Toward the second generation synthesis of aplyronine A: Stereocontrolled assembly of the C1-C19 segment by using an asymmetric Nozaki-Hiyama-Kishi coupling

Article abstract of DOI:10.1021/ol1029657

An efficient synthesis of the C1-C19 segment of aplyronine A is described. Stereoselective construction of the C14-C15 (E)-trisubstituted double bond and the C13 stereocenter was achieved by using an asymmetric Nozaki-Hiyama-Kishi coupling.(Figure Presented)

Full text of DOI:10.1021/ol1029657

ORGANIC
LETTERS
2011
Vol. 13, No. 5
900–903
Toward the Second Generation Synthesis
of Aplyronine A: Stereocontrolled
Assembly of the C1-C19 Segment
by Using an Asymmetric
Nozaki-Hiyama-Kishi Coupling
Kenichi Kobayashi, Yusuke Fujii, Ichiro Hayakawa, and Hideo Kigoshi*
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Ibaraki 305-8571, Japan
kigoshi@chem.tsukuba.ac.jp
Received December 7, 2010
ABSTRACT
An efficient synthesis of the C1-C19 segment of aplyronine A is described. Stereoselective construction of the C14-C15 (E)-trisubstituted
double bond and the C13 stereocenter was achieved by using an asymmetric Nozaki-Hiyama-Kishi coupling.
Aplyronine A (1), isolated from the sea hare Aplysia
kurodai in 1993 by Yamada and co-workers, is a potent
cytotoxic and antitumor macrolide (Figure 1).1 Further-
more, aplyronine A (1) inhibits the polymerization of
globular actin (G-actin) to fibrous actin (F-actin) by
sequestering G-actin and forming a 1:1 complex, and also
depolymerizes F-actin by a severing mechanism.2 Thus,
aplyronine A (1) is expected to be a new type of anticancer
chemotherapeutic agent. Its complex structure and potent
biological activities have attracted considerable attention
from the synthetic community.3
Although we have previously accomplished the first
total synthesis of aplyronine A (1),4 our previous route
involved a few steps that showed both low yield and poor
selectivity. In particular, Julia coupling between ketone 2
(3) (a) Paterson, I.; Cowden, C. J.; Woodrow, M. D. Tetrahedron
Lett. 1998, 39, 6037. (b) Paterson, I.; Woodrow, M. D.; Cowden, C. J.
Tetrahedron Lett. 1998, 39, 6041. (c) Paterson, I.; Blakey, S. B.; Cowden,
C. J. Tetrahedron Lett. 2002, 43, 6005. (d) Calter, M. A.; Guo, X.
Tetrahedron 2002, 58, 7093. (e) Calter, M. A.; Zhou, J. Tetrahedron Lett.
2004, 45, 4847. (f) Marshall, J. A.; Johns, B. A. J. Org. Chem. 2000, 65,
1501. (g) El-Awa, A.; Fuchs, P. Org. Lett. 2006, 8, 2905.
(4) (a) Kigoshi, H.; Ojika, M.; Suenaga, K.; Mutou, T.; Hirano, J.;
Sakakura, A.; Ogawa, T.; Nisiwaki, M.; Yamada, K. Tetrahedron Lett.
1994, 35, 1247. (b) Kigoshi, H.; Ojika, M.; Ishigaki, T.; Suenaga, K.;
Mutou, T.; Sakakura, A.; Ogawa, T.; Yamada, K. J. Am. Chem. Soc.
1994, 116, 7443. (c) Suenaga, K.; Ishigaki, T.; Sakakura, A.; Kigoshi, H.;
Yamada, K. Tetrahedron Lett. 1995, 36, 5053. (d) Kigoshi, H.; Suenaga,
K.; Mutou, T.; Ishigaki, T.; Atsumi, T.; Ishikawa, H.; Sakakura, A.;
Ogawa, T.; Ojika, M.; Yamada, K. J. Org. Chem. 1996, 61, 5326.
(1) (a) Yamada, K.; Ojika, M.; Ishigaki, T.; Yoshida, Y.; Ekimoto,
H.; Arakawa, M. J. Am. Chem. Soc. 1993, 115, 11020. (b) Ojika, M.;
Kigoshi, H.; Ishigaki, T.; Yamada, K. Tetrahedron Lett. 1993, 34, 8501.
(c) Ojika, M.; Kigoshi, H.; Ishigaki, T.; Nisiwaki, M.; Tsukada, I.;
Mizuta, K.; Yamada, K. Tetrahedron Lett. 1993, 34, 8505. (d) Ojika, M.;
Kigoshi, H.; Ishigaki, T.; Tsukada, I.; Tsuboi, T.; Ogawa, T.; Yamada,
K. J. Am. Chem. Soc. 1994, 116, 7441.
(2) Saito, S.; Watabe, S.; Ozaki, H.; Kigoshi, H.; Yamada, K.;
Fusetani, N.; Karaki, H. J. Biochem. 1996, 120, 552.
r
10.1021/ol1029657
Published on Web 01/26/2011
2011 American Chemical Society

