Enantioselective synthesis of a diastereomer of iriomoteolide-1a. What is the correct structure of the natural product?

Article abstract of DOI:10.1021/ol1011423

(Figure Presented) An enantioselective approach to a diastereomer of iriomoteolide-1a is described. Highlighted is a SmI₂-mediated intramolecular reductive cyclization approach to complex cyclic hemiketals. An acetylide-chloroformate coupling strategy is also featured. Our results show that the structures of iriomoteolide-1a-1c require careful reassessment.

Full text of DOI:10.1021/ol1011423

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3124-3127
Enantioselective Synthesis of a
Diastereomer of Iriomoteolide-1a. What
Is the Correct Structure of the Natural
Product?
Lijing Fang, Jiong Yang,* and Fei Yang
Department of Chemistry, Texas A&M UniVersity, College Station, Texas 77843-3255
yang@mail.chem.tamu.edu
Received May 18, 2010
ABSTRACT
An enantioselective approach to a diastereomer of iriomoteolide-1a is described. Highlighted is a SmI2-mediated intramolecular reductive
cyclization approach to complex cyclic hemiketals. An acetylide-chloroformate coupling strategy is also featured. Our results show that the
structures of iriomoteolide-1a-1c require careful reassessment.
Amphidinolides are a group of macrolides isolated from
marine dinoflagellates Amphidinium sp.1 In addition to
exhibiting unique molecular structures, many of these natural
products show potent cytotoxicity against human cancer cell
lines. Total syntheses of a number of amphidinolides have
been reported,2 leading to reassignment of the relative and/
or absolute configuration of several members of the group.3
Iriomoteolide-1a-1c are recent additions to this interesting
group of natural products.4 Isolated from a benthic HYA024
strain of Amphidinium sp., iriomoteolide-1a was characterized
as a unique 20-membered macrolide by 1D and 2D NMR
analysis, while iriomoteolide-1b and -1c were described as
isomeric and homologous to iriomoteolide-1a (Figure 1).
Iriomoteolide-1a was reported to be cytotoxic toward human
B lymphocyte DG-75 cells (IC50 2 ng/mL) and Epstein-Barr
virus infected B lymphocyte Raji cells (IC50 3 ng/mL). This
exceptional cytotoxicity rivals that of many well-known
natural anticancer agents in clinical use. The unique molec-
ular structure and potent cytotoxicity of iriomoteolide-1a
attracted the attention of synthetic chemists and a number
of synthetic studies have been reported.5,6 Recently, Horne
and co-workers completed the first synthesis of the originally
proposed structure of iriomoteolide-1a and reported the
inconsistency of its spectra with those of the natural product.7
This prompted us to report our synthetic studies toward
iriomoteolide-1a.
(1) For some recent reviews: (a) Kobayashi, J. J. Antibiot. 2008, 61,
271–284. (b) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460.
(c) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93.
(2) For a list of these total syntheses, see the Supporting Information of
Bates, R. H.; Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 10, 4343–
4346. See also the references cited in refs 5b and 6.
(3) For some examples, see: (a) Lu, L.; Zhang, W.; Carter, R. G. J. Am.
Chem. Soc. 2008, 130, 7253–7255. (b) Ghosh, A. K.; Gong, G. J. Am. Chem.
Soc. 2004, 126, 3704–3705. (c) Trost, B. M.; Harrington, P. E. J. Am. Chem.
Soc. 2004, 126, 5028–5029. (d) Williams, D. R.; Meyer, K. G. J. Am.
Chem. Soc. 2001, 123, 765–766. (e) Williams, D. R.; Myers, D. R.; Mi, L.
Org. Lett. 2000, 2, 945–948.
(4) (a) 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. (b) Tsuda, M.; Oguchi, K.; Iwamoto,
R.; Okamoto, Y.; Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A. J.
Nat. Prod. 2007, 70, 1661–1663.
(5) Part of this work has been presented at the 239th ACS National
Meeting: (a) Yang, J.; Fang, L.; Yang, F. Abstracts of Papers. 239th ACS
National Meeting; Mar 21-25, 2010, San Francisco, CA; American
Chemical Society: Washington, DC, 2010; ORGN-123. (b) Fang, L.; Xue,
H.; Yang, J. Org. Lett. 2008, 10, 4645–4648
.
10.1021/ol1011423  2010 American Chemical Society
Published on Web 06/18/2010

