Second-generation total synthesis of aplyronine A featuring Ni/Cr-mediated coupling reactions

Article abstract of DOI:10.1039/c6ob02241c

Second-generation total synthesis of aplyronine A, a potent antitumor marine macrolide, was achieved using Ni/Cr-mediated coupling reactions as key steps. The overall yield of the second-generation synthetic pathway of aplyronine A was 1.4%, obtained in 38 steps based on the longest linear sequence. Compared to our first-generation synthetic pathway of aplyronine A, the second-generation synthesis greatly improved both the yield and number of steps. In particular, we improved the stereoselectivity in the construction of the C13 stereogenic center and the C14-C15 (E)-trisubstituted double bond using the asymmetric Ni/Cr-mediated coupling reaction. Furthermore, we established efficient reaction conditions for the asymmetric Ni/Cr-mediated coupling reaction between the C21-C28 segment and C29-C34 segment. Thus, this coupling reaction proceeded with an equimolar ratio of each segment.

Full text of DOI:10.1039/c6ob02241c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Second-generation total synthesis of aplyronine A featuring Ni/Cr-
mediated coupling reaction
Ichiro Hayakawa,a* Keita Saito,b Sachiko Matsumoto,b Shinichi Kobayashi,b Ayaka Taniguchi,b
Kenichi Kobayashi,b Yusuke Fujii,b Takahiro Kanekob and Hideo Kigoshib*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Second-generation total synthesis of aplyronine A, a potent antitumor marine macrolide, was achieved using Ni/Cr-
mediated coupling reactions as key steps. The overall yield of the second-generation synthetic pathway of aplyronine A
was 1.4%, obtained in 38 steps based on the longest linear sequence. Compared to our first-generation synthetic pathway
of aplyronine A, the second-generation synthesis greatly improved both the yield and number of steps. In particular, we
improved the stereoselectivity in the construction of the C13 stereogenic center and the C14–C15 (E)-trisubstituted double
bond using the asymmetric Ni/Cr-mediated coupling reaction. Furthermore, we established efficient reaction conditions
for the asymmetric Ni/Cr-mediated coupling reaction between the C21–C28 segment and C29–C34 segment. Thus, this
www.rsc.org/
coupling
reaction
proceeded
with
an
equimolar
ratio
of
each
segment.
possesses unique mechanisms of action. Thus, aplyronine A (
forms a 1 : 1 : 1 heterotrimeric complex with actin and tubulin,
and inhibits tubulin polymerization. Like aplyronine A ( ), FK-
1)
Introduction
1
Aplyronine A (
Japanese sea hare Aplysia kurodai by Yamada and co-workers
(Fig. 1).1 Aplyronine A (
) exhibited strong cytotoxicity against
1) is a marine macrolide isolated from the
506 and rapamycin are known to induce protein–protein
interactions (PPIs) in natural products.6 In addition, inhibitors
of tubulin polymerization, such as vinblastine, have been
clinically important drugs, especially for breast cancer.7
1
HeLa S3 cells in vitro, and potent antitumor activities in vivo
against P388 leukemia, Lewis lung carcinoma, and Ehrlich
carcinoma.2 Previously, we have revealed structure–activity
relationships,3 target proteins,4 and mechanisms of action of
Therefore, aplyronine A (1) can be expected to become a lead
compound in novel-type anticancer drugs.
aplyronine A (1 1)
)5 based on organic synthesis. Aplyronine A (
Fig. 1 Structure of aplyronine A (1)
The potent and unique biological activities of aplyronine A (1)
have made it an attractive synthetic target.8 Several groups
have reported approaches to synthesizing aplyronine A (1) and
its related derivatives. In 2013, Paterson and co-workers
achieved total synthesis of aplyronine C,9 which is a natural
analogue of aplyronine A (
1
). Prior to that report, we described
).10 This synthesis
the first total synthesis of aplyronine A (
1
made it possible to evaluate in vivo antitumor activities, and to
prepare chemical probes to elucidate the mechanisms of
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action of aplyronine A (1). However, our previous synthetic possible reaction sites, was conducted under the modified
route included
stereoselectivity. We therefore sought an efficient second- and the undesired 26-membered lactone
generation route to aplyronine A ( ) and its derivatives that ratio of ca. 4 : 3. Therefore, the undesired 26-membered
could provide a practical supply for further biological studies. lactone had to be isomerized to 24-membered lactone via
Here, we describe the efficient second-generation total an ester exchange reaction with Ti(OiPr)4 (Scheme 1B). We
a
few steps with low yield and poor Yamaguchi conditions,12 the desired 24-membered lactone
were produced in a
8
9
1
9
8
synthesis of aplyronine
A
(
1), featuring Ni/Cr-mediated consider that these problems of poor stereoselectivity and/or
coupling reactions as key steps.
