Two concise total syntheses of (-)-bitungolide F

Article abstract of DOI:10.1021/ol101659y

The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6% overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy.

Full text of DOI:10.1021/ol101659y

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4074-4077
Two Concise Total Syntheses of
(-)-Bitungolide F
Abdelatif ElMarrouni, Shyamsunder R. Joolakanti, Aude Colon,
Montserrat Heras,† Stellios Arseniyadis,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
stellios.arseniyadis@espci.fr; janine.cossy@espci.fr
Received July 17, 2010
ABSTRACT
The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent
routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction
in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6%
overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly
enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy.
Natural products that incorporate a γ-ethyl substituted R,ꢀ-
unsaturated δ-lactone moiety such as the leustroducsins,1 the
phoslactomycins,2 and pironetin3 have attracted considerable
attention over the past two decades due to their promising
pharmacological properties. More recently, Tanaka et al.4
isolated a new family of structurally related polyketides from
the Indonesian sponge Theonella cf. swinhoei, bitungolides
A-F, which incorporate, in addition to the 5,6-dihydropyran-
2-one motif, an anti-1,3-diol unit and a diene attached to a
substituted arene (Figure 1).5 These compounds exhibited
cytotoxic effects against 3Y1 rat normal fibroblast cells and
inhibition toward VH1-related (VHR) dual-specificity phos-
phatase, thus becoming attractive targets for both synthetic
and medicinal chemists.
† Department of Chemistry, Faculty of Sciences, University of Girona,
Campus de Montilivi, E-17071 Girona, Spain.
(1) (a) Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka, H.; Torikata,
A.; Inukai, M.; Kaneko, I.; Kagasaki, T.; Sakaida, Y.; Satoh, A.; Shiraishi,
A. J. Antibiot. 1993, 46, 1503–1511. (b) Kohama, T.; Nakamura, T.;
Kinoshita, T.; Kaneko, I.; Shiraishi, A. J. Antibiot. 1993, 46, 1512–1519.
(c) Matsuhashi, H.; Shimada, K. Tetrahedron 2002, 58, 5619–5626.
(2) (a) Fushimi, S.; Nishikawa, S.; Shimazu, A.; Seto, H. J. Antibiot.
1989, 42, 1019–1025. (b) Fushimi, S.; Furihata, K.; Seto, H. J. Antibiot.
1989, 42, 1026–1036. (c) Ozasa, T.; Suzuki, K.; Sasamata, M.; Tanaka,
K.; Kobori, M.; Kadota, S.; Nagai, K.; Saito, T.; Watanabe, S.; Iwanami,
M. J. Antibiot. 1989, 42, 1331–1338. (d) Ozasa, T.; Tanaka, K.; Sasamata,
M.; Kaniwa, H.; Shimizu, M.; Matsumoto, H.; Iwanami, M. J. Antibiot.
1989, 42, 1339–1343. (e) Shibata, T.; Kurihara, S.; Yoda, K.; Haruyama,
H. Tetrahedron 1995, 51, 11999–12012. (f) Sekiyama, Y.; Palaniappan,
N.; Reynolds, K. A.; Osada, H. Tetrahedron 2003, 59, 7465-
7471. (g) Choudhuri, S. D.; Ayers, S.; Soine, W. H.; Reynolds, K. A. J.
Antibiot. 2005, 58, 573–582. (h) Mizuhara, N.; Usuki, Y.; Ogita, M.; Fujita,
K.; Kuroda, M.; Doe, M.; Lio, H.; Tanaka, T. J. Antibiot. 2007, 60, 762–
765.
Figure 1. Structures of natural bitungolides.
As part of our ongoing efforts in developing synthetically
useful methods6-8 and applying them to the synthesis of
structurally intriguing molecules, we became particularly
interested in using a stereoselective boron-mediated pente-
10.1021/ol101659y  2010 American Chemical Society
Published on Web 08/20/2010

