide

The anti-cancer properties of Discodermolide (3) were exciting enough that Novartis undertook a commercial-scale total synthesis. While initial clinical trials were not successful, it is still a very promising lead structure. James P. Morken of Boston College developed (Angew. Chem. Int. Ed. 2014, 53, 9632. DOI: 10.1002/anie.201405455) a practical approach, based on the Still-Gennari coupling of the phosphonate 1 with the aldehyde 2.

The preparation both of 1 and of 2 showed to advantage the diene borylations that have been developed by the Morken group over the past several years. The aldehyde 5 was prepared by enantioselective hydroformylation of the protected acrolein 4. Borylation of pentadiene 6 followed by diastereoselective addition to 5 set, after oxidation, the three new stereogenic centers of 7. Ir-catalyzed hydroboration led to the primary alcohol, that was carried through aldehyde deprotection and oxidation to the ester 8. Oxidation of the alcohol to the acid followed by activation and coupling with the anion 11 then completed the synthesis of 1.

The preparation of the key Z-trisubstituted alkene chiron 16 again began with enantioselective hydroformylation, of the allyl silyl ether 12. The addition of 14 proceeded with high diastereoselectivity. Nickel-catalyzed borylation of 15 was also highly diastereoselective, leading to an intermediate that was oxidized to the primary alcohol, then carried on the iodide 16.

Pt-catalyzed enantioselective borylation of 6 followed by the addition of chloromethyl lithium led, after oxidation, to the diol 17. Exposure of the derived bis tosylate to potassium t-butoxide led to facile elimination of the homoallylic tosylate. The remaining tosyl protecting group was then removed reductively to give 18. The Roush reductive aldol protocol was applied to the derived aldehyde, leading to 20, that was carried on to 21.

Under carefully defined conditions, the E-enolate of 21 coupled efficiently with the allylic iodide 17 to give 2. Still-Gennari coupling with 1 followed by selective reduction, deprotection and lactonization then completed the synthesis of (+)-Discodermolide (3).

D. F. Taber, Org. Chem. Highlights 2015, June 1.