Asymmetric synthesis of the C(7)-C(23) fragment of lriomoteolide-1a

Article abstract of DOI:10.1021/ol902110a

An efficient synthesis of the C(7)-C(23) fragment 2 of iriomoteolide-1a (1) has been accomplished via a S-alkyl Suzuki-Miyaura crosscoupling reaction followed by deprotection and cyclization to form the cyclic hemiketal core.

Full text of DOI:10.1021/ol902110a

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5082-5084
Asymmetric Synthesis of the C(7)-C(23)
Fragment of Iriomoteolide-1a
Jun Xie, Yuelong Ma, and David A Horne*
Department of Molecular Medicine, Beckman Research Institute at City of Hope,
Duarte, California 91010
dhorne@coh.org
Received September 11, 2009
ABSTRACT
An efficient synthesis of the C(7)-C(23) fragment 2 of iriomoteolide-1a (1) has been accomplished via a B-alkyl Suzuki-Miyaura cross-
coupling reaction followed by deprotection and cyclization to form the cyclic hemiketal core.
Iriomoteolide-1a (1) is a potent cytotoxic 20-membered ring
macrolide isolated from the Amphidinium sp. strain HYA024.
The structure of 1 was elucidated by Tsuda’s group in 2007.1
IC50 values for 1 against human B lymphocyte DG-75 cells
and Epstein-Barr virus infected human B lymphocytes (Raji
cells) are an impressive 2 and 3 ng/mL, repectively.
Structurally, iriomoteolide-1a contains several unique struc-
tural features. Among them is the cyclic hemiketal core that
bears an exocyclic methylene unit. Appended to this core is
the C(14)-C(23) fragment that is composed of a chiral
tertiary allylic alcohol side chain. This side chain is further
asymmetrically juxtaposed with two different sets of methyl
and alcohol groups. Herein, we describe an efficient asym-
metric approach to construct the entire C(7)-C(23) fragment
of iriomoteolide-1a, which includes the cyclic hemiketal core.
Thus far, the total synthesis of irimoteolide-1a has not been
reported, but several laboratories have completed the syn-
thesis of various fragments. Yang’s group2a and Ghosh’s
group2b have reported the synthesis of fragment C(1)-C(12)
of iriomoteolide-1a. Recently, our group2c described the
synthesis of the hemiketal core of iriomoteolide-1a. Finally,
(1) 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.
(2) (a) Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4645. (b) Ghosh,
Figure 1. Retrosythetic analysis of iriomoteolide-1a.
A. K.; Yuan, H. Tetrahedron Lett. 2009, 50, 1416. (c) Xie, J.; Horne, D. A.
Tetrahedron Lett. 2009, 50, 4485. (d) Chin, Y. J.; Wang, S. Y.; Loh, T. P.
Org. Lett. 2009, 11, 3674.
10.1021/ol902110a CCC: $40.75
Published on Web 10/02/2009
 2009 American Chemical Society

Scheme 1
.
Synthesis of 4
Scheme 2. Synthesis of 20
Starting from (3S)-methyl hydroxybutyrate, allylation
provided 5 in good yield with high dr.4 Reduction of 5 with
LiAlH4 followed by treatment with 4-methoxybenzaldehyde
dimethyl acetal afforded acetal 6. Selective reduction with
DIBAL-H generated primary alcohol 7, which was converted
to 8 via mesylation and reduction. Ozonolysis of the terminal
alkene provided aldehyde 9. In the presence of 10 and (c-
Hex)2BOTf the anti-aldol product, 11, was obtained in
excellent yield and good dr.5 The newly formed secondary
alcohol was protected as its TES ether. DIBAL-H reduction
of 12 yielded the corrseponding primary alcohol, but because
of difficulties in separation of the desired product from the
chiral auxiliary, the crude mixture was treated with excess
TsCl. This afforded tosylate 13 in pure form and excellent
yield as well as recovery of the chiral auxiliary after
purification by chromatography. Displacement of tosylate 13
with iodide under Finkelstein conditions afforded the
Suzuki-Miyaura coupling partner, 4.
Loh’s group2d recently reported the synthesis of the
C(13)-C(23) fragment.
Our attention next turned to the preparation of Suzuki-
Miyaura coupling partner 3, which began with aldehyde 14.2c
Homologation of 14 with Bestmann-Ohira reagent 156
produced alkyne 16. Hydrohalogenation7 of 16 by sequential
treatment with tributyltin hydride in the presence of Pd-
The retrosynthetic strategy for iriomoteolide-1a is shown
in Figure 1. The final assembly of 1 consists of combining
fragment C(1)-C(6) to the relatively large C(7)-C(23)
fragment 2. The C(7)-C(23) fragment can be further
dissected into smaller subunits 3 and 4, which can be joined
by a B-alkyl Suzuki-Miyaura cross-coupling reaction.3 Vinyl
and alkyl iodides 3 and 4 are approached using Sakurai and
anti-aldol reactions, respectively.
(4) (a) Zuger, M.; Weller, T.; seebach, D. HelV. Chim. Acta 1980, 63,
2005. (b) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269.
(c) Kraft, P.; Tochtermann, W. Tetrahedron 1995, 51, 10875.
(5) (a) Abiko, A.; Liu, J. F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586. (b) Inoue, T.; Liu, J. F.; Buske, D. C.; Abiko, A. J. Org. Chem.
2002, 67, 5250.
(3) (a) Suzuki, A.; Miyaura, N. Chem. ReV. 1995, 95, 2457. (b) Chemler,
S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4544.
(6) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Muller, S.; Liepold,
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(7) Olpp, T.; Bru¨ckner, R. Angew. Chem., Int. Ed. 2005, 44, 1553.
Org. Lett., Vol. 11, No. 21, 2009
5083