Scheme 1. First Strategy for the Synthesis of (-)-Bitungolide F
Scheme 2
.
Synthesis of (-)-Bitungolide F Via an Asymmetric
Evans Alkylation
nylation6,9 as a key step in the synthesis of (-)-bitungolide
F. We therefore embarked in this project with the aim of
developing a highly straightforward and flexible route that
would allow an easy access to the natural product as well as
to various analogues thereof. We report here the results of
our endeavor.
In order to guarantee high efficacy as well as potential
late-stage diversification, our initial strategy relied on four
key reactions: a chiral boron-mediated aldolization to gener-
ate the C10-C11 bond and concomitantly set the C11
stereogenic center, a stereoselective pentenylation to intro-
duce the ethyl side chain at C4, an asymmetric Evans alkyl-
ation to install the C6 stereogenic center, and a ring-closing
metathesis (RCM) to build the lactone ring (Scheme 1). Two
key fragments, 8 and 9, were therefore identified. The
synthesis of the C1-C10 fragment 8 began by converting
levulinic acid 1 to the corresponding chiral N-acyloxazoli-
dinone [t-BuCOCl, DMAP, 40 °C, followed by (R)-4-benzyl-
1,3-oxazolidinone (2)] and protecting the ketone [HO-
(CH2)2OH, pTsOH, benzene, reflux] as a ketal (Scheme 2).
The resulting chiral N-acyloxazolidinone was then subjected
to a highly diastereoselective Evans alkylation10 (NaHMDS,
MeI, THF, -40 °C) to afford the corresponding methylated
product 4 in 73% yield (dr >95:5).11 Removal of the chiral
auxiliary12 using LiBH4 (87%) followed by the oxidation of
the resulting allylic alcohol under standard Swern conditions
(3) (a) Yoshida, T.; Koizumi, K.; Kawamura, Y.; Matsumoto, K.; Itazaki,
H. Japan Patent Kokai 5-310726, 1993. (b) Yoshida, T.; Koizumi, K.;
Kawamura, Y.; Matsumoto, K.; Itazaki, H. European Patent 560389 A1,
1993. (c) Yasui, K.; Tamura, Y.; Nakatani, T.; Kawada, K.; Ohtani, M. J.
Org. Chem. 1995, 60, 7567–7574. (d) Kobayashi, S.; Tsuchiya, K.; Harada,
T.; Nishide, M.; Kurokawa, T.; Nakagawa, T.; Shimada, N.; Kobayashi,
K. J. Antibiot. 1994, 47, 697–702. (e) Kobayashi, S.; Tsuchiya, K.; Harada,
T.; Nishide, M.; Kurokawa, T.; Nakagawa, T.; Shimada, N.; Iitaka, T. J.
Antibiot. 1994, 47, 703–707.
(4) Sirirath, S.; Tanaka, J.; Ohtani, I. I.; Ichiba, T.; Rachmat, R.; Ueda,
K.; Usui, T.; Osada, H.; Higa, T. J. Nat. Prod. 2002, 65, 1820–1823.
(5) While the structure of these new Theonella metabolites was
elucidated by X-ray diffraction, the absolute stereochemistry was secured
by total synthesis, first by Ghosh et al. and then by She et al.; see: (a)
Ghosh, S.; Kumar, S. U.; Shashidhar, J. J. Org. Chem. 2008, 73, 1582–
1585. (b) Xu, Y.; Huo, X.; Li, X.; Zheng, H.; She, X.; Pan, X. Synlett
2008, 1665–1668. (c) Su, Y.; Xu, Y.; Han, J.; Zheng, J.; Qi, J.; Jiang, T.;
Pan, X.; She, X. J. Org. Chem. 2009, 74, 2743–2749.
(9) Hatakeyama et al. have very recently used a similar procedure in
their synthesis of phoslactomycin B; see: Shibahara, S.; Fujino, M.; Tashiro,
Y.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2008, 10, 2139–
2142.
(6) For the development of an asymmetric Brown-type pentenylation,
see: (a) Sonawane, R. P.; Joolakanti, S. R.; Arseniyadis, S.; Cossy, J. Synlett
2009, 213–216. For applications in natural product synthesis, see: Bressy,
C.; Vors, J.-P.; Hillebrand, S.; Arseniyadis, S.; Cossy, J. Angew. Chem,
Int. Ed. 2008, 47, 10137–10140. (b) Mo¨ıse, J.; Sonawane, R. P.; Corsi, C.;
Wendeborn, S. V.; Arseniyadis, S.; Cossy, J. Synlett 2008, 2617–2620.
(7) For the development of a cross-metathesis involving vinyl-function-
alized azoles, see: (a) Dash, J.; Arseniyadis, S.; Cossy, J. AdV. Synth. Catal.
2007, 349, 152–156. (b) Hoffman, T. J.; Rigby, J. H.; Arseniyadis, S.; Cossy,
J. J. Org. Chem. 2008, 73, 2400–2403. For applications in natural product
synthesis, see: (c) Gebauer, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007,
9, 3425–3427. (d) Gebauer, J.; Arseniyadis, S.; Cossy, J. Eur. J. Org. Chem.
2008, 2701–2704.
(10) (a) Evans, D. A.; Kim, A. S. In Handbook of Reagents for Organic
Synthesis: Reagents, Auxiliaries, and Catalysts for C-C bond Formation;
Coates, R. M., Denmark, S. E., Eds.; John Wiley and Sons: New York,
1999; pp 91-101. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica
Acta 1997, 30, 3–12. (c) Evans, D. A. Aldrichimica Acta 1982, 15, 23–32.
(d) Smith, T. E.; Richardson, D. P.; Truran, G. A.; Belecki, K.; Onishi, M.
J. Chem. Ed. 2008, 85, 695–697.
(11) The second diastereomer could not be detected by either 1H or 13
C
NMR of the crude reaction mixture, thus suggesting a dr > 95:5.
(12) Smith, A. B., III; Lee, D. J. Am. Chem. Soc. 2007, 129, 10957–
10962.
(13) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293–294.
(14) (a) Schlosser, A.; Despond, O.; Lehmann, R.; Moret, E.; Rauch-
schwalbe, G. Tetrahedron 1993, 49, 10175–10203. (b) Schlosser, A.;
Hartmann, J. J. Am. Chem. Soc. 1976, 98, 4674–4676. (c) Roush, W.; Adam,
M.; Walts, A.; Harris, D. J. Am. Chem. Soc. 1986, 108, 3422–3434.
(8) For the development of an enantioselective organocatalytic conjugate
reduction of ꢀ-azole R,ꢀ-unsaturated aldehydes and its application in natural
product synthesis, see: Hoffman, T. J.; Dash, J.; Rigby, J. H.; Arseniyadis,
S.; Cossy, J. Org. Lett. 2009, 11, 2756–2759.
Org. Lett., Vol. 12, No. 18, 2010
4075