Scheme 2. Second-Generation Retrosynthetic Analysis of
Aplyronine A (1)
Figure 1. Structure of aplyronine A (1).
Scheme 1. Our Previous Work
and sulfone 3 and subsequent reduction yielded the un-
desired (Z)-olefin 5 (19%) and the C14 tertiary alcohol 6
(25%) along with the desired (E)-olefin 4 (44%) (Scheme 1).
Therefore we planned to develop stereoselective construc-
tion of the C14-C15 (E)-trisubstituted double bond for
the second generation total synthesis of aplyronine A
(1), which would provide a practical supply of 1 for
further biological studies. Herein we describe an efficient
stereocontrolled construction of the C1-C19 segment of
aplyronine A (1).
The second generation retrosynthetic analysis of aplyr-
onine A (1) is shown in Scheme 2. Aplyronine A (1) would
be obtained from 7, the same intermediate as that in the
first generation synthesis.4b,c The macrolactone part in7can
be constructed by an intramolecular Nozaki-Hiyama-
Kishi (NHK) reaction5 of compound 8. Disconnection of
the ester moiety of 8 provides carboxylic acid 9 and alcohol
10. The C1-C19 segment 9 can be derived from aldehyde
11 and iodoolefin 12 by an asymmetric NHK coupling6 as
a key step. This strategy has the benefit of constructing the
C14-C15 (E)-trisubstituted double bond and the C13
stereocenter at once. Also, construction of trisubstituted
olefins by using an asymmetric NHK coupling has never
been reported to date, and investigation of this reaction
was a synthetic challenge.
Synthesis of the C5-C13 segment 11 started from
alcohol 13,4b,c which was the intermediate in our first gene-
ration synthesis of aplyronine A (1) (Scheme 3). The
secondary hydroxy group in 13 was protected as a TES
ether, and the benzyl group was removed. The resulting
primary alcohol was converted into tosylate 14. We next
attempted three-carbon homologation of 14 using allyl-
magnesium bromide in the presence of Cu(I) salt7 to
obtain not the homologue compound but the depivaloyl
compound. However, the use of excess allylmagnesium
bromide without Cu(I) salt in boiling Et2O gave the
terminal olefin 15 in good yield (92%) with concomitant
cleavage of the pivaloyl group. Reprotection of the
resulting hydroxy group in 15 with a pivaloyl group
and dihydroxylation of the terminal olefin gave a diol,
which was readily converted into the desired aldehyde 11
as a C5-C13 segment by oxidative cleavage in two steps
and 97% yield.
(5) (a) Jin, H.; Uenichi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.;
€
Nozaki, H. Tetrahedron Lett. 1983, 24, 5281. (c) Furstner, A. Chem. Rev.
Iodoolefin 12 as a C14-C19 segment was prepared as
1999, 99, 991.
follows (Scheme 4). Oxidation of alcohol 168 provided
(6) (a) Wan, Z.-K.; Choi, H.; Kang, F.-A.; Nakajima, K.; Demeke,
D.; Kishi, Y. Org. Lett. 2002, 4, 4431. (b) Choi, H.; Nakajima, K.;
Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett.
2002, 4, 4435. (c) Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031. (d)
Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7, 5417. (e) Guo,
H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.;
Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387.
(7) (a) Kotsuki, H.; Miyazaki, A.; Ochi, M.; Sims, J. J. Bull. Chem.
Soc. Jpn. 1991, 64, 721. (b) Wipf, P.; Uto, Y.; Yoshimura, S. Chem.;
Eur. J. 2002, 8, 1670.
(8) Ito, H.; Inoue, T.; Iguchi, K. Org. Lett. 2008, 10, 3873.
Org. Lett., Vol. 13, No. 5, 2011
901

