Formal total synthesis of (-)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation

Article abstract of DOI:10.1002/chem.201404295

A formal total synthesis of (-)-taxol by a convergent approach utilizing Pd-catalyzed intramolecular alkenylation is described. Formation of the eight-membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd-catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97 %), indicating the high efficiency of the Pd-catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5-hydride shift, generating the C3 stereogenic center and subsequently forming the C1-C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd-catalyzed reaction.

Full text of DOI:10.1002/chem.201404295

DOI: 10.1002/chem.201404295
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Natural Products |Hot Paper|
Formal Total Synthesis of (À)-Taxol through Pd-Catalyzed Eight-
Membered Carbocyclic Ring Formation
Sho Hirai, Masayuki Utsugi, Mitsuhiro Iwamoto, and Masahisa Nakada*[a]
Abstract:
A
formal total synthesis of (À)-taxol by
a
efficiency of the Pd-catalyzed intramolecular alkenylation.
Rearrangement of the epoxy benzyl ether through a 1,5-hy-
dride shift, generating the C3 stereogenic center and subse-
quently forming the C1–C2 benzylidene, was discovered and
utilized in the preparation of a substrate for the Pd-catalyzed
reaction.
convergent approach utilizing Pd-catalyzed intramolecular
alkenylation is described. Formation of the eight-membered
carbocyclic ring has been a problem in the convergent total
synthesis of taxol but it was solved by the Pd-catalyzed in-
tramolecular alkenylation of a methyl ketone affording the
cyclized product in excellent yield (97%), indicating the high
Introduction
Although taxol and its congener, taxotere (Figure 1), are clin-
ically important anticancer agents, some problems have been
reported such as low water solubility, side effects, and the
emergence of taxol-resistant tumors.[2] Thus, new derivatives of
taxol have been studied to solve these problems; however,
most of the structure-activity relationship studies have been
initiated from baccatin III (Figure 1), thus, the diversity of
derivatives is limited.
(À)-Taxol (Figure 1), which was isolated from the bark of the
Pacific yew tree (Taxus brevifolia) by Wani et al.,[1,2] has been
widely used as an anticancer drug.[3] In addition to the potent
bioactivity of taxol, its complex structural features—a highly
distorted 6-8-6 taxane scaffold with nine stereogenic centers
including an all-carbon quaternary stereogenic center, diverse
functional groups such as oxetane, trans-1,2-diol, acyloin, and
a bridgehead double bond—make taxol an attractively chal-
lenging synthetic target. Indeed, over 200 papers describing
synthetic studies of taxol have been published so far,[4–13] and
further studies on the total synthesis of taxol are underway.[5]
We envisioned that a convergent total synthesis of taxol
would enable the synthesis of diverse taxol derivatives. Herein,
we report the formal total synthesis of (À)-taxol through a con-
vergent approach based on the stereoselective construction of
the C3 stereogenic center by a 1,5-hydrogen shift–benzylidene
formation sequence and the highly efficient formation of the
eight-membered carbocyclic B-ring of taxol by Pd-catalyzed
intramolecular alkenylation of a methyl ketone.
However, only seven total syntheses including
a formal
synthesis have been accomplished so far,[6–12] indicating the
difficulties encountered in its total synthesis.
Results and Discussion
A convergent total synthesis allows the parallel preparation of
building blocks, thus reducing time and also providing the ad-
vantage of the independent transformations of functional
groups that are otherwise incompatible with each other. More-
over, a convergent synthesis is useful for affording derivatives
with diverse structures. Thus, the convergent syntheses of
taxol, that is, the preparation and coupling of the A- and C-
rings, followed by the formation of the eight-membered B-ring
and further transformations, have been studied by many
research groups, and four convergent total syntheses of
taxol[7,8,11] including a formal synthesis[12] have been reported.
