Synthesis of the macrocyclic core of laulimalide

Article abstract of DOI:10.1021/ol000342+

equation presented A stereoselective synthesis of 3, corresponding to the fully functionalized macrocyclic core of the novel microtubule-stabilizing agent, laulimalide, has been completed. Efficient macrolactonization was achieved by a Mitsunobu reaction,

Full text of DOI:10.1021/ol000342+

ORGANIC
LETTERS
2001
Vol. 3, No. 2
213-216
Synthesis of the Macrocyclic Core of
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 November 8, 2000
ABSTRACT
A stereoselective synthesis of 3, corresponding to the fully functionalized macrocyclic core of the novel microtubule-stabilizing agent, laulimalide,
has been completed. Efficient macrolactonization was achieved by a Mitsunobu reaction, installing the sensitive (Z)-enoate, and macrocyclic
stereocontrol was then exploited to introduce the methyl group and trans-epoxide.
Laulimalide,1a also known as fijianolide B,1b is a potent
cytotoxic macrolide with IC50 values in the nanomolar range
and is isolated from the Indonesian sponge Hyattella sp. and
the Okinawan sponge Fasciospongia rimosa.1c Its full
structure and absolute stereochemistry were determined to
be 1 by X-ray crystallographic analysis.1c Laulimalide has a
20-membered macrolide ring with two dihydropyran rings
and an acid-labile epoxide and contains nine stereogenic
centers and five double bonds. It co-occurs with the less
active, tetrahydrofuran-containing metabolite, isolaulimalide
(2), which is derived from 1 via epoxide opening at C17 by
the C20 hydroxyl group.
Recent studies2 have shown that laulimalide shares the
same mechanism of action3 as the anticancer drug Taxol
(paclitaxel) and, notably, is both more effective in stimulating
tubulin polymerization and in circumventing P-glycoprotein-
mediated drug resistance. Previously, only three other
nontaxane classes of natural products (the epothilones,4
discodermolide,5 and the eleutherobins6a/sarcodictyins6b) have
been identified that possess properties similar to those of
Taxol. Hence, laulimalide represents an entirely new class
(1) (a) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J.
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Org. Chem. 1988, 53, 3642. (c) Jefford, C. W.; Bernardinelli, G.; Tanaka,
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2325.
10.1021/ol000342+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/28/2000

of microtubule-stabilizing anticancer agents with activities
that may provide therapeutic utility. As the natural supply
from the sponge source is restricted, an efficient and flexible
synthesis of laulimalide is required in order to provide
material to further evaluate its anticancer activity, together
with that of novel structural analogues. To date, several
synthetic approaches to fragments of laulimalide have been
reported,7a-g,8 including a completed total synthesis by Ghosh
and Wang.7h Herein, we report a stereocontrolled synthesis
of 3, which corresponds to the fully functionalized macro-
cyclic core of laulimalide, employing a novel strategy.
By exploiting macrocyclic control,9 our planned route is
based around the sequential elaboration of the macrolide
template 4 (Scheme 1). We need to introduce into 4, in turn,
Scheme 2
Scheme 1
7 (used previously in the total synthesis of swinholide A10a,b
and scytophycin C10c), prepared by asymmetric aldol meth-
odology.11 Aldehyde 7 was converted directly into the (Z)-
enoate 8 using the Still-Gennari HWE variant12 in 92% yield
(Z/E 10:1). A marked decrease in Z:E selectivity was
observed if more than 1 equiv of KHMDS was used and if
the reaction temperature was not maintained at -78 °C
throughout. Presumably, this was due to base-mediated
isomerization of the enoate in 8. Benzoyl deprotection with
K2CO3 in MeOH, followed by Dess-Martin oxidation, gave
aldehyde 9 (75%, 2 steps). Homologation of aldehyde 9 in
a further HWE reaction13 provided the required subunit 5.
The preparation of the C15-C20 subunit is shown in
Scheme 3 and commences with the known diol 10,14 obtained
Scheme 3
(i) the isolated methyl-bearing stereocenter at C11 by
conjugate addition, (ii) the exocyclic methylene at C13, and
(iii) the sensitive C16-C17 trans-epoxide. An aldol discon-
nection at the C14-C15 bond in 4 and opening of the
macrolactone (with inversion at C19) leads back to the C1-
C14 and C15-C20 subunits 5 and 6, respectively. In this
modular approach, the two building blocks 5 and 6 selected
are relatively simple with one or two stereocenters and, as
such, should be readily prepared in multigram quantities. Key
concerns throughout were avoiding opening of the epoxide
to generate a tetrahydrofuran, as occurs in isolaulimalide (2),
and maintaining the cis-geometry of the enoate, as well as
securing the correct configuration at several of the stereo-
centers.
from dimethyl (R)-malate. Differential bis-protection of the
diol gave ether 11. DIBAL-mediated reduction at -100 °C,
followed directly by homologation of the resulting aldehyde
using Masamune-Roush HWE conditions,13 yielded the (E)-
enoate 12 (62%). Final reduction/oxidation provided the
required enal 6 in 82% yield.
The synthesis of the C1-C14 subunit 5 is outlined in
Scheme 2. This makes use of the enantiopure dihydropyran
Having both major subunits in hand, we turned to coupling
these together (Scheme 4). The aldol reaction between methyl
214
Org. Lett., Vol. 3, No. 2, 2001