Figure 1. Original iriomoteolide-1a-1c and compound 1.
Figure 2. Synthetic plan.
From the outset, we aimed to develop a flexible synthetic
route that would enable subsequent structure-activity rela-
tionship (SAR) and mode-of-action studies of this potent
cytotoxin. To maximize synthetic convergency, our synthetic
plan relied on a late-stage intramolecular reductive cycliza-
tion of iodoester 2 to introduce the six-membered hemiketal
(Figure 2). We previously reported the synthesis of the
C1-C12 fragment of the originally proposed iriomoteolide-
1a by sequential catalytic asymmetric vinylogous aldol
reactions.5 However, during our studies, it became clear that
the C2-C3 double bond of the natural product should be
revised to 2E instead of the originally proposed 2Z config-
uration.8 Thus, we adjusted our synthetic plan to target the
diastereomeric 2E isomer 1 rather than the originally
proposed iriomoteolide-1a. In the revised synthetic plan,
macrocycle 2 would be prepared by ring-closing metathesis
across the C15-C16 double bond of diene 3, which in turn
would be assembled from building blocks 4-6. Importantly,
it was expected that coupling of terminal alkyne 4 and
chloroformate 5 followed by conjugate addition of the
Gilman reagent would allow stereoselective formation of the
trisubstituted C1-alkenoic ester moiety. The C13-ester of 3
would be prepared by the Mitsunobu reaction of carboxylic
acid 6 and the C9-alcohol derived from 4.
Our synthesis commenced with aldehyde 7, prepared from
ꢀ-methallyl alcohol in eight steps as we had previously
described (Scheme 1).5 In the presence of Pd(OAc)2·PPh3,
the anti-homopropargylic alcohol 8 was prepared from
aldehyde 7 by addition of the triisopropylsilylallenylindium
reagent generated in situ from (S)-4-triisopropylsilyl-3-butyn-
2-yl mesylate.9 Global desilylation of alkyne 8 with TBAF
followed by reprotection of the diol allowed efficient
synthesis of building block 4.
Scheme 1. Synthesis of Building Block 4
Preparation of chloroformate 5 started from the known
alcohol 9 (Scheme 2).10 Silylation of 9 followed by hy-
droboration and Swern oxidation gave aldehyde 10.11 Brown
asymmetric crotylation of 10 and protection of the resulting
secondary hydroxy group as the PMB ether led to alkene
11,10 which was subjected to a three-step homologation
sequence (hydroboration, Swern oxidation, and Wittig ole-
fination) to give homologated alkene 12. The PMB ether 12
was oxidatively hydrolyzed with DDQ, and building block
5 was synthesized by reaction of the secondary alcohol with
triphosgene.12
(6) (a) Ghosh, A. K.; Yuan, H. Tetrahedron Lett. 2009, 50, 1416–1418.
(b) Xie, J.; Horne, D. A. Tetrahedron Lett. 2009, 50, 4485–4487. (c) Chin,
Y.-J.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2009, 11, 3674–3676. (d) Ye, Z.;
Deng, L.; Qian, S.; Zhao, G. Synlett 2009, 2469–2472. (e) Xie, J.; Ma, Y.;
Horne, D. A. Org. Lett. 2009, 11, 5082–5084. (f) Wang, S.-Y.; Chin, Y.-
J.; Loh, T.-P. Synthesis 2009, 3557–3564. (g) Paterson, I.; Rubenbauer, P.
Synlett. 2010, 571–574. (h) Li, S.; Chen, Z.; Xu, Z.; Ye, T. Chem. Commun.
2010, 46, Advance Article, DOI: 10.1039/c0cc00915f.
(7) (a) Xie, J.; Ma, Y.; Horne, D. A. Chem. Commun. 2010, 46, Advance
Article, DOI: 10.1039/c0cc00628a. (b) Xie, J.; Ma, Y.; Horne, D. A.
Abstracts of Papers. 239th ACS National Meeting; March 21-25, 2010,
San Francisco, CA; American Chemical Society: Washington, DC, 2010;
ORGN-131.
With both of the key building blocks in hand, our attention
was turned to their coupling and conversion to the trisub-
stituted 2E-alkenoic ester 14. For this purpose, deprotonation
(8) In ref 4a, the C2-C3 double bond was assigned as Z based on the
chemical shift (δH 2.12, δC 23.8) of Me-24 and the ROESY correlation for
1
H2 (δH 6.02)/Me-24 (δH 2.10) in C6D6. However, the reported H NMR
chemical shift of Me-24 is actually consistent with an E- rather than
Z-alkenoic ester (see ref 13), and we suspect that the aforementioned weak
ROESY correlation is actually due to H2/Me-24 COSY correlation. It is
known that COSY correlations are also present in ROESY spectra. These
correlations are superfluous and should be ignored. (For a reference, see:
Macura, S.; Huang, Y.; Suter, D.; Ernst, R. R. J. Magn. Reson. 1981, 43,
259–281). In addition, we observed a strong ROESY correlation for H-2/
Me-25 in both CDCl3 and C6D6 from the spectra provided in the Supporting
Information of ref 4a. This also strongly supports a 2E-alkenonic ester rather
than the originally assigned 2Z-isomer.
(9) (a) Marshall, J. A. J. Org. Chem. 2007, 72, 8153–8166. (b) Marshall,
J. A.; Eidam, P.; Eidam, H. S. J. Org. Chem. 2006, 71, 4840–4844.
(10) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293–
294. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919–
5923.
(11) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
(12) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888.
Org. Lett., Vol. 12, No. 14, 2010
3125

