ReferencesNicolaou, K. C.; Sorensen, E. J. Taxol. In Classis in Total Synthesis, Targets, Strategies, Methods; Schmidt-Radde, R.; VCH: New York, 1996, 655-672
Nicolaou, K., C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature 1994, 367, 630-634
Nicolaou, K., C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1995, 117, 624-633
Nicolaou, K., C.; Liu, J. J.; Yang, Z.; Ueno, H.; .; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M. Nantermet, P. G. J. Am. Chem. Soc. 1995, 117, 634-644
Nicolaou, K., C.; Yang, Z.; Liu, J. J.; Nantermet, P. G.; Claiborne, C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995, 117, 645-652
Nicolaou, K., C.; Ueno, H.; Liu, J. J.; Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995, 117, 653-659
Arthur Barclay(1962)
Taxus brevifoliaPacific Yew
Dr. Monroe Wall and Dr. Mansukh Wani
Natural Products Laboratory of the Research Triangle
Institute(1971)
TaxolPaclitaxel (PTX)
ACS Education Resources for Chemistry Students and Educators. https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/camptothecintaxol.htm (accessed Tuesday 14, 2017)
Dr. Susan B. Horwitz (1979)
Albert Einstein College of Medicine
of Yeshiva University
Taxol
α tubulin subunit
β tubulin subunit
10 000 lb Pacific yew/year = 0.5 – 1 kg taxol
Dr. Robert HoltonFlorida State University
Taxus baccata
European Yew
Ovarian cancer (1992)Breast cancer (1994)
10-deacetylbaccatin
ACS Education Resources for Chemistry Students and Educators. https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/camptothecintaxol.htm (accessed Tuesday 14, 2017)
Total Synthesis of TaxolDr. Robert
HoltonFlorida State
UniversitySubmitted: 12/21/1993
Dr. Kyriacos Costa Nicolaou
ScrippsSubmitted: 1/24/1994
A B C
Ester chain
Vs
D
C47H51NO14 11 stereocenters
Ring A
KeteneEquivalent
Diels Alder Reaction
Only regioisomerformed
Electronically favoredStructure probed by X-
ray crystallography
Formation of the cyclohexene ring
Shiner’s protocol
Mechanism:
Shiner, C. S.; Fisher, A. M.; Yacoby, F. Tetrahedron Lett. 1983, 24, 5687-5690
Shiner’s protocol
Mechanism:
Shiner, C. S.; Fisher, A. M.; Yacoby, F. Tetrahedron Lett. 1983, 24, 5687-5690
Shiner’s protocol
Mechanism:
Intermediate Isolated
Identified by Liebig
Titration
Shiner, C. S.; Fisher, A. M.; Yacoby, F. Tetrahedron Lett. 1983, 24, 5687-5690
Ring A
Many attempts to use this compound as an electrophile were unsuccessful for his tendency to enolized
TBSCl =
Is going to be converted to a nucleophile
Sharplessepoxidation
Vs
A1,2
strain
Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron Lett. 1979, 49, 4733-4736
Ring B: Formation
This cyclic protective group helps the formation of the eight
member ring in the next steps
Ring B: Resolution
(1S)-(-)camphanic chloride DMAP Resolution method used before for other taxoids
Camphanic ester formed at C9 probably because this OH is less
hindered than the OH on C10
Ring B: Functionalization
Oxetane ring has to be formed in this stage of the synthesis to avoid side reactions in previous steps:• Formation of the C2 aldehyde in ring C• Oxetane ring does not let McMurry coupling• Insertion of the hydroxyl group on C1 via formation
of an epoxide
Final Step
▪Boron mediated Diels-Alder reaction: highly functionalized C-ring framework
▪Shapiro reaction: Place A-ring and C-ring together
▪McMurry Coupling: Make an 8 member ring B
▪Regio- and stereocontrolled incorporation of the oxygen functionalities in the 8 member ring 51 steps
0.03 % overall yield from butene diol