Halichondrin B: Synthesis of a C1-C14 model via desymmetrization of (+)-conduritol E

Article abstract of DOI:10.1021/ol027389a

(Matrix presented) A model C1-C14 segment (1) of halichondrin B was synthesized from (+)-conduritol E (7) in 18 steps and 2.9% overall yield. Key features of the synthesis include the novel ozonolytic desymmetrization of C₂-symmetric diol 6, th

Full text of DOI:10.1021/ol027389a

ORGANIC
LETTERS
2003
Vol. 5, No. 4
515-518
Halichondrin B: Synthesis of a C1−C14
Model via Desymmetrization of
(+)-Conduritol E
William T. Lambert and Steven D. Burke*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received December 2, 2002
ABSTRACT
A model C1−C14 segment (1) of halichondrin B was synthesized from (+)-conduritol E (7) in 18 steps and 2.9% overall yield. Key features of
the synthesis include the novel ozonolytic desymmetrization of C -symmetric diol 6, the early-stage construction of the C-ring which accompanies
2
installation of the crucial C12 stereocenter, and the use of an enol ether C14-ketone surrogate as a precursor to the CDE-“caged” ketal.
Halichondrin B (Figure 1) is the most potent member of a
family of cytotoxic polyether macrolides isolated in low yield
mechanism of action, halichondrin B displays potent in vivo
activity against various human solid tumor xenografts,
including LOX melanoma, KM20L colon, FEMX melanoma,
and OVCAR-3 ovarian tumors.2 It has also shown excellent
in vitro activity against L1210 leukemia (IC50 ) 0.3 nM).3
Although halichondrin B has been recommended for stage
A preclinical development by the National Cancer Institute
(NCI), the scarce supply available from natural sources has
made it difficult to proceed.
One potential solution to this supply issue lies in the work
of Munro and co-workers on the aquacultural production of
the marine sponge Lissodendoryx n. sp.4 However, it has
been noted that the generation of halichondrin B in quantities
D. L.; Boyd, M. R.; Hamel, E.; Bai, R.; Schmidt, J. M.; Tackett, L. P.;
Rutzler, K. Gazz. Chim. Ital. 1993, 123, 371-377. (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, 2538-2543. (e) Litaudon, M.; Hart, J. B.; Blunt, J. W.;
Lake, R. J.; Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435-9438.
(2) (a) Personal correspondence with M. R. Boyd, M.D., Ph.D., Cancer
Research Center, Frederick, MD, National Cancer Institute. Dr. Boyd shared
with us data and slides that resulted in the NCI Decision Network
Committee’s selection of halichondrin B for drug development. (b) Personal
correspondence with E. Hamel, M.D., Ph.D., National Institutes of Health,
National Cancer Institute. Dr. Hamel informed us that halichondrin B cures
in vivo human tumor xenografts transplanted in immune-deficient mice.
Figure 1. Halichondrin B.
(1.8 × 10-8% to 4.0 × 10-5%) from four different sponge
genera.1 As a mitotic inhibitor featuring a tubulin-based
(1) (a) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701-710.
(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.; Rutzler, K.
C. J. Med. Chem. 1991, 34, 3339-3340. (c) Pettit, G. R.; Gao, F.; Doubek,
10.1021/ol027389a CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/24/2003