regioselectivity could be improved by using the Ni/Cr-
In our first-generation total synthesis of aplyronine A (
constructed the C14–C15 (E)-trisubstituted double bond using synthesis of the aplyronine A–mycalolide B hybrid molecule
Julia coupling because of the advantage that recovering the consisting of the macrolactone portion in aplyronine A ( ) and
1
),10 we mediated coupling reaction.13 In 2012, we reported the
1
unreacted sulfone segment was much easier than using Wittig the side chain portion in mycalolide B, with featuring Ni/Cr-
phosphonium salts.11 However, Julia coupling between ketone mediated coupling reactions as key steps.14 This synthesis
2
and sulfone
sulfone, produced undesired (Z)-olefin
alcohol (25%), along with the desired (E)-olefin
(Scheme 1A). In addition, when macrolactonization of seco- molecule.
acid , which has two hydroxy groups at C23 and C25 as
3
, and the subsequent reduction of the hydroxy improved the problems outlined above. Thus, we planned the
(19%) and C14 tertiary second-generation total synthesis of aplyronine A ( ) based on
(44%) the synthetic strategy of the aplyronine A–mycalolide B hybrid
5
1
6
4
7
Scheme 1 First-generation synthetic route; A: Julia coupling; B: modified Yamaguchi lactonization and isomerization
synthesis.10 The macrolactone portion in 10 might be
assembled from cyclization precursor 11 using the
intramolecular Ni/Cr-mediated coupling (Nozaki–Hiyama–
Takai–Kishi coupling) reaction.13 Cyclization precursor 11 can
be constructed by intermolecular esterification between
carboxylic acid 12 and alcohol 13. In our previous work,15
carboxylic acid 12, which is the C1–C19 segment, was prepared
Results and discussion
The second-generation retrosynthetic pathway of aplyronine A
(1) is shown in Scheme 2. Aplyronine A (1) would be obtained
from 10, the same intermediate as in our first-generation
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from aldehyde 14 and iodoolefin 15 by an asymmetric Ni/Cr- C34 segment 13 might also be obtained from iodoolefin 16 and
mediated coupling reaction.16 This strategy has the benefit of aldehyde 1714 by an asymmetric Ni/Cr-mediated coupling
forming the C14–C15 (E)-trisubstituted double bond and the reaction followed by hydrogenation.
C13 stereogenic center simultaneously. In addition, the C20–
Scheme 2 Retrosynthetic pathway of aplyronine A (1)
In our preliminary report,15 iodoolefin 15 was stereoselectively
constructed from compound 18 by
a
regioselective
hydrozirconation with Schwartz's reagent (Scheme 3).17
However, this reaction was not reproducible (0–70%) and
afforded reduced compounds, such as 19, as by-products in
some cases. Thus, preparation of iodoolefin 15 required
optimization.
Scheme 3 Previous synthetic route: hydrozirconation of 18
We attempted the silylcupration of internal alkyne in 18, with
subsequent iododesilylation (Table 1).18 Thus, treatment of 18
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with CuCN and PhMe2SiLi19 gave vinylsilane 20 as a single tBu group on the oxazoline ring, a small methyl group on the
isomer with quantitative yield. We next tried iododesilylation sulfonamide group, and three methoxy groups on the benzene
of 20 with NIS. The Holton and Zakarian groups reported ring, based on the chiral sulfonamide ligands developed by
stereoselective
iododesilylation
with
NIS
in Kishi (Fig. 2).15
hexafluoroisopropanol.20 We attempted to reproduce the We used our modified ligand 21 to carry out an asymmetric
Zakarian-reported conditions20b to obtain the desired Ni/Cr-mediated coupling reaction between the C5–C13
iodoolefin 15 in moderate yields (entries 1 and 2). Treatment segment 14 and C14–C19 segment 15 (Table 2). In entry 1, the
of vinylsilane 20 with NIS in MeCN–THF (3 : 1) afforded the coupling reaction with ligand 21 (8.0 equiv) and CrCl2 (8.0
desired iodoolefin 15 as a single isomer (entry 3).21 This equiv) yielded the coupling compound 22 as a diastereomeric
modification made the reaction reproducible and increased mixture (22a/
22b = 3.7 : 1, quantitative yield).15,23 We
the yield of the desired iodoolefin 15 to 96% in two steps.