obtained in decent yield and 4:1 dr. The configuration of
the newly formed chiral center was not determined at this
time; however, a chelation-controlled addition product is
anticipated. Note that the chirality at this center is lost in
subsequent steps via oxidation to the ketone functionality.
To prevent migration of the TES group in 22 during the
Suzuki-Miyaura coupling, the alcohol moiety was protected
as the corresponding acetate to furnish 3 in high overall
efficiency.
Scheme 3. Synthesis of 2
With the two Suzuki-Miyaura coupling fragments in
hand, vinyl iodide 3 and alkyl iodide 4 underwent smooth
coupling10 in excellent yield to afford the linear C(7)-C(23)
fragment 23 of iriomoteolide-1a. Upon LiAlH4 cleavage of
the acetate functionality of 23, concomitant deprotection of
the vicinal tertiary TES group was observed, producing diol
24 in excellent yield. The secondary TES group was
untouched during this process. Interestingly, this sequence
may have general implications for the selective removal of
TES groups over others that are not vicinal to acetates.
Oxidation of diol 23 produced ꢀ,γ-unsaturated ketone 25.
Following conditions previously developed by our lab for
cyclization to the hemiketal unit,2c treatment of 25 with
HF·pyridine produced 2. Under these conditions, double bond
migration of the ꢀ,γ-unsaturated ketone to an R,ꢀ-unsaturated
system was not observed.
In summary, an asymmetric synthesis of the C(7)-C(23)
fragment of iriomoteolide-1a has been achieved in a relatively
efficient manner using a B-alkyl Suzuki-Miyaura cross-
coupling approach. This is the most advanced intermediate
en route to the natural product to date. Pivotal to the synthesis
is aldehyde 20, which bears the requisite tertiary chiral center
and vinyl iodide group and serves as a versatile intermediate
to which the remaining structural components can be
assembled in a bidirectional manner. The viability of a late
stage hemiketal formation has also been demonstrated. With
the construction of fragment 2, efforts toward the completion
of the natural product are currently ongoing.
Acknowledgment. Support from Chugai Pharmaceutical
Co. and the Caltech/City of Hope Medical Research Fund
is gratefully acknowledged. We thank the Irell and Manella
Graduate School of Biological Sciences at City of Hope for
a merit fellowship to Y.M. and Professor Brian Stoltz of the
California Institute of Technology.
(PPh3)4 followed by iodination afforded E-vinyl iodide 17.
Conversion of acetal 17 into bisTES ether 19 allowed for
selective deprotection of the primary TES group and
subsequent oxidation8 to yield aldehyde 20. This versatile
intermediate respresents a key structural component to which
the remainder of the fragment can be linked in a bidirectional
manner.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Sakurai reaction9 between aldehyde 20 and allylsilane 212c
was initially attempted with BF3·OEt2. Although these
conditions were successfully adopted in our previous model
system, only a trace amount of desired product 22 was
observed. Fortunately, when SnCl4 was used, product 22 was
OL902110A
(8) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(9) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295.
(10) (a) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885. (b)
Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67, 2751.
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Org. Lett., Vol. 11, No. 21, 2009