Synthetic efforts toward the C22-C36 subunit of halichondrin B utilizing local and imposed symmetry

Article abstract of DOI:10.1021/ol0473400

(Chemical Equation Presented) The C22-C34 portion (2) of halichondrin B was synthesized from meso-symmetric bis-silyl protected cyclopentenediol (7) in 20 steps and 7% overall yield. This was accomplished through a two-directional synthesis/terminus diffe

Full text of DOI:10.1021/ol0473400

ORGANIC
LETTERS
2005
Vol. 7, No. 4
737-740
Synthetic Efforts toward the C22−C36
Subunit of Halichondrin B Utilizing
Local and Imposed Symmetry
Valerie A. Keller, Ikyon Kim, and Steven D. Burke*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received December 24, 2004
ABSTRACT
The C22−C34 portion (2) of halichondrin B was synthesized from meso-symmetric bis-silyl protected cyclopentenediol (7) in 20 steps and 7%
overall yield. This was accomplished through a two-directional synthesis/terminus differentiation strategy that proceeded via achiral, meso-
symmetric intermediates for eight steps and employed a Pd(0)-mediated asymmetric double cycloetherification to establish both tetrahydropyran
rings.
Halichondrin B (Figure 1) is the most potent member of the
halichondrin family of polyether macrolides and has been
tubulin polymerization by binding near the vinca domain.2
Because of its potential as an effective anticancer agent, the
National Cancer Institute has recommended halichondrin B
for stage A preclinical trials, although development has been
impeded by low isolated yield from natural sources.
Several efforts have been made to address the demand for
halichondrin B including aquaculture3 and total synthesis.
Kishi4,5 has published the only total synthesis of halichondrin
(1) (a) Hirata, Y.; Uemura, K. Pure Appl. Chem. 1986, 58, 701. (b) Pettit,
G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.; Doubek, D.
L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N. A.; Ru¨tzler, K. C. J. Med.
Chem. 1991, 34, 3339. (c) Pettit, G. R.; Gao, F.; Doubek, D. L.; Boyd, M.
R.; Hamel, E.; Bai, R.; Schmidt, J. M.; Tackett, L. P.; Ru¨tzler, K. Gazz.
Chim. Ital. 1993, 123, 371. (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.
Figure 1. Halichondrin B.
(2) (a) Bai, R.; Paull, K. D.; Herald, C. L.; Malspeis, L.; Pettit, G. R.;
Hamel, E. J. Biol. Chem. 1991, 266, 15882. (b) Hamel, E. Pharmacol. Ther.
1992, 55, 31. (c) Luduen˜a, R. F.; Roach, M. C.; Prasad, V.; Pettit, G. R.
Biochem. Pharmacol. 1993, 45, 421. (d) Roberson, R. W.; Tucker, B.; Pettit,
G. R. Mycol. Res. 1998, 102, 378.
(3) Munro, M. H. G.; Blunt, J. W.; Dumdei, E. J.; Hickford, S. J. H.;
Lill, R. E.; Li, S.; Battershill, C. N.; Duckworth, A. R. J. Biotechnol. 1999,
70, 15.
isolated from several different sponge genera in extremely
low yield (1.8 × 10-8 to 4.0 × 10-5 %).1 This high potency
is exemplified by its in vivo activity against various chemo-
resistant human solid tumor xenografts. Binding studies
showed that its mechanism of action is the inhibition of
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B to date and Yonemitsu6 and Salomon7 have each published
subunit syntheses. We have completed the synthesis of the
C1-C14,8 C14-C21,9 and C37-C5410 subunits, and in this
Letter we describe a route to the remaining C22-C3611
subunit of halichondrin B.
Our approach to this structurally complex natural product
has been to utilize both subunit convergence and imbedded
symmetry elements to significantly simplify the subunit
syntheses. The retrosynthesis (Scheme 1) of this G,H,I-ring
local meso-symmetry about C28, extending from C25
through C31, which would allow substrate-controlled, two-
directional synthesis. However, because C23 and C33 have
the same configuration, as do C24 and C32, reagent-con-
trolled introduction of these stereocenters in 3 via two-
directional synthesis was indicated. The construction of the
G- and H-rings in 3 was anticipated based on earlier success
with Pd(0)-mediated asymmetric double cycloetherification,13
leaving intermediate 4 to serve as the cyclization substrate.
Our previous efforts toward the G,H-ring system revealed
that introduction of the C32 oxygen functionality could not
be accomplished on the dihydropyran H-ring.14 Therefore,
the C32 hydroxyl would have to be installed prior to ring
formation to avoid this difficulty. Chiral cyclization precursor
4 could be obtained from meso-symmetric 5 after two-
directional chain extension, Sharpless asymmetric epoxida-
tion (SAE)15 to install the C24 and C32 oxygen functionalites,
and further two-directional chain extension. Finally, diol 5
could be formed from cis-4-cyclopentene-1,3-diol 616 through
two-directional elaboration.
Scheme 1. Retrosynthesis
The synthesis began with the known bis-silyl protected
cyclopentenediol (7),17 which was oxidatively cleaved and
exposed to the Still-Gennari18 reagent 8 to give the Z,Z-
diester 9 in good yield (Scheme 2). Reduction of the diester
Scheme 2
system (1) begins with the disconnection of the I-ring at C34
and differentiation of C23 and C33 vinyl groups to give 2.
It was envisioned that the C19 and C26 exo-methylenes in
halichondrin B could be introduced simultaneously at a late
stage in the synthesis in order to increase efficiency. It was
anticipated that imposing a full measure of stereochemical
and functional group symmetry, as in 3, would optimize a
two-directional synthesis strategy.12 Note that in 3 there is
(4) Synthesis of subunits: (a) Namba, K.; Jun, H.-S.; Kishi, Y. J. Am.
Chem. Soc. 2004, 126, 7770. (b) 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 therein.
(5) Total synthesis of halichondrin B: 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.
(6) Horita, K.; Nishibe, S.; Yonemitsu, O. Phytochem. Phytopharm. 2000,
386 and references therein.
(7) Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34,
8193 and references therein.
with DIBAL gave the bis(allylic alcohol) 10 in 83% overall
yield from 7. Hydroboration with BH3‚THF occurred selec-
tively according to Kishi’s empirical rule,19 establishing
(8) (a) Lambert, W. T.; Burke, S. D. Org. Lett. 2003, 5, 515. (b) Burke,
S. D.; Jung, K. W.; Lambert, W. T.; Phillips, J. R.; Kloving, J. J. J. Org.
Chem. 2000, 65, 4070. (c) Burke, S. D.; Phillips, J. R.; Quinn, K. J.; Zhang,
G.; Jung, K. W.; Buchanan, J. L.; Perri, R. E. In Anti-InfectiVes: Recent
AdVances in Chemistry and Structure-ActiVity Relationships; Bentley, P.
H., O’Hanlon, P. J., Eds.; The Royal Society of Chemistry: Cambridge,
1997; p 73. (d) Burke, S. D.; Jung, K. W.; Phillips, J. R.; Perri, R. E.
Tetrahedron Lett. 1994, 35, 703.
(9) (a) Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68,
1150. (b) Jiang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411.
(10) (a) Austad, B. C.; Hart, A. C.; Burke, S. D. Tetrahedron 2002, 58,
2011. (b) Burke, S. D.; Austad, B. C.; Hart, A. C. J. Org. Chem. 1998, 63,
6770.
(12) (a) Magnuson, S. R. Tetrahedron 1995, 51, 2167. (b) Poss, C. S.;
Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9.
(13) (a) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915. (b) Burke,
S. D.; Jiang, L. Org. Lett. 2001, 3, 1953.
(14) Quinn, K. J. Ph.D. Thesis, University of Wisconsin-Madison, 2000.
(15) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Katsuki, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(16) Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876.
(17) Theil, F.; Schick, H.; Winter, G.; Reck, G. Tetrahedron 1991, 47,
7569.
(11) (a) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63,
8626. (b) Burke, S. D.; Zhang, G.; Buchanan, J. L. Tetrahedron Lett. 1995,
36, 7023. (c) Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett.
1991, 32, 3961.
(18) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
738
Org. Lett., Vol. 7, No. 4, 2005