Scheme 2
.
Synthesis of Building Block 5
Scheme 3. Synthesis of 1
of acetylene 4 with n-BuLi followed by reaction with
chloroformate 5 generated the desired alkynoic ester 13 in
94% yield (Scheme 3). This alkynoic ester could be
conveniently converted to either of the two isomeric trisub-
stituted alkenoic esters by conjugate addition of Me2CuLi.
A Z-configuration of the C2-C3 double bond could be
secured when the conjugate addition was carried out at -20
°C and quenched at low temperature (not shown). The 2E-
trisubstituted alkenoic ester 14 was selectively generated (Z:E
∼ 1:10) when the reaction was carried out in the presence
of TMSCl and the silyl ketene acetal intermediate hydrolyzed
by standard aqueous workup. The assignment of the C2-C3
double-bond geometry was straightforward based on the
1
characteristic chemical shift of Me-24 in the 300 MHz H
NMR spectrum in CDCl3. A δΗ (Me-24) of 2.13 ppm for
14 is consistent with an E-trisubstituted alkenoic ester, while
a δΗ (Me-24) of 1.83 ppm for the other isomer (not shown)
is consistent with a Z-alkenoic ester.13 Mechanistic consid-
erations of the carbocupration reaction, which has been well
studied,14 are also consistent with these assignments. Im-
portantly, the reported δΗ (Me-24) of 2.12 ppm for the
natural product is consistent with that observed for the (2E)-
alkenoic ester 14.
With the C1-trisubstituted alkenoic ester functionality
secured, the C13 ester was introduced by oxidative hydrolysis
of the C9 PMB ether of 14 with DDQ followed by the
Mitsunobu reaction with R-hydroxy acid 6.15,16 The strategic
decision of carrying out macrocyclization of 3 by ring-closing
metathesis was quite demanding.17 It required selective
activation of two of the five double bonds of the cyclization
precursor. Moreover, stereochemical control of the resulting
C15-C16 double bond was also necessary. Thus, we were
gratified to observe that ring-closing metathesis of 3 indeed
provided the macrocyclic bis-lactone 15 in 62% yield with
the second-generation Grubb’s catalyst, with the desired
E-isomer being formed exclusively. To prepare for the
intramolecular reductive cyclization, compound 15 was
converted to allyl iodide 2 by standard functional group
manipulations. Employing the intramolecular reductive cy-
clization conditions recently reported by Keck,18 formation
of the six-membered hemiketal of 17 was successfully
implemented as originally planned by treating the iodoester
2 with SmI2.19 It is noteworthy that the desired reductive
cyclization occurred selectively in the presence of a myriad
of other functional groups. Finally, the hemiketal 1, which
existed as an equilibrating mixture with the ketol form (∼
5:1), was obtained by global desilylation of 17 with TBAF-
(13) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91,
1851–1852.
(14) Nilsson, K.; Andersson, K.; Ullenius, C.; Gerold, A.; Krause, N.
Chem.sEur. J. 1998, 4, 2051, and references cited therein.
(15) For two reviews of the Mitsunobu reaction, see: (a) Mitsunobu, O.
Synthesis 1981, 1–28. (b) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.;
HF-py.20 The H and 13C NMR spectra of 1 were in full
1
agreement with the structure assigned. However, they did
Balaraman, E.; Pavan Kumar, K. V. P. Chem. ReV. 2009, 109, 2551–2651
(16) Zhang, D.; Bleasdale, C.; Golding, B. T.; Watson, W. P. Chem.
Commun. 2000, 1141–1142
.
.
(18) Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 9, 1951–1954.
(19) Preliminary studies using model substrates showed that the tertiary
C14 hydroxy group had to be protected. Fang, L. Yang, J. Unpublished
results.
(20) (a) Gaffney, B. L.; Jones, R. A. Tetrahedron Lett. 1982, 23, 2257–
2260. (b) Coleman, R. S.; Li, J.; Navarro, A. Angew. Chem., Int. Ed. 2001,
40, 1736–1739.
(17) For some reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012–3043. (c) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592–4633. (d) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199–2238. (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490–4527.
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Org. Lett., Vol. 12, No. 14, 2010

