Enantioselective syntheses of the proposed structures of cytotoxic macrolides iriomoteolide-1a and -1b

Article abstract of DOI:10.1021/ol101105v

(Figure Presented) Enantioselective total syntheses of the proposed structures of macrolide cytotoxic agents iriomoteolide-1a and -1b have been accomplished. The synthesis was carried out in a convergent and stereoselective manner. However, the present wo

Full text of DOI:10.1021/ol101105v

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3120-3123
Enantioselective Syntheses of the
Proposed Structures of Cytotoxic
Macrolides Iriomoteolide-1a and -1b
Arun K. Ghosh* and Hao Yuan
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity, 560 OVal
DriVe, West Lafayette, Indiana 47907
akghosh@purdue.edu
Received May 13, 2010
ABSTRACT
Enantioselective total syntheses of the proposed structures of macrolide cytotoxic agents iriomoteolide-1a and -1b have been accomplished.
The synthesis was carried out in a convergent and stereoselective manner. However, the present work suggests that the reported structures
have been assigned incorrectly. The synthesis features Julia-Kocienski olefination, Sharpless asymmetric epoxidation, Brown asymmetric
crotylboration, a Sakurai reaction, an aldol reaction, and enzymatic resolution as the key steps.
Marine dinoflagellates are a rich source of diverse macrolide
natural products known as amphidinolides.1 In 2007, Tsuda
and co-workers isolated iriomoteolide-1a (1), a 20-membered
macrolide from a benthic dinoflagellate Amphidinium sp.
(strain HYA024) collected off Iriomote Island in Japan.2 It
exhibited potent cytotoxicity against human B lymphocyte
DG-75 cells with an IC50 value of 2 ng/mL. It also showed
excellent cytotoxicity against Epstein-Barr virus (EBV)-
infected human lymphocyte Raji cells (IC50 ) 3 ng/mL).
The structure of iriomoteolide-1a (1, Figure 1) was elucidated
on the basis of extensive 2D-NMR and mass spectroscopic
studies. The relative and absolute configurations were
assigned using NMR through conformational analyses and
derivatization of 1 with Mosher’s reagent.2
products laulimalide and peloruside A and B.3,4 We have
established that both laulimalide and pelorusides A and B
are novel microtubule-stabilizing agents that have shown
synergistic effects with Taxol.5 Furthermore, they arrest the
cell cycle at the G2/M phase, but they do not bind to the
taxoid site of ꢀ-tubulin.6 Interestingly, iriomoteolide-1a (1)
possesses common structural features inherent to both
laulimalide and pelorusides. Thus far, the biological mech-
anism of action of iriomoteolide-1a has not been elucidated.
(3) (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122, 11027.
(b) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973–
8982
.
(4) (a) Ghosh, A. K.; Xu, X.; Kim, J.-H.; Xu, C.-X. Org. Lett. 2008,
10, 1001–1004. (b) Singh, A. J.; Xu, C.-X.; Xu, X.; West, L. M.; Wilmes,
A.; Chan, A.; Hamel, E.; Miller, J. H.; Northcote, P. T.; Ghosh, A. K. J.
Org. Chem. 2010, 72, 2–10
.
As part of our continuing interests in the chemistry and
biology of macrolide antitumor agents, we recently reported
the synthesis and biological evaluation of marine natural
(5) (a) Pryor, D. E.; O’Brate, A.; Bilcer, G.; Diaz, J. F.; Wang, Y.;
Kabaki, M.; Jung, M. K.; Andreu, J. M.; Ghosh, A. K.; Giannakakou, P.;
Hamel, E. Biochemistry 2002, 41, 9109–9115. (b) Gaitanos, T. N.; Buey,
R. M.; Diaz, J. F.; Northcote, P. T.; Teesdale-Spittle, P.; Andreu, J. M.;
Miller, J. H. Cancer Res. 2004, 64, 5063–5067.
(1) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460.
(2) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.; Kobayashi, J.;
Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A.; Kitaya, Y.; Omasa, K.
J. Org. Chem. 2007, 72, 4469–4474.
(6) (a) Gapud, E. J.; Bai, R.; Ghosh, A. K.; Hamel, E. Mol. Pharmacol.
2004, 66, 113–121. (b) Hamel, E.; Day, B. W.; Miller, J. H.; Jung, M. K.;
Northcote, P. T.; Ghosh, A. K.; Curan, D. P.; Cushman, M.; Nicolaou, K. C.;
Paterson, I.; Sorenson, E. J. Mol. Pharmacol. 2006, 70, 1555–1564.
10.1021/ol101105v  2010 American Chemical Society
Published on Web 06/18/2010