speculated that one reason for the low diastereoselectivity
was that there was insufficient formation of the Cr–ligand
complex. Thus, we next tried a coupling reaction with CrCl2 (3.1
equiv) and a small excess (against CrCl2) of ligand 21 (3.5
equiv), and found that the diastereoselectivity was greatly
Table 1 Iododesilylation of 18
improved (22a/22b = 7.3 : 1, 88% yield) (entry 2). The C13
isomers 22a and 22b were separated by silica gel column
chromatography, and the desired 22a was converted into the
C1–C19 segment 12 by our previously established synthetic
route (63% in eight steps).15 The undesired 22b could be
inverted into the former by Mitsunobu reaction24 or the
oxidation–asymmetric reduction sequence.
Table
2 Optimization of the asymmetric Ni/Cr-mediated coupling reaction for
improving stereoselectivity
We next investigated the Ni/Cr-mediated coupling reaction
between the C5–C13 segment 1415 and C14–C19 segment 15
(Table 2). The constructions of trisubstituted olefins via
asymmetric Ni/Cr-mediated coupling reaction have been few
and far between, and investigation of this reaction was a
synthetic challenge.22 We first tried the Ni/Cr-mediated
coupling reaction under standard conditions (0.1 w/w%
NiCl2/CrCl2, DMSO)13 without a chiral ligand. We found the
reaction was completed to give the desired coupling
compound 22 in 96% yield as a 1 : 1 diastereomixture at C13.
This result suggested that the stereochemistry of C13 could be
controlled by the Ni/Cr-mediated coupling reaction with a
chiral ligand. Thus, we screened several known chiral
sulfonamide ligands for the asymmetric Ni/Cr-mediated
coupling reactions,15 but known sulfonamide ligands with high
yield and stereoselectivity were not found in this screening.15b
Results of the screening, however, led to the following
conclusions: (1) a large substituent on the sulfonamide group
prevented the transmetalation of the vinyl-Ni(II) species to
Cr(III) ones and thereby decreased the yield of the coupling
product; (2) a large substituent on the oxazoline ring induced
the high stereoselectivity because of its steric hindrance; and
(3) electron-donating substituents on the benzene ring
improved the stereoselectivity due to enhanced affinity to Cr,
which reduced the ligand-free Ni/Cr-mediated coupling
reaction.15 Therefore, in consideration of all the above, we
designed and synthesized chiral ligand 21, which has a large
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Table 3 Optimization of the asymmetric Ni/Cr-mediated coupling reaction
Fig. 2 Modified chiral sulfonamide ligand 21
We next examined the synthesis of the C20–C34 segment 13
The C21–C28 segment 16 and C29–C34 segment 17 were
synthesized using as key steps the Mukaiyama Sn(II)-promoted
.
aldol
reaction,25
Takai
olefination,26
and
Roush
crotylboration,27 respectively (see the ESI†). Thus, we
attempted the Ni/Cr-mediated coupling reaction between the
C21–C28 segment 16 and C29–C34 segment 17 (Table 3). We
first checked the substrate controllability of the chiral methyl
group at the
α-position of the aldehyde group in 17. The
ligand-free Ni/Cr-mediated coupling reaction (1 w/w%
NiCl2/CrCl2, DMSO)13 proceeded through the Felkin–Anh model
to give priority to the desired diastereomer 23. However, the
yield and diastereoselectivity were moderate (50% yield, 4.6 :
1). Thus, we next examined the Ni/Cr-mediated coupling
reaction with our modified chiral sulfonamide ligand 21 15
In
.
