Synthetic Study toward the Total Synthesis of Taxezopidines A and B

Article abstract of DOI:10.1021/acs.orglett.8b02571

A concise synthetic approach to construct the [6,8,6]-tricyclic core of taxezopidines A and B, which contains a synthetically challenging bridged bicyclo[5.3.1]undecane ring system bearing most of the desired functionalized groups and stereocenters, has b

Full text of DOI:10.1021/acs.orglett.8b02571

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthetic Study toward the Total Synthesis of Taxezopidines A and
B
Ya-Jian Hu,†,‡,§ Jian-Hong Fan,†,‡,§ Shaoping Li,† Jing Zhao,*,† and Chuang-Chuang Li*,‡
†Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
‡Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055,
China
S
* Supporting Information
ABSTRACT: A concise synthetic approach to construct the [6,8,6]-tricyclic core of taxezopidines A and B, which contains a
synthetically challenging bridged bicyclo[5.3.1]undecane ring system bearing most of the desired functionalized groups and
stereocenters, has been established. This approach features a diastereoselective type II intramolecular Diels−Alder furan
reaction. The stereochemistry of the acetoxy group at the allylic position of the dienophile alkene group, such as in 6a, was
found to be critical for achieving the desired highly diastereoselective outcome.
axol (1, Figure 1) is a widely used anticancer drug with
some harmful side effects.1 Taxezopidines, which are a
distorted [6,8,6]-tricyclic bridged framework containing 8−9
stereogenic centers, including an all-carbon quaternary stereo-
center at C8. Unlike Taxol, taxezopidine A (2) contains an all-
carbon quaternary stereocenter at C15 and an
oxabicyclo[2.2.2]octane moiety with a cagelike backbone
conformation, which pose further considerable synthetic
challenges. In addition to their structural complexity,
taxezopidines markedly inhibit the Ca2+-induced depolymeri-
zation of microtubules.2 However, the relative scarcity of
taxezopidine natural sources has impeded a more systematic
evaluation of their biological activity. Therefore, the develop-
ment of an efficient synthesis for the construction of these
complex molecules and Taxol analogues is highly desirable.
Owing to its unusual structural motifs and promising
pharmacological properties, Taxol (1) has attracted consid-
erable attention from synthetic chemists, which has resulted in
seven total syntheses4 and three formal syntheses.5 However,
no synthetic studies or total syntheses of taxezopidines A and B
have been reported. As part of our continuing efforts toward
the synthesis of biologically active natural products,6 we herein
report a concise synthetic approach to the construction of the
core of taxezopidines A and B, which contains a [6,8,6]-
tricyclic bridged ring system, using a type II intramolecular
Diels−Alder furan (IMDAF) reaction.
T
Figure 1. Structures of Taxol and taxezopidines A and B.
series of bioactive taxane-type diterpenoid natural products,
have been isolated from seeds of the Japanese yew (Taxus
cuspidata Sieb. et Zucc.) and characterized by Kobayashi et al.2
Taxezopidine A (2) is the first taxoid isolated from yew trees
bearing a hemiketal ring comprising C11−C13, C15, and
C17,2a while taxezopidine B (3) is the first taxoid bearing a
double bond between C3 and C4.2b Similar to Taxol (1), the
structures of taxezopidines A and B contain several syntheti-
cally challenging features found in numerous oxygenated
terpenoid natural products,3 such as a highly strained and
Figure 2 shows the bond disconnections of taxezopidines A
(2) and B (3) used to develop the concise synthetic strategy
employed in this study. Taxezopidines A (2) and B (3) were
Received: August 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02571
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Diastereoselectivity in Shea’s Work and This
Work
to afford the desired stereochemistry at C1 in 5 (Scheme 1).
However, the presence of four substituents on the furan ring
system of 6 would result in increased strain, which has rarely
been reported in substrates for IMDAF reactions,12 making
this reaction particularly challenging. To achieve the proposed
synthetic transformation, compound 6a (R = H) was selected
as a test substrate to assess the cyclization tendency of this
IMDAF reaction.
Our synthesis began with the preparation of aldehyde 8
using a previously reported procedure with modifications
(Scheme 2).9 Subsequent 1,2-addition of the lithium reagent
resulting from the reaction of BuLi with 1413 to 8 (5.0 g scale),
followed by treatment with NaH and BnBr, gave 15 in 70%
overall yield (>10:1 dr). Next, 1,2-addition of the lithium
Figure 2. Retrosynthetic analysis of taxezopidines A and B.
envisioned to be generated from tricyclic core 4 (R = CH2OBn
or Me) through a series of functional group transformations.
Compound 4 could be synthesized through chemoselective
alkylation or methylation at the allylic C15 position in 5.7 This
approach could be used to obtain structurally diverse analogues
at C15 for structure−activity relationship (SAR) studies.
Furthermore, compound 5, containing a bridgehead double
bond, could be synthesized diastereoselectively from 6 through
a type-II IMDAF reaction. Finally, compound 6 could be
prepared from readily available bromofuran 7, known aldehyde
8,9 and acrolein (9) through successive 1,2-additions.
Scheme 2. Synthesis of 6a
The key step in our proposed synthesis was the type-II