Scheme 1. Synthesis of C1-C15 Subunit 2
Julia-Kocienski olefination9 of aldehyde 2 and sulfone 3
followed by a Yamaguchi macrolactonization10 to form the
20-membered macrolide. The C1-C15 subunit 2 can be
obtained by another Julia-Kocienski olefination9 of sulfone
4 and aldehyde 5. Sulfone 4 would be derived from a Sakurai
reaction11 of allyl silane 6 and aldehyde 7. Both aldehyde 5
and sulfide 6 were synthesized by us previously.7a The
synthesis of C16-C23 fragment 3 can be carried out by
hydroboration of olefin 8 followed by conversion of the
resulting alcohol to sulfone 3. Alcohol 8 would be obtained
by an asymmetric crotylboration reaction on an aldehyde
derived from 9.12 Asymmetric crotylboration of acetaldehyde
will provide (2S,3S)-3-methyl-4-penten-2-ol (9).12
Figure 1. Retrosynthetic analysis of iriomoteolide-1a.
The unique structural features, potent cytotoxic properties
and lack of detailed biological studies related to mechanism
of action, attracted our interest in the synthesis and biological
studies of iriomoteolide-1a. So far, a number of synthetic
studies of fragments have been reported,7 and a total
synthesis of the proposed structure has been disclosed
recently.8 Herein, we report our preliminary investigation
leading to a convergent and highly stereoselective synthesis
of the proposed structure of iriomoteolide-1a. The present
work suggested an incorrect assignment of the reported
structure of iriomoteolide-1a.
As outlined in Scheme 1, Sharpless asymmetric epoxida-
tion13 of 10 provided optically active epoxide 11. Epoxide
ring scission utilizing LAH produced the corresponding diol,
which was oxidized by a Parikh-Doering oxidation14 to
furnish aldehyde 7 which was used for the next step without
At the outset, we planned to develop a highly convergent
and asymmetric synthesis route to provide access to a variety
of designed structural variants for biological studies. As
shown in Figure 1, our convergent strategy relies upon a
(9) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, P. J.
Synlett 1998, 26–28. (b) Blakemore, P. R. J. Chem. Soc. Perkin Trans. 1
2002, 2563–2585.
(10) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993. (b) For a recent review of
macrolactonization, see: Parenty, A.; Moreau, X.; Campagne, J. M. Chem.
ReV. 2006, 106, 911–939.
(7) (a) Ghosh, A. K.; Yuan, H. Tetrahedron Lett. 2009, 50, 1416–1418.
(b) Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4645–4648. (c) Chin,
Y.; Wang, S.; Loh, T. Org. Lett. 2009, 11, 3674–3676. (d) Xie, J.; Horne,
D. A. Tetrahedron Lett. 2009, 50, 4485–4487. (e) Xie, J.; Ma, Y.; Horne,
D. A. Org. Lett. 2009, 11, 5082–5084. (f) Wang, S.; Chin, Y.; Loh, T.
Synthesis 2009, 3557–3564. (g) Ye, Z.; Deng, L.; Qian, S.; Zhao, G. Synlett
2009, 2469–2472. (h) Paterson, I.; Rubenbauer, P. Synlett 2010, 571–574.
(8) Xie, J.; Ma, Y.; Horne, D. A. Chem. Commun. 2010, advanced
article.
(11) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295–1298.
(12) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293–294.
(13) (a) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922–
1925. (b) Tanner, D.; Somfai, P. Tetrahedron 1986, 42, 5985–5990.
(14) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
Org. Lett., Vol. 12, No. 14, 2010
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Scheme 2
.
Synthesis of C16-C23 Sulfone 3
Scheme 3. Synthesis of Macrolactone 20
further purification. Sakurai reaction11 between aldehyde 7
and allyl silane 6 in the presence of TiCl4 and triethylamine
provided the corresponding alcohol in 83% yield (8:1 dr).
A chelation-controlled addition15 with the R-hydroxyl group
resulted in high diastereoselectivity, and the absolute con-
figuration at C13 was identified as R by observed NOESY as
shown in the corresponding acetonide 12. However, this
center will be removed in a late stage via oxidation to the
corresponding ketone. Protection of the resulting diol with
2-methoxypropene in the presence of a catalytic amount of
PPTS afforded 12. It was oxidized by ammonium molybdate
and hydrogen peroxide to afford sulfone 4.
The synthesis of aldehyde 5 was carried out as described
previously.7a A Julia-Kocienski olefination9 between alde-
hyde 5 and sulfone 4 utilizing KHMDS furnished the E-olefin
13 as a single isomer in 83% yield. Removal of the benzyl
group with lithium and liquid ammonia in the presence of
allyl ethyl ether followed by Dess-Martin oxidation17
produced the C1-C15 fragment, aldehyde 2.
The synthesis of sulfone 3 is shown in Scheme 2. Brown’s
crotylboration reaction using cis-2-butene, (+)-B-methoxy-
diisopinocampheylborane, and acetaldehyde gave syn-alcohol
9.12 Protection of the alcohol with tert-butyldimethylsilyl
chloride and imidazole followed by hydroboration of the
olefin afforded alcohol 14. Swern oxidation furnished the
aldehyde 15. A second Brown crotylboration utilizing (-)-
B-methoxydiisopinocampheylborane and trans-2-butene led
to anti-alcohol 16 as a mixture (10:1) of diastereomers (by
1H NMR analysis). Protection of alcohol 16 with 4-meth-
oxybenzyl chloride followed by hydroboration with 9-BBN
afforded the alcohol 17. A Mitsunobu reaction between
alcohol 17 and 1-phenyl-1H-tetrazole-5-thiol followed by
oxidation of the corresponding sulfide with ammonium
molybdate and hydrogen peroxide led to C16-C23 fragment,
sulfone 3.
As shown in Scheme 3, a Julia-Kocienski olefination9
between aldehyde 2 and sulfone 3 using KHMDS in 1,2-
dimethoxyethane furnished olefin 18. Treatment of 18 with
DDQ in DCM and pH 7 buffer followed by ammonium
fluoride in methanol produced diol 19. Selective oxidation
of the allyl alcohol with MnO2 followed by oxidation of the
resulting aldehyde with sodium chlorite led to the corre-
sponding seco-acid. Yamaguchi macrolactonization condi-
tions10 produced the macrolactone 20.
The completion of the synthesis of the proposed structure
of iriomoteolide-1a is shown in Scheme 4. Removal of silyl
ether and acetonide protecting groups was carried out by
sequential treatment with HF·Py and aqueous acetic acid to
provide 21. Removal of the MOM-protecting group was
effected by exposure to bromocatechol borane.16 The free
alcohols were selectively protected with triethylsilyl chloride
in the presence of DMAP to afford diol 22. Oxidation of
(15) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 1879–
1882. (b) Review: Reetz, M. T. Angew. Chem. Int. Ed 1984, 23, 556–569.
(16) Boeckman, R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411–
1414.
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Org. Lett., Vol. 12, No. 14, 2010