four stereocenters via substrate-controlled asymmetric induc-
tion to set the two stereotriads at C27-C25 and C29-C31
in 11. Selective protection of the C30 and C26 secondary
alcohols in 11 while leaving the primary alcohols at C32
and C24 unmasked was accomplished via the bis(p-meth-
oxybenzylidine acetal), which was reduced to the diol 5 with
DIBAL.20
Two-directional chain elongation of 5 via Horner-
Wadsworth-Emmons (HWE) olefination of the derived
dialdehyde and DIBAL reduction gave the meso-bis(allylic
alcohol) 13 (Scheme 3). Symmetry breaking in 13 was
in double SN2 displacement and reductive fragmentation of
the bis(iodo epoxide) using Zn powder in refluxing MeOH
provided bis(allylic alcohol) 15 in good yield. Cross-
metathesis employing the Grubbs catalyst 1621 occurred
readily to install both allylic acetates in 18.
Finally, cleavage of both TBS ethers using TBAF yielded
4, the double cycloetherification substrate. Treatment of
tetraol 4 with Pd2dba3‚CHCl3 and the Trost (R,R)-DPPBA
ligand 1922 established the bis(tetrahydropyran) G,H-rings
in 3 with control of the absolute stereochemistry at C23 and
C33 (Scheme 5). The stereochemistry of the product was
Scheme 3
Scheme 5
determined by 1D NOESY experiments, which gave the
enhancements shown in Figure 2.
accomplished via SAE15 at each allylic alcohol unit. This
(bis)epoxidation set the key C32 stereocenter along with
introduction of an extraneous oxygen at C24, resulting in
two sets of five contiguous stereocenters on the acyclic chain
in 14.
Installation of the allylic acetates needed for the Pd(0)-
mediated asymmetric double cycloetherification started with
the activation of the two primary alcohols in 14 as mesylates
(Scheme 4). Treatment of the dimesylate with NaI resulted
Scheme 4
Figure 2. 1D NOESY enhancements in 3.
At this point, differentiation of the C24 and C32 alcohols
was needed in order to activate the former for removal
(Scheme 6). The equatorial alcohol at C32 proved to be more
reactive than the axial alcohol at C24. Selective protection
using BzOH, DIC, and DMAP resulted in the ester 20 with
Org. Lett., Vol. 7, No. 4, 2005
739

