A novel route to the F-ring of halichondrin B. Diastereoselection in Pd(0)-mediated meso and C2 diol desymmetrization

Article abstract of DOI:10.1021/ol026504e

(matrix presented) Both σ and C₂ symmetric diol diacetates were synthesized via two-directional chain elongation. A palladium-mediated, ligand-controlled C₂ diol desymmetrization provided the desired tetrahydrofuran with the correct

Full text of DOI:10.1021/ol026504e

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3411-3414
A Novel Route to the F-Ring of
Halichondrin B. Diastereoselection in
Pd(0)-Mediated meso and C Diol
2
Desymmetrization
Lei Jiang and Steven D. Burke*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received July 11, 2002
ABSTRACT
Both σ and C symmetric diol diacetates were synthesized via two-directional chain elongation. A palladium-mediated, ligand-controlled C
2
2
diol desymmetrization provided the desired tetrahydrofuran with the correct relative and absolute stereochemistries. Simple functional group
manipulation led to the desired F-ring of halichondrin B. Desymmetrization of the meso substrate enantioselectively provided the diastereomer,
leading to a refinement of our understanding of the transition state model.
Halichondrins are a family of eight polyether macrolides that
were isolated from marine sponges.1 Among them, halichon-
drin B (Figure 1) was found to possess the most potent
biological activity. It displays an in vitro IC50 value of 0.3
nM against L1210 leukemia, as well as remarkable in vivo
activities against various chemoresistant human solid tumor
xenographs. Potent activity against LOX melanoma, KM20L
colon, FEMx melanoma, and OVCAR-3 ovarian cancer cell
lines has been observed.2
The National Cancer Institute has recommended halichon-
drin B for stage A preclinical trials,2c but limited availability
has made it difficult to proceed. Synthetic efforts have been
devoted to halichondrin B by several groups, highlighted by
Kishi’s total synthesis.3 Recently, it was reported that the
(1) For isolation, see: (a) Hirata, Y.; Uemura, D. 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.; Rutzler,
K. C. J. Med. Chem. 1991, 34, 3339. (c) Pettit, G. R.; Ichihara, Y.; Wurzel,
G.; Williams, M. D.; Schmidt, J. M.; Chapuis, J. C. J. Chem. Soc., Chem.
Commun. 1995, 383. (d) Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.;
Doubek, D. L.; Boyd, M. R.; Schmidt, J. M.; Chapuis, J.; Hamel, E.; Bai,
R.; Hooper, J. N. A.; Tackett, L. P. J. Org. Chem. 1993, 58, 2538. (e)
Pettit, G. R.; Gao, F.; Doubek, D. L.; Boyd, M. R.; Hamel, E.; Bai, R.;
Schmidt, J. M.; Tackett, L. P.; Rutzler, K. C. Gazz. Chim. Ital. 1993, 123,
371. (f) Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.; Munro, M. H.
G. Tetrahedron Lett. 1994, 35, 9435.
Figure 1.
10.1021/ol026504e CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/04/2002