The formation of the eight-membered carbocyclic ring has
been a synthetic problem because of its highly strained nature
arising from the transannular strain. Indeed, the three conver-
gent total syntheses of taxol suffered from difficulties in the
formation of the eight-membered carbocyclic B-ring
(Scheme 1). Thus, pinacol coupling,[7] the Heck reaction,[8] and
Figure 1. Structures of (À)-taxol, taxotere, and baccatin III. Boc=tert-butoxy-
carbonyl.
[a] S. Hirai, M. Utsugi, M. Iwamoto, Prof. Dr. M. Nakada
Department of Chemistry and Biochemistry
School of Advanced Science and Engineering
Waseda University
3-4-1 Ohkubo, Shinjuku-ku
Tokyo 169-8555 (Japan)
Fax: (+81)3-5286-3240
E-mail: mnakada@waseda.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404295.
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Scheme 2. Eight-membered carbocyclic ring formations by Pd-catalyzed
reactions reported by our group. 9-BBN=9-borabicyclo[3.3.1]nonane.
Scheme 1. Eight-membered carbocyclic B-ring formation in convergent total
syntheses of taxol. Bn=benzyl; OTf=triflate; TBS=tert-butyldimethylsilyl;
TIPS=triisopropylsilyl; EE=ethoxyethyl; Ts=tosyl; BOM=benzyloxymethyl.
alkylation[12] were used for formation of the B-ring. However,
the yield did not exceed 49%, indicating that the formation of
the B-ring is challenging. An exceptional example is the effi-
cient closure of the B-ring in Kuwajima’s total synthesis,[11]
which afforded the desired product in at least 76% yield, al-
though the substrate is relatively simple and it required many
further steps to realize the total synthesis.
Scheme 3. Coupling reaction of 1 and 2, and attempted preparation of 5.
We reported CÀC bond-forming reactions using transition-
metals that effectively formed eight-membered carbocyclic
rings.[13c,e,g,14] In particular, Pd-catalyzed reactions; that is, intra-
molecular B-alkyl Suzuki–Miyaura coupling reactions[13c] and
intramolecular alkenylation of methyl ketone[13g] to efficiently
afford taxol model compounds (Scheme 2). Whereas the
former reaction product has an ethylene at the C9–C10 posi-
tion, which is difficult to selectively functionalize because our
substrate possesses oxidation- and radical-sensitive functional
groups such as a benzylidene acetal and a benzyl ether, the
latter reaction product has a keto group at the C10 position,
which enables facile functionalization. Therefore, to examine
the applicability of the latter method for the formation of the
B-ring of taxol, the substrate was prepared starting with the
[16a,b]
dation of olefin 3-I using TBHP and VO(acac)2
afforded ep-
oxide 4-I as a single isomer, but the yield was improved
[16c]
(87%) by using VO(OEt)3
as the catalyst. Construction of the
C3 stereogenic center was then attempted by the reduction of
[17]
epoxide 4-I. The reduction of 4-I with NaBH3CN and BF3·OEt2
was expected to take place at the more substituted carbon to
afford compound 5-I under acidic conditions. However, exten-
sive structural analysis of the major product using NMR tech-
niques revealed that compound 6-I (Scheme 4) was obtained
instead of 5-I. The oxidation state of 6-I was the same as that
of 4-I, indicating that the reaction proceeded without the
action of the reducing agent, NaBH3CN. Further optimization
of the reaction under several acidic conditions improved the
yield of 6-I to 66%.[18]
coupling reaction of compounds
1 with 2-I and 2-Br
(Scheme 3), which were, in turn, prepared from known
compounds[13b–d,i,15] reported by us.
The reaction of compound 4-I can be explained as follows
(Scheme 4): First, BF3·OEt2 activated epoxide 4-I, thus inducing
the 1,5-hydride shift from the proximal benzylic hydrogen of
the C1 benzyl ether to the C3 position; that is, a hydride de-
rived from the C1 benzyl ether underwent backside attack at
The coupling reaction of 1 with 2-I was successfully carried
out through
a halogen–Li exchange reaction to afford
compound 3-I as the sole product (Scheme 3). Sharpless epoxi-
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complete under the same reaction conditions, and the yield
was 89%. The maximum yield of the B-ring formation in the
convergent total syntheses of taxol reported so far was 76%
(Scheme 1); therefore, the Pd-catalyzed intramolecular
alkenylation was highly efficient.