not agree with those reported for iriomoteolide-1a. Even
though we were unable to obtain a single crystal of 1 or an
advanced intermediate for X-ray crystallographic analysis,
the stereochemistry of the chiral centers of 1 was indepen-
dently verified by the modified Mosher’s ester method,21
comparison with known compounds, or comparison with
samples prepared by other methods (see the Supporting
Information).
Figure 3. Diastereomers 18 and 19.
Comparison of the 500 MHz 1H and 125 MHz 13C NMR
spectra of 1 with those reported for iriomoteolide-1a suggests
that we have prepared a diastereomer of iriomoteolide-1a,
and it appears that the natural product is epimeric to 1 at
one or more stereocenters.22 Tsuda and co-workers assigned
the plannar structure of iriomoteolide-1a by standard 2D
NMR techniques, while the relative and absolute configura-
tions of its chiral centers were assigned by J-based config-
uration analysis and the modified Mosher’s ester method,
respectively.21,23 The J-based configuration analysis has been
extremely useful for conformational and stereochemical
studies of organic compounds and has been widely used to
elucidate the relative stereochemical relationships of chiral
centers of complex organic compounds. However, we were
puzzled by the configuration analysis of the C4-C5 and
C21-C22 stereocenters in the original report.4a Specifically,
Tsuda and co-workers reported the values of the 13C-1H
coupling constants JC5/H25, JC21/H23, and JC22/H29 as part of
their J-based configuration analysis. However, H23, H25,
and H29 each belongs to a conformationally unbiased methyl
group, and thus, these coupling constants, to the best of our
knowledge, provide no stereochemical information. While
their original intention of measuring those coupling constants
is not clear to us, it appears that the reported J-configuration
analysis is questionable and the original assignment of the
relative stereochemical configurations at C4-C5 and
C21-C22 is not reliable. Since the rest of the chiral centers
of iriomoteolide 1a were to a large part assigned by
correlation with C4-C5 and C21-C22, their assignments
are also questionable.
Even though the stereochemical structure of iriomoteolide-
1a still awaits elucidation, we have developed a concise and
flexible synthetic route for this purpose. It proceeds in 22
steps for the longest linear sequence to arrive at 1, a likely
diastereomer of iriomoteolide-1a. Importantly, our synthetic
route, which relies on reagent control to introduce most of
the chiral centers, is flexible enough to allow systematic
variations of the stereocenters that are required to elucidate
the stereochemical structure of the natural product. High-
lighted is an unprecedented strategic application of SmI2-
mediated intramolecular reductive cyclization to synthesize
complex cyclic hemiketals.24 The synthesis also features an
acetylide-chloroformate coupling strategy which, to the best
of our knowledge, has rarely been applied in such a complex
setting. Our results show that the structure of iriomoteolide-
1a requires careful reassessment. Since the structures of
iriomoteolide-1b and -1c were assigned by analogy to that
of iriomoteolide-1a,4b our results also bring into question
their structures. Our current efforts are focused on applying
this synthetic route to prepare select diastereomers of 1 to
identify the stereochemical structure of the natural product.
3
3
3
Acknowledgment. Financial support was provided by
Texas A&M University and The Welch Foundation (A-
1700). We thank Prof. David Horne of Beckman Research
Institute at City of Hope for sharing his results. We thank
Prof. Daniel Romo of Texas A&M University, Prof. Dirk
Menche of Ruprecht-Karls-Universita¨t Heidelberg, and Prof.
Tadeusz Molinski of University of California, San Diego,
for helpful discussions.
We synthesized additional diastereomers 18 and 19 fol-
lowing similar routes (Figure 3). However, their spectra are
also different from those of the natural product.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4095. (b) Seco, J. M.; Quinoa, E.; Riguera, R. Chem.
ReV. 2004, 104, 17–117.
(22) For two recent reviews for structural misassignment of natural
products, see: (a) Nicolaou, K. C.; Snyder, S. C. Angew. Chem., Int. Ed.
2005, 44, 1012-1044. (b) Maier, M. E. Nat. Prod. Rep. 2009, 26, 1105–
1124.
OL1011423
(23) (a) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866–876. (b) Bifulco, G.;
Dambruoso, P.; Gomez-Paloma, L.; Riccio, R. Chem. ReV. 2007, 107, 3744–
(24) Williams and co-workers recently described a similar intramolecular
Nozaki-Hiyama reductive cyclization of formate esters: Williams, D. R.;
Walsh, M. J.; Miller, N. A. J. Am. Chem. Soc. 2009, 131, 9038–9045.
3779
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