Scheme 4
ketone 5 and enal 6 required the correct introduction of the
treatment with DDQ to cleave the PMB ether to give the
alcohol 16 (77%). Mitsunobu macrolactonization16 proceeded
smoothly to deliver macrocycles 4 and 17 (70% combined
yield after HPLC separation). This Mitsunobu protocol was
essential, as attempts to macrolactonize the C19-epi seco-
acid 18 (prepared according to Schemes 3 and 4 starting with
dimethyl (S)-malate), under both Yamaguchi17 and Keck18
conditions (Scheme 5), resulted in concomitant, base-
remote C15 stereocenter, necessitating the use of reagent
control.11a,b Boron aldol coupling using (+)-Ipc2BCl/Et3N in
Et2O gave 13 as a 3:1 mixture in favor of the desired (15S)-
1
adduct (91% combined yield), as confirmed by H NMR
analysis of the corresponding (R)- and (S)-MTPA esters using
the advanced Mosher method.15 Protection of the resultant
secondary hydroxy group gave the TBS ethers 14. Attempts
to hydrolyze the methyl ester by standard means (viz. KOH/
THF/MeOH, LiOH, Ba(OH)2, etc.) failed. Thus, a three-step
sequence of reduction with DIBAL, followed by Dess-
Martin oxidation and subsequent NaClO2 oxidation, was
employed to reveal the acid 15 in 85% yield, followed by
Scheme 5
(5) (a) Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996, 3, 287.
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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) Mulzer, J.; Ohler, E.; Dorling, K. E.
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(8) For a review on marine macrolide synthesis, see: Norcross, R. D.;
Paterson, I. Chem. ReV. 1995, 95, 2041.
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synthesis, see: (a) Still, W. C.; Novack, V. J. J. Am. Chem. Soc. 1984,
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induced, scrambling of the (Z)-enoate, leading to the
undesired trans-macrocycle 19 and the required macrocycle
4 (6:1 ratio, respectively).
(10) (a) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51,
9413. (b) Paterson, I.; Cumming, J. G.; Ward, R. A.; Lamboley, S.
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The controlled elaboration of the 20-membered macrolide
4 into the laulimalide core was now investigated (Scheme
(12) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
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Org. Lett., Vol. 3, No. 2, 2001
215

treatment of macrocycle 4 with Me2CuLi at -10 °C delivered
a single adduct in a highly selective manner (72%). In
contrast, the 15-epi macrolide 17 was relatively nonselective
in addition of Me2CuLi to the enone (1.7:1 mixture of
diastereomers). While the stereochemistry at C11 has not been
rigorously proven at this point, it is assigned in 20 as 11R
Scheme 6
1
on the basis of diagnostic H and 13C NMR resonances of
the laulimalide core (3) (see Supporting Information).
Introduction of the exocyclic methylene at C13 was achieved
by employing the Takai reagent (Zn/PbI2/CH2I2/TiCl4).20
Reaction of ketone 20 with excess reagent gave alkene 21
in 65% yield. Deprotection of both silicon protecting groups
occurred using HF‚pyr in THF, providing the macrocyclic
diol 22 in 90% yield. The stage was now set for the
controlled introduction of the C16-C17 trans-epoxide directed
by the adjacent C15 hydroxyl group. Sharpless epoxidation21
with (+)-DIPT gave solely epoxide 3 in 68% yield, achieved
without any detectable epoxide opening by the C20 hydroxyl
1
group (cf. 1 f 2). In the H (500 MHz, COSY) and 13C
NMR (125 MHz) spectra of 3, the data for all diagnostic
signals agreed with the corresponding data1c for laulimalide
(1), providing support for the stereochemical assignments
in Scheme 6.
In conclusion, the synthesis of the laulimalide core (3)
has been achieved in a stereoselective manner, exploiting
macrocyclic conformational bias in the installation of the
remote methyl-bearing stereocenter at C11. In addition, the
sensitive C2-C3 (Z)-enoate has been preserved throughout
the synthesis by careful selection of reagents and experi-
mental protocols. The synthesis of the macrolide core serves
a dual purpose of providing an advanced intermediate toward
laulimalide and entry into an array of analogues through the
attachment of various side chains at C20. Studies toward this
end are underway.
6). First, the diastereoselective methylation at C11 by
conjugate addition was required to proceed under macrocy-
clic stereocontrol to generate the desired (11R)-configuration.
Notably, MM2 calculations (MacroModel v4.5,19 Monte
Carlo) on the bis-TMS protected version of macrolide 4
(Figure 1) show that in the global minimum conformation
Acknowledgment. We thank the EPSRC (GR/N08520),
EC (HPRN-CT-2000-00018), and Queens’ College, Cam-
bridge (Research Fellowship to C.D.S), for support and Setu
Roday (Cambridge) for assistance with molecular modeling.
Supporting Information Available: Spectroscopic data
for diol 22 and epoxide 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL000342+
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Figure 1.
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one face of the s-trans enone double bond is exposed to
external reagents. Assuming this same conformational bias
extends to the reaction transition state, conjugate addition
of an appropriate organometallic reagent would be expected
to occur preferentially from the outer face of the alkene and
deliver the required stereochemistry at C11. In practice,
216
Org. Lett., Vol. 3, No. 2, 2001