C1-C38 fragment possesses a potency similar to the natural
product.3a Our group has successfully synthesized segments
of halichondrin B including C1-C15, C20-C36, and C37-
C54.4 Herein we would like to report our synthesis of the
C14-C22 portion of halichondrin B, comprising the F-ring
of the natural product.
because they are less substrate-limited. Chiral palladium
reagents have been used extensively in desymmetrization
reactions.7 We present herein the further development and
application of this tactic, which leads to a better understand-
ing of the transition state of Pd/DPPBA8-catalyzed allylation
reactions.
Retrosynthetically (Scheme 1), the F-ring of halichondrin
B is viewed as a bridge between the C1-C13 and C23-
Two-directional synthesis by simultaneous chain homolo-
gation and terminus differentiation5 has been one of our main
strategies in the synthesis of complex natural products.6 It
offers not only intrinsic efficiency in skeleton synthesis but
also the possibility of higher enantio- and diastereoselectivity.
One possibility involves the synthesis of a meso symmetric
intermediate. Differentiation of the termini can be simplified
as a result of the fact that the two ends are enantiotopic. Of
the methods commonly employed in the desymmetrization,
enzymatic or chemical, the latter have the obvious advantage
Scheme 1. Retrosynthetic Analysis
(2) For biological activities, see: (a) Hamel, E. H. Pharmacol. Ther.
1992, 55, 31. (b) Bai, R.; Paull, K. D.; Herald, C. L.; Malspeis, L.; Pettit,
G. R.; Hamel, E. J. Biol. Chem. 1991, 266, 15882. (c) Luduena, R. F.;
Roach, M. C.; Prasad, V.; Pettit, G. R. Biochem. Pharmacol. 1993, 45,
421. (d) Pettit, G. R. Pure Appl. Chem. 1994, 66, 2271.
(3) For synthesis of halichondrin B, see: (a) Stamos, D. P.; Chen, S. S.;
Kishi, Y. J. Org. Chem. 1997, 62, 7552. (b) Kishi, Y.; Fang, F. G.; Forsyth,
C. J.; Scola, P. M.; Yoon, S. K. U.S. Patent 5,436,238, 1995. (c) Wang,
Y.; Habgood, G. J.; Christ, W. J.; Kishi, Y.; Littlefield, B. A.; Yu, M. J.
Bioorg. Med. Chem. Lett. 2000, 10, 1029. (d) Towle, M. J.; Salvato, K. A.;
Budrow, J.; Wels, B. F.; Kuznetsov, G.; Aalfs, K. K.; Welch, S.; Zheng,
W.; Seletsky, B. M.; Palme, M. H.; Habgood, G. J.; Singer, L. A.; DiPietro,
L. V.; Wang, Y.; Chen, J. J.; Quincy, D. A.; Davis, A.; Yoshimatsu, K.;
Kishi, Y.; Yu, M. J.; Littlefield, B. A. Cancer Res. 2001, 61, 1013. (e)
Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463. (f) 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. (g) Buszek, K. R.; Fang, F.
G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y. Tetrahedron Lett. 1992, 33, 1553-
1556. (h) Duan, J. J. W.; Kishi, Y. Tetrahedron Lett. 1993, 34, 7541-
7544. (i) Fang, F. G.; Kishi, Y.; Matelich, M. C.; Scola, P. M. Tetrahedron
Lett. 1992, 33, 1557-1560. (j) Stamos, D. P.; Kishi, Y. Tetrahedron Lett.
1996, 37, 8643-8646. (k) 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. (l) Kim, S.; Salomon,
R. G. Tetrahedron Lett. 1989, 30, 6279. (m) Cooper, A. J.; Salomon, R. G.
Tetrahedron Lett. 1990, 31, 3813-3816. (n) DiFranco, E.; Ravikumar, V.
T.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 3247. (o) Cooper, A. J.;
Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193-8196. (p) Horita,
K.; Hachiya, S.; Nagasawa, M.; Hikota, M.; Yonemitsu, O. Synlett 1994,
38-40. (q) Horita, K.; Nagasawa, M.; Hachiya, S.; Yonemitsu, O. Synlett
1994, 40-43. (r) Horita, K.; Sakurai, Y.; Nagasawa, M.; Hachiya, S.;
Yonemitsu, O. Synlett 1994, 43-45. (s) Horita, K.; Sakurai, Y.; Nagasawa,
M.; Maeno, K.; Hachiya, S.; Yonemitsu, O. Synlett 1994, 46-48. (t) Horita,
K.; Hachiya, S.; Ogihara, K.; Yoshida, Y.; Nagasawa, M.; Yonemitsu, O.
Heterocycles 1996, 42, 99-104. (u) Horita, K.; Nagasawa, M.; Hachiya,
S.; Sakurai, Y.; Yamazaki, T.; Uenishi, J.; Yonemitsu, O. Tetrahedron Lett.
1997, 38, 8965. (v) Horita, K.; Sakurai, Y.; Nagasawa, M.; Yonemitsu, O.
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Yamazaki, T.; Naitou, T.; Uenishi, J.; Yonemitsu, O. Chem. Pharm. Bull.
1997, 45, 1265-1281.
C36 subunits of the molecule. Given the success observed
in selectively accessing the (trans, threo, trans)- and (cis,
threo, cis)-bis(tetrahydrofuran) annonaceous acetogenin core
structures via DPPBA-mediated π-allyl palladium cycliza-
tion,9 we evaluated structure 1 in relation to that chemistry.
There exists an element of hidden meso or C2 symmetry
about C18 in 2a and 2b, respectively, in that the flanking
stereocenters (see 2a) at C17 and C19 are oppositely
configured and have three carbon extensions (C16-C14 and
C20-C22, respectively). We recognized the possibility of a
palladium-mediated, DPPBA-controlled desymmetrization
reaction to set the desired stereochemistries. It was envisioned
that the meso diol bis(allylic acetate) 3, which should be
accessible from cis-1,4-diacetoxy-2-cyclopentene, would only
undergo monocyclization and that the biscyclization product
would be too strained to form. According to the model
proposed by Trost and Toste, the C20 stereochemistry would
be controlled via one of the (R,R)-DPPBA π-allyl palladium
intermediates shown (Figure 2). Less obvious was which of
the two hydroxyl/distal allyl acetate pairs would be reactive.
Although the allyl acetate groups in meso 3 are enantiotopic,
involvement of the chiral ligand renders the two π-allyl
complexes in Figure 2 diastereomeric. We reasoned (incor-
rectly, vide infra) that there are two factors that favor the
transition state labeled Chelation: (1) a potentially favorable
interaction between palladium and adjacent free hydroxyl
in the Chelation Model; (2) the unfavorable steric interaction
between the palladium π-allyl complex and the spectator allyl
acetate chain in the Non-chelation model.
(4) (a) Burke S. D.; Jung, K. W.; Philips, J. R.; Perri, R. E. Tetrahedron
Lett. 1994, 35, 703. (b) Burke S. D.; Jung, K. W.; Lambert, W. T.; Philips,
J. R.; Klovning, J. J. J. Org. Chem. 2000, 65, 4070. (c) Burke, S. D.;
Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett. 1991, 32, 3961-3964. (d)
Burke S. D.; Zhang, G.; Buchanan, J. L. Tetrahedron Lett. 1995, 36, 7023.
(e) Burke S. D.; Philips, 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.; Royal Society of Chemistry: Cambridge, 1997; p 73. (e) Burke
S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem. 1998, 63, 8626-8627. (f)
Burke, S. D.; Austad, B. C.; Hart, A. C. J. Org. Chem. 1998, 63, 6770-
6771. (g) Austad, B. C.; Hart, A. C.; Burke, S. D. Tetrahedron 2002, 58,
2011.
(5) (a) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17.
(7) (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b)
Trost, B. M.; Dudash, Jr. J.; Hembre, E. J. Chem. Eur. J. 2001, 7, 1619.
(8) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545-
4554.
(b) Magnuson, S. R. Tetrahedron 1995, 51, 2167-2213.
(6) (a) Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett.
1991, 32, 3961-3964. (b) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org.
Chem. 1998, 63, 8626-8627.
(9) Burke, S. D.; Jiang, L. Org. Lett. 2001, 3, 1953-1955.
3412
Org. Lett., Vol. 4, No. 20, 2002

