Concise and highly stereoselective synthesis of the C20-C26 building block of halichondrins and Eribulin

Article abstract of DOI:10.1021/ol203373d

A concise, stereoselective, and scalable synthesis of the C20-C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselectiv

Full text of DOI:10.1021/ol203373d

ORGANIC
LETTERS
2012
Vol. 14, No. 2
660–663
Concise and Highly Stereoselective
Synthesis of the C20ꢀC26 Building Block
of Halichondrins and Eribulin
Mingde Shan and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, United States
kishi@chemistry.harvard.edu
Received December 17, 2011
ABSTRACT
A concise, stereoselective, and scalable synthesis of the C20ꢀC26 building block of halichondrins and Eribulin is reported. The synthesis relies
on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective SN20 substitution, and selective
conversion of a CꢀSi to CꢀI bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration
through a silica-gel plug, to give the C20ꢀC26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.
Halichondrins are polyether macrolides, originally iso-
lated from the marine sponge Halichondria okadai by
Uemura, Hirata and co-workers, which have received
much attention due to their intriguing structure and
extraordinary in vitro and in vivo antitumor activity.1,2
On completion of the total synthesis of halichondrin B
(Figure 1),3,4 we asked the late Dr. Suffness at the
National Cancer Institute (NCI) and Dr. Littlefield at
Eisai Research Institute (ERI) to test the in vitro and in
vivo antitumor activities of the totally synthetic halichon-
drins as well as several synthetic intermediates. The re-
sults were sensational; their experiments clearly demon-
strated that the antitumor activities of halichondrin B
reside in the right portion of the molecule,5 which have
served as the foundation for the successful develop-
ment of the antitumor drug Halaven (Eribulin, E7389;
Figure 1).6 This was 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 che-
motherapy. However, we should point out that, to the
best of our knowledge, the structural complexity of
the right half of halichondrin B, or Eribulin, exceeds the
structural complexity of synthetic drugs on the market
and/or synthetic drug candidates under development.
Thus, an economically feasible synthesis of the right half
of halichondrin B and/or Eribulin will play the key role
(1) (a) Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.;
Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796.
(b) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701.
(2) For isolation of the halichondrins from different species of
sponges, see: (a) Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.;
Doubek, D. L.; Boyd, M. R.; Schmidt, J. M.; Chapuis, J.-C.; Hamel, E.;
Bai, R.; Hooper, J. N. A.; Tackett, L. P. J. Org. Chem. 1993, 58, 2538 and
references cited therein. (b) Hickford, S. J. H.; Blunt, J. W.; Munro,
M. H. G. Bioorg. Med. Chem. 2009, 17, 2199 and references cited therein.
(3) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung,
S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K.
J. Am. Chem. Soc. 1992, 114, 3162 and references cited therein.
(4) For synthetic work by Phillips, Salomon, Burke, and Yonemitsu,
see: (a) 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. (b)
Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193
and references cited therein. (c) Lambert, W. T.; Hanson, G. H.;
Benayoud, F.; Burke, S. D. J. Org. Chem. 2005, 70, 9382 and references
cited therein. (d) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota, M.;
Yonemitsu, O. Synlett 1994, 38.
(5) Kishi, Y.; Fang, F. G.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K. U.S.
Patent 5338866, International Patent WO93/17650.
(6) (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)
Yu, M. J.; Kishi, Y.; Littlefield, B. A. In Anticancer Agents from Natural
Products; Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC Press:
Boca Raton, FL, 2005; p 41.
r
10.1021/ol203373d
Published on Web 01/11/2012
2012 American Chemical Society