entry 1, the asymmetric Ni/Cr-mediated coupling reaction
proceeded smoothly to afford coupling compound 23 at an
80% yield as a single diastereomer.23 In this case, the coupling
Next, we attempted to synthesize the C20–C34 segment 13
from the desired coupling compound 23. Reduction of the
olefin in 23 and subsequent protection of the secondary
reaction was performed with 2.0 equiv of vinyl iodide 16
.
hydroxy
group
gave
DMBOM
[{(3,4-
dimethoxybenzyl)oxy}methyl] ether,10 which was converted
into diol 24 by selective desilylation of the silylene acetal
group. Silylation of the diol group in 24 with TES groups gave
di-TES ether, which was transformed into aldehyde 25 by
selective removal of the primary TES group and oxidation of
the resultant primary hydroxy group. Aldehyde 25 was
converted into the C20–C34 segment 13 by Takai olefination26
and selective removal of the TES group. Although C20–C34
segment 13 was obtained as an inseparable mixture of olefin
stereoisomers (E / Z = 4.5 : 1), the stereoisomers could be
chromatographically separated after several steps.
Generally, ca. 1.5–2.0 equiv of a vinyl iodide against an
aldehyde is used for the Ni/Cr-mediated coupling reaction.
However, because the preparation of vinyl iodide 16 required
more steps than that of aldehyde 17 in this case, we
investigated the molar ratio of vinyl iodide 16 and aldehyde 17
in this asymmetric Ni/Cr-mediated coupling reaction.28 In entry
2, the asymmetric Ni/Cr-mediated coupling reaction with an
equimolar mixture of vinyl iodide 16 and aldehyde 17 gave the
desired allylic alcohol 23 in 56% yield. Also, this coupling
reaction proceeded slowly, and led to the decomposition of
aldehyde 17. In this result, the coupling yield was decreased
from entry 1. However, the yield in entry 2 was acceptable
when the consumption of vinyl iodide 16 was considered.
Thus, we next optimized the coupling conditions using an
equimolar mixture of vinyl iodide 16 and aldehyde 17. For the
enhanced reaction rate, we attempted this coupling reaction
at a higher concentration, but the yield was slightly decreased
(entry 3). We assumed that the cause of the decreased yield
was that the reaction system was rendered acidic by the
sulfonamide proton in ligand 21. In entry 4, the reduction of
each reagent to half the original amount was found to give the
best yield (64%). Therefore, we improved the condition of the
asymmetric Ni/Cr-mediated coupling reaction with an
equimolar mixture of vinyl iodide 16 and aldehyde 17
.
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With both fragments C1–C19 segment 12 and C20–C34
segment 13 in hand, synthesis of precursor for
a
intramolecular Ni/Cr-mediated coupling reaction was
examined next. In preparation for this, we followed our
synthetic route for the aplyronine A–mycalolide B hybrid
molecule (Scheme 5).14 Thus, the C1–C19 segment 12 and
C20–C34 segment 13 were esterified via Yamaguchi
conditions29 to give ester 26, the O19 TBS group of which was
selectively removed to provide alcohol 27. The resultant
primary hydroxy group of 27 was oxidized to afford aldehyde
11 as a cyclization precursor.
Scheme
4 Synthesis of C20–C34 segment 13. Reagents and conditions: (a) H2,
Pd(OH)2/C, NaHCO3, EtOH, rt, 92%; (b) DMBOMCl, iPr2NEt, CH2Cl2, 30 °C, 94%; (c)
nBu4NF, AcOH, THF, –5 °C, 91%; (d) TESCl, imidazole, DMF, rt, quant; (e) NH4F, MeOH,
rt, quant; (f) Dess–Martin peropdinane, py, CH2Cl2, rt, 93%; (g) CrCl2, CHI3, THF, rt, 91%,
E/Z = 4.5 : 1; (h) AcOH, H2O, THF, rt, 86%.
