Synthesis of paclitaxel. 1. synthesis of the abc ring of paclitaxel by SmI2-mediated cyclization

Article abstract of DOI:10.1021/acs.orglett.5b01173

A convergent synthesis of the ABC ring of antitumor natural product paclitaxel (Taxol) is described. SmI₂-mediated reductive cyclization of an allylic benzoate possessing an aldehyde function, synthesized from tri-O-acetyl-d-glucal and 1,3-cyclohexanedione, smoothly afforded the highly strained 6-8-6 tricarbocyclic structure in 66% yield.

Full text of DOI:10.1021/acs.orglett.5b01173

Letter
pubs.acs.org/OrgLett
Synthesis of Paclitaxel. 1. Synthesis of the ABC Ring of Paclitaxel by
SmI2‑Mediated Cyclization
Keisuke Fukaya,† Yuta Tanaka,† Ayako C. Sato,† Keisuke Kodama,† Hirohisa Yamazaki,†
Takeru Ishimoto,† Yasuyoshi Nozaki,† Yuki M. Iwaki,† Yohei Yuki,† Kentaro Umei,† Tomoya Sugai,†
Yu Yamaguchi,† Ami Watanabe,† Takeshi Oishi,‡ Takaaki Sato,† and Noritaka Chida*,†
†Department Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan
‡School of Medicine, Keio University, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan
S
* Supporting Information
ABSTRACT: A convergent synthesis of the ABC ring of
antitumor natural product paclitaxel (Taxol) is described.
SmI2-mediated reductive cyclization of an allylic benzoate
possessing an aldehyde function, synthesized from tri-O-acetyl-
D-glucal and 1,3-cyclohexanedione, smoothly afforded the
highly strained 6−8−6 tricarbocyclic structure in 66% yield.
aclitaxel (Taxol, 1) is a well-documented natural
P
diterpenoid that has been used as an anticancer drug.1−3
The challenging structure, a highly strained 6−8−6 tricarbo-
cyclic framework with a bridgehead olefin and an oxetane ring,
as well as important biological activities of 1 have naturally
attracted much attention from the synthetic community, and
many studies toward the synthesis of 1 have been reported.4
Although nine successful total and formal syntheses of 1 have
been documented to date,5−13 for the creation of novel
anticancer agents, development of an efficient synthetic route
to chiral 1 and its derivatives starting from readily available
materials is still an important issue in the field of organic and
medicinal chemistry. In this paper, we report the convergent
synthesis of the ABC ring 3 of paclitaxel starting from tri-O-
acetyl-D-glucal and 1,3-cyclohexanedione employing the SmI2-
mediated cyclization reaction as the key step.
Our retrosynthetic analysis of 1 based on the chiral pool
approach utilizing D-glucal as the starting material14 suggested
that Takahashi’s oxetane intermediate 212 would be a suitable
target molecule for the paclitaxel synthesis (Figure 1). For the
preparation of 2, the ABC ring intermediate 3 was expected to
be a potential precursor. Construction of the strained 6−8−6
tricarbocyclic structure 3 was perceived to be the most
challenging issue, and we reasoned that bond formation
between C10 and C11 by the SmI2-mediated reaction15,16 of
allylic benzoate 4 having an aldehyde function would provide a
feasible approach to 3.17
Figure 1. Retrosynthetic analysis of paclitaxel (1).
closure, suggested the possibility of our approach.18,19 The
substrate for the SmI2-mediated cyclization, ABC precursor 4,
in turn was planned to be obtained by the Shapiro coupling of
the A-ring hydrazone 5 with C-ring 6.
The pioneering work of Molander18a and Matsuda18b,c has
revealed that the SmI2-mediated reductive cyclization of
carbonyl compounds possessing allylic acetate or allylic chloride
functionalities is a powerful reaction for the construction of
eight-membered carbocycles. Their successful results, as well as
previous syntheses of ABC rings of paclitaxel by a C10−C11
Received: April 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01173
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Our synthetic endeavors started with the synthesis of the C
ring (Scheme 1). Treatment of optically pure cyclohexenone 7,
Scheme 2. Preparation of the A−C Rings of Paclitaxel
Scheme 1. Synthesis of the C Ring of Paclitaxel
then the allylic position to provide cyclohexenone 18 in 20%
and 50% yields, respectively. Reoxidation of benzoate 17 under
the same reaction conditions afforded an additional amount of
18 in 44% yield.
With the appropriately functionalized AC ring of paclitaxel in
hand, transformation of 18 into the cyclization precursor 4 was
carried out (Scheme 3). While reduction of 18 with NaBH4
prepared from tri-O-acetyl-D-glucal,20 with vinylmagnesium
chloride in the presence of CuI afforded a 1,4-addition product,
which was trapped with TMSCl to give a TMS enol ether.
Without purification, the enol ether was treated with formalin
Scheme 3. Preparation of the ABC Precursor 4
21
and Sc(OTf)3 to give 8a and 8b in 60% and 23% isolated
yields, respectively.22 Protection of the primary hydroxy group
in 8a as a THP ether afforded 9 (93% yield), whose ketone
carbonyl was reduced to give secondary alcohol 10 (50% yield)
and its 4-epimer (50% yield).23 After conversion of the
secondary alcohol in 10 to a MOM ether, hydroboration−
oxidation of the resulting 11 afforded primary alcohol 12 in
88% yield from 10. Formation of the O-TBDPS ether, removal
of the THP group, and subsequent oxidation of the resulting
primary alcohol with Pr4NRuO4 (TPAP) provided C-ring 6 in
80% yield from 12.
Coupling of C-ring 6 with A-ring 5 was achieved by the