Table 1. Optimization of Reaction Conditions: Solvent and Ni
Catalyst
Scheme 3. Synthesis of C5-C13 Segment 11
entry
Ni catalyst
NiCl2
solvent
base
yield (%)a
1
2
THF
THF
Et3N
proton-
sponge
proton-
sponge
proton-
sponge
proton-
sponge
proton-
sponge
7c
NiCl2 DMPb
58c
3
Scheme 4. Synthesis of C14-C19 Segment 12
3
4
5
6
NiCl2 DMPb
DME
0
3
NiCl2 DMPb
CH3CN
CH3CN
CH3CN
86c
82c
96
3
NiCl2
NiCl2(dppp)
(S/R = 2.8:1)d
a Isolated yield calculatedfrom 11. b NiCl2 DMP: 2,9-dimethyl-1,10-
3
phenanthroline-NiCl2 complex. c The stereoselectivity was not deter-
mined. d The stereochemistry was confirmed by modified Mosher’s
method.
aldehyde 17, which was subjected to an Ohira-Bestmann
reaction9 to yield acetylene 18 with concomitant transes-
terification by MeOH. The methyl ester group in 18 was
reduced by DIBALH, and the resulting alcohol was sub-
sequently converted into the TBS ether 19. Introduction of
the methyl group to the terminal alkyne of 19 with n-BuLi/
MeI gave 20 in 72% yield from 16 (five steps). Regioselec-
tive hydrozirconation of compound 20 by Schwartz’s
reagent10 followed by quenching with iodine afforded the
C14-C19 segment 12 in 70% yield. The stereochemistry of
the resulting (E)-trisubstituted double bond of 12 was
determined by the NOESY correlation between the allylic
methylene protons and the vinyl methyl protons.
With both fragments 11 and 12 in hand, an asymmetric
NHK coupling reaction was next examined. First, we
optimized the solvent and Ni catalyst (Table 1). The
coupling reaction between 11 and 12 using CrCl2/NiCl2/
ligand 21/Et3N/THF reported by Kishi and co-workers6a
gave the coupling product 22, but the yield was only 7%
(S/R = 2.8:1).11 Therefore, we next screened chiral sulfo-
namide ligands of an asymmetric NHK coupling.
The investigation of an asymmetric NHK coupling with
several chiral sulfonamide ligands is summarized in Table 2.
Attempts at an asymmetric NHK coupling with chiral
sulfonamide ligands, such as 236a,c or 24,6d improved the
stereoselectivity, but the yields were low (entries 1 and 2).
The ligand 25 recently developed by Kishi and co-workers6e
and its diastereomer 26 were also tested and gave excellent
yields, but the stereoselectivities were low (2.8:1 for 25,
2.0:1 for 26) (entries 3 and 4). From these results, we
assumed that (1) a large substituent on the sulfonamide
group prevented the transmetalation of the vinyl-Ni(II)
species to Cr(III) 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 the
enhanced affinity toCr. Thus, we designed and synthesized
ligand 27,12 which has a large tBu group on the oxazoline
ring, a small methyl group on the sulfonamide group, and
three electron-donating methoxy groups on the benzene
ring. Asexpected, thecouplingreaction withligand27gave
the best result: 22a/22b = 3.7:1, 100% yield (entry 5). Fur-
thermore, the reagent loadings were successfully reduced
(entry 1). Next, we screened solvents by using NiCl2 DMP
3
as a Ni catalyst and proton-sponge as a base (entries
2-4).6c,d From these results, this coupling reaction was
the most efficient in CH3CN (entry 4).6c,d In entries 4-6,
we screened an assortment of Ni catalysts based on
Kishi’s reports.6c,d The reaction with NiCl2(dppp) in CH3-
CN gave the best result in this case (entry 6); however, we
could not satisfy the stereoselectivity under this condition
(11) (a) The stereochemistry was confirmed by the modified
Mosher’s method (see Supporting Information). (b) Ohtani, I.; Kusumi,
T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(12) Ligand 27 was prepared from a known aniline (see Supporting
Information).6c
(9) Ohira, S. Synth. Commun. 1989, 58, 561.
(10) Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. 1976, 15,
333.
902
Org. Lett., Vol. 13, No. 5, 2011