Figure 3. X-ray structure of carbamate 6.
philic hydroxyl and the hydrophobic phenyl group of the
ligand disfavored the proposed chelation transition state.
In light of these results, we revisited our retrosynthetic
analysis (Scheme 3) and recognized that the desired stereo-
chemistry could be set simply by switching the incipient C17
hydroxyl stereocenter on the starting diol diacetate, using 4
instead of 3. The palladium-mediated DPPBA controlled
desymmetrization reaction should be simplified since the two
ends of the chain are now identical. This C2 symmetric (R,R)-
diol diacetate 4 was expected to be available from the diene
diol 7.
Figure 2. T.S. Model for desymmetrization of meso 3.
Commercially available cis-1,4-diacetoxy-2-cyclopentene
(Scheme 2) was converted via a straightforward sequence
to the diacetate 3 via two-directional synthesis in good yield
and selectivity.10 The proposed desymmetrization of this
meso diol diacetate proceeded smoothly, providing the
tetrahydrofuran 5 (not 2a) as the major product. To determine
the stereochemical outcome of the desymmetrization, this
cyclized product was transformed to a carbamate in two steps
to provide the crystalline compound 6.
Scheme 3. Refined Analysis and T.S. Model for
Desymmetrization of C2 4.
Scheme 2. Attempted Cyclizations
The C2 symmetric diene diol 711 was straightforwardly
transformed into the desired diol diacetate 4 via two-
directional synthesis in 78% overall yield. Initially, attempted
desymmetrization resulted in competitive formation of the
double cyclization product along with the desired mono-
cyclized product. Gratifyingly, when the reaction temperature
was lowered to 0 °C, the proposed desymmetrization of this
C2 diol diacetate 4 proceeded smoothly, providing a 5:1
mixture of diastereomers (1H NMR). This mixture of
diastereomers was treated with p-methoxybenzyl trichloro-
As revealed in Figure 3, the undesired C17-C20 cis
stereochemistry resulted in the newly formed THF ring in
5. Apparently, an unfavorable interaction between hydro-
(11) For the synthesis of diene diol 7, see: Hoffmann, R. W.; Kahrs, B.
C.; Schiffer, J.; Fleischhauer, J. J. Chem. Soc., Perkin Trans. 2, 1996, 2407-
2413.
(10) For details, see Supporting Information.
Org. Lett., Vol. 4, No. 20, 2002
3413

