Selective synthesis of epolactaene featuring efficient construction of methyl (Z)-2-iodo-2-butenoate and (2R,3S,4S)-2-trimethylsilyl-2,3-epoxy-4- methyl-γ-butyrolactone

Article abstract of DOI:10.1021/ol060856u

(+)-Epolactaene was synthesized in 14 steps in the longest linear sequence. The synthesis is highlighted by a highly efficient preparation of the lactone intermediate 4, which only requires three steps from the commercially available (S)-3-butyn-2-ol. It also features a fully stereocontrolled synthesis of the intermediate 9, which was constructed through the use of Zr-catalyzed methylalumination of alkynes and a series of Pd-catalyzed organozinc cross-coupling reactions, such as homopropargylation, direct ethynylation, and alkenylation of the methyl ester of (Z)-α-iodocrotonic acid (3).

Full text of DOI:10.1021/ol060856u

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2783-2785
Selective Synthesis of Epolactaene
Featuring Efficient Construction of
Methyl (Z)-2-Iodo-2-butenoate and
(2R,3S,4S)-2-Trimethylsilyl-2,3-epoxy-4-methyl-
γ
-butyrolactone
Ze Tan and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received April 9, 2006
ABSTRACT
(+)-Epolactaene was synthesized in 14 steps in the longest linear sequence. The synthesis is highlighted by a highly efficient preparation of
the lactone intermediate 4, which only requires three steps from the commercially available (S)-3-butyn-2-ol. It also features a fully stereocontrolled
synthesis of the intermediate 9, which was constructed through the use of Zr-catalyzed methylalumination of alkynes and a series of Pd-
catalyzed organozinc cross-coupling reactions, such as homopropargylation, direct ethynylation, and alkenylation of the methyl ester of (Z)-
r
-iodocrotonic acid (3).
Epolactaene (1) is a microbial metabolite isolated from the
fungal strain Penicillium sp. BM 1689-P.1 Because of its
effectiveness in promoting neurite outgrowth and arresting
the cell cycle at the G1 phase in a human neuroblastoma
cell line, it has been considered for the treatment of neuro-
degenerative diseases such as dementia.2 It has also been
found recently that epolactaene inhibits the activities of
mammalian DNA polymerases and human DNA topo-
isomerase II.3
Scheme 1
Epolactaene (1) has previously been synthesized by three
groups.4-6 We became interested in the synthesis of 1
primarily because of the presence of a conjugated triene
moiety featuring an R-alkenylated (E)-crotonic ester, and we
hoped to prepare the side chain via a Pd-catalyzed R-al-
kenylation7,8 involving the use of 2 and 3 (Scheme 1). We
(6) (a) Kuramochi, K.; Nagata, S.; Itaya, H.; Takao, K.; Kobayashi, S.
Tetrahedron Lett. 1999, 40, 7367. (b) Kuramochi, K.; Nagata, S.; Itaya,
H.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 7371. (c)
Kuramochi, K.; Nagata, H.; Matsubara, Y.; Sunoki, T.; Uchiro, H.; Takao,
K.; Kobayashi, S. Tetrahedron 2003, 59, 9743.
(7) Negishi, E.; Alimardanov, A. In The Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; J. Wiley & Sons: New
York, 2002; Sect. III.2.14.2, pp 721-766.
(8) For R-alkenylation of carbonyl compounds by Negishi coupling,
see: (a) Negishi, E.; Owczarczyk, Z.; Swanson, D. R. Tetrahedron Lett.
1991, 32, 4453. (b) Pour, M.; Negishi, E. Tetrahedron Lett. 1996, 37, 4679.
(c) Pour, M.; Negishi, E. Tetrahedron Lett. 1997, 38, 525. (d) Negishi, E.;
Pour, M.; Cederbaum, F. E.; Kotora, M. Tetrahedron 1998, 54, 7057. (e)
Negishi, E.; Tan, Z.; Liou, S. Y.; Liao, B. Tetrahedron 2000, 56, 10197.
(1) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada, H. J. Antibiot.
1995, 48, 733.
(2) (a) Kakeya, H.; Onozawa, C.; Sato, M.; Arai, K.; Osada, H. J. Med.
Chem. 1997, 40, 391. (b) Vatini, G.; Skaper, S. D. Pharmacol. Res. 1992,
26, 1. (c) Dicicco-Bloom, E.; Friedman, W. J.; Black, I. B. Neuron 1993,
11, 1101.
(3) Mizushima, Y.; Kobayashi, S.; Kuramochi, K.; Nagata, S.; Sugawara,
F.; Sakaguchi, K. Biochem. Biophys. Res. Commun. 2000, 273, 784.
(4) (a) Hayashi, Y.; Narasaka, K. Chem. Lett. 1998, 313. (b) Hayashi,
Y.; Kanayama, J.; Yamaguchi, J.; Shoji, M. J. Org. Chem. 2002, 67, 9443.
(5) (a) Marumoto, S.; Kogen, H.; Naruto, S. J. Org. Chem. 1998, 63,
2068. (b) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999, 55, 7129.
(c) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999, 55, 7145.
10.1021/ol060856u CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/03/2006

