Total syntheses of amphidinolides B, G, and H

Article abstract of DOI:10.1002/anie.201204992

Not one, not two, but three: Total syntheses of amphidinolides B, G, and H, which exhibit strong, nanogram-scale cytotoxicity against various tumor cell lines, have been executed. The synthetic strategy relied on implementation of a diene construction protocol and a diastereoselective aldol process. The 26- and 27-membered macrocyclic lactone rings were efficiently constructed by using ring-closing metathesis (RCM). Copyright

Full text of DOI:10.1002/anie.201204992

Angewandte
Chemie
DOI: 10.1002/anie.201204992
Natural Products
Total Syntheses of Amphidinolides B, G, and H**
Akihiro Hara, Ryo Morimoto, Yuki Iwasaki, Tsuyoshi Saitoh, Yuichi Ishikawa, and
Shigeru Nishiyama*
Beginning in 1986, investigations by Kobayashi and co-
workers led to the isolation of a series of amphidinolide
natural products which possess complex macrolide structures.
These substances were found to display several interesting
biological effects on tumor cell lines.[1] In particular, amphi-
dinolides B,[2] G,[3] and H[3] (1–3; Figure 1) exhibited strong,
Fꢀrstner et al. in 2007 resulted in the total synthesis of
amphidinolides G and H (2 and 3).[7] Synthesis of amphidi-
nolide B (1) was successively achieved by Carter and co-
workers[8] in 2008, and Fꢀrstner et al.[9] in 2009.
In the investigation described below, we have devised and
executed the total syntheses of 1–3 by utilizing sequences
which relied on the implementation of a diene construction
protocol developed in our laboratory,[5 g] and a diastereose-
lective aldol process. The synthetic strategy used for 1 is
shown in Scheme 1. We envisioned that the 26-membered
macrolide in 1 would be constructed by using ring-closing
Figure 1. Structures of amphidinolides B (1), G (2), and H (3).
nanogram range cytotoxicity against L1210 murine lym-
phoma and KB human epidermoid carcinoma, and 3 was
observed to stimulate actin polymerization by covalently
bonding to the actin cytoskeleton.[4] From a structural per-
spective, the amphidinolides 1–3 contain 26- and 27-mem-
bered macrolide systems incorporating allylic epoxide and s-
cis-diene moieties. Along with the presence of five hydroxy
groups and nine stereogenic centers, the structural features of
these substances present a considerable challenge to the
development of efficient routes for their preparation, partic-
ularly from the perspective of stereochemical control and
reaction conditions which address the sensitivity of key
functional groups to basic conditions.
Scheme 1. Retrosynthetic analysis of amphidinolide B (1).
Owing to their interesting biological properties and
intriguing structural motifs, the amphidinolides have attracted
the attention of synthetic chemists.[5,6] Among many synthetic
studies targeted at members of this family, work from
metathesis (RCM)[10] following condensation of the alcohol 4
with carboxylic acid 5. In addition, the plan was to install the
allylic epoxide unit at a late stage of the sequence because of
its anticipated fragile nature. Moreover, the protected b-
hydroxyketone moiety in 4 could be generated by condensa-
tion of the aldehyde 6 and ketone 7 with subsequent
protection.
In earlier synthetic studies focusing on the amphidinoli-
des,[5s,7] chelation-controlled, aldol processes were employed
to construct fragments containing the desired C18 stereo-
chemistry. Although approaches for stereoselective synthesis
of the b-hydroxyketones in these targets that did not depend
on chelation effects remained challenging, they had the
advantage of avoiding the need for complicated protecting-
group regimes.[11] Consequently, we decided to construct the
key fragment without using chelation control in the aldol
process.[12] The approach utilizes the aldehyde 6, which would
be efficiently synthesized from the aldehyde 8 and alkyne 9 by
[*] A. Hara, R. Morimoto, Y. Iwasaki, Dr. T. Saitoh, Dr. Y. Ishikawa,
Prof. Dr. S. Nishiyama
Department of Chemistry, Faculty of Science and Technology
Keio University
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522 (Japan)
E-mail: nisiyama@chem.keio.ac.jp
[**] This work was financially supported by The Science Research
Promotion Fund from The Promotion and Mutual Aid Corporation
for Private Schools of Japan from MEXT. A.H. was indebted to the
Sasagawa Foundation. We thank Prof. Dr. J. Kobayashi and Prof. Dr.
