Second generation synthesis of C27 - C35 Building block of E7389, a synthetic halichondrin analogue

Article abstract of DOI:10.1021/ol9016589

A practical method is reported to synthesize E7389 C27-C35 building block 13 from 1,2-O-isopropylidene-α-D-5-deoxyglucurono-6,3-lactone (3). This synthesis relies on two key processes: (1) C34/C35-diol is introduced via asymmetric dihydroxylation with dr

Full text of DOI:10.1021/ol9016589

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4516-4519
Second Generation Synthesis of
C27-C35 Building Block of E7389, a
Synthetic Halichondrin Analogue
Yu-Rong Yang, Dae-Shik Kim, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received July 21, 2009
ABSTRACT
A practical method is reported to synthesize E7389 C27-C35 building block 13 from 1,2-O-isopropylidene-r-D-5-deoxyglucurono-6,3-lactone
(3). This synthesis relies on two key processes: (1) C34/C35-diol is introduced via asymmetric dihydroxylation with dr ) 3:1, with the undesired
C34-diastereomer effectively removed by crystallization of 11, and (2) the C30 PhSO2CH2 group is introduced stereoselectively (>100:1) via
hydrogenation of 12 in the presence of the Crabtree catalyst. The reported synthesis is practically free from chromatographic separation.
Halichondrins are polyether macrolides, originally isolated
from the marine sponge Halichondria okadai by Hirata and
Uemura, which have received much attention due to their
intriguing structure and extraordinary in vitro and in vivo
antitumor activity.1 On completion of the total synthesis of
halichondrin B, norhalichondrin B, and homohalichondrin
B,2,3 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 halichondrins as well as several synthetic
(2) For the synthetic work on the marine natural product halichondrins
from this laboratory, see: (a) 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. (b) Stamos, D. P.;
Chen, S. S.; Kishi, Y. J. Org. Chem. 1997, 62, 7552. (c) Choi, H.-W.;
Demeke, D.; Kang, F. A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-
K.; Xie, C. Pure Appl. Chem. 2003, 75, 1. (d) Namba, K.; Jun, H.-S.; Kishi,
Y. J. Am. Chem. Soc. 2004, 126, 7770. (e) Namba, K.; Kishi, Y. J. Am.
Chem. Soc. 2005, 127, 15382. (f) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007,
9, 723. (g) Zhang, Z.; Huang, J.; Ma, B.; Kishi, Y. Org. Lett. 2008, 10,
3073. (h) Chen, C.-L.; Namba, K.; Kishi, Y. Org. Lett. 2009, 11, 409, and
references cited therein.
(1) For the isolation of the halichondrins from a marine sponge
Halichondria okadai Kadota, see: (a) Uemura, D.; Takahashi, K.; Yama-
moto, 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. For isolation of the halichondrins from different species of sponges,
see: (c) Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.;
Doubek, D. L.; Schmidt, J. M.; Cerny, R. J.; Hooper, J. N. A.; Ru¨tzler,
K. C. J. Med. Chem. 1991, 34, 3339. (d) 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. (e) Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.;
Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435. (f) Litaudon, M.;
Hickford, S. J. H.; Lill, R. E.; Lake, R. J.; Blunt, J. W.; Munro, M. H. G.
J. Org. Chem. 1997, 62, 1868. (g) Hickford, S. J. H.; Blunt, J. W.; Munro,
(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.; Buckanan, J. L.; Rovin, J. D.
Tetrahedron Lett. 1991, 32, 3961. Lambert, W. R.; 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.
PhytochemPhytopharm. 2000, 386, and references cited therein. (d) Hend-
erson, 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.
M. H. G. Bioorg. Med. Chem. 2009, 17, 2199
.
10.1021/ol9016589 CCC: $40.75
Published on Web 09/16/2009
 2009 American Chemical Society