IMDA reaction, which is a powerful synthetic tool first
developed by Shea et al. in 19788a for the direct construction
of synthetically challenging bridged cyclohexene bicyclic
skeletons. The reaction has subsequently been used to
construct a number of complex natural products.8d−h In
1994, Shea et al. attempted to construct the taxane core
structure through the type-II IMDA reaction of compound
10.9 Unfortunately, the reaction afforded tricyclic core 11 with
the undesired stereochemistry at C1 in 44% yield (Scheme 1).
We speculated that using a type-II IMDAF reaction in our
strategy, as well as taking advantage of the conformationally
preorganized feature10 of substrate 6, would proceed differ-
ently to the IMDA reaction of 10. In our previous study on
type II intramolecular [5 + 2] cycloaddition reactions,11 the
acetoxy group at the allylic position of the dienophile alkene
group was found to be crucial for high diastereoselectivity
(>20:1 dr). Therefore, it was anticipated that the C2 acetoxy
group in 6 could control the diastereoselectivity of the reaction
B
DOI: 10.1021/acs.orglett.8b02571
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Letter
reagent resulting from the reaction of t-BuLi with bromide 15
to acrolein gave 6b as the major product (6b/C2-epi-6b =
3.1:1, 2.1 g scale), followed by acylation of the secondary
hydroxyl group in 6b to afford desired precursor 6a in 60%
overall yield.
which was the first taxoid containing a double bond at C3−C4.
Notably, in previous studies, generating the C2 hydroxyl group
diastereoselectively through reduction of the corresponding
ketone was problematic.14 In contrast, the current work
allowed efficient, direct construction of the C2 hydroxyl group.
Interestingly, we found that heating 6b, bearing a free
alcohol at C2, in PhMe afforded desired product 5b and
undesired epimer 5c (5b/5c = 1:1) in 35% combined yield
(Scheme 4). Surprisingly, when compound 6b underwent
With 6a in hand, we proceeded to investigate the proposed
type-II IMDAF reaction for the synthesis of 5a. Pleasingly, the
type-II IMDAF reaction of 6a in PhMe with heating gave 5a
containing the [6,8,6]-tricyclic core as a single diastereomer in
55% yield. The structure of 5a with the desired functional
groups, including a bridgehead double bond at C11−C12 and
the correct relative stereochemistry at C1, C2, C8, C9, C10,
C13, and C15 of taxezopidine A (as highlighted in red), was
unambiguously confirmed by X-ray crystallographic analysis of
derivative 16 (Scheme 3). Substrate-controlled stereoselective
epoxidation of 5a with m-CPBA in CH2Cl2 provided desired
epoxide 17 in 70% yield. The structure of 17 was determined
using two-dimensional NMR spectroscopy, which contained
the desired double bond at C3−C4 and other functional
groups, including the desired stereochemistry at C1, C2, C8,
C9, C10, and C11 of taxezopidine B (as highlighted in red),
Scheme 4. Syntheses of 5b, 5c, and 19
Scheme 3. Syntheses of 5a and 17
oxidations with Dess−Martin periodinane (DMP) at room
temperature, compound 18 and its DA cycloadduct 19 were
obtained (18/19 = 1:1). However, after many attempts (see
the Supporting Information for details), 18 and 19 could not
be separated, showing that the type-II IMDAF reaction of 18
was reversible. The relative stereochemistry at C1 in 19 was
too difficult to determine, owing to 18 and 19 being
inseparable. Based on these results, we concluded that the
stereochemistry of the acetoxy group at the allylic position of
the dienophile alkene group, such as in 6a, was critical for the
desired highly diastereoselective outcome of this type II
IMDAF reaction.
Additionally, we have also tested a type-II IMDAF reaction
of the compounds C2-epi-6b and C2-epi-6a which possessed
an incorrect configuration of the C2 hydroxyl group (Scheme
4). To our surprise, when the two compounds were treated
under the same conditions, we could not isolate any DA
cycloadduct; only decomposition of the starting materials
resulted. Therefore, we speculated that the correct config-
uration of the C2 hydroxyl group is essential for the type-II
IMDAF reaction.
In summary, a concise synthetic approach to construct the
[6,8,6]-tricyclic core of taxezopidines A (2) and B (3), which
contains a synthetically challenging bridged bicyclo[5.3.1]-
undecane ring system, has been developed. This approach
features a diastereoselective type-II IMDAF reaction. Seven of
C
DOI: 10.1021/acs.orglett.8b02571
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Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02571.
■
S
Detailed experimental procedures, H NMR and 13C
NMR spectra, as well as X-ray data information (PDF)
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Accession Codes
CCDC 1861400 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ccli@sustc.edu.cn.
*E-mail: jingzhao@umac.mo.
ORCID
Chuang-Chuang Li: 0000-0003-4344-0498
Author Contributions
§Y.-J.H. and J.-H.F. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (Grant Nos. 21672095, 21602100, 21522204, and
21472081), Guangdong Science and Technology Department
(2016A050503011), the Shenzhen Science and Technology
Innovation Committee (Grant Nos. JCYJ20170412152454807
and JSGG20160301103446375), the Shenzhen Nobel Prize
Scientists Laboratory Project (C17213101), and Project
KQTD2016053117035204 supported by the Shenzhen Pea-
cock Plan.
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