T. Kubota (University of Hokkaido) for a gift of their spectral data.
We are also grateful to T. Wakamatsu and K. Kariya for technical
assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204992.
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using the diene construction protocol we have previously
described (Scheme 1).[5g] The viability of this convergent and
flexible strategy was demonstrated by its application to
syntheses of 1–3.
The route for the synthesis of 1 commenced with
preparation of the alkyne 9 (Scheme 2). Treatment of the
treatment of 9 with nBuLi, was reacted with 8 to furnish an
alcohol which was then subjected to TPAP oxidation[14] to
produce the ketone 13 in 81% yield (2 steps). Treatment of 13
with the Gilman reagent led to formation of the desired
E enone (81%, E/Z = 9:1), which was then converted into the
diene 14 by Wittig olefination.[5g] Removal of the TES group
in 14 and subsequent Dess–Martin oxidation[16] afforded the
key intermediate 6.
The ketone 7, utilized in our convergent approach
(Scheme 1), was prepared from the known nitrile 15[5f]
(Scheme 4). DIBAL-H reduction of the nitrile produced the
Scheme 2. Synthesis of alkyne 9. Reagents and conditions: a) PivCl,
pyridine, RT, 95%; b) TBSOTf, 2,6-lutidine, RT, 98%; c) DIBAL-H,
CH2Cl2, ꢀ788C, 95%; d) SO3-pyridine, DIPEA, DMSO, CH2Cl2, RT,
98%; e) CBr4, PPh3, Et3N, toluene, RT, 98%; f) EtMgBr, THF, 08C,
96%; g) CAN, MeCN, H2O, RT, 94%; h) TESCl, imidazole, CH2Cl2, RT,
95%. CAN=cerium ammonium nitrate, DIBAL-H=diisobutylalumi-
num hydride, DIPEA=diisopropylethylamine, DMSO=dimethyl sulf-
oxide, MP=methoxyphenyl, Piv=pivaloyl, TBS=tert-butyldimethylsilyl,
TES=triethylsilyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran,
Ts =para-toluenesulfonyl.
Scheme 4. Syntheses of carboxylic acid 5 and ketone 7. Reagents and
conditions: a) DIBAL-H, CH2Cl2, ꢀ788C; b) Ph3PCHCO2Me, CH2Cl2,
RT, 76% (2 steps); c) AD-mix-a, MeSO2NH2, tBuOH, H2O, 08C, 90%;
d) TBSOTf, 2,6-lutidine, CH2Cl2, RT, 88%; e) DIBAL-H, CH2Cl2, ꢀ788C,
91%; f) SO3-pyridine, DIPEA, DMSO, CH2Cl2, RT; g) MeLi, Et2O,
ꢀ788C; h) SO3-pyridine, DIPEA, DMSO, CH2Cl2, RT, 75% (3 steps);
i) PCC, CH2Cl2, RT; j) Ph3PC(CH3)CO2Me, benzene, RT, 34% (2 steps);
k) NaOH, THF, H2O, 808C, 93%. AD=asymmetric dihydroxylation,
PMB=para-methoxybenzyl, PCC=pyridinium chlorochromate.
known diol 10[5m] with PivCl and Et3N, followed by protection
of the resulting tertiary monoalcohol as a TBS ether, and
reductive removal of the pivalate ester provided the alcohol
11. Parikh–Doering oxidation[13] of 11 and subsequent reac-
tion with PPh3 and CBr4 gave the corresponding 1,1-dibromo
alkene, which was treated with EtMgBr[14] to afford the
alkyne 12 in 92% yield (3 steps). Removal of the methoxy-
phenyl group in 12 using CAN gave the corresponding
alcohol, which upon protection as a TES ether afforded the
desired alkyne 9.
corresponding aldehyde, which was transformed into the
unsaturated ester 16 by using a Wittig olefination. Sharpless
asymmetric dihydroxylation[17] of 16 proceeded smoothly to
afford the corresponding diol as a single diastereomer, which
was then converted into the ester 17 (79%, 2 steps) using
TBSOTf and 2,6-lutidine. The DIBAL-H reduction of 17,
followed by oxidation and addition of MeLi furnished the
corresponding secondary alcohol, which was oxidatively
transformed into the ketone 7. The carboxylic acid 5, the
final component needed in the convergent approach, was
prepared from 4-penten-1-ol by a PCC oxidation,[18] Wittig
olefination, and hydrolysis sequence.