Shapiro reaction, which had been employed for the coupling of
similar A and C rings in the synthesis of paclitaxel reported by
Nicolaou,6 Danishefsky,7 and Takahashi.12 Thus, treatment of
hydrazone 5, synthesized from 1,3-cyclohexanedione in six
steps,24 with BuLi afforded a vinyl anion species, which was
then reacted with C-ring 6 (Scheme 2). The reaction
proceeded under chelation control6c to produce 13 in 92%
yield as a single isomer. The hydroxy-directed epoxidation6c of
13 gave β-epoxide 14 as the sole product in 91% yield.
Regioselective reduction of 14 with DIBAL afforded diol 15,
which was then treated with triphosgene to give cyclic
carbonate 16 in 90% yield from 14. Reaction of 16 with
CrO3 in the presence of 3,5-dimethylpyrazole (3,5-DMP)25 in
CH2Cl2 first oxidized a benzylic carbon to give benzoate 17 and
B
DOI: 10.1021/acs.orglett.5b01173
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afforded a mixture of allylic alcohols 19a and 19b (75% yield,
1.8:1), reaction with L-Selectride stereoselectively generated
19b in 68% yield. Esterification of the allylic alcohol in 19b with
benzoic acid cleanly provided benzoate 20b (80% yield), whose
TBDPS group was removed to give 21b in 99% yield. The
structure of 21b was unambiguously confirmed by X-ray
analysis.26,27 Oxidation of 21b with Dess−Martin periodinane
(DMP) furnished cyclization precursor 4b (91% yield). The
same reaction sequence was applied to 19a to provide another
precursor, epimeric benzoate 4a, in 50% overall yield.
allylic benzoate to generate an allylic radical or allylic samarium
species smoothly,31 which afforded eight-membered carbo-
cycles 3 and 22 with high efficiency (95% combined yield).
In summary, the ABC ring of paclitaxel 3, based on the chiral
pool approach using tri-O-acetyl-D-glucal as the starting
material, has been synthesized. The key SmI2-mediated
reductive cyclization of allylic benzoate possessing an aldehyde
function 4b proved to be a powerful reaction for the
construction of the eight-membered ring and successfully
provided the highly strained 6−8−6 tricarbocycle 3 in 66%
yield. Since compound 3 has the basic framework of paclitaxel
with appropriate functionalities, it is expected to be a promising
intermediate for the synthesis of paclitaxel. Efforts for
conversion of 3 to paclitaxel are the subject of the following
paper.4d
Next, the crucial SmI2-mediated cyclization was investigated
(Scheme 4). After many attempts, it was found that when
Scheme 4. Construction of ABC Ring of Paclitaxel 3
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures; copies of H and 13C NMR spectra
■
S
1
of new compounds; the crystallographic data of 3a, 3b, and
21b. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01173.
AUTHOR INFORMATION
Corresponding Author
■
* E-mail: chida@applc.keio.ac.jp.
Notes
The authors declare no competing financial interest.
compound 4b was treated with SmI2 in HMPA−THF at 40 °C,
the desired reductive cyclization took place to generate the
eight-membered carbocycle, ABC ring 3, in 66% yield as an
epimeric mixture (3a:3b = 1.5:1). The isomeric tricarbocycle
22 in which carbon−carbon bond formation occurred between
C10 and C13 was also isolated in 29% yield. The structures of
3a and 3b were fully confirmed by X-ray analyses,27,28 and the
structure of 22 was assigned on the basis of 1H NMR
experiments. In the SmI2-mediated reaction of 4b, the use of
HMPA as a cosolvent was found to be essential for the
successful cyclization: the reaction in the absence of HMPA
gave no cyclized product but afforded primary alcohol 21b. The
configuration of the allylic benzoate was also an important
factor. Under the same reaction conditions as employed for 4b,
epimeric benzoate 4a gave many unidentified products, and no
cyclized product (3 nor 22) was detected in the reaction
mixture.
Although the detailed mechanism of the cyclization reaction
has been unclear so far, the reaction of 4b would proceed via an
allylic organosamarium species (Barbier-type reaction) and/or a
biradical intermediate (coupling of ketyl and allylic radi-
cals).15,29 In the absence of HMPA, the less reactive SmI2 did
not affect the allylic benzoate but reduced only the aldehyde
function.30 The striking difference in the experimental results
between 4a and 4b implied that the chelation of SmI2 might be
important for cyclization. In compound 4b, having a syn
relationship of the benzoate group at C13 and the oxygen at
C1, chelation between SmI2 and the C13-benzoyl/C1-oxygen
would be possible, whereas epimeric 4a would be unlikely to
have a stable chelated structure due to its anti relationship of
the C13-benzoate and the C1-oxygen. The chelation pathway
in 4b might have accelerated the rate of the reduction of the
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in Aid for Scientific
Research (B) from JSPS (26288018). We thank Prof. Takeshi
Noda (Kanagawa Institute of Technology, Japan) for mass
spectrometric measurements. Prof. Fuyuhiko Matsuda (Hok-
kaido University, Japan) is gratefully acknowledged for useful
discussions on SmI2 chemistry. We also thank Dr. Hitoshi
Tamura, Dr. Masaki Setoguchi, Dr. Takayuki Momose, Toshiki
Fujita, and Shin Ashihara (Keio University) for their
contributions to this project at an early stage.
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