also hoped to apply the Pd-catalyzed homoallyl-alkenyl
coupling protocol developed by us9 to the preparation of 2.
For the construction of the ring moiety and its union with
the side chain, the strategy involving carbonyl addition of
the oxiranyl anion derived from 4 reported by S. Kobayashi
et al.6 appealed to us as being convergent and fundamentally
attractive. At the time our work was started, however, 4 had
not been synthesized asymmetrically. Although their recent
report6c described its synthesis, it required 12 steps from (S)-
lactic acid ethyl ester.
We envisioned a short synthesis of (-)-4 via F. Sato’s
Ti-catalyzed trans-hydromagnesation of propargyl alcohol10
and indeed achieved its synthesis in just three steps from
commercially available (S)-3-butyn-2-ol in 32% overall yield,
as outlined in Scheme 2. The crucial trans-hydromagnesation
anywhere in the synthesis of 2. To develop a more
convergent route to 2, 1-trimethylsilyl-6-iodo-3-hexen-1-yne
(6) was prepared via hydrozirconation-iodinolysis of 4-iodo-
1-butyne and a subsequent Pd-catalyzed alkynyl-alkenyl
coupling14 with TMSCtCZnBr. After lithiation with tBuLi
(2 equiv) and zincation with dry ZnBr2, its Pd-catalyzed
cross-coupling with 5 led to a disappointingly low yield of
TMS-protected 7 (41%) along with byproducts containing a
cyclopropyl group. Evidently, metalation of 6 must be
accompanied by metallotropy involving 8a and 8b (Scheme
3) similar to that reported previously by us in a related
homoallyl-alkenyl cross-coupling reaction.9c
For conversion of 2 into the fully structured side chain 9,
we hoped to develop an efficient and selective synthesis of
the methyl ester of (Z)-R-iodocrotonic acid (3) rather than
its R-bromo analogue, which was previously used by Kogen5b
for the construction of the C1-C6 moiety via Stille coup-
ling15 in only 47% yield. To this end, methyl propiolate was
carbocuprated with MeCu-TMEDA16 and treated with I2
to give >98% pure 3 in 62% yield (Scheme 4). Its cross-
Scheme 2
Scheme 4
i
with BuMgCl in the presence of 3 mol % of Cp2TiCl2
followed by carboxylation with CO2 and lactonization
proceeded in one pot in 71% yield. Epoxidation of the lactone
thus obtained with NaOCl in pyridine at 0 °C afforded the
desired product 4 as a single diastereoisomer in 51% yield.
A fully (>98%) stereocontrolled synthesis of 2 was
achieved in seven steps by using the Zr-catalyzed carboalu-
mination of alkynes11 and the Pd-catalyzed cross-coupling
with organozincs7-9 as well as hydrozirconation12 with
HZrCp2Cl conveniently generated in situ by a recently
coupling with the zinc derivative of 2 in the presence of 2.5
mol % of Pd2(dba)3 and 10 mol % of tris(o-furyl)phosphine
(TFP)17 proceeded smoothly and selectively to give the
desired cross-coupling product 10 in 76% yield. Noticing
that Pd-catalyzed cross-coupling of R-Bu3Sn-substituted
methyl crotonate with a related dienyl iodide was reported
to give a 91% yield of the C1-C10 fragment,6b we also ran
the corresponding Stille reaction of 2. In our hands, however,
i
developed Bu2AlH-ZrCp2Cl2 protocol13 (Scheme 3). Al-
though the preparation of 5, specifically its modest yield of
55%, needs to be further improved, no delicate and poten-
tially tedious stereo- or regioisomeric separation is required
Scheme 3
2784
Org. Lett., Vol. 8, No. 13, 2006

the yield of 10 has been in the 70-80% range. Desilylation
with TBAF followed by oxidation with MnO2 provided 9 in
g98% isomeric purity in 72% yield over two steps (Scheme
4).
The final assembly of epolactaene from 4 and 9 was
performed as summarized in Scheme 5 by closely following
convergent, the yield over four steps has been limited to 18%,
but it is comparable to that previously reported (15%). No
efforts have been made in this study to further improve this
part of the synthesis. Clearly, such efforts are highly
desirable, and the efficient and selective synthesis of several
key intermediates including 2-4, 9, and 10 herein reported
1
should significantly facilitate such efforts. The H and 13C
NMR spectra of (+)-epolactaene obtained as a mixture of
1.8:1 epimers at C15 [[R]23 +36.3° (c 0.38 MeOH) lit.1
D
Scheme 5
[R]22 +32° (c 0.1 MeOH)] match very well with those
D
previously reported.4-6
Acknowledgment. We thank the National Institutes of
Health (GM 36792) and Purdue University for support of
this research. Drs. F. Zeng and M. Qian performed related
experiments not described in this paper. We thank Professor
Susumu Kobayashi of Science University of Tokyo for
providing us with valuable and helpful information.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060856U
the protocol developed by S. Kobayashi et al.6a,b The
stereochemical details have been established by a combina-
tion of NOEs and coupling constant measurements performed
on the lactone intermediate 11. Although efficient and
(12) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. (b)
Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl. 1976, 15, 333.
(13) Huang, Z.; Negishi, E., submitted for publication.
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Commun. 1977, 683. (b) Kotora, M.; Xu, C.; Negishi, E. J. Org. Chem.
1997, 62, 8957. (c) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski,
D. Org. Lett. 2003, 5, 1597. (d) Negishi, E.; Anastasia, L. Chem. ReV. 2003,
103, 1979.
(15) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
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29, 6043. (b) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
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1980, 102, 3298. (b) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45,
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(10) Sato, F.; Ishikawa, H.; Watanabe, H.; Miyake, T.; Sato, M. J. Chem.
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(b) Negishi, E.; van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,
107, 6639. (c) Liu, F.; Negishi, E. J. Org. Chem. 1997, 62, 8591.
Org. Lett., Vol. 8, No. 13, 2006
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