Total synthesis of the proposed structure of iriomoteolide-1a

Article abstract of DOI:10.1039/c0cc00628a

The total synthesis of the proposed structure of iriomoteolide-1a has been accomplished via a Yamaguchi esterification and ring closing metathesis sequence between the C(7)-C(23) and newly synthesized Z-alkenoic acid C(1)-C(6) fragments. The spectral data of the synthetic 1, however, is at odds with data reported for the natural product, thus bringing into question the original structural assignment.

Full text of DOI:10.1039/c0cc00628a

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Total synthesis of the proposed structure of iriomoteolide-1aw
Jun Xie, Yuelong Ma and David A Horne*
Received 28th March 2010, Accepted 21st April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c0cc00628a
The total synthesis of the proposed structure of iriomoteolide-1a
has been accomplished via a Yamaguchi esterification and ring
closing metathesis sequence between the C(7)–C(23) and newly
synthesized Z-alkenoic acid C(1)–C(6) fragments. The spectral
data of the synthetic 1, however, is at odds with data reported for
the natural product, thus bringing into question the original
structural assignment.
desired product 9 in 50–60% yield, with some decomposed
material due to instability of the exocyclic methylene-bearing
ketal unit.10 Deprotection of the PMB group afforded
precursor 10, which is primed for ring closing metathesis.
To improve the yield of the above esterification step
and avoid a difficult chromatographic separation from side-
products, an alternative strategy for preparing the penultimate
intermediate 10 was pursued. This approach involved performing
the esterification prior to the hemiketal ring formation.
Starting with the previously synthesized fragment 11,3b
PMB exchange of the TES protecting group was successfully
achieved in three steps to afford vinyl iodide 14.11 Suzuki–
Miyaura coupling12 between 14 and 153b produced C(7)–C(23)
fragment 16 in good yield. Selective deprotection of the TES
protecting group afforded alcohol 17 for Yamaguchi esterifi-
cation. As anticipated, the yield of esterification between 17
and acid 3 jumped to 93%, avoiding decomposition of the
sensitive hemiketal functionality experienced in the conversion
of 2 to 9. Removal of the two Si protecting groups with TBAF
produced 19 (Scheme 3).
In 2007, Tsuda’s group isolated a potent cytotoxic 20-membered
ring macrolide iriomoteolide-1a1 (1) from the Amphidinium sp.
strain HYA024. The structure elucidation was mainly based
on 2D-NMR spectroscopy and mass spectral analysis. Because
iriomoteolide-1a possesses extremely potent biological activity
against human B lymphocyte DG-75 cells and Epstein-Barr
virus-infected human B lymphocytes (Raji cells), the total
synthesis of this cytotoxic 20-membered ring macrolide is
being pursued by a number of different groups. Thus far, the
total synthesis of iriomoteolide-1a has not been reported, but
several laboratories have completed the synthesis of various
advanced fragments.2,3
All that remained in the completion of the total synthesis of
1 (Scheme 4) was two key synthetic manoeuvres: hemiketal
ring formation and ring closure. Diol 19 was oxidized to
b,g-unsaturated ketone 20 with SO3ÁPy. Global deprotection
along with concomitant hemiketal cyclization was observed
upon treatment of 20 with DDQ, to afford intermediate 10 in
67% yield. The C(13) stereochemistry of ketal 10 was
Herein, we report the total synthesis of the proposed
structure of iriomoteolide-1a, which we and others4 inde-
pendently found at odds with the original structural assignment
of the natural product.
The retrosynthetic strategy for iriomoteolide-1a is shown in
Fig. 1. The final assembly of 1 by this route consists of
coupling the previously synthesized hemiketal fragment 23b
with acid fragment C(1)–C(6) 3 via an esterification and ring
closing metathesis.5 Fragment 3 can be prepared from known
diol 46 which harbors the two requisite chiral centers.
The preparation of acid fragment 3 starts from known diol 4
(Scheme 1). Treatment of diol 4 with 4-methoxybenzaldehyde
dimethyl acetal followed by selective reduction with DIBAL-H
afforded primary alcohol 5, which was oxidized to aldehyde
6 with Dess–Martin periodinane.7 Conversion of 6 to propio-