Scheme 3. Second Strategy for the Synthesis of (-)-Bitungolide F
Scheme 4. Synthesis of (-)-Bitungolide F Via an
Enantioselective Organocatalyzed Michael Addition
led to the corresponding aldehyde 5, which was engaged in
a newly developed boron-mediated asymmetric pentenylation
reaction6 inspired by the asymmetric crotylation procedure
developed by Brown et al.13 Hence, aldehyde 5 was subjected
to a chiral (Z)-pentenylborane reagent generated in situ from
(Z)-2-pentene [n-BuLi/t-BuOK, (-)-Ipc2B(OMe), BF3·OEt2,
THF, -78 °C]14 affording the corresponding homoallylic
alcohol 6 (dr ) 9:1) in 59% yield (2 steps) with a complete
control of the syn-relationship between the two substituents
at C4 and C5.15 The latter was then efficiently converted
into the corresponding R,ꢀ-unsaturated δ-lactone using an
acylation/RCM sequence, thus affording compound 7 in 67%
yield over the two steps.16 The ketone was eventually
deprotected17 upon refluxing in an acetone/H2O mixture in
the presence of a catalytic amount of p-TsOH (95%), thus
setting the stage for the chiral boron enolate mediated
asymmetric aldol reaction.18 In order to perform this key
transformation, we first needed to prepare the required (E,E)-
dienal 9. The latter was synthesized in 75% overall yield
starting from cinnamaldehyde Via a three-step sequence that
involved a Wittig olefination (Ph3PdC(Me)CO2Et, THF, rt),
a DIBAL-H mediated reduction, and a final oxidation with
MnO2.19 With the two units 8 and 9 in hand, we were fi-
nally ready to perform the key chiral boron-mediated
aldol reaction that would lead to the entire carbon backbone
of (-)-bitungolide F. Ketone 8 was thus treated with
(+)-Ipc2BCl (Et3N, Et2O, -78 °C) to afford the chiral boron
enolate intermediate, which was then reacted with aldehyde
9. The resulting aldol adduct (dr ) 5:1) was directly reduced
to the corresponding 1,3-anti diol (Me4NB(OAc)3, AcOH/
CH3CN, -20 °C) in order to prevent any partial elimination
that could occur on such systems.20 To our delight, we were
able to isolate (-)-bitungolide F as a single diastereoisomer
in 82% yield (2 steps). As expected, the spectroscopic and
physical data of 10 were identical with those reported for
the natural product except for the optical rotation, which was
of opposite sign {[R]20 -51.6 (c 1.56, CHCl3); lit.4 [R]22
D
D
+43.0 (c 0.85, CHCl3)}.
Having completed the synthesis of (-)-bitungolide F, we
continued our efforts to conceive a slightly more flexible
route, which would allow access to a variety of analogues
for further biological screening and structure-activity rela-
tionship (SAR) studies. In this context, we decided to modify
the synthesis of fragment 8 while keeping the asymmetric
aldol/1,3-anti reduction end game. In order to gain maximum
versatility, we therefore devised our synthesis around an
enantioselective organocatalyzed Michael addition, which
would afford the C5-C10 aldehyde in one step, and the
boron-mediated asymmetric pentenylation/acylation/RCM
sequence disclosed previously (Scheme 3).
(15) The second diastereomer could not be detected by either 1H or 13
C
NMR of the crude reaction mixture, thus suggesting a a dr > 95:5.
(16) (a) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130–9136. (b) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett.
1998, 39, 4651–4654. (c) Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron
Lett. 1999, 40, 4187–4188. (d) Boucard, V.; Broustal, G.; Campagne, J. M.
Eur. J. Org. Chem. 2007, 225–236.
(17) Meissner, R. S.; Perkins, J. J.; Duong, L. T.; Hartman, G. D.;
Hoffman, W. F.; Huff, J. R.; Ihle, N. C.; Leu, C.-T.; Nagy, R. M.; Naylor-
Olsen, A.; Rodan, G. A.; Rodan, S. B.; Whitman, D. B.; Wesolowski, G. A.;
Duggan, M. E. Bioorg. Med. Chem. Lett. 2002, 12, 25–29.
(18) (a) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1–200. (b)
Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997–1000. (c)
Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663–4684. (d) Cergol, K. M.;
Coster, M. J. Nat. Protoc. 2007, 10, 2568–2573.
The synthesis of ketone 8 commenced with Chi’s and
Gellman’s recently reported highly enantioselective organo-
(20) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578.
(19) Cao, X.-P. Tetrahedron 2002, 58, 1301–1307.
4076
Org. Lett., Vol. 12, No. 18, 2010