This necessitated that the G-ring vinyl substituent be
converted into a spectator group to prevent any unwanted
cyclization and to allow subsequent elaboration of the C33
vinyl group. Selective Sharpless asymmetric dihydroxylation
of the C23 equatorial vinyl group over the C33 axial one27
was accomplished with the (DHQ)2AQN ligand28 to give the
diol, which was protected as an acetonide to furnish 22 in
moderate yield, accompanied by 30% recovery of 21.
Exposure of 22 to Ph3SnH and AIBN led to the deoxy-
genated product 2 in high yield. This resulted in the fully
functionalized G- and H-rings needed for the C22-C36
segment 1.
Scheme 6
In summary, C22-C34 intermediate 2 was synthesized
in 20 steps and 7% overall yield from the meso-symmetric
cyclopentene 7. Four of the stereogenic centers were set in
the hydroboration of diol 10 using substrate control to form
the stereotriads at C27-C25 and C29-C31. Desymmetri-
zation was accomplished by SAE, which set the key C32
oxygen stereocenter as well as introduction of an extraneous
alcohol at C24. Double cycloetherification to form the G-
and H-rings simultaneously occurred using Pd2dba3‚CHCl3
and Trost’s chiral ligand 19 to establish the C23 and C33
stereocenters. Finally, removal of the extra hydroxyl group
at C24 under Barton-McCombie conditions furnished the
fully elaborated G- and H-rings in 2.
no discernible formation of the regioisomeric benzoate. This
transformation allowed for the activation of the C24 alcohol
as a xanthate using standard conditions23 to give 21 in
excellent yield. Xanthate 21 was then treated with Ph3SnH24
and AIBN in refluxing benzene in order to promote the
Barton-McCombie deoxygenation;23 however, this resulted
in a mixture of unidentifiable products, all of which appeared
to be more polar than the starting 21. Precedent exists for
the deoxygenation of a homoallylic xanthate,25 but also for
its failure due to competing radical cyclization reactions.26
Acknowledgment. We thank the NIH [CA74394] for the
generous support of this work. The NIH (1S10 RR08389-
01) and NSF (CHE-9208463) are acknowledged for their
support of the NMR facilities at the University of Wisconsin-
Madison Department of Chemistry. Ramon O. Sanchez is
acknowledged for the preparation of early-stage intermedi-
ates.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 2-5, 9-18, and
20-22. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Kishi’s empirical rule: (a) Cha, J. K.; Christ, W. J.; Kishi, Y.
Tetrahedron 1984, 40, 2247. For theoretical studies on this model see: (b)
Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J. T.; Paddon-Row, M. N.
Tetrahedron 1984, 40, 2257. (c) Paddon-Row, M. N.; Rondan, N. G.; Houk,
K. N. J. Am. Chem. Soc. 1982, 104, 7162.
(20) Peng, Z.-H.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 6018.
(21) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
(22) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
(b) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992,
114, 9327.
(23) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(24) Newcomb, M. Tetrahedron 1993, 49, 1151.
OL0473400
(25) Honda, T.; Kametani, T.; Kanai, K.; Tatsuzaki, Y.; Tsubuki, M. J.
Chem. Soc., Perkin Trans. 1 1990, 1733.
(26) (a) Liu, P.; Panek, J. S. Tetrahedron Lett. 1998, 39, 6147. (b)
Mander, L. N.; Sherburn, M. S. Tetrahedron Lett. 1996, 37, 4255.
(27) Lucas, B. S.; Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965.
(28) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448.
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