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Organic Chemistry Highlights

Total Synthesis

Monday, November 2, 2020
Douglass F. Taber
University of Delaware

The Baran Synthesis of Paclitaxel (TaxolŽ)

Paclitaxel (TaxolŽ) (2) has become a mainstay of cancer chemotherapy. Phil S. Baran of Scripps/La Jolla developed a two-stage route to 2, based on the preparation and oxidation of 1 (J. Am. Chem. Soc. 2020, 142, 10526, DOI: 10.1021/jacs.0c03592; J. Org. Chem. 2020, 85, 10293, DOI: 10.1021/acs.joc.0c01287).

The assembly of 1 began with the commercial vinylogous ester 3. Michael addition of the vinyl magnesium bromide 4 followed by hydrolysis led to the dienone 5. Copper-mediated 1,6-addition of the alkenyl lithium derived from 6 delivered 7. Enantioselective conjugate addition of CH3MgBr followed by trapping with acrolein gave, after oxidation, the dione 8. Intramolecular Diels-Alder cycloaddition then completed the assembly of the tricyclic 1, that could be recrystallized to high ee.

A great deal of effort, that cannot even be summarized here, led to the elucidation of the protocol for the conversion of 1 to 2. As developed, the critical first two steps were allylic oxidation, to give 9, followed by selective bromination, leading to 10. Allylic bromination followed by Ag-mediated ionization and coupling with triethyl silanol then delivered 11. At this point, functionality was in place to complete the synthesis.

Elimination of the bromide led to the enone. Addition of methyl magnesium bromide gave the allylic alcohol, that was reduced first with Dibal, then with lithium aluminum deuteride, before protection. The deuterated alcohol 12 was resistant to unwanted oxidation. DMDO epoxidation followed by reduction and protection led to the carbonate 13, that was opened with iodide, then eliminated and epoxidized, to give 14. Regioselective reduction, protection and dehydration completed the assembly of 15. The remainder of the synthesis of paclitaxel (TaxolŽ) (2) used conversions largely based on those developed in previous total syntheses.

D. F. Taber, Org. Chem. Highlights 2020, November 2.