Table 2. Optimization of Chiral Sulfonamide Ligands
Scheme 5. Synthesis of C1-C19 Segment 9
drc,d
entry
ligand
yield (%)b
22a/22b
1
2
3
4
5
23
24
25
26
27
46
40
3.4:1
3.9:1
2.8:1
2.0:1
3.7:1
secondary hydroxy group was protected as an MTM ether
to give compound 30. Reductive cleavage of the pivaloyl
group in 30 by DIBALH and oxidation of the resulting
hydroxy group with Dess-Martin periodinane gave
aldehyde 31. The Horner-Wadsworth-Emmons reac-
tion of 31 with (EtO)2P(O)CH2CHdCHCO2Et afforded
R,β,γ,δ-unsaturated ester in 86% yield, which contained
a small amount (about 5%) of (4Z)-isomer. The minor
(4Z)-isomer can be separated by HPLC at a later stage
in the synthesis.4b,d Finally, hydrolysis of the ethyl
ester group with LiOH in aqueous methanol afforded
C1-C19 segment 9.
In conclusion, we have developed a stereocontrolled
synthesis of the C1-C19 segment 9 of aplyronine A,
featuring an asymmetric NHK coupling reaction be-
tween aldehyde 11 and iodoolefin 12 to construct the
C14-C15 (E)-trisubstituted double bond and the C13
stereocenter in one step. Studies on the synthesis of the
C20-C34 segment 10 and further investigation toward
the second generation total synthesis of aplyronine A
are in progress.
98
100
100
a Conditions A: (1) Dess-Martin periodinane, py, CH2Cl2, 98%, (2)
(R)-CBS catalyst, BH3 SMe2, THF, 89% (>95:5 dr). Conditions B: (1)
p-NO2C6H4CO2H, PPh3, DEAD, THF, 97%, (2) K2CO3, MeOH, 96%.
b Isolated yield calculated from 11. c The ratio was determined by 1H
NMR analysis. d The stereochemistry was confirmed by modified
Mosher’s method.
3
to 4 equiv of CrCl2, 0.1 equiv of NiCl2(dppp), 4 equiv of
proton-sponge, and 4 equiv of ligand 27 without loss of
product yield or stereoselectivity. The two diastereomers
22a and 22b were separated by flash column chromato-
graphy. Paterson and co-workers achieved stereoselective
introduction of the C13 hydroxy group by using CBS
reduction13 of a similar ketone.3b We followed this proce-
dure, and oxidation of C13 epimer 22b with Dess-Martin
periodinane followed by CBS reduction13 afforded the
desired isomer 22a. Alternatively, C13 epimer 22b could
be converted to the desired isomer 22a via a Mitsunobu
reaction14 in good yield.
To convert 22a intoC1-C19 segment 9, wefollowed our
first generation synthetic strategy (Scheme 5). O-Methyla-
tion of the C13 hydroxy group in 22a with NaH/MeI gave
methyl ether 28 in quantitative yield. Treatment of 28 with
aqueous acetic acid in THF afforded diol 29a (88%) along
with alcohol 29b (10%). The C19 hydroxy group in 29a
was reprotected as a TBS ether, and the remaining C7
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research, from the Ministry of Edu-
cation, Culture, Sports, Science and Technology (MEXT),
Japan; by a grant from the Uehara Memorial Foundation;
and by a grant from the Suntory Institute for Bioorganic
Research (SUNBOR GRANT).
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 5551.
(14) Mitsunobu, O. Synthesis 1981, 1.
Org. Lett., Vol. 13, No. 5, 2011
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