of 5 kg/year for clinical use would require quantities of
sponge in excess of 5000 tons/year. Synthesis has also been
explored as a means of accessing the requisite amount of
natural product. Kishi and co-workers have reported syn-
theses of several subunits of halichondrin B5 and have
achieved the only total synthesis of this molecule to date.5h
Salomon6 and Yonemitsu7 have also published synthetic
approaches to halichondrin B. We have devoted considerable
effort to this endeavor as well,8 including a recent report of
a synthesis of the C1-C15 subunit in 16 steps and 0.6%
overall yield from inexpensive R-D-glucoheptonic acid
γ-lactone.8g In this paper, we describe the synthesis of the
known5b C1-C14 subunit model 1 from the C2-symmetric
natural product (+)-conduritol E.9
Scheme 1. Retrosynthetic Analysis of Caged Ketal 1
Our retrosynthesis of ketal 1 is depicted in Scheme 1.
Hydrolysis of the enol ether and silyl ether functionalities
of compound 2 was expected to lead directly to the 2,6,9-
(3) (a) Hamel, E. Pharmac. Ther. 1992, 55, 31-51. (b) Bai, R.; Paull,
K. D.; Herald, C. L.; Malspeis, L.; Pettit, G. R.; Hamel, E. J. Biol. Chem.
1991, 266, 15882-15889. (c) Paull, K. D.; Lin, C. M.; Malspeis, L.; Hamel,
E. Cancer Res. 1992, 52, 3892-3900. (d) Luduena, R. F.; Roach, M. C.;
Prasad, V.; Pettit, G. R. Biochem. Pharmacol. 1993, 45, 421-427. (e)
Roberson, R. W.; Tucker, B.; Pettit, G. R. Mycol. Res. 1998, 102, 378-
382.
(4) 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. Biotech. 1999,
70, 15-25.
(5) (a) Stamos, D. P.; Chen, S. S.; Kishi, Y. J. Org. Chem. 1997, 62,
7552-7553. (b) Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463-
3466. (c) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung,
S. H.; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992, 33, 1549-1552. (d)
Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Scola, P.
M.; Yoon, S. K. Tetrahedron Lett. 1992, 33, 1553-1556. (e) Fang, F. G.;
Kishi, Y.; Matelich, M. C.; Scola, P. M. Tetrahedron Lett. 1992, 33, 1557-
1560. (f) Duan, J. J.-W.; Kishi, Y. Tetrahedron Lett. 1993, 34, 7541-7544.
(g) Stamos, D. P.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8643-8646. (h)
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, 3162-3164.
(6) (a) Kim, S.; Salomon, R. G. Tetrahedron Lett. 1989, 30, 6279-6282.
(b) Cooper, A. J.; Salomon, R. G. Tetrahedron Lett. 1990, 31, 3813-3816.
(c) DiFranco, E.; Ravikumar, V. T.; Salomon, R. G. Tetrahedron Lett. 1993,
34, 3247-3250. (d) Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron
Lett. 1993, 34, 8193-8196.
(7) (a) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota, M.; Yonemitsu,
O. Synlett 1994, 38-40. (b) Horita, K.; Nagasawa, M.; Hachiya, S.;
Yonemitsu, O. Synlett 1994, 40-43. (c) Horita, K.; Sakurai, Y.; Nagasawa,
M.; Hachiya, S.; Yonemitsu, O. Synlett 1994, 43-45. (d) Horita, K.; Sakurai,
Y.; Nagasawa, M.; Maeno, K.; Hachiya, S.; Yonemitsu, O. Synlett 1994,
46-48. (e) Horita, K.; Hachiya, S.; Ogihara, K.; Yoshida, Y.; Nagasawa,
M.; Yonemitsu, O. Heterocycles 1996, 42, 99-104. (f) Horita, K.;
Nagasawa, M.; Hachiya, S.-i.; Sakurai, Y.; Yamazaki, T.; Uenishi, J.;
Yonemitsu, O. Tetrahedron Lett. 1997, 38, 8965-8968. (g) Horita, K.;
Hachiya, S.-i.; Yamazaki, T.; Naitou, T.; Uenishi, J.; Yonemitsu, O. Chem.
Pharm. Bull. 1997, 45, 1265-1281. (h) Horita, K.; Sakurai, Y.; Nagasawa,
M.; Yonemitsu, O. Chem. Pharm. Bull. 1997, 45, 1558-1572. (i) Yone-
mitsu, O.; Yamazaki, T.; Uenishi, J.-i. Heterocycles 1998, 49, 89-92. (j)
Horita, K.; Nagasawa, M.; Sakurai, Y.; Yonemitsu, O. Chem. Pharm. Bull.
1998, 46, 1199-1216.
(8) (a) Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett.
1991, 32, 3961-3964. (b) Burke, S. D.; Jung, K. W.; Phillips, J. R.; Perri,
R. E. Tetrahedron Lett. 1994, 35, 703-706. (c) Burke, S. D.; Zhang, G.;
Buchanan, J. L. Tetrahedron Lett. 1995, 36, 7023-7026. (d) Burke, S. D.;
Phillips, J. R.; Quinn, K. J.; Zhang, G.; Jung, K. W.; Buchanan, J. L.; Perri,
R. E. Synthetic Studies Toward Complex Polyether Macrolides of Marine
Origin. 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; pp 73-85. (e) Burke, S. D.;
Austad, B. C.; Hart, A. C. J. Org. Chem. 1998, 63, 6770-6771. (f) Burke,
S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626-8627. (g)
Burke, S. D.; Jung, K. W.; Lambert, W. T.; Phillips, J. R.; Klovning, J. J.
J. Org. Chem. 2000, 65, 4070-4087. (h) Burke, S. D.; Austad, B. C.; Hart,
A. C. Tetrahedron Lett. 2002, 58, 2011. (i) Jiang, L.; Burke, S. D. Organic
Lett. 2002, 4, 3411-3414.
trioxatricyclo[3.2.2.03,7]decane framework (the CDE-ring
“cage”) of 1 via dehydration of the ketodiol. We were
hopeful that the proximity of reactive functionality, enforced
by the pre-set stereochemical configuration at C12 (hali-
chondrin B numbering), would facilitate the desired ketal-
ization relative to our previous work,8g where low and
variable yields of caged ketal were attributed to poor control
over the C12 stereochemistry in the final one-pot deprotec-
tion/Michael addition/ketalization cascade. Deprotonation of
phosphonium salt 3 and reaction of the resultant ylide with
aldehyde 4 should lead to 2. Compound 4, in turn, should
be available from elaboration of γ-lactone 5. Recognizing
an element of local C2-symmetry in the C8-C11 portion of
5, we anticipated that it could be assembled from the C2-
symmetric (+)-conduritol E derivative 6 via a symmetry-
breaking oxidative cleavage of the carbon-carbon double
bond. The parent tetraol, (+)-conduritol E (7), is a known
natural product which can be readily prepared from L-diethyl
tartrate.9
Our synthesis commenced with the bis(silylation) of 7 with
TBDPSCl/py to provide diol 6 in good yield10 (Scheme 2).
Ozonolysis of 6 resulted in the formation of a dioxabicyclo-
[3.3.0]octane bearing a peroxyacetal residue at C12, which
readily suffered dehydration with Ac2O/Et3N to provide the
C7 hemiacetal 8 as a ca. 2:1 mixture of anomers. This
desymmetrization protocol combines Criegee’s tactic of
(9) (a) Jørgensen, M.; Iversen, E. H.; Paulsen, A. L.; Madsen, R. J. Org.
Chem. 2001, 66, 4630-4634. (b) Ackermann, El Tom, D.; Fu¨rstner, A.
Tetrahedron 2000, 56, 2195-2202. (c) Lee, W.-W.; Chang, S. Tetrahedron:
Asymmetry 1999, 10, 4473-4475.
(10) A regioisomeric diol was also isolated in 19% yield.
516
Org. Lett., Vol. 5, No. 4, 2003

