Total Synthesis of Taxol - Home - Department of ChemistryArthur Barclay (1962) Taxus brevifolia Pacific Yew Dr. Monroe Wall and Dr. Mansukh Wani Natural Products Laboratory of the

Total Synthesis of TaxolK. C. NICOLAOU (1994)

JOSE R. MONTERO

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)

https://www.acs.org/content/

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)

https://www.acs.org/content/

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

Retrosynthesis: Nicolaou Approach

A B C

Ester chain

D

Ring A

KeteneEquivalent

Diels Alder Reaction

Only regioisomerformed

Electronically favoredStructure probed by X-

ray crystallography

Formation of the cyclohexene ring

Ring A

Shiner’s protocol

Chloronitrile

Shiner’s protocol

Mechanism:

Shiner, C. S.; Fisher, A. M.; Yacoby, F. Tetrahedron Lett. 1983, 24, 5687-5690

Shiner’s protocol

Mechanism:


Shiner’s protocol

Mechanism:

Intermediate Isolated

Identified by Liebig

Titration


Ring A

Shiner’s protocol

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

Ring A

Is going to be converted into a vinyllithium reactant to be used as a nucleophile

Retrosynthesis

A B C

Ester chain

D

Ring C


Ring C


Ring C


Ring C


Ring C


Ring C


Ring C

TBSOTf =

2,6-lutidine =

4-DMAP =

Ring C

CSA = CamphorSulfonic Acid

Selective deprotection of

the less hindered alcohol

Ring C

TPSCl =

BnBr =

Ring C

Ring C

Five member ring preferred in contrast

to seven member ring

Ring C

Ley-Griffith Oxidation


TPAP NMO

Retrosynthesis

A B C

Ester chain

D

Ring B: Formation

Shapiro Reaction

Ring B: Formation

Re face

Si face

Nu

Ring B: Formation

Sharpless epoxidation

Sharplessepoxidation

Vs

A1,2

strain

Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B. Tetrahedron Lett. 1979, 49, 4733-4736

Ring B: Formation

Sharpless epoxidation

Ring B: Formation

Ring opening regioselectivity based

on steric hindrance

Ring B: Formation

This cyclic protective group helps the formation of the eight

member ring in the next steps

Ring B: Formation


Ring B: Formation

McMurry Coupling

McMurry Coupling

McMurry Coupling

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: Resolution

Ring B: Functionalization

DMAP

OH at C9 is more reactive




• α face preferred• 22 % of C6-OH product



DMAP


TESCl =

MsCl =


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


DMAP


DMAP



Retrosynthesis

A B C

Ester chain

D

Ester Chain

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

Taxol

Nicolaou

Danishefsky

Wender

Kuwajima

MukaiyamaTakahashi

Sato-Chida

Nakada

Holton

Documents

Total Synthesis of Taxol - Home - Department of ChemistryArthur Barclay (1962) Taxus brevifolia Pacific Yew Dr. Monroe Wall and Dr. Mansukh Wani Natural Products Laboratory of the