acetimidate under acidic conditions. The desired p-meth-
oxybenzyl ether 8 was isolated as the major product (Scheme
4).
Scheme 4
Figure 4. NOE studies.
observable epimerization. To confirm the stereochemistry of
the THF ring, NOE experiments on both 11 and 12 (derived
from 5 in a similar way as 11 was from 2b) were performed
(Figure 4). The allylic alcohol 12 displayed significant
enhancement, whereas alcohol 11 did not show any NOE
between Ha and Hb. Isomerization of the allylic alcohol with
a cationic Ir catalyst gave aldehyde 1.13
In summary, an efficient synthesis of the C14-C22
segment of halichondrin B has been realized, featuring the
desymmetrization of a C2 symmetric diol diacetate via
palladium/(R,R)-DPPBA catalysis. In this context, a refined
understanding of the stereoselective desymmetrization of
meso and C2 symmetric substrates via this protocol has
emerged.
Acknowledgment. We thank the NIH [Grant CA74394
(S.D.B.)] for generous support of this research. The NIH (1
S10 RR08389-01) and NSF (CHE-9208463) are acknowl-
edged for their support of the NMR facilities of the
University of Wisconsin-Madison Department of Chemistry.
We thank Dr. Ilia Guzei for solving the crystal structure of
6. William D. Thomas is acknowledged for running the NOE
experiments, and we thank Joseph R. Martinelli for preparing
diene diol 7.
Selective hydroboration of the terminal alkene afforded
alcohol 9a, providing the functionality for the future coupling
of the C23-C36 subunit. Protection of the primary alcohol
as TBDPS ether 9b and subsequent removal of the PMB
group with DDQ gave the secondary alcohol 10. Oxidation
of the resulting alcohol 10 with Dess-Martin periodinane
proceeded uneventfully, providing the corresponding ketone.
The installation of the exo-methylene and concomitant
deacylation was accomplished with excess methylenetri-
phenylphosphorane to give allylic alcohol 11,12 without
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1-12 and crystal-
lographic data for compound 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL026504E
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Org. Lett., Vol. 4, No. 20, 2002