Scheme 2. Fully Elaborated C-Ring Assembly
Scheme 3. B-Ring Assembly
trapping carbonyl oxides with suitably positioned internal
nucleophiles11 with Schreiber’s ozonolytic desymmetrization
of simple cycloalkenes.12 Protection of 8 with TESCl/
imidazole yielded lactone 5 as a single diastereomer, and
methylenation of 5 with dimethyltitanocene13 afforded enol
ether 9, which was purified by chromatography on silica gel
without decomposition. Treatment of 9 with borane-methyl
sulfide8h,14 followed by exposure to basic hydrogen peroxide
solution provided the desired 12(R)-hydroxymethyl-substi-
tuted C-ring 10 in good yield.15 Use of catecholborane gave
inferior yields, while 9-BBN failed to react with 9 altogether.
With the C-ring of the natural product installed, we
directed our attention to the installation of the B and A rings.
Pivaloate ester formation and triethylsilyl ether cleavage in
a one-pot procedure starting from 10 furnished hemiacetal
11 (Scheme 3). From this point, B-ring construction was
accomplished using methods previously employed by Kishi
for a similar C7 hemiacetal.5f,g One-carbon Wittig homolo-
gation with methoxymethylene(triphenylphosphorane) pro-
vided enol ether 12, which was subjected to catalytic
osmylation to give 13 as a ca. 5:1 mixture of anomers,
thereby setting the C7 carbinol center.16 This diastereomer
is predicted to be the major one based on Kishi’s empirical
rule.17 Acetylation of 13 was rather sluggish, presumably
due to the steric bulk of the C8 TBDPS ether, providing
diacetate 14 as a single diastereomer in acceptable yield.
Treatment of 14 with BF3‚OEt2 in the presence of the
known5g allylic silane 15 afforded compound 16 as a ca. 3:1
(E)- to (Z)-mixture of olefin isomers, which contains the
completed BC-ring system with a pendant â,γ-unsaturated
ester moiety at C6 as a handle for A-ring construction.
It was hoped that isomerization of the carbon-carbon
double bond in 16 to the R,â-unsaturated isomer would be
accompanied by acetate ester cleavage and Michael addition
of the resulting C7 alcohol to C3 of the enoate, thereby
completing construction of the A-ring. Although Triton-B
methoxide has traditionally been employed to effect similar
transformations,5f,g,8g the acetate ester of 16 proved resistant
to cleavage with this reagent. Attributing this sluggish
reactivity again to the adjacent TBDPS ether, these bulky
protecting groups were removed with TBAF buffered with
acetic acid (Scheme 4). Subsequent treatment with a basic
resin in methanol effected cleavage of the C7 acetate ester,
providing triol 17.18 Exposure of this material to 10 equiv
of DBU in refluxing toluene then afforded diol 18 as a single
stereoisomer. When this reaction was conducted in refluxing
benzene, a 2.9:1 mixture of 18 (major) and its C3 epimer
was isolated in 94% yield. Apparently, higher temperatures
are required to effect equilibration of this mixture via a retro-
Michael/Michael addition pathway to the thermodynamically
more stable isomer 18, in which the C3 substituent is
equatorially deployed with respect to the newly formed
A-ring. Pivaloate cleavage was effected with a basic resin
in refluxing methanol to give triol 19. Protection of 19 as
its tris(TES ether) and chemoselective oxidation of the
primary TES ether under Swern conditions19 then afforded
aldehyde 4.
(11) Criegee, R.; Banciu, A.; Keul, H. Chem. Ber. 1975, 108, 1642-
1654.
(12) Schrieber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982,
23, 3867-3870.
(13) (a) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141-144.
(b) For the preparation of dimethyltitanocene, see: Payack, J. F.; Hughes,
D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth. 2002, 79, 19-
26.
(14) Untersteller, E.; Xin, Y. C.; Sinay¨, P. Tetrahedron Lett. 1994, 35,
2537-2540.
(15) The C12 epimer of 11 was also isolated in 13% yield.
(16) The C7 epimer of 13 was also isolated in 22% yield.
(17) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247-
2255. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24,
3943-3946. (c) Christ, W. J.; Cha, J. K.; Kishi, Y. Tetrahedron Lett. 1983,
24, 3947-3950.
(18) A triol which had suffered C13 pivaloate migration was also isolated
in 8% yield. This compound could be converted to the ABC-ring diol 18
using DBU in refluxing PhCH3 as well.
Org. Lett., Vol. 5, No. 4, 2003
517

