Synthesis of the C1-C12 fragment of iriomoteolide 1a by sequential catalytic asymmetric vinylogous aldol reactions

Article abstract of DOI:10.1021/ol801940r

(Chemical Equation Presented) An efficient synthesis of the C1-C12 fragment of iriomoteolide 1a has been accomplished via sequential application of two catalytic, asymmetric, vinylogous aldol reactions: a catalytic vinylogous aldol reaction was used to enantioselectively introduce the C5-C8 segment, and a second catalytic vinylogous aldol reaction was used to install the remaining two stereocenters and a stereodefined alkene in the form of an α,β- unsaturated δ-lactone in one step.

Full text of DOI:10.1021/ol801940r

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4645-4648
Synthesis of the C1-C12 Fragment of
Iriomoteolide 1a by Sequential Catalytic
Asymmetric Vinylogous Aldol Reactions
Lijing Fang, Haoran Xue, and Jiong Yang*
Department of Chemistry, Texas A&M UniVersity, College Station, Texas 77842-3092
yang@mail.chem.tamu.edu
Received August 19, 2008
ABSTRACT
An efficient synthesis of the C1-C12 fragment of iriomoteolide 1a has been accomplished via sequential application of two catalytic, asymmetric,
vinylogous aldol reactions: a catalytic vinylogous aldol reaction was used to enantioselectively introduce the C5-C8 segment, and a second
catalytic vinylogous aldol reaction was used to install the remaining two stereocenters and a stereodefined alkene in the form of an r,ꢀ-
unsaturated δ-lactone in one step.
Marine dinoflagellates of the genus Amphidinium produce
a variety of structurally unique cyclic and acyclic polyketide
natural products.1 One class are macrolides, collectively
designated as amphidinolides. They are characterized by
highly oxygenated macrolactones of various ring sizes and
side chains of different lengths and substitutions. The
potent cytotoxicity and the unique molecular structure of
amphidinolides attracted the attention of synthetic chemists
and the syntheses of several of these macrolides have been
reported.2 Continued research of Amphidinium species in
the laboratory of Tsuda led to the isolation of three related
macrolides that were previously unknown.3 These 20-
membered macrolides were named iriomoteolides, pre-
sumably because the macrolide-producing strain (HYA024)
was collected off the Iriomote Island of Japan. Iriomo-
teolide 1a was shown to be potently cytotoxic to human
BlymphocyteDG-75cells(IC50 2ng/mL)andEpstein-Barr
virus infected human B lymphocyte Raji cells (IC50 3 ng/
mL).3b We recently initiated a research program aimed at
synthesizing and functionally characterizing natural prod-
(1) (a) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451. (b)
Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(2) For some examples since 2006, see: (a) Lu, L.; Zhang, W.; Carter,
R. J. Am. Chem. Soc. 2008, 130, 7253. (b) Fu¨rstner, A.; Bouchez, L. C.;
Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.; Beaufils, F.; Laurich,
D.; Tamiya, M. Angew. Chem., Int. Ed. 2007, 46, 9265. (c) Fu¨rstner, A.;
Larionov, O.; Fluegge, S. Angew. Chem., Int. Ed. 2007, 46, 5545. (d) Jin,
J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9, 2585. (e) Va,
P.; Roush, W. R. Tetrahedron 2007, 63, 5768. (f) Kim, C. H.; An, H. J.;
Shin, W. K.; Yu, W.; Woo, S. K.; Jung, S. K.; Lee, E. Angew. Chem., Int.
Ed. 2006, 45, 8019. (g) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128,
15960. (h) Fu¨rstner, A.; Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006,
128, 9194. (i) Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem. 2006,
71, 4625. (j) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085.
(3) (a) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.; Fukushi, E.;
Kawabata, J.; Ozawa, T.; Masuda, A. J. Nat. Prod. 2007, 70, 1661. (b)
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.
10.1021/ol801940r CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society

