Total synthesis of the microtubule-stabilizing agent (-)-laulimalide

Article abstract of DOI:10.1021/ol010150u

(Figure Presented) The total synthesis of the potent microtubule-stabilizing anticancer agent (-)-laulimalide has been achieved in 27 steps and 2.9% overall yield. Notable features are the use of Jacobsen HDA chemistry for the enantioselective constructio

Full text of DOI:10.1021/ol010150u

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3149-3152
Total Synthesis of the
Microtubule-Stabilizing Agent
(−)-Laulimalide
Ian Paterson,* Chris De Savi, and Matthew Tudge
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ip100@cus.cam.ac.uk
Received July 13, 2001
ABSTRACT
The total synthesis of the potent microtubule-stabilizing anticancer agent (−)-laulimalide has been achieved in 27 steps and 2.9% overall yield.
Notable features are the use of Jacobsen HDA chemistry for the enantioselective construction of the side chain dihydropyran, a diastereoselective
aldol coupling using chiral boron enolate methodology, a Mitsunobu macrolactonization, and a Sharpless AE to introduce the epoxide onto
des-epoxy-laulimalide.
Laulimalide (1),1a also known as fijianolide B,1b is a unique
antimitotic macrolide, isolated from the Pacific sponges
Hyatella sp. and Spongia mycofijiensis and the Okinawan
sponge Fasciospongia rimosa,1c which potently inhibits the
proliferation of numerous cancer cell lines with IC50 values
in the low nanomolar range, while retaining activity against
multi-drug-resistant cancer cells. In the cell cycle, it initiates
mitotic arrest, micronuclei formation, and ultimately apop-
tosis. The full configurational assignment was determined
by X-ray crystallographic analysis.1c Laulimalide occurs with
the less active congener isolaulimalide (2), having micro-
molar IC50 values, which arises from facile epoxide opening
at C17 by the C20 hydroxyl group.
mediated drug resistance and more effective in stimulating
tubulin polymerization.3
Recently, both laulimalide and isolaulimalide were identi-
fied as sharing the same microtubule-stabilizing mechanism
of action2 as the clinically validated anticancer drug Taxol
(paclitaxel). Notably, laulimalide was found to be both
superior to Taxol in its ability to circumvent P-glycoprotein-
As with some other cytotoxic natural products (including
the epothilones,4 discodermolide,5 and the eleutherobins6),
(1) (a) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J.
J. Org. Chem. 1988, 53, 3644. (b) Quinoa, E.; Kakou, Y.; Crews, P. J.
Org. Chem. 1988, 53, 3642. (c) Jefford, C. W.; Bernardinelli, G.; Tanaka,
J.; Higa, T. Tetrahedron Lett. 1996, 37, 159.
(2) Schiff, P. B.; Horwitz, S. B. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
1561.
(3) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn, A.;
Davidson, B. S. Cancer Res. 1999, 59, 653.
(4) Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.;
Liesch, J.; Goetz, M.; Lazirides, E.; Woods, C. M. Cancer Res. 1995, 55,
2325.
10.1021/ol010150u CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/06/2001