hydrolysis with p-TsOH in a mixture of CH2Cl2/MeOH/H2O
(ca. 4:2:1). We were pleased to observe the formation of
the desired CDE-caged ketal 1 in 67% yield (two steps from
Scheme 4. Synthesis of Aldehyde 4
1
4) under these conditions. The H NMR data for 1 were in
excellent agreement with those in the literature.5b Although
the acid-labile ketal was stable to these conditions for several
hours at ambient temperature,21 other conditions (aq HCl/
THF; aq HF/MeCN; p-TsOH/CHCl3) gave significant amounts
of C11-C14 furan byproducts. We have previously observed
this undesirable reactivity manifold with related substrates
and have discussed the mechanism elsewhere.8g
In conclusion, we have achieved the synthesis of the
known ketal 1 containing the ABCDE-ring system of
halichondrin B in 18 steps and 2.9% overall yield from (+)-
conduritol E (7). This work features a novel desymmetriza-
tion of C2-symmetric diol 6, an early-stage installation of
the densely functionalized C-ring, and takes advantage of
seldom-employed R-methoxyphosphorane chemistry to ex-
tend the carbon chain at C13 and set the stage for the crucial
caged ketal formation. The conjecture that control of the C12
stereocenter would improve the caged ketal formation was
validated by the clean, high-yielding conversion of 4 to 1.
With 4 in hand, we focused on the simultaneous chain
homologation of the C13 aldehyde and installation of an
appropriate C14 ketone precursor by a method adaptable to
subunit convergence in the total synthesis. For this purpose,
the phosphonium tetrafluoroborate salt 320 was deprotonated
with n-BuLi at -40 °C, and the resultant ylide was allowed
to react with aldehyde 4 at -78 °C followed by warming to
room temperature (Scheme 5). Enol ethers 2(Z) and 2(E)
Acknowledgment. We thank the NIH [Grant No. CA
74394 (S.D.B)] for their generous support of this work. An
NIH CBI training grant [5 T32 GM08505 (W.T.L.)] and an
Abbott Fellowship [133-4-CL09 (W.T.L.)] are also acknowl-
edged. The NIH (1S10 RR08389-01) and NSF (CHE-
9208463) are acknowledged for their support of the NMR
facilities of the University of WisconsinsMadison Depart-
ment of Chemistry. Russell H. Tobe and Christopher M.
Marvin are acknowledged for the preparation of early-stage
intermediates.
Scheme 5. Assembly of Caged Ketal 1
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1-6, 8-14, 16-
19, and unnumbered intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL027389A
(19) (a) Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1999, 40, 5161-5164. (b) For a review on the oxidative
deprotection of silyl ethers, see: Muzart, J. Synthesis 1993, 11-27.
(20) For a general preparation of R-methoxyalkyl triphenylphosphonium
tetrafluoroborates, see: (a) Tu¨ckmantel, W.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1986, 27, 5617-5618. (b) Coulson, D. R. Tetrahedron
Lett. 1964, 5, 3323-3326.
were isolated in 37% and 42% yield, respectively, after
chromatography on Florisil. Although we were successful
in separating and purifying these sensitive compounds, it was
more convenient to simply subject the crude mixture to acidic
(21) For a study on the acid lability of the halichondrins, see: Hart, J.
B.; Blunt, J. W.; Munro, M. H. G. J. Org. Chem. 1996, 61, 2888-2890.
518
Org. Lett., Vol. 5, No. 4, 2003