As shown in Figure 2, X-ray crystallographic analysis of 8
clearly confirmed its highly distorted taxane scaffold and the
stereochemistry of the C1–C2 benzylidene.
Scheme 4. The BF3·OEt2 induced 1,5-hydride shift–benzylidene formation
cascade.
the C3 position. Next, benzylidene formation, proton transfer,
and treatment with 2m HCl afforded compound 6-I.
To investigate the Pd-catalyzed intramolecular alkenylation,
compound 6-I was converted into methyl ketone 7-I
(Scheme 5). The primary hydroxyl group of 6-I was selectively
oxidized to an aldehyde group, followed by TES ether forma-
tion at the C4 axial secondary hydroxyl group to an OTES
Figure 2. X-ray crystallographic structure of 8.
We next addressed the introduction of a hydroxy group at
the C10 position and carried out oxidation of the enolate of
ketone 8. Considering the structure of ketone 8, the oxidation
was expected to occur from the less hindered side of the eno-
late to introduce an a-hydroxy group at the C10 position.
Thus, epimerization of the C10 configuration would be
required after introduction of the C10 hydroxy group.
Hence, we screened a range of derivatives that were suitable
for C10 epimerization by considering the stereochemistry of
the substrate. After extensive studies, the derivative of 11
(Scheme 6) afforded satisfactory results. Thus, compound 8
was converted into 9 by removal of the TES group, Dess–
Martin oxidation, and Takai methylenation, then 9 was convert-
ed into 11 via intermediate 10, based on the reported reaction
conditions.[7] The hydroxylation at the C10 position of 11 with
potassium hexamethyl disilazide (KHMDS) and Davis’ reagent[20]
afforded the product with an a-hydroxy group at the C10 posi-
tion, as expected. Gratifyingly, acetylation of the C4 and C10
hydroxyl groups of the resultant diol and subsequent treat-
ment with DBN in the same pot induced C10 epimerization to
afford 12. Notably, the compounds with C1 hydroxy and C2
benzoate moieties did not undergo C10 epimerization and C4
acetylation under the conditions used for the preparation of
12.
Scheme 5. Eight-membered carbocyclic B-ring formation by Pd-catalyzed in-
tramolecular alkenylation. DMP=Dess–Martin periodinane; TES=triethylsilyl;
DIPEA=N,N-diisopropylethylamine.
group, the reaction of the aldehyde group with methylmagne-
sium bromide to form the CH(OH)Me group, and Dess–Martin
oxidation of the CH(OH)Me group to the COMe group, thus
affording 7-I. Compound 7-Br was also successfully prepared
from 2-Br[13i] according to the transformations used to prepare
7-I from 2-I.
The Pd-catalyzed intramolecular alkenylation of compound
7-I under the optimized reaction conditions previously report-
ed by us[13h] afforded the desired product, 8, in 97% yield
(Scheme 5).[19] The reaction of compound 7-Br required 6 h to
Removal of the C1–C2 benzylidene moiety on the taxane
scaffold under catalytic hydrogenation conditions has been
known to form the tetrahydrofuran (THF) ring,[12] which can be
attributed to the reaction of the liberated C2 hydroxyl group
with the adjacent oxetane moiety. However, the reaction using
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because of steric strain. Allylic oxidation at the C13 position
was not observed in the Ru-catalyzed reaction. The reaction of
[22a,b]
12 using KBrO3/Na2S2O3
action with Ph3CBF4
resulted in no reaction and the re-
[22c]
caused ring-opening reaction of the ox-
etane. Subsequent removal of the benzyl group and formation
of a TES ether afforded 14. The yield from 12 to 14 was low,
but further optimization may improve the yield.
