Total synthesis of (-)-exiguolide

Article abstract of DOI:10.1021/ol902778y

[Chemical equation presented] Total synthesis of (-)-exiguolide, the natural enantiomer, has been accomplished for the first time. The bis(tetrahydropyran) subunit was efficiently synthesized via consecutive olefin cross-metathesis/intramolecular oxa-conj

Full text of DOI:10.1021/ol902778y

ORGANIC
LETTERS
2010
Vol. 12, No. 3
584-587
Total Synthesis of (-)-Exiguolide
Haruhiko Fuwa* and Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku
UniVersity, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
hfuwa@bios.tohoku.ac.jp
Received December 2, 2009
ABSTRACT
Total synthesis of (-)-exiguolide, the natural enantiomer, has been accomplished for the first time. The bis(tetrahydropyran) subunit was
efficiently synthesized via consecutive olefin cross-metathesis/intramolecular oxa-conjugate addition/reductive etherification. Construction of
the 20-membered macrocycle was achieved by Yamaguchi macrolactonization. Stereoselective introduction of the (E,Z,E)-triene side chain via
Suzuki-Miyaura coupling completed the total synthesis.
(-)-Exiguolide (1, Figure 1) was isolated from the methanol
extract of the marine sponge Geodia exigua Thiele (order
Astrophorida, family Geodiidae) by Ohta, Ikegami, and co-
workers.1 The gross structure including relative stereochem-
istry was determined by the combination of extensive 2D
NMR analysis, conformational analysis based on NOESY
3
correlations, and JH,H values and the J-based configuration
analysis.2 Subsequently, Lee et al. reported a total synthesis
of the unnatural enantiomer of 1, which established the
absolute configuration of this natural product.3 It is reported
that (-)-1 specifically inhibits fertilization of sea urchin
(Hemicentrotus pulcherrimus) gametes but not embryogen-
esis of the fertilized egg. The complex 20-membered
macrolactone core embedded with the methylene bis-THP
(THP ) tetrahydropyran) subunit, a common structural motif
that can be found in marine antineoplastic agents bryostatins,4
Figure 1. Structure of (-)-exiguolide (1).
is not only synthetically challenging but also biologically
intriguing as (-)-1 might represent a structurally simplified,
naturally occurring bryostatin analogue.5 We describe herein
our total synthesis of (-)-exiguolide, the natural enantiomer.
(1) Ohta, S.; Uy, M. M.; Yanai, M.; Ohta, E.; Hirata, T.; Ikegami, S.
Tetrahedron Lett. 2006, 47, 1957.
(2) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866.
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Ed. 2008, 47, 1733.
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E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846.
10.1021/ol902778y  2010 American Chemical Society
Published on Web 01/11/2010