for ultimate success of this program. It is our belief that
contemporary synthetic organic chemistry has the capac-
ity and potential to meet this type of challenge.
well for the ongoing work in this laboratory. Nonetheless,
we wished to improve two particular steps: (1) eliminate
the use of potentially toxic chemicals such as n-Bu3SnH
and (2) improve the stereoselectivity of the SN20 process
with lithium dimethylcuprate. With this goal in mind, we
studied several synthetic routes, leading to the discovery
of some interesting chemistry. However, these studies
resulted in only marginal improvements in the overall
efficiency of the synthesis.
Scheme 1. First Generation Synthesis of the C20ꢀC26 Building
Block
Figure 1. Structure of Halichondrin B and Eribulin (E7389),
with the C20ꢀC26 moiety highlighted in red.
With this analysis in mind, we have continued our
synthetic work on the halichondrins with two major focuses:
(1) design and synthesis of building blocks and (2) catalytic
asymmetric Cr-mediated coupling reactions.7,8 In this letter,
we report a concise, highly stereoselective, and scalable
synthesis of the C20ꢀC26 building block.
In an attempt to avoid the use of n-Bu3SnH, we initially
studied various hydrometalation of the acetylenic bond in
the diol obtained at the first step, but without much
success. One of the problems encountered was the site
selectivity of hydrometalation. To overcome this diffi-
culty, we shifted our focus to the selectively protected
homopropargyl alcohol, cf., 4 in Scheme 2, with the hope
that the secondary alcohol could be used as a directing
group to achieve the desired regioselective hydrometala-
tion. In particular, the recent Trost work10 encouraged us
to explore an intramolecular hydrosilylation.
With this background, we began the synthesis
(Scheme 2). The method of Yamaguchi11 was employed
to couple optically active epoxide 1, obtained by the
Jacobsen kinetic resolution,12 with triethylsilyl (TES)
protected propargyl alcohol, to give homopropargyl al-
cohol 4 (Scheme 2). Following the Trost protocol,10 4 was
first treated with 2.5 equiv of 1,1,3,3-tetramethyldisilazane
at 50 °C (neat) and, after the removal of excess reagent
under vacuum, treated with the ruthenium complex
(2 mol %) in methylene chloride at rt, to give a single
product. Upon brief treatment of the product with
K2CO3 in methanol, the TES group was selectively
removed to furnish cyclic vinylsilane 5 in excellent overall
yield. The structure of the product was established via
In 2002, we reported a short synthesis of the C20ꢀC26
building block (Scheme 1).9 This synthesis has served us
(7) For syntheses of building blocks from this laboratory, see: (a)
C1ꢀC13: Duan, J. J.-W.; Kishi, Y. Tetrahedron Lett. 1993, 34, 7541.
Stamos, D. P.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8643. Choi, H.;
Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan,
Z.-K.; Xie, C. Pure Appl. Chem. 2003, 75, 1 and references cited therein.
(b) C14ꢀC19: Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc.
2004, 126, 12248. Liu, S.; Kim, J. T.; Dong, C.-G.; Kishi, Y. Org. Lett.
2009, 11, 4520 and references cited therein. (c) C20ꢀC26: See ref 9. (d)
C14ꢀC26: see refs 3 and 7. Kim, D.-S.; Dong, C.-G.; Kim, J. T.; Guo,
H.; Huang, J.; Tiseni, P. S.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15636.
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, 131,
15642 and references cited therein. (e) C27ꢀC38 building block of
halichondrins: Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth,
C. J.; Jung, S. H.; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992, 33,
1549. Chen, C.-L.; Namba, K.; Kishi, Y. Org. Lett. 2009, 11, 409. (f)
C27ꢀC35 building block of Eribulin: ref 8a. Yang, Y.-R.; Kim, D.-S.;
Kishi, Y. Org. Lett. 2009, 11, 4516. (g) C14ꢀC38 building block of
halichondrins: refs 3, 7, and 8b,c. Stamos, D. P.; Chen, S. S.; Kishi, Y.
J. Org. Chem. 1997, 62, 7552. Wan, Z.-K.; Choi, H.-w.; Kang, F.-A.;
Nakajima, K.; Demeke, D.; Kishi, Y. Org. Lett. 2002, 4, 4431 and
references cited therein. (h) C1ꢀC38 of halichondrins and C1ꢀC35 of
eribulin: Namba, K.; Jun, H.-S.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
7770. Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382.
Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723 and references cited
therein.
(8) For Cr-mediated coupling reactions from this laboratory, see: (a)
Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986,
108, 5644. (b) 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,
15387. (c) Liu, X.; Henderson, J. A.; Sasaki, T.; Kishi, Y J. Am. Chem.
Soc. 2009, 131, 16678 and references cited therein.
(10) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc 2003, 125, 30. (b)
Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc. 2005,
127, 10028.
(11) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(12) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936.
(9) Xie, C.; Nowak, P.; Kishi, Y. Org. Lett. 2002, 4, 4427.
Org. Lett., Vol. 14, No. 2, 2012
661