Conclusion
The problem of forming the eight-membered carbocyclic ring
in the convergent total synthesis of taxol was solved by using
the Pd-catalyzed intramolecular alkenylation of
a methyl
ketone, thus affording the cyclized product in an excellent
yield (96%), which allowed the efficient formal total synthesis
of (À)-taxol by a convergent approach. To our knowledge, this
is a first example of Pd-catalyzed intramolecular alkenylation
that is used for the formation of an eight-membered carbocy-
clic ring in natural product synthesis. The maximum yield for
B-ring formation of taxol in the convergent total syntheses re-
ported so far was 49%, indicating the high efficiency of the
Pd-catalyzed intramolecular alkenylation reaction. During the
preparation of a substrate for the Pd-catalyzed reaction, the re-
arrangement of the epoxy benzyl ether including a 1,5-hydride
shift, generating the C3 stereogenic center and subsequently
forming the C1–C2 benzylidene, was discovered and success-
fully utilized. The longest linear steps via 14 from a commercial-
ly available compound to (À)-taxol based on this synthesis was
37 when 2-Br was used, although some steps require optimiz-
ation to improve the overall yield.[23] Further efforts towards
reducing the number of synthetic steps as well as improving
the overall yield are underway.
Scheme 6. Formal total synthesis of (À)-taxol. TBAF=tetrabutylammonium
fluoride; TMEDA=N,N,N’,N’-tetramethylethylenediamine; Py=pyridine;
Ms=methane sulfonyl; DMAP=4-dimethylaminopyridine; DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene; DBN=1,5-diazabicyclo[4.3.0]non-5-ene.
Pearlman’s catalyst with basic alumina in cyclopentyl methyl
ether (CPME) at À58C in a hydrogen atmosphere cleanly
cleaved the benzylidene acetal and the C-7 benzyl ether of 12
without forming the THF ring. Finally, formation of C1–C2
carbonate and C7 TES ether afforded 13, which was found to
be spectroscopically identical to the synthetic intermediate of
taxol reported by Nicolaou,[7] confirming that the formal total
synthesis of (À)-taxol has been achieved.
Experimental Section
A full account of the experimental procedures, characterization
data and spectra for compounds reported in this manuscript can
be found in the Supporting Information.
Acknowledgements
Compound 12 was also converted into compound 14,
which is a more advanced Nicolaou’s synthetic intermediate
derived from 13 (Scheme 7). Thus, a Ru-catalyzed oxidation,
which was reported to be used for allylic oxidation,[21] was
found to convert the C1–C2 benzylidene moiety of 12 into C2
benzoate. The Ru-catalyzed reaction afforded only the C2 ben-
zoate because the C1 benzoate was probably difficult to form
This work was financially supported in part by a Grant-in-Aid
for Scientific Research on Innovative Areas (No. 21106009, No.
2105) by MEXT and a Waseda University Grant for Special Re-
search Projects. We are indebted to Dr. Motoo Shiro of Rigaku
for assistance with X-ray crystallography.
Keywords: cyclization · enantioselectivity · natural products ·
palladium · total synthesis
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Received: July 8, 2014
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FULL PAPER
&
Natural Products
S. Hirai, M. Utsugi, M. Iwamoto,
M. Nakada*
&& – &&
Formal Total Synthesis of (À)-Taxol
through Pd-Catalyzed Eight-
Membered Carbocyclic Ring
Formation
A less taxing route to taxol: The Pd-
catalyzed intramolecular alkenylation of
a methyl ketone affords a key cyclized
intermediate for the synthesis of
ether through a 1,5-hydride shift,
generating the C3 stereogenic center
and subsequently forming the C1–C2
benzylidene, was discovered during the
preparation of a substrate for the
Pd-catalyzed reaction.
(À)-taxol in excellent yield (97%) (see
scheme; Bn=benzyl; TES=triethylsilyl).
Rearrangement of an epoxy benzyl
&
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Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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