ucts that may be biologically useful. Iriomoteolide 1a (1)
is one of the molecules of interest because of its unique
molecular structure, potent cytotoxicity, and unknown
mode of action.4
Scheme 1. Synthesis of 6
We planned to develop a convergent and flexible route
that would allow efficient preparation of iriomoteolide 1a
and its analogues for biological studies. As shown in
Figure 1, synthesis of the six-membered cyclic hemiketal
to double bond migration to give rise to the thermodynami-
cally more stable R,ꢀ-unsaturated aldehydes. Indeed, oxida-
tion of 56 under a variety of conditions (Jone’s, PDC, Swern,
IBX, etc.) generated R,ꢀ-unsaturated aldehyde 7 as the only
product. While the combination of CrO3 and pyridine7 turned
out to be marginally useful and gave rise to a mixture of 6
and 7 (∼3:1, 70% overall), we decided to search for an
alternative route because of the low efficiencies involved in
both the preparation of 5 and the oxidation step. We resorted
to oxidative cleavage of the vicinal diol derived from 86 by
LiAlH4 reduction to synthesize 6. Oxidative cleavage of the
diol with NaIO4 again gave rise to a mixture of 6 and 7 (∼1:
2) under standard conditions.8 Fortunately, we discovered
during reaction optimization that the double bond migration
can be suppressed by addition of 0.4 equiv of acetic acid,
and the ꢀ,γ-unsaturated aldehyde 6 was isolated as the only
product under these conditions. Aldehyde 6 can be stored at
-20 °C for at least four months without significant rear-
rangement or decomposition.
With aldehyde 6 in hand, we sought to use a catalytic,
enantioselective, vinylogous aldol reaction to efficiently
install the C5-C8 fragment.9 We were pleased to find
that the coupling of 6 and the ethyl crotonate-derived silyl
dienolate 9 was effected under the Lewis base catalyzed,
Lewis acid mediated conditions developed by Denmark
with S,S-bisphosphoramide I as a chiral ligand (Scheme
2).10 The coupled product 10 was generated in 72% yield
with >95% enantiomeric excess. The absolute configu-
ration of the newly generated C9 stereocenter was assigned
as S by analogy to that reported for this catalytic system.10
The secondary hydroxyl group in 10 was protected as the
p-methoxybenzyl ether, and the resulting ester 11 was converted
to aldehyde 12 by DIBAL-H reduction and PCC oxidation.
Figure 1. Retrosynthetic analysis.
would employ a late-stage intramolecular nucleophilic
cyclization of an allylmetal species derived from allyl
chloride 2.5 The macrocycle of 2 in turn can be prepared
by sequential inter- and intramolecular esterifications of
two subunits (3 and 4) of comparable complexity. We
report herein the successful synthesis of 4 using a strategy
based on sequential application of catalytic asymmetric
vinylogous aldol reactions.
The synthesis started from preparation of aldehyde 6
(Scheme 1). Aldehydes with ꢀ,γ-unsaturation are susceptible
(6) (a) Mikami, K.; Ohmura, H.; Yamanaka, M. J. Org. Chem. 2002,
68, 1081. (b) Mikami, K.; Shimizu, M.; Nakai, T. J. Org. Chem. 1991, 56,
2952.
(7) Sanchez, C. C.; Keck, G. E. Org. Lett. 2005, 7, 3053.
(8) Wee, A. G.; Slobodian, J. Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley and Sons: New York, NY, 1995;
Vol. 7, pp 4613-4616.
(4) Amphidinolide H, a member of this class of natural products, has
been shown to target Actin: (a) Saito, S.-Y.; Feng, J.; Kira, A.; Kobayashi,
J.; Ohizumi, Y. Biochem. Biophys. Res. Commun. 2004, 320, 961. (b) Usui,
T.; Kazami, S.; Dohmae, N.; Mashimo, Y.; Kondo, H.; Tsuda, M.; Terasaki,
A. G.; Ohashi, K.; Kobayashi, J.; Osada, H. Chem. Biol. 2004, 11, 1269.
However, its molecular structure is very different from that of iriomoteolide
1a.
(9) (a) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew.
Chem., Int. Ed. 2005, 44, 4682. (b) Casiraghi, G.; Zanardi, F. Chem. ReV.
2000, 100, 1929.
(10) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
47, 1560. (b) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D.
J. Am. Chem. Soc. 2005, 127, 3774. (c) Denmark, S. E.; Beutner, G. L.
J. Am. Chem. Soc. 2003, 125, 7800.
(5) For examples: (a) Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 9,
1951. (b) Smith, A. B., III; Razler, T. M.; Meis, R. M.; Pettit, G. R. Org.
Lett. 2006, 8, 797.
4646
Org. Lett., Vol. 10, No. 20, 2008