An acetylide coupling reaction between the previously
prepared aldehyde 8[6i] and 9 was employed to construct the
aldehyde 6 (Scheme 3). The acetylide anion, generated by
With the requisite fragments in hand, the key aldol
reaction between 6 and 7, which were produced in six and
twelve steps, respectively, from readily available derivatives,
was investigated (Table 1).[12] An initial reaction using LDA
as the base afforded the desired aldol 18 in 43% yield, but the
C18 stereochemistry (R configuration) of the resulting b-
hydroxyketone was different than was expected (entry 1). In
an extensive exploration, we observed that reaction at ꢀ208C
led to formation of the aldol product in a 72% yield with an
optimal C18 S/R diastereomer ratio of 2.5:1 (entry 6).
Scheme 3. Synthesis of aldehyde 6. Reagents and conditions: a) nBuLi,
THF, ꢀ78!08C, 96%; b) TPAP, NMO, M.S. 4ꢀ, CH2Cl2, RT, 84%;
c) MeLi, CuI, THF, Et2O, ꢀ78!-308C, 90% (E/Z=9:1); d) nBuLi,
Ph3PCH3Br, THF, 08C!RT, 91%; e) PPTS, CH2Cl2, MeOH, 08C, 93%;
f) DMP, CH2Cl2, pyridine, RT, 96%. DMP=Dess–Martin periodinane,
M.S.=molecular sieves, NMO=N-methylmorpholine N-oxide,
Ph=phenyl, PPTS=pyridinium para-toluenesulfonate, TPAP=tetra-
propylammonium perruthenate.
The next phase involved construction of the macrocyclic
lactone system in the target (Scheme 5). The aldol product
(S)-18 was converted into the corresponding TBS ether, from
which the TBDPS group was selectively removed using
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TBAF/AcOH/H2O in THF and DMF.[19] This process gen-
Table 1: Optimization of the reaction conditions for the aldol reaction
between 6 and 7.
erated the alcohol 19, which was then subjected to Sharpless
asymmetric epoxidation[20] to afford the corresponding epoxy
alcohol as a single diastereomer. A Dess–Martin oxidation
and Wittig olefination sequence efficiently provided the
allylic epoxide 20 which was subjected to selective removal
of the PMB group. Yamaguchi esterification[21] of the result-
ing alcohol with 5 gave the ester 21 in 81% yield (2 steps).
RCM utilizing Grubbsꢁ second-generation catalyst[22] trans-
formed 21 into the target 26-membered 22 (81%) without
producing the undesired Z isomer. Finally, cleavage of the
TBS group in 22 produced 1, which was determined to be
identical in all respects (1H NMR and 13C NMR spectroscopy,
IR, optical rotation, and mass spectrometry)[2b] to the natural
product.
Our attention then turned to the synthesis of amphidino-
lides G (2) and H (3). In an initial effort, we observed that the
intermediate 26 could be generated by an aldol reaction
between the aldehyde 23 and ketone 24[6i] (Scheme 6).
However, an ensuing investigation revealed that the aldol
product 27 could be produced in a higher yield and
Entry
Base
T [8C][a]
Yield [%][b]
S/R[c]
1
2
3
4
5
6
LDA
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ40
ꢀ20
43
1:5.4
[d]
[d]
NaHMDS
KHMDS
LiHMDS
LiHMDS
LiHMDS
–
–
–
–
[d]
[d]
81
63
72
1:4.1
1.3:1
2.5:1
[a] Aldehyde 6 was added to a solution of the enolate of ketone 7 in THF
at the indicated temperature. The enolate was obtained by treatment of 7
with a base at room temperature. [b] Combined yield of (S)-18 and (R)-
1
18. [c] The ratio was determined by H NMR spectroscopy. [d] No
reaction. KHMDS=potassium hexamethyldisilazide, LDA=lithium di-
isopropyl amide, LiHMDS=lithium hexamethyldisilazide, NaHMDS=
sodium hexamethyldisilazide.