spectroscopic analyses; in particular, the 1H NMR estab-
lished the site of the intramolecular hydrosilylation.
reason, the reaction mixture of methanesulfonylation
was used directly in the SN20 substitution with lithium
cyano(methyl)cuprate.
The stereochemistry of the major product was estab-
lished via correlation of 7 with the diol derived from 3
synthesized by the previous route (vide infra). It is worth-
while to make a few additional comments on the SN20
process. First, the preferential facial selectivity observed
for the SN20 substitution matches that reported for the
dimethyldioxirane oxidation of a similar six-member
vinylsilane by Trost.10 Second, we would assume that
the SN20 substitution took place through a transition state
resemblant to conformer A or B, but it is not immediately
apparent why the R-face attack is much preferred to the
β-face attack. This surprisingly dominant R-face attack
warrants, in our view, further studies on the stereochem-
ical course of this process.
Scheme 2. Second Generation Synthesis of the C20ꢀC26
Building Block
The next stage of the synthesis was to convert the CꢀSi
bond at C26 into a CꢀI bond. In the ophiobolin C
synthesis,15 we required a similar transformation, which
was achieved with iodine monochloride, followed by
tetra-n-butylammonium fluoride (TBAF) treatment.
Based on this precedent, 6 was treated with iodine mono-
chloride, to yield a ca. 4:1 diastereomeric mixture of the
intermediate, cf., the partial structure shown in brack-
ets under the arrow in Scheme 2. Upon treatment with
TBAF or HF-pyridine,16 this intermediate cleanly
furnished the desired product 7 (oil). The diastereo-
meric ratio of 7 (>200:1) was estimated from a HPLC
analysis of its bis-p-nitrobenzoate, whereas the optical
1
purity (>99%) was from a H NMR analysis of its
bis-(R)- and (S)-Mosher esters. The structure of 7 was
established via its correlation with the diol derived
from 3 and, in addition, an X-ray analysis of its bis-
p-nitrobenzoate.
For preparative purposes, the synthesis was carried out
in a 5-pot/4-workup operation without chromatographic
purification, except for filtration through a silica-gel plug
at each step and an ion-exchange resin based workup for
the TBAF step.17 The overall yield of 7 from 1 is ca. 60%,
and the purity of 7 thus obtained is pure enough for our
work. If further purification is required, bis-p-nitro-
benzoate of 7 is crystalline and suitable for recrystalliza-
tion from aqueous isopropanol.
In conclusion, we have reported a concise, highly
stereoselective, and scalable synthesis of the C20ꢀC26
building block of halichondrins and Eribulin. The synthe-
sis relies on three key transformations: regiospecific Ru-
catalyzed intramolecular hydrosilylation, stereoselective
SN20 substitution, and selective conversion of a CꢀSi to
CꢀI bond. The synthesis is carried out in a 5-pot/
4-workup operation without chromatographic purifica-
tion, except for filtration through a silica-gel plug at each
We planned to incorporate the C5 methyl group via the
addition of a “Me” anion to an activated form of 5 in an
SN20 process. In practice, the primary alcohol 5 was
converted to its methanesulfonate (Ms) and then treated
with lithium cyano(methyl)cuprate to furnish the desired
SN20 product 6 in an excellent overall yield.13 This trans-
1
formation deserves several comments. First, H NMR
analysis of the crude product showed that there was no
detectable amount of SN2 product formed.14 Second, the
SN20 substitution yielded one major diastereomer, along
with a very minor diastereomer; the stereoselectivity esti-
mated from 1H NMR spectrum was ca. 150:1, which was
later confirmed via HPLC analysis of bis-p-nitrobenzoate
of 7 (vide infra). Interestingly, treatment of the corre-
sponding p-toluenesulfonate (pTs) with lithium cyano-
(methyl)cuprate gave 6 as the major product, but with a
lower stereoselectivity (dr = ca. 80:1). Third, the meth-
anesulfonate was stable in solution but exhibited a ten-
dency of decomposition upon evaporation. For this
(15) (a) Rowley, M.; Kishi, Y. Tetrahedron Lett. 1988, 29, 4909. (b)
Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989, 111,
2735.
(16) TBAF-deprotection gave a slightly higher yield than HF-
deprotection.
(13) For a recent review on organocopper(I) reactions, see: Yoshikai,
N.; Nakamura, E. Chem. Rev. ASAP (DOI: 10.1021/cr200241f).
(14) With LiCu(Me)2, a 2:1 mixture of the SN20 and SN2 product was
obtained.
(17) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723.
662
Org. Lett., Vol. 14, No. 2, 2012

stage, to give the C20ꢀC26 building block (dr: >200:1
and ee: >99%) in ca. 60% overall yield from epoxide 1
(ee: >99%) in a 10-g scale.
Chemical Biology, Harvard University, for his help with
X-ray data collection and structure determination.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of spectra, and
crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org
Acknowledgment. Financial support from the Eisai
USA Foundation is gratefully acknowledged. We thank
Dr. Shao-Liang Zheng, Department of Chemistry and
Org. Lett., Vol. 14, No. 2, 2012
663