New Syntheses of E7389 and Halichondrin Building Blocks
A R T I C L E S
of phase III clinical trials.5 This is exciting news for us, partly
because we have been involved in the chemistry of halichondrins
from its infancy, but largely because we believe in the potential
that the halichondrins offer to cancer chemotherapy. However,
we should point out that, to our best knowledge, the structural
complexity of the right half of halichondrin B, or E7389 (Figure
1), exceeds by far the structural complexity of synthetic drugs
on the market and/or synthetic drug candidates under develop-
ment. Thus, an economically feasible synthesis of the right half
of halichondrin B and/or Eisai’s drug candidate will play the
key role for ultimate success of this program. It is our belief
that contemporary synthetic organic chemistry has the capacity
and potential to meet this type of challenge.
With this analysis in mind, we have continued synthesis
of the halichondrins, with one of the major focuses being
development of catalytic asymmetric Cr-mediated coupling
reactions.2,6 In this and the following paper,7 we report the
impact of the newly developed methods on the overall
efficiency of synthesis: they allow us to shorten the synthesis,
improve the overall yield, and incorporate a high degree of
flexibility in synthesis.
Scheme 1. Three C-C Bond-Forming Sites in the First-Generation
Synthesis
and (3) Co/Cr-mediated alkylation to form the C23-C24
bond (Scheme 2); we reported preliminary results on the
Scheme 2. C-C Bond Formations Based on the Cr-Mediated
Coupling Reactions
second and third bond-forming processes.2c Since then, our
efforts have been focused on how to realize each of the Cr-
mediated couplings in a catalytic asymmetric process at a
synthetically useful level.9
The new synthesis of 4 started with a catalytic asymmetric
Co/Cr-mediated 2-iodoallylation in the presence of Cr catalyst
derived from (S)-sulfonamide A (Scheme 3). With 10 mol %
catalyst loading, the coupling of aldehyde 5 with 2-iodoallyl
bromide 6 furnished the desired 2-iodoolefin 7 in 85% yield
with 93% ee.2g The undesired enantiomer could be removed at
this stage,10 but for practical purposes, this enantiomer mixture
was directly used for the following steps (Vide infra).
After activation of the secondary alcohol as its 2-mesityl-
enesulfonate (MES), the vinyl iodide was subjected to
catalytic asymmetric Ni/Cr-mediated coupling with aldehyde
9 in the presence of the catalyst prepared in situ from CrCl2
and (R)-sulfonamide B. It is noteworthy that, considering its
structural complexity compared with 9, we planned to use
8a as the limiting substrate for this coupling. Usually, Ni/
Cr-mediated couplings are carried out with a slight excess
of nucleophiles, because this process often gives byproduct
through leakage in the Ni catalytic cycle.11 Under the
conditions developed for the catalytic asymmetric Cr-
mediated couplings, these byproducts are detected only at a
low-to-insignificant level.9 Nonetheless, the plan of using 8a
as the limiting substrate gave us an opportunity to rigorously
assess leakage through the Ni catalytic cycle. Experimentally,
2. Results and Discussions
2.1. Synthesis of the C14-C26 Building Block. In the first-
generation synthesis, we synthesized the C14-C26 building
block 4 from 2-deoxy-L-arabinose diethylthioacetal 4,5-
acetonide8 in 18 steps in approximately 20% overall yield.2a
This synthesis relied on three C-C bond-forming reactions:
(1) stereoselective C-allylation to form the C16-C17 bond,
(2) Tebbe olefination to incorporate the exocyclic olefin at
C19, and (3) Horner-Emmons olefination, followed by
conjugate hydride reduction with the Stryker reagent, to form
the C21-C22 bond (Scheme 1). Although lengthy, this
synthesis served well not only for the first-generation total
synthesis of the halichondrins but also for the discovery and
development of E7389.
For the past several years, we have been exploring a new
synthetic route and recognized the possibility of synthesizing
4 via three consecutive Cr-mediated coupling reactions: (1)
Co/Cr-mediated 2-iodoallylation to form the C17-C18 bond,
(2) Ni/Cr-mediated alkenylation to form the C19-C20 bond,
(3) For synthetic work by Salomon, Burke, Yonemitsu, and Phillips, see:
(a) Kim, S.; Salomon, R. G Tetrahedron Lett. 1989, 30, 6279. Cooper,
A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193, and
references cited therein. (b) Burke, S. D.; Buchanan, J. L.; Rovin,
J. D. Tetrahedron Lett. 1991, 32, 3961. Lambert, W. T.; Hanson, G. H.;
Benayoud, F.; Burke, S. D. J. Org. Chem. 2005, 70, 9382, and
references cited therein. (c) Horita, K.; Hachiya, S.; Nagasawa, M.;
Hikota, M.; Yonemitsu, O. Synlett 1994, 38. Horita, K.; Nishibe, S.;
Yonemitsu, O. Phytochem. Phytopharm. 2000, 386, and references
cited therein. (d) Henderson, J. A.; Jackson, K. L.; Phillips, A. J. Org.
Lett. 2007, 9, 5299. Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.;
Phillips, A. J. Angew. Chem., Int. Ed. 2009, 48, 2346, and references
cited therein.
(6) For reviews on Cr-mediated C-C bond-forming reactions, see ref 2
in ref 7.
(7) Dong, C.-G.; Henderson, J. A.; Kaburagi, Y.; Sasaki, T.; Kim, D.-S.;
Kim, J. T.; Urabe, D.; Guo, H.; Kishi, Y J. Am. Chem. Soc. 2009,
(4) Kishi, Y.; Fang, F. G.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K. U.S.
Patent 5338866; International Patent WO93/17650.
(8) Wong, M. Y. H.; Gray, G. R. J. Am. Chem. Soc. 1978, 100, 3548.
(9) Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.;
Liu, X.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131; http://
dx.doi.org/10.1021/ja905843e.
(5) (a) Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer,
L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay,
L.; Towle, M. J.; Salvato, K. A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.;
Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551.
(b) Littlefield, B. A.; Palme, M. H.; Seletsky, B. M.; Towle, M. J.;
Yu, M. J.; Zheng, W. U.S. Patents 6214865, 6365759; International
Patent WO99/65894. (c) Yu, M. J.; Kishi, Y.; Littlefield, B. A. In
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(10) The optical purity of 7 was enhanced via recrystallization of its
4-acetylphenylcarbamate and 4-[4-carbomethoxyphenyl]benzoate.
(11) Ni-mediated homodimerization of a vinyl iodide is known to be one
of side reactions: see ref 1 in ref 7. For Ni(0)-mediated dimerization
of aryl and alkenyl halides, see: (a) Semmelhack, M. F.; Helquist,
P. M.; Jones, L. D. J. Am. Chem. Soc. 1971, 93, 5908. (b) Semmelhack,
M. F.; Helquist, P. M.; Jones, L. D. J. Am. Chem. Soc. 1972, 94,
9234.
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