addition.10 Enone 8 was expected to be prepared from 9 and
10 via olefin cross-metathesis (CM).11 Notably, our strategy
takes advantage of the high chemoselectivity of CM and the
inherent reactivity of the functional groups present in 9 and
10.
Scheme 1. Synthesis Plan toward (-)-Exiguolide (1)
Scheme 2. Synthesis of Alcohol 9
The synthesis of alcohol 9 is illustrated in Scheme 2.
Protection of 11 (>95% ee by Mosher ester analysis)12 as
its MPM ether followed by oxidative cleavage of the double
bond delivered aldehyde 12 in 69% yield (two steps).
Chelation-controlled allylation of 12 afforded homoallylic
alcohol 13 in 84% yield as a single diastereomer (dr > 20:
1). Silylation of 13 was followed by deprotection of the MPM
group to give alcohol 9 in 97% yield (two steps).
Scheme 3. Synthesis of Enone 10
Our synthetic plan toward 1 is summarized in Scheme 1.
Stereoselective construction of the (E,Z,E)-triene side chain
would be viable by Suzuki-Miyaura coupling6 of (Z)-vinyl
boronate 2 and (E)-vinyl iodide 3. The 20-membered
macrolactone core of 3 would be accessible through mac-
rolactonization of hydroxy acid 4. The C16-C177 double
bond of 4 was envisaged to be formed by Julia-Kocienski
coupling8 of aldehyde 5 and sulfone 6. Lee et al. have
synthesized the methylene bis-THP subunit of (+)-1 in a
linear manner via intramolecular Prins and radical cycliza-
tions.3 In contrast, we planned an efficient and convergent
entry to 5 from the readily available acyclic fragments 9 and
10 via the intermediacy of silyloxy ketone 7 and enone 8.
Thus, bicyclic ether 5 could be delivered from silyloxy
ketone 7 via reductive etherification,9 and the latter could
originate from enone 8 by intramolecular oxa-conjugate
(5) For a review, see: Cossy, J. C. R. Chimie 2008, 11, 1477.
(6) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457. (b) Suzuki, A. Chem. Commun. 2005, 4759.
(7) The carbon numbering in this paper corresponds to that of the natural
product.
The synthesis of enone 10 commenced with Brown asym-
metric allylation13 of the known aldehyde 1414 (Scheme 3).
(8) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26. (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(c) Aïssa, C. Eur. J. Org. Chem. 2009, 1831.
(10) For a recent review, see: Larrosa, I.; Romea, P.; Urpi, F.
Tetrahedron 2008, 64, 2683.
(9) Lewis, D. L.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976.
(11) For a recent review, see: Hoveyda, A. H.; Zhugralin, A. R. Nature
2007, 450, 243.
Org. Lett., Vol. 12, No. 3, 2010
585

Subsequent olefin cross-metathesis with methyl acrylate using
Grubbs second-generation catalyst (G-II)15 led to enoate 15
in 72% yield (two steps). After hydrogenation of the double
bond, the resulting ester was transformed to the correspond-
ing Weinreb amide. The remaining hydroxy group was
masked as its TES ether to give 16 in 92% yield (three steps).
Exposure of 16 to vinyllithium generated in situ from
tetra(vinyl)tin and MeLi furnished enone 10 in 96% yield.
Scheme 5. Synthesis of Sulfone 6
Scheme 4. Construction of the bis-THP Subunit 5
alcohol 18,17 available in four steps from (S)-Roche ester,
giving epoxy alcohol 19 in 89% yield (dr > 20:1). Chlorina-
tion of 1918 followed by exposure of the resultant chloroe-
poxide to LDA19 gave propargylic alcohol 20 in 84% yield
(two steps). After conversion of 20 to the corresponding
bromoalkyne, palladium-catalyzed hydrostannylation20 and
subsequent iododestannylation delivered (E)-vinyl iodide 21
in 94% yield (three steps). Protection of 21 as the MPM
ether was followed by desilylation to give alcohol 22 in 71%
yield (two steps). Mitsunobu coupling of 22 with 1-phenyl-
1H-tetrazole-5-thiol and ensuing peroxide treatment afforded
sulfone 6 in 89% yield (two steps).
Completion of the total synthesis of (-)-1 is illustrated in
Scheme 6. Cleavage of the benzyl ether of 17 by hydro-
genolysis gave alcohol 23 in 90% yield after removal of the
minor C9 epimer by flash chromatography on silica gel.
Oxidation of 23 with Dess-Martin periodinane gave alde-
hyde 5 in 97% yield. Julia-Kocienski coupling of an anion
derived in situ from sulfone 6 and aldehyde 5 was examined
under several conditions. This coupling reaction initially
suffered from poor conversion under the standard conditions
(e.g., KHMDS, DME, -55 °C to rt, 18% yield, 35% yield
based on recovered 5, E:Z > 20:1). However, we eventually
found that treatment of sulfone 6 (2.2 equiv) with LHMDS
With the requisite fragments in hand, we proceeded to
build up the methylene bis-THP subunit of 1 (Scheme 4).
First, assembly of the fragments 9 and 10 was accomplished
via CM using 10 mol % of Hoveyda-Grubbs second-
generation catalyst (HG-II)16 in CH2Cl2 at 35 °C, leading
to (E)-enone 8 in 93% yield as a single stereoisomer (E:Z >
20:1). Exposure of 8 to 20 mol % of KOt-Bu in THF at 0
°C smoothly effected intramolecular oxa-conjugate addition
to afford silyloxy ketone 7 in 95% yield as a single
stereoisomer (dr >20:1). The resultant silyloxy ketone 7 was
directly treated with BF3·OEt2 in 1:5 Et3SiH/CH2Cl2 (-60
to -25 °C) to furnish the methylene bis-THP 17 in 98%
yield with an approximately 10:1 diastereoselectivity at the
C9 stereogenic center. At this stage, the newly generated
stereogenic centers were established by NOE experiments
as shown. Thus, the methylene bis-THP subunit of 1 was
successfully constructed in a highly stereocontrolled manner
in only three steps from acyclic fragments 9 and 10.
(18) Nagamitsu, T.; Takano, D.; Seki, M.; Arima, S.; Ohtawa, M.;
j
The synthesis of sulfone 6 (Scheme 5) started with
Sharpless asymmetric epoxidation of the known allylic
Shiomi, K.; Harigaya, Y.; Omura, S. Tetrahedron 2008, 64, 8117.
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1, 953.
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586
Org. Lett., Vol. 12, No. 3, 2010