laulimalide constitutes an entirely novel class of microtubule-
stabilizing antimitotic agent, with activities that may provide
therapeutic utility, particularly against multi-drug-resistant
cancers.
As the natural supply is restricted, an efficient and flexible
synthesis is essential to provide further material for biological
evaluation, along with access to novel analogues. Several
synthetic endeavors toward laulimalide have been des-
cribed,7a-k leading to various fragments, including an ad-
vanced macrolide core,8 with the first total synthesis achieved
recently by Ghosh and Wang.7h Herein, we report the second
total synthesis of (-)-laulimalide (1), which follows an
entirely different strategy.
isolaulimalide (2). Recognizing that des-epoxy-laulimalide
(3) possesses two allylic alcohols at C15 and C20, which are
pseudo-enantiomeric as well as being in different steric
environments, discriminating between them by hydroxyl-
directed asymmetric epoxidation (in a manner similar to a
kinetic resolution of a racemic allylic alcohol) was proposed
by using the Sharpless Ti(OiPr)4-tartrate protocol.9 The 20-
membered macrolide 3 would then be assembled from two
fragments of similar complexity, i.e., the C1-C14 subunit 4,
incorporating the trans-dihydropyran and (Z)-enoate, and the
C15-C27 subunit 5, incorporating the terminal dihydropyran
and a protected 1,2-anti diol (where the C19 center would
be inverted on Mitsunobu macrocyclization), which in turn
would be derived from 6 and 7.
Our synthetic plan (Scheme 1) relied on installing the
sensitive trans-epoxide of laulimalide (1) in the final step,
As outlined in Scheme 2, the asymmetric synthesis of the
dihydropyran unit 6, for incorporation into the C15-C27
Scheme 1
Scheme 2
subunit 5, exploited Jacobsen’s recently introduced hetero-
Diels-Alder (HDA) reaction,10 involving catalysis by the
preformed chromium(III) Lewis acid 10. Exposure of a neat
mixture of diene 9 and aldehyde 8 (in the presence of
molecular sieves) to catalyst 10 (5 mol %) gave the HDA
adduct 11 in >95% ee and 71% yield.11 Treatment of acetal
11 with Et3SiH in the presence of BF3‚OEt2 displaced the
anomeric methoxy group and deprotection gave the volatile
alcohol 12,11 which on Swern oxidation generated aldehyde
6 (58% over three steps).
without invoking protection of the C20 hydroxyl in the side
chain and, importantly, avoiding concomitant formation of
(5) (a) Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996, 3, 287.
(b) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R. E.;
Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35,
243.
(8) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 213.
(9) (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) Johnson, R.
A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH
Publishers: New York, 1993; p 103.
(10) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398.
(11) The enantiomeric purity was determined by Mosher ester analysis
of 12, while the configuration predicted from Jacobsen’s results was
confirmed by correlation with material prepared from (R)-glycidol:
(6) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.;
Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744.
(7) (a) Shimizu, A.; Nishiyama, S. Synlett 1998, 1209. (b) Shimizu, A.;
Nishiyama, S. Tetrahedron Lett. 1997, 38, 6011. (c) Ghosh, A. K.;
Mathivanan, P.; Cappiello, J. Tetrahedron Lett. 1997, 38, 2427. (d) Mulzer,
J.; Hanbauer, M. Tetrahedron Lett. 2000, 41, 33. (e) Ghosh, A. K.; Wang,
Y. Tetrahedron Lett. 2000, 41, 2319. (f) Ghosh, A. K.; Wang, Y.
Tetrahedron Lett. 2000, 41, 4705. (g) Dorling, E. K.; Ohler, E.; Mulzer, J.
Tetrahedron Lett. 2000, 41, 6323. (h) Ghosh, A. K.; Wang, Y. J. Am. Chem.
Soc. 2000, 122, 11027. (i) Nadolski, G. T.; Davidson, B. S. Tetrahedron
Lett. 2001, 42, 797. (j) Messenger, B. T.; Davidson, B. S. Tetrahedron
Lett. 2001, 42, 801. (k) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2001,
42, 3399.
3150
Org. Lett., Vol. 3, No. 20, 2001