Scheme 5 Synthesis of a precursor for the intramolecular Ni/Cr-mediated coupling reaction. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, THF,
toluene, rt, 96%; (b) AcOH, H2O, THF, rt, 93%; (c) Dess–Martin periodinane, CH2Cl2, rt, 90%.
aplyronine A (1
) (c = 0.39 mM).30 The stereoisomer at the C20–
The intramolecular Ni/Cr-mediated coupling reaction was C21 double bond could be separated after the intramolecular
examined next (Table 4). Treatment of aldehyde 11 with 2.0 Ni/Cr-mediated coupling reaction of 11. Then, we examined
w/w% NiCl2/CrCl2 in DMSO (c = 10 mM)13 gave the desired the asymmetric intramolecular Ni/Cr-mediated coupling
cyclization compound 28 (54%) and its diastereomer 29 (35%) reaction of 11 using our modified chiral ligand 30 (ent-21
(entry 1).23 This intramolecular Ni/Cr-mediated coupling (entry 2). Unexpectedly, the yield and diastereoselectivity of
reaction proceeded smoothly at 26-times higher this cyclization were not improved (28: 41%, 29: 18%). We
)
a
concentration than that of the modified Yamaguchi thought that steric hindrance of vinyl–Cr(III)/ligand complex of
macrolactonization12 in our first-generation total synthesis of 11 interfered with the intramolecular addition to the aldehyde
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group. The undesired diastereomer 29 could be converted into convert undesired diastereomer 29 into desired allylic alcohol
the desired allylic alcohol 28 by oxidation of by using a 28, we followed the procedure reported by Paterson.9b
sequence of Dess–Martin oxidation and CBS reduction.31 To
Table 4 Intramolecular Ni/Cr-mediated coupling reaction of 11
Methylation of the hydroxy group at C19 in allylic alcohol 28
afforded methyl ether 10, which was our intermediate in the
first-generation total synthesis of aplyronine A (1) (Scheme
6).10 The methyl ether 10 gave spectral data (1H NMR and 13C
NMR spectroscopy, HRMS, and optical rotation) that were in
full agreement with those of our authentic intermediate.3a To
convert methyl ether 10 into aplyronine A (
first-generation total synthesis (see the ESI†). The 1H NMR data
of synthetically obtained aplyronine A ( ) were in good
) (see the
1), we followed our
1
agreement with those of natural aplyronine A (
ESI†).
1
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Scheme 6 Second-generation total synthesis of aplyronine A (1). Reagents and conditions: (a) MeI, NaH, THF, 35 °C, 90%.
Products’ (Grant Number JP23102014) and for Scientific
Research (Grant Number JP26242073) from the Ministry of
Education, Culture, Sports, Science and Technology
(MEXT)/Japanese Society for the Promotion of Science (JSPS).
I.H. thanks the Okayama Foundation for Science and
Technology, the Naito Foundation, the Kurata Grant awarded
by the Kurata Memorial Hitachi Science and Technology
Foundation, the NOVARTIS Foundation (Japan) for the
Promotion of Science, and the Suzuken Memorial Foundation
for their financial supports.
Conclusions
In conclusion, we achieved second-generation total synthesis
of aplyronine A (
1
). The overall yield of the second-generation
), based on the longest
synthetic pathway of aplyronine A (
1
linear sequence, was 1.4% in 38 steps (the total number of
steps was 80 from the commercial materials.), a considerable
improvement over our first-generation synthetic pathway of
aplyronine A (1), which gave 0.39% overall yield in 47 steps in
the longest linear sequence. We especially improved the
stereoselectivity of the construction of the C13 stereogenic
center and the C14–C15 (E)-trisubstituted double bond using
the asymmetric Ni/Cr-mediated coupling reaction. Moreover,
we established efficient reaction conditions for the asymmetric
Ni/Cr-mediated coupling reaction between the C21–C28
segment 16 and the C29–C34 segment 17. This coupling
reaction proceeded well with an equimolar ratio of each
segment. We consider that this synthetic strategy, which uses
Ni/Cr-mediated coupling reactions as key steps, could be
useful for the preparation of structurally diverse derivatives of
Notes and references
1
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3
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and an aplyronine A–mycalolide B hybrid molecule using this
strategy. The strategy is now being applied to the synthesis of
other derivatives based on aplyronine A (1) for development of
lead compounds of novel-type anticancer agents.
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Acknowledgements
This work was supported by Grants-in-Aid for Scientific
Research on Innovative Areas ‘Chemical Biology of Natural
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