efficiently. Selective deprotection of the TBDPS group under
basic conditions afforded alcohol 25 in 94% yield. A two-
stage oxidation followed by esterification gave methyl ester
26 in 94% yield for the three steps. Cleavage of the MPM
group and subsequent saponification of the methyl ester21
afforded hydroxy acid 4, which underwent smooth macro-
cyclization under Yamaguchi conditions22 to furnish the 20-
membered lactone 27 in 84% yield (three steps). Deprotection
of the TIPS group of 27 was followed by oxidation of the
resultant alcohol to give ketone 28 in 100% yield (two steps).
The exocyclic enoate functionality was introduced to 28 by
Horner-Wadsworth-Emmons reaction using chiral phos-
phonate 29 developed by Fuji et al.,23 giving a separable
5:1 mixture of stereoisomers favoring the desired (Z)-isomer
3. Finally, stereoselective incorporation of the triene side
chain was realized through Suzuki-Miyaura coupling of 3
with (Z)-vinyl boronate 224 under exceptionally mild condi-
tions (Pd2(dba)3, Ph3As, Ag2O, THF, room temperature),25
leading to (-)-exiguolide (1) in 73% yield. The spectroscopic
data of synthetic 1 (1H and 13C NMR, HRMS, and [R]D)
were in full accordance with those reported.1,3
Scheme 6. Completion of the Total Synthesis of (-)-Exiguolide
In conclusion, the total synthesis of (-)-exiguolide (1),
the naturally occurring enantiomer, was accomplished for
the first time. Our strategy for the construction of the
methylene bis-THP subunit of 1 harnessed the high chemose-
lectivity of olefin metathesis reactions that allowed for direct
utilization of the pre-existing functionalities of 9 and 10 in
subsequent ring-forming events, thereby maximizing the
overall efficiency of the strategy. The sterically encumbered
C16-C17 double bond was constructed in a stereoselective
manner via Julia-Kocienski coupling under the modified
conditions. The 20-membered macrocycle was efficiently
assembled based on Yamaguchi macrolactonization. Finally,
the stereoselective construction of the (E,Z,E)-triene side
chain via Suzuki-Miyaura coupling under exceptionally mild
conditions successfully completed the total synthesis.
Acknowledgment. We thank Professor Shinji Ohta (Na-
gahama Institute of Bio-Science and Technology) for kindly
1
providing us with copies of H and 13C NMR spectra of
natural exiguolide. This work was supported in part by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL902778Y
(2.2 equiv) in THF/HMPA (4:1) at -78 °C followed by
addition of aldehyde 5 and warming the reaction mixture to
room temperature afforded the desired (E)-olefin 24 in 63%
yield (81% yield based on recovered 5, E:Z > 20:1). The
unreacted 5 and excess 6 could be recovered and recycled
(24) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000,
122, 4990.
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T.; Weeber, T. Synlett 1994, 649. (c) Uenishi, J.; Beau, J.-M.; Armstrong,
R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756.
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