Scheme 5. Total synthesis of amphidinolide B (1). Reagents and con-
ditions: a) TBSOTf, 2,6-lutidine, CH2Cl2, RT, 98%; (b) TBAF, AcOH,
H2O, DMF, THF, RT, 79% (89% conv.); c) Ti(OiPr)4, TBHP, (+)-DIPT,
M.S. 4ꢀ, CH2Cl2, ꢀ208C, 84% (92% conv.); d) DMP, pyridine, 08C,
97%; e) NaHMDS, Ph3PCH3Br, CH2Cl2, 08C!RT, 98%; f) DDQ,
CH2Cl2, phosphate buffer (pH 7.0), RT, 83%; g) 5, 2,4,6-trichloroben-
zoyl chloride, DMAP, Et3N, 08C, 98%; h) Grubbs’ 2nd generation
catalyst, benzene, RT, 81%. i) TASF, THF, DMF, H2O, RT, 86%.
DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone, DIPT=diisopropyl
tartrate, DMAP=N,N-dimethyl-4-aminopyridine, DMF=N,N-dimethyl-
formamide, TASF=tris(dimethylamino)sulfonium difluorotrimethylsili-
cate, TBAF=tetra-n-butylammonium fluoride, TBHP=tert-butyl hydro-
peroxide.
Scheme 6. Total synthesis of amphidinolide G (2). Reagents and
conditions: a) 25, LiHMDS, THF, ꢀ108C, 87% (S/R=1.7:1);
b) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ108C, 98%; c) PPTS, CH2Cl2, MeOH,
08C, 78%; d) 5, 2,4,6-trichlorobenzoyl chloride, DMAP, Et3N, RT, 98%;
e) TBAF, AcOH, H2O, DMF, THF, RT, 82% (87% conv.); f) Ti(OiPr)4,
TBHP, (+)-DET, M.S. 4ꢀ, CH2Cl2, ꢀ208C, 54% (75% conv.); g) DMP,
pyridine, 08C, 91%; h) NaHMDS, Ph3PCH3Br, CH2Cl2, 08C, 80%;
i) Grubbs’ 2nd generation catalyst, benzene, RT, 95%. j) TASF, THF,
DMF, H2O, RT, 72%. DET=diethyl tartrate.
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Ishiyama, T. Takemura, M. Tsuda, J. Kobayashi, Tetrahedron
1999, 55, 4583 – 4594; l) T. K. Chakraborty, D. Thippewamy,
Synlett 1999, 150 – 152; m) H. Ishiyama, T. Takemura, M. Tsuda,
J. Kobayashi, J. Chem. Soc. Perkin Trans. 1 1999, 1163 – 1166;
n) D. H. Lee, M. D. Rho, Tetrahedron Lett. 2000, 41, 2573 – 2576;
o) M. B. Cid, G. Pattenden, Tetrahedron Lett. 2000, 41, 7373 –
7378; p) G. Pattenden, D. J. Sinclair, J. Organomet. Chem. 2002,
653, 261 – 268; q) W. Zhang, R. G. Carter, A. F. T. Yokochi, J.
Org. Chem. 2004, 69, 2569 – 2572; r) A. K. Mandal, J. S. Schnee-
kloth, Jr., C. M. Crews, Org. Lett. 2005, 7, 3645 – 3648; s) W.
Zhang, R. G. Carter, Org. Lett. 2005, 7, 4209 – 4212; t) A. K.
Mandal, J. S. Schneekloth, Jr., C. M. Crews, Org. Lett. 2005, 7,
5347 – 5348; u) A. Gopalarathnam, S. G. Nelson, Org. Lett. 2006,
8, 7 – 10; v) A. K. Mandal, J. S. Schneekloth, Jr., K. Kuramochi,
C. M. Crews, Org. Lett. 2006, 8, 427 – 430; w) M. Sidera, A. M.
Costa, J. Vilarrasa, Org. Lett. 2011, 13, 4934 – 4937.
stereoselectively when the TES-protected ketone 25 was
employed as the coupling partner. After protection of 27 as
a TBS ether, selective deprotection with PPTS afforded the
alcohol 28. Esterification of 28 with 5 by using the Yamaguchi
protocol took place smoothly to give nearly quantitatively the
corresponding ester, which was treated with TBAF/AcOH/
H2O to afford the alcohol 29. Essentially the same synthetic
procedure used to transform 21 into 1 was used for the allylic
epoxide 30 to afford 2, which was shown to have spectroscopic
properties that were identical to those of the natural product.