catalytic Michael addition of simple aldehydes to non-
activated enones (Scheme 4).21 Hence, by subjecting pro-
panal 11 and methyl vinyl ketone 12 to diphenylprolinol
methyl ether 13 (5 mol %) and catechol 14 (20 mol %), we
were able to isolate aldehyde 15 in a moderate 58% yield
but with an excellent enantioselectivity (er > 95:5).22 The
latter was then engaged in the same boron-mediated asym-
metric pentenylation reaction as previously to afford the
corresponding homoallylic alcohol, which spontaneously
underwent hemiketalization.23 After failing to selectively
acylate the homoallylic alcohol by pushing the hemiacetal/
hydroxy ketone equilibrium, we decided to directly reduce
the crude reaction mixture with LiAlH4 (THF, 0 °C, 94%)
and bis-acylate the resulting diol (acryloyl chloride, Et3N,
CH2Cl2, quant). This three-step sequence resulted in the
isolation of the RCM precursor 17 in 57% yield. The latter
then underwent a RCM with the Grubbs second generation
catalyst (CH2Cl2, 40 °C, 66%), followed by the saponification
of the acrylate (K2CO3, MeOH, rt, 75%) and the oxidation
of the resulting secondary alcohol (DMP, CH2Cl2, rt, 84%)
to give the desired ketone 8 in seven steps and 13.9% overall
yield starting from propanal 11 and methyl vinyl ketone 12.
(-)-Bitungolide F was eventually isolated after the chiral
boron-mediated aldol reaction/1,3-anti reduction sequence
thus validating this second strategy.
In conclusion, we have completed the synthesis
(-)-bitungolide F using two very convergent routes that
feature an asymmetric boron-mediated pentenylation, a
stereoselective aldol and a hydroxyl-directed 1,3-anti-reduc-
tion to control the stereogenic centers at C4, C5, C9 and
C11. The first strategy was achieved in 11 steps and 14.6%
overall yield using an Evans-type asymmetric alkylation to
control the stereogenic centers at C6, while the second
strategy was completed in only nine steps and 11.4% overall
yield using a highly enantioselective organocatalytic Michael
addition. It is worth pointing out that while both syntheses
are considerably shorter than the ones reported so far,24 the
second approach is particularly appealing as it is highly
flexible, does not involve the use of any protecting group,
and is therefore amenable to a wide variety of potentially
useful synthetic analogues.
Acknowledgment. We would like to thank Generalitat de
Catalunya and the Ministe`re de l’Enseignement Supe´rieur
et de la Recherche for financial support to A.E. and A.C.,
respectively.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 19, 4253–4256.
(22) The enantiomeric excess was determined by crude 1H NMR analysis
after subjecting aldehyde 15 to an oxidation/peptide coupling sequence,
L-alanine methyl ester being the amine coupling partner.
(23) Unfortunately, we were unable to determine the selectivity of the
boron-mediated asymmetric pentenylation from the crude 1H NMR due to
overlapping signals.
OL101659Y
(24) She et al. synthesis of (-)-bitungolide F was achieved in 21
steps starting from (-)-malic acid, whereas Ghosh et al. synthesis of
(-)-bitungolide F was completed in 22 steps starting from the same
starting material.
Org. Lett., Vol. 12, No. 18, 2010
4077