in a mixture (3:1) of the proposed structure of iriomoteolide-
1a (1) and iriomoteolide-1b (23).18 Both products were
separated by silica gel chromatography. The H NMR and
Scheme 4. Synthesis of the Proposed Structure of Iriomoteolides
1
13C NMR spectral data of synthetic iriomoteolide-1a (1) or
synthetic iriomoteolide-1b (23), however, did not match with
the data reported for natural iriomoteolide-1a and -1b. Our
syntheses of both iriomoteolide-1a (structure 1) and iriomo-
teolide-1b (structure 23) now suggested that the structures
of both natural iriomoteolide-1a and iriomoteolide-1b have
been assigned incorrectly. While there are many minor
differences between the two spectra, the major discrepancy
1
of H and 13C shifts is at C4 (3.98 ppm and 40.6 ppm for
synthetic iriomoteolide-1a compared to 2.46 ppm and 47.9
ppm for the natural product) which suggests an epimer at
the C4 position. Also a distinction of chemical shifts at C24
(1.96 and 20.8 ppm for synthetic 1 compared to 2.12 and
23.8 ppm for natural 1) reveals that the enoate double bond
configuration might be E instead of Z. The detailed com-
parison of NMR data including 2D-NMR of iriomoteolide-
1a and histogram charts of δ 13C shifts are shown in the
Supporting Information.
In summary, we have achieved the enantioselective
syntheses of the proposed structures of iriomoteolide-1a and
iriomoteolide-1b. The synthesis featured a very effective
Sakurai reaction and Julia-Kocienski olefinations. Other key
reactions included Sharpless asymmetric epoxidation and
Brown asymmetric crotylboration reactions. The synthesis
will also provide convenient access to a variety of derivatives.
Further investigations related to structural assignments as
well as biological studies are in progress.
Acknowledgment. This research is supported in part by
the National Institutes of Health. We thank Mr. David D.
Anderson (Purdue University) for his assistance with NOESY
studies.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
alcohol 22 with Dess-Martin periodinane17 followed by
removal of the silyl ethers with HF·Py complex7d resulted
OL101105V
(17) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
(18) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.; Fukushi, E.;
Kawabata, J.; Ozawa, T.; Maduda, A. J. Nat. Prod. 2007, 70, 1661–1663.
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