Because the transformation from 2 into 3 under mildly basic
conditions has been reported by Kobayashi and co-work-
ers,[3b] the successful synthesis of 2 corresponds to a formal
synthesis of 3.
[6] Synthetic studies targeted at amphidinolides G and H: a) T. K.
Chakraborty, V. R. Suresh, Tetrahedron Lett. 1998, 39, 9109 –
9112; b) T. K. Chakraborty, V. R. Suresh, Tetrahedron Lett. 1998,
39, 7775 – 7778; c) F. P. Liesener, M. Kalesse, Synlett 2005, 2236 –
2238; d) F. P. Liesener, U. Jannsen, M. Kalesse, Synthesis 2006,
2590 – 2602; e) P. Formentꢂn, J. Murga, M. Carda, J. A. Marco,
Tetrahedron: Asymmetry 2006, 17, 2938 – 2942; f) A. F. Petri, J. S.
Schneekloth, Jr., A. K. Mandal, C. M. Crews, Org. Lett. 2007, 9,
3001 – 3004; g) L. Deng, Z. Ma, Y. Zhang, G. Zhao, Synlett 2007,
87 – 90; h) L. Deng, Z. Ma, G. Zhao, Synlett 2008, 728 – 732; i) A.
Hara, R. Morimoto, Y. Ishikawa, S. Nishiyama, Org. Lett. 2011,
13, 4036 – 4039.
The investigation described above has resulted in the
syntheses of the amphidinolides B (1; 6.9% overall yield in 21
steps), G (2; 3.2% overall yield in 23 steps) and H (3) based
on routes that employ a previously developed diene con-
struction protocol and a diastereoselective aldol reaction in
the key steps. Notable features of the strategy are its high
degrees of flexibility and convergency, both of which should
make it applicable to the preparation of a broad range of
other amphidinolides and related substances. Additional
studies of approaches to the syntheses of amphidinolide
congeners will be reported in due course.
[7] A. Fꢀrstner, L. C. Bouchez, J.-A. Funel, V. Liepins, F.-H. Porꢃe,
R. Gilmour, F. Beaufils, D. Laurich, M. Tamiya, Angew. Chem.
2007, 119, 9425 – 9430; Angew. Chem. Int. Ed. 2007, 46, 9265 –
9270.
Received: June 26, 2012
Published online: && &&, &&&&
[8] L. Lu, W. Zhang, R. G. Carter, J. Am. Chem. Soc. 2008, 130,
7253 – 7255.
[9] A. Fꢀrstner, L. C. Bouchez, L. Morency, J.-A. Funel, V. Liepins,
F.-H. Porꢃe, R. Gilmour, D. Laurich, F. Beaufils, M. Tamiya,
Chem. Eur. J. 2009, 15, 3983 – 4010.
Keywords: aldol reaction · antitumor agents · natural products ·
synthetic methods · total synthesis
.
[10] The macrolactone ring was constructed by the same RCM
approach as those used by Fꢀrstner et al. (Ref. [7, 9]).
[11] The O-PMB (Refs. [5r] and [7]) and O-MOM (Refs. [6g and h])
substituents at C21 are known to induce the formation of
diastereomers, having the S configuration at C18, as a result of
a strong 1,4-anti chelation effect. However, removal of these
groups at the final stage of the synthesis employing standard
reaction conditions was found to be troublesome owing to the
labile character of the s-cis diene and allylic epoxide moieties.
[12] Although Carter and co-workers described the same nonchela-
tion and temperature control strategy (Ref. [8]), our substrates 6
and 7 provided effective results to construct C18 with an S
configuration.
[13] J. P. Parikh, W. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505 –
5507.
[14] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769 – 3772.
[15] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639 – 666.
[16] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 – 4156.
[17] E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroder, K. B.