Scheme 3
The methyl ketone 7 required for assembly of the full side
of the side chains using consecutive HWE reactions,8 the
(E)-enone 19 was submitted to reaction with Me2Zn in the
presence of catalytic Ni(acac)2.16 This resulted in clean
conjugate attack at the enone, generating a separable mixture
of adducts in 99% yield, favoring the desired (11R)-isomer
4 (62:38 dr).17
chain was prepared in a straightforward sequence (Scheme
3) on a multigram scale, starting from the diol 13, derived
from dimethyl (R)-malate.12 This involved Horner-Wad-
sworth-Emmons (HWE) olefination to give 14, followed
by conversion via alcohol 15 into ketone 7. Aldol coupling
of ketone 7 with aldehyde 6 was best performed using the
boron enolate, generated using (c-Hex)2BCl in the presence
of Et3N, followed by base-induced elimination of the adduct
via the corresponding mesylate, providing the (E)-enone 16
exclusively in 87% yield. Treatment of 16 with freshly
prepared Zn(BH4)2 led to chelation-controlled reduction,13
giving the allylic alcohol 17 cleanly with >97% diastereo-
selectivity.14 Following protection of 17 as the TBS ether,
the primary TBDPS ether was cleaved selectively using
TBAF buffered with AcOH. Dess-Martin oxidation of the
resulting alcohol then completed the C15-C27 subunit 5 (74%
over three steps).
At this point, the controlled aldol coupling of the two
subunits 4 and 5, installing the remote C15 stereocenter, was
addressed by use of a suitable chiral boron reagent (Scheme
5).18 Enolization of the ketone 4 with (+)-Ipc2BCl/Et3N in
Et2O, followed by addition of the enal 5 gave 20, as
predominantly the desired (15S)-adduct (81:19 dr; 87%
yield).
Following hydroxyl protection, the TBS ethers 21 (88%)
were converted readily into the corresponding seco-acids 22
(68%) by a sequence involving DIBAL reduction, Dess-
Martin periodinane and NaClO2 oxidation, and DDQ depro-
tection of the PMB ether. A Mitsunobu-type macrolacton-
ization19 of 22, mediated by DEAD/PPh3, then gave the 20-
membered macrolide 23 (along with the separable (15S)-
epimer in 68% combined yield) with inversion of the C19
configuration. Notably, this Mitsunobu protocol avoided any
complications of isomerization of the (Z)-enoate geometry.8
Introduction of the exocyclic methylene was then achieved
by exposure of ketone 23 to a Takai reagent system (CH2I2,
The corresponding C1-C14 subunit 4 was conveniently
prepared from the enantiomerically pure trans-dihydropyran
18 (Scheme 4), obtained by asymmetric boron aldol meth-
Scheme 4
(14) The (19R,20S) configurational assignment was confirmed by NOE
analysis of the PMP acetal obtained by DDQ treatment of 17:
(15) (a) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51,
9413. (b) Paterson, I.; Cumming, J. G.; Ward, R. A.; Lamboley, S.
Tetrahedron 1995, 51, 9393. (c) Paterson, I.; Watson, C.; Yeung, K. -S.;
Wallace, P. A.; Ward, R. A. J. Org. Chem. 1997, 62, 452.
(16) Luche, J.-L.; Petrier, C.; Lansard, J.-P.; Greene, A. E. J. Org. Chem.
1983, 48, 3837 and references therein.
(17) We are currently investigating a reagent-controlled version of this
conjugate addition reaction in the presence of suitable chiral ligand
modifiers. The (11R) configuration of the methyl-bearing stereocentre in
adduct 4 was established by conversion into laulimalide.
odology and employed earlier in our syntheses of swinholide
A15a,b and scytophycin C.15c Following sequential elaboration
(18) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Paterson,
I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996, 37, 8581.
(19) Mitsunobu, O. Synthesis 1981, 1.
(12) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067.
(13) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
Org. Lett., Vol. 3, No. 20, 2001
3151

Scheme 5
had spectroscopic and physical data (1H, 13C NMR, MS, IR,
Zn, TiCl4, PbI2),20 leading on deprotection with HF‚pyr to 3
(77%).
Completion of the total synthesis of laulimalide (Scheme
6) now required kinetic discrimination of the C15 and C20
HPLC, [R]20D -192 (c 0.2, CHCl3); cf. [R]20D -200 (c 1.03,
CHCl3)1c) identical in all respects to a natural sample kindly
provided by Professor Higa. Notably, the mild conditions
of this final Sharpless epoxidation step prevented the
formation of any detectable isolaulimalide (2). However, a
sample of isolaulimalide was readily prepared by exposure
of 1 to acid (CSA, CDCl3).
Scheme 6
In conclusion, this total synthesis of the potent microtu-
bule-stabilizing anticancer agent (-)-laulimalide (1) proceeds
in 27 steps and 2.9% overall yield (from diol 13). Notable
features are the novel use of Jacobsen HDA chemistry for
the enantioselective construction of the side chain dihydro-
pyran, a diastereoselective aldol coupling using our chiral
boron enolate methodology, a Mitsunobu macrolactonization,
and last, a highly effective Sharpless AE enabling the
controlled introduction of the epoxide onto the unsaturated
diol 3. Further optimization of the synthesis, as well as
application to the preparation of novel structural analogues
of laulimalide, is underway.
Acknowledgment. We thank the EPSRC (GR/N08520),
EC (HPRN-CT-2000-00018), and Queens' College, Cam-
bridge (Research Fellowship to C.D.S), and Merck for
support. We thank Prof. Tatsuo Higa (University of the
Ryukyus) for an authentic sample of laulimalide and copies
of NMR spectra.
allylic alcohols in 3, with hydroxyl-directed epoxidation9 of
only the C16 alkene contained within the macrocyclic ring.
Treatment of diol 3 with tBuOOH/Ti(OiPr)4 in the presence
of (+)-DIPT in CH2Cl2 at -27 °C for 15 h resulted in
controlled formation of a single epoxide product. On workup,
this led to isolation of (-)-laulimalide in 73% yield, which
Supporting Information Available: Spectroscopic data
for diol 3 and synthetic and natural (-)-laulimalide 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 5579. (b) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J.
Org. Chem. 1994, 59, 2668.
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