nate 7 was achieved via two steps. Addition of propionate 7
with methyllithium in the presence of copper(I) iodide8 gener-
ated Z-alkenoic ester 8. Ester saponification using 1 M LiOH
in MeOH–THF gave acid fragment 3 in high yield upon acid
work-up.
With secondary alcohol 2 and acid 3 in hand, esterification
was accomplished under Yamaguchi conditions9 (Scheme 2).
Treatment of 3 with 2,4,6-trichlorobenzoyl chloride and Et3N,
followed by addition of DMAP and alcohol 2 generated
Department of Molecular Medicine, Beckman Research Institute at
City of Hope, Duarte, CA 91010, USA. E-mail: dhorne@coh.org
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. See
DOI: 10.1039/c0cc00628a
Fig. 1 Retrosynthetic analysis of iriomoteolide-1a.
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Scheme 1 Synthesis of acid fragment 3.
Scheme 3 Synthesis of 19.
shifts at C(4). The H(4) hydrogen resonates at 3.95 ppm
and the carbon-13 shift occurs at 41.0 ppm for synthetic
iriomoteolide-1a (1) compared to 2.46 ppm and 47.9 ppm
for the natural compound 1, respectively. Attempts to prepare
crystalline derivatives of 1 have not been successful; however,
the significant difference in NMR spectral data brings into
question the original structural assignment of the natural
product. Based on the chemical shift of H(4) in the natural
product, it is likely that the C(2)–C(3) double bond configura-
tion of natural product is E instead of Z. Finally, anticancer
activity for synthetic 1 was examined in two different cell lines
(Raji and A431) and no significant cytotoxicity was observed
at 10 mM concentration.
In summary, the first total synthesis of the proposed struc-
ture of iriomoteolide-1a has been accomplished by applying a
late stage Yamaguchi esterification and ring closing metathesis
reaction. The key advanced ring closing metathesis pre-
cursor, 10, was prepared by two different routes, the latter
of which proved more efficient. At this stage, we do not have
Scheme 2 Synthesis of 10.
confirmed through an observed ROSEY interaction between
H(9) and C(13)–OH. After the successful preparation of 10 by
two different strategies, treatment with 2nd generation
Grubbs’ catalyst13 gave E- and Z-products iriomoteolide-1a
(1) and 21 in 2.5 : 1 ratio, respectively. 1H and 13C NMR
spectral data of synthetic iriomoteolide-1a (1) did not agree
with that reported for the natural material.1,14 While minor
inconsistencies are noted throughout the spectra, the main
discrepancies reside with the proton and carbon chemicals
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Notes and references
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(b) J. Xie, Y. Ma and D. A. Horne, Org. Lett., 2009, 11, 5082.
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National Meeting, San Francisco, CA, United States, March
21–25, 2010, ORGN-123; (b) this work was initially presented at
the 2010 ACS Meeting. J. Xie, Y. Ma and D. A. Horne, Abstracts
of Papers, 239th ACS National Meeting, San Francisco, CA,
United States, March 21–25, 2010, ORGN-131.
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9 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi,
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10 Only a trace amount of the product was generated on applying other
conditions such as EDCI, MNBA (2-methyl-6-nitrobenzoic anhydride).
11 (a) B. M. Trost, J. Waser and A. Meyer, J. Am. Chem. Soc., 2007,
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Scheme 4 Completion of the total synthesis of 1.
an alternative structure for iriomoteolide-1a. Efforts along
these lines are currently in-progress.
Support from Chugai Pharmaceutical Co. and the Caltech/
City of Hope Medical Research Fund is gratefully acknow-
ledged. Y. M. is supported by an Irell and Manella Graduate
School Merit Fellowship. The authors thank Professor Jiong
Yang for kindly sharing his results on iriomoteolide-1a and
Brian Stoltz for helpful discussions.
13 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett.,
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Res., 2001, 34, 18.
14 A complete listing of 1H and 13C NMR spectral data for natural
and synthetic iriomoteolide-1a is provided in the ESI w.
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4772 | Chem. Commun., 2010, 46, 4770–4772