Sharpless, J. Am. Chem. Soc. 1988, 110, 1968 – 1970.
[18] J. E. Baldwin, R. C. Burrell, J. Org. Chem. 2002, 67, 3249 – 3256.
[19] S. Higashibayashi, K. Shinko, T. Ishizu, K. Hashimoto, H.
Shirahama, M. Nakata, Synlett 2000, 1306 – 1308.
[1] a) J. Kobayashi, M. Tsuda, Nat. Prod. Rep. 2004, 21, 77 – 93; b) J.
Kobayashi, T. Kubota, J. Nat. Prod. 2007, 70, 451 – 460; c) J.
Kobayashi, J. Antibiot. 2008, 61, 271 – 284.
[2] Amphidinolide B (or B1):a) M. Ishibashi, Y. Ohizumi, M.
Hamashima, H. Nakamura, Y. Hirata, T. Sasaki, J. Kobayashi,
J. Chem. Soc. Chem. Commun. 1987, 1127 – 1129; b) M. Ishiba-
shi, H. Ishiyama, J. Kobayashi, Tetrahedron Lett. 1994, 35, 8241 –
8242; c) M. Tsuda, T. Kubota, Y. Sakuma, J. Kobayashi, Chem.
Pharm. Bull. 2001, 49, 1366 – 1367; (Amphdinolides B1 – B3)
d) I. Bauer, L. Maranda, Y. Shimizu, R. W. Peterson, L. Cornell,
J. R. Steiner, J. Clardy, J. Am. Chem. Soc. 1994, 116, 2657 – 2658.
[3] Amphidinolides G (or G1), H (or H1): a) J. Kobayashi, H.
Shigemori, M. Ishibashi, T. Yamasu, H. Hirota, T. Sasaki, J. Org.
Chem. 1991, 56, 5221 – 5224; b) J. Kobayashi, K. Shimbo, M.
Sato, M. Shiro, M. Tsuda, Org. Lett. 2000, 2, 2805 – 2807.
[4] T. Usui, S. Kazami, N. Dohmae, Y. Mashimo, H. Kondo, M.
Tsuda, A. G. Terasaki, K. Ohashi, J. Kobayashi, H. Osada,
Chem. Biol. 2004, 11, 1269 – 1277.
[5] Synthetic studies of amphidinolide B: a) T. K. Chakraborty, D.
Thippewamy, V. R. Suresh, S. Jayaprakash, Chem. Lett. 1997,
563 – 564; b) T. K. Chakraborty, V. R. Suresh, Chem. Lett. 1997,
565 – 566; c) D. H. Lee, S.-W. Lee, Tetrahedron Lett. 1997, 38,
7909 – 7910; d) K. Ohi, K. Shima, K. Hamada, Y. Saito, N.
Yamada, S. Ohba, S. Nishiyama, Bull. Chem. Soc. Jpn. 1998, 71,
2433 – 2440; e) J. Kobayashi, A. Hatakeyama, M. Tsuda, Tetra-
hedron 1998, 54, 697 – 704; f) M. B. Cid, G. Pattenden, Synlett
1998, 540 – 542; g) K. Ohi, S. Nishiyama, Synlett 1999, 571 – 572;
h) K. Ohi, S. Nishiyama, Synlett 1999, 573 – 575; i) H. M. Eng,
D. C. Myles, Tetrahedron Lett. 1999, 40, 2275 – 2278; j) H. M.
Eng, D. C. Myles, Tetrahedron Lett. 1999, 40, 2279 – 2282; k) H.
[20] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974 –
5976.
[21] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 – 1993.
[22] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 956.
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Chemie
Communications
Natural Products
Not one, not two, but three: Total syn-
theses of amphidinolides B, G, and H,
which exhibit strong, nanogram-scale
cytotoxicity against various tumor cell
lines, have been executed. The synthetic
strategy relied on implementation of
a diene construction protocol and a dia-
stereoselective aldol process. The 26- and
27-membered macrocyclic lactone rings
were efficiently constructed by using ring-
closing metathesis (RCM).
A. Hara, R. Morimoto, Y. Iwasaki,
T. Saitoh, Y. Ishikawa,
S. Nishiyama*
&&&& — &&&&
Total Syntheses of Amphidinolides B, G,
and H
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!