intermediates. The results were sensational; their experiments
clearly demonstrated that the antitumor activity of halichon-
drin B resides in the right portion of the molecule. With this
crucial information,4 a massive drug discovery effort was
undertaken by ERI, resulting in two exceptional drug
candidates, one (E7389, Figure 1) of which is currently in
glucurono-6,3-lactone (3) as the starting material.2c This
synthesis relies on two key processes (Scheme 1). First, the
Scheme 1. Two Key Processes Used in the First-Generation
Synthesis of C27-C35 Building Block 4 from
1,2-O-Isopropylidene-R-D-5-deoxyglucurono-6,3-lactone2c
C34/C35-diol was incorporated via catalytic asymmetric
dihydroxylation. Asymmetric dihydroxylation of terminal
olefins is known to often proceed with relatively low
asymmetric induction; for the case of 5, asymmetric dihy-
droxylation was best achieved with Sharpless (DHQ)2PYR
to yield a 3:1 mixture of the C34 diastereomers.7,8 Fortu-
nately, the undesired C34-diastereomer was effectively
removed by crystallization of 6. Second, the C30 stereocenter
was stereospecifically introduced via NaBH(OAc)3 reduction
under the influence of the C31 hydroxyl group, cf. 7 f 8.9
For this reason, the synthesis was carried out with the C31
hydroxyl group protected as a benzyl ether.
Although lengthy, the first-generation synthesis has at-
tractive features, including the high overall yield and only
one required chromatographic purification. In this paper, we
report two major modifications that make this synthesis even
more practical.
As outlined in Scheme 1, we utilized the C31-hydroxyl
group to stereoselectively reduce the R,ꢀ-unsaturated phe-
nylsulfone. In principle, either the C27- or C34-hydroxyl
group could serve the same purpose, but a molecular model
analysis suggested that the C27-hydroxyl group might give
a better chance of success. If successful, we could eliminate
two steps required for the temporary protection/deprotection
of the C31-hydroxyl group (Scheme 1). Then, our concern
was how effectively the desired C34-diastereomer could be
isolated after the asymmetric dihydroxylation. We made a
primitive, and wishful, assumption that, because of their
structure similarity, C and D (Scheme 2) might exhibit the
Figure 1. Structure of halichondrin B and E7389, an analogue of
the right half of halichondrin B.
the late stage 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 the best of our knowledge, the structural complexity
of the right half of halichondrin B, or E7389, exceeds by
far 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 Eisai’s drug candidate will play the
key role for ultimate success of this program. With this
analysis in mind, we have continued the synthetic studies
on the halichondrins.6 In this paper, we report a second-
generation synthesis of the E7389 C27-C35 building block,
which has several appealing features, including overall
efficiency, operational simplicity, and scalability.
In the first generation synthesis of E7389 C27-C35
building block, we chose 1,2-O-isopropylidene-R-D-5-deoxy-
(4) Kishi, Y.; Fang, F. G.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K.
U.S. Patent 5338866 and International Patent WO93/17650.
(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, and International Patent WO99/65894. (c)
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; pp 241-265. (d) E7389 website: http://
www.drugs.com/nda/e7389_080201.html.
(7) For a review on this subject, see: Kolb, H. C.; VanNieuwenhze,
M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483
.
(8) Asymmetric dihydroxylation of terminal olefins often suffers from
a low degree of asymmetric induction. Replacement of the terminal olefin
in 5 for the (E)-TMS-CHdCH- resulted in much-improved asymmetric
induction (dr ) 16:1) in the presence of (DHQ)2PYR.
(6) One of the research focuses has been the development and application
of catalytic asymmetric Cr-mediated coupling reactions. Recent results on
this subject will be reported in separate papers.
(9) For a review on substrate-directable chemical reactions, see: Hoveyda,
A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
Org. Lett., Vol. 11, No. 20, 2009
4517

Once again, we were delighted to observe that the R-C-
allylated product 11 derived from the desired, major product
formed in the dihydroxylation exhibited an excellent crystal-
linity, whereas the R-C-allylated product derived from the
undesired, minor product remained as oil. This remarkable
difference in chemical property allowed us to isolate stere-
ochemically homogeneous 11 (mp 112-113 °C; colorless
needles) by simple crystallization in >55% overall yield from
3. The 1H NMR spectra included in Supporting Information
illustrate the exceptional effectiveness to isolate 11.12
Although the major part of the new synthesis is very similar
to the first generation of synthesis, we should note that it
has several appealing features, including the overall yield
and operational simplicity.13,14 We routinely carried out the
synthesis of 11 from 3 on a 20 g scale without chromato-
graphic purification, except for filtration through a silica gel
pad (one to two times the substrate weight).
Scheme 2. Two Key Questions in the New Synthesis
chemical property parallel to that of 6 and its C34-
diastereomer (Scheme 1), respectively, thereby allowing us
to isolate the desired C34 diastereomer C effectively by
simple crystallization.
In order to test the assumption mentioned above, single
crystals of 6 and 11 were grown and subjected to X-ray
analysis, thereby revealing that their crystal packing is very
different from each other (Figure 2). After all, the wishful
notion was simply premature and incorrect.
The synthesis began with 1,2-O-isopropylidene-R-D-5-
deoxyglucurono-6,3-lactone (3). Following the previous
route, except the O-methylation step, 3 was uneventfully
converted to 9 in three steps (Scheme 3). As with the benzyl
Scheme 3
.
Second-Generation Synthesis of E7389 C27-C35
Building Block
Figure 2. X-ray structures of 6 and 11. For their crystal-packing
mode, see the Supporting Information.
Dess-Martin oxidation15 of 11, followed by Horner-
Emmons reaction with PhSO2CH2P(O)(OEt)2/LiHMDS in
toluene,2c furnished the corresponding R,ꢀ-unsaturated phe-
nylsulfone as a 30:1 mixture of the Z/E-isomers (Scheme
4). There are two potentially enolizable sites in the ketone
and R,ꢀ-unsaturated phenylsulfone, but no epimerized prod-
uct was detected in this transformation. The terminal olefin
was selectively cleaved, followed by reduction, to furnish
the primary alcohol 12 as a 30:1 Z/E-mixture.
We planned to use the C27-hydroxyl group to reduce the
R,ꢀ-unsaturated phenylsulfone from the concave face, based
series, catalytic asymmetric dihydroxylation of 9 was best
achieved with Sharpless (DHQ)2PYR,10 to give a 3:1 mixture
of the C34 diastereomers, which was directly subjected to
benzoylation and then C-allylation. It should be noted that
this C-allylation is closely related to an example reported in
the literature11 and that, under the specified conditions, the
R-/ꢀ-selectivity was estimated to be at least 60:1 (1H NMR).
(12) This crystallization was also effective to isolate the stereochemically
homogeneous 11 from a 1:1 mixture of the C34 diastereomers obtained
via osmylation with OsO4/NMO (22% overall yield from 3).
(13) In the new synthesis, the overall yield of 3 f 13 was 45%, whereas
that of 3 f the intermediate synthetically equivalent to 13 was 13% in the
previous synthesis. The over three-time improvement in overall yield is
primarily attributed to (1) higher overall yield from 3 to 11, (2) elimination
of the benzylation (90%)/debenzylation (75%) steps, and (3) higher
efficiency of the hydroxyl-directed reduction (vide infra).
(14) The C31 BnO-deprotection required FeCl3 or TMS-I under the
carefully monitored conditions. In addition, only (Z)-R,ꢀ-unsaturated
phenylsulfone was efficiently reduced under the hydroxyl-directed NaB-
H(OAc)3 in the previous synthesis, whereas both (Z)- and (E)-R,ꢀ-
unsaturated phenylsulfones were smoothly reduced in the new synthesis
(vide infra).
(10) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (b) Sharpless, K. B.;
Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.;
Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org.
Chem. 1992, 57, 2768. (c) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang,
Z.-M.; Xu, D.; Sharpless, K. B. J. Org. Chem. 1992, 58, 3785. (d) Becker,
H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 448.
(11) Garcia-Tellado, F.; Armas, P.; Marrero-Tellado, J. J. Angew. Chem.,
Int. Ed. 2000, 39, 2727.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(16) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
4518
Org. Lett., Vol. 11, No. 20, 2009

