Taxol molecule with labeled carbons (Holton, 1994)
Patchoulene oxide (starting compound) (Holton, 1994)
Compound
Molecular
Formula
Molecular
weight
Melting
Point
Appearance
at room
temperature
CAS
Number
Specific
optical
rotation
Paclitaxel
(generic)
Or Taxol
C47H51NO14
853.906
g/mol
213-216  C
White
crystalline
powder
33069-62-4 - 49  -55
Bond types:
The bond types that are present in the Taxol molecule are all covalent bonds. The
carbonyl and ketone groups are nonpolar covalent bonds while the alcohol and the
secondary amine are polar covalent bonds. There are three aromatic benzene rings in the
molecule, however, the molecule is non-aromatic. While 45 out of the 47 carbon atoms in
the molecule are sp3 hybridized the remaining two are sp2 hybridized.
Functional groups:
There are many functional groups on this molecule. The groups that are duplicated
are noted in the parentheses: Phenyl (3), Amide, Alcohol (3), Carbonyl (2), Ester (3),
Epoxide ring and an Alkene.
Chiral centers:
There are eleven chiral centers in the Taxol molecule. In the structure pictured the
chiral centers are numbers 1, 2, 3, 4, 5, 7, 8, 10, 13, 2' and 3'. Nine of the eleven chirality
centers can be found in what can be called the ABCD ring framework. The A is the
hexene ring; the B is the eight carbon ring that together with A comprise an unfused
bicyclo ring; C is a six carbon ring that is fused with B and D is referring to the epoxide.
Synthesis:
The synthesis for Taxol is very long and complicated. The Holton Taxol total
synthesis will be the particular synthesis that is elaborated. The Holton synthesis was the
first complete synthesis of Taxol that was published in 1994, by Robert A. Holton and
colleagues at Florida State University.
The reaction is in fact so complex that there is a long list of the groups that were
required as they were protecting groups. Benzyloxymethyl, Carbonate, cyclic carbonate,
2-methoxy-2-propyl, tert-butyldimethylsilyl, triethylsilyl, and trimethylsilyl to name a
few.
The Holton team began with a patchoulol. One reason Holton and his team chose to
start the synthesis with patchoulene oxide is the structure of the compound already
contains three quarters of the carbons that are needed to comprise the ABCD ring
framework.
Two important reactions in the total synthesis are enolate oxidation by sulfonyl
oxaziridines and a Chan rearrangement. The enolate oxidation happens in the tenth step
in the synthesis when a ketone in the number nine position becomes an enolate by
oxidation with (+)-camphorsulfonyl oxaziridine. This gives an -hydroxyketone. The
importance of this step of the reaction lies in ABCD framework. This sets the stage for
the formation of the C ring. The first step in the formation of the C ring is the Chan
rearrangement. This is the rearrangement of a carbonate ester in the presence of a strong
base (lithium tetramethylpiperidide) to make an -hydroxy ester. There are many more
steps in the reaction but few are more important than those that form the ring framework
(Horowitz, 1994).
The mechanism is enantioselective in that synthesizing Taxol from (-)-patchoulene
oxide will give the (+)-Taxol enantiomer. The other enantiomer, (-)-Taxol enantiomer,
can be obtained by synthesizing Taxol from (-)-borneol.
The synthesis is complete, however, initially, Dr. Holton himself claimed that the
process was not commercially viable. A big reason for this is that the reaction is an
example of linear synthesis, where each subsequent step in the reaction significantly
reduces the yield until the final product is exponentially less that all the required
reactants. After a series of months the Holton team managed to refine the process, of each
step, so that the average chemical yield reached 93 %. Attached is a copy of a summary
for the retrosynthesis of Taxol from patchoulene oxide.
The retrosynthesis of Taxol total synthesis (Holton, 1994)
Holton, Robert A., Hyeong Baik Kim, Carmen Somoza, Feng Liang, Ronald J. Biediger,
P. Douglas Boatman, Mitsuru Shindo, Chase C. Smith, and Soekchan Kim.
"First Total Synthesis of Taxol." Journal of The American Chemical Society 4th
ser. 1994.116 (1994): 1599-600. ACS Publications. Web. 15 Feb. 2010.