Scheme 2. Synthesis of 12
Scheme 3. Second Vinylogous Aldol Reaction
silyl dienolate 15.12 The R,ꢀ-unsaturated δ-lactone 16 was
isolated as a ∼5:1 mixture with its 4S,5S diastereomer. It
was converted to 14 by 1,4-addition with Me2CuLi and
PhSeCl mediated dehydrogenation to introduce the C3
methyl group. Consistent with previous reports, formation
of diastereomeric mixtures of linear coupling products is the
reaction pathway that is responsible for most of the side
products in both of these vinylogous aldol reactions.12
The TBS protection of 14 was removed by HF·py, and
the resulting allylic alcohol was converted to chloride 17 by
standard conditions (Scheme 4). Finally, basic hydrolysis of
17 and selective silylation of the C5 hydroxyl group by
TBSOTf allowed preparation of 4 in 71% yield.
With efficient access to 12 secured, we turned our attention
to the assembly of the remaining part of 4. We envisioned R,ꢀ-
unsaturated δ-lactone 14 as a convenient intermediate since it
houses all the necessary structural elements in the form of a
multisubstituted lactone. A variety of methods have been
reported for the stereoselective synthesis of R,ꢀ-unsaturated
δ-lactones.11 However, they all require the use of a stoichio-
metric amount of chiral auxiliaries and/or multiple steps. We
were attracted to reports by Campagne that catalytic vinylogous
aldol coupling of γ-substituted silyl dienolates with aldehydes
led to enantioselective formation of trans-disubstituted R,ꢀ-
unsaturated δ-lactones in the presence of Carreira’s catalyst.12,13
The possibility of applying this transformation to introduce
the remaining part of 4 in one step was too tantalizing to
ignore. However, we were not without concern since ethyl
silyl dienolate 13,14 which was required for the synthesis of
14, was C3 substituted, and the influence of this methyl
substitution over the coupling reaction was unknown. Our
experiments showed that vinylogous aldol coupling between
12 and 13 did occur, and a mixture of 14 and its 4S,5S
diastereomer (∼1.3:1) was generated in a yield of 55-60%
(Scheme 3). Unfortunately, the diastereoselectivity of this
coupling could not be improved despite extensive experi-
mentation. A solution was eventually found that involved
vinylogous aldol coupling between aldehyde 12 and ethyl
In summary, an efficient approach for the synthesis of the
C1-C12 fragment of iriomoteolide 1a has been developed. All
stereocenters of this fragment were constructed by catalytic
asymmetric reactions involving reagent control. A catalytic
vinylogous aldol reaction was used to introduce the C5-C8
Scheme 4. Synthesis of 4
(11) (a) Boucard, V.; Broustal, G.; Campagne, J. M. Eur. J. Org. Chem.
2007, 225. (b) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron
2007, 63, 2929.
(12) (a) Baza´n-Tejeda, E.; Bluet, G.; Broustal, G.; Campagne, J.-M.
Chem. Eur. J. 2006, 12, 8358. (b) Bluet, G.; Ba´zan-Tejeda, B.; Campagne,
J.-M. Org. Lett. 2001, 3, 3807
.
(13) (a) Pagenkopf, B. L.; Kru¨ger, J. K.; Stojanovic, A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 3124. (b) Kru¨ger, J.; Carreira, E. M. J. Am.
Chem. Soc. 1998, 120, 837
(14) Cameron, D. W.; Looney, M. G.; Pattermann, J. A. Tetrahedron
Lett. 1995, 36, 7555.
.
Org. Lett., Vol. 10, No. 20, 2008
4647

fragment enantioselectively. A second catalytic vinylogous aldol
reaction was used to install the remaining two stereocenters and
a stereodefined alkene in the form of an R,ꢀ-unsaturated
δ-lactone in one step. The synthesis of building block 3 and its
coupling with 4 to synthesize iriomoteolide 1a is in progress
and will be reported in due course.
thank Dr. Shane Tichy, Laboratory for Biological Mass
Spectrometry (TAMU), for mass spectral analyses. We thank
Professor Daniel Romo of Texas A&M University for helpful
discussions.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
Texas A&M University and The Welch Foundation. We
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Org. Lett., Vol. 10, No. 20, 2008