Scheme 4
.
Second-Generation Synthesis of the E7389
C27-C35 Building Block
Scheme 5. Three Substrates Studied for the C27-Hydroxyl
Group Directed Hydrogenation in the Presence of Crabtree
Catalyst E
In summary, a practical route has been developed to
synthesize E7389 C27-C35 building block 13 from 1,2-O-
isopropylidene-R-D-5-deoxyglucurono-6,3-lactone (3). This
synthesis relies on two key processes: (1) the C34/C35-diol
is introduced via asymmetric dihydroxylation with dr ) 3:1,
with the undesired C34-diastereomer effectively removed by
crystallization of 11, and (2) the C30 PhSO2CH2 group is
introduced with high stereoselectivity (>100:1) via the
Stork-Kahne hydrogenation of 12 in the presence of
Crabtree catalyst E. Except for filtration through a silica gel
pad (one to two times the substrate weight), this synthesis
is practically free from chromatographic separation.
on literature precedent reported by Stork and Kahne.16
Indeed, hydrogenation of 12 in the presence of Crabtree
catalyst E17 (Scheme 5) in methylene chloride at 0 °C
smoothly proceeded to furnish the C27-C35 building block
13 in 95% yield with a >100:1 stereoselectivity (1H NMR).
The C30 stereochemistry of 13 was assigned first by NOE
studies and later confirmed by X-ray analysis of its 3,5-
dinitrobenzoate. We should note that, if needed, the protect-
ing group of 13 can be easily adjusted in two steps, cf.,
13 f 14.18
It is noteworthy that Crabtree catalyst E exhibited a high
tolerance against the functional groups present in the current
system. For example, both Z- and E-geometric isomers of
12 were smoothly reduced to furnish 13 with a >100:1
stereoselectivity (Scheme 5).14 R,ꢀ-Unsaturated phenylsul-
fones with C34/C35 bis-TBS were reduced well, to give the
desired, expected product in a high stereoselectivity, cf., 15
f 16. Similarly, the reduction of R,ꢀ-unsaturated esters gave
the expected product in a high yield, cf., 17 f 18.
Acknowledgment. Financial support from the National
Institutes of Health (CA 22215) and Eisai Research Institute
is gratefully acknowledged. We thank Drs. T. Sasaki and
C.-G. Dong in this laboratory for collecting the spectroscopic
data for some of the synthetic intermediates.
Supporting Information Available: Experimental details
and analytical data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Crabtree, R. H.; Felkin, H.; Fellebeen-Khan, T.; Morris, G. E. J.
Organomet. Chem. 1979, 168, 183.
(18) In the previous syntheses, we used 14 and 16 as the C27-C35
building block. However, our recent studies demonstrate that 13 is an ideal
C27-C35 building block (ref 6).
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