Synthesis of novel 11-desmethyl analogues of laulimalide by Nozaki-Kishi coupling

Article abstract of DOI:10.1021/ol049791q

As a first entry into structurally simplified analogues of the anticancer agent laulimalide, 11-desmethyl compounds 2 and 3 were selected by molecular modeling. The unfavorable diastereoselectivity in the key synthetic step, a Nozaki-Kishi coupling betwee

Full text of DOI:10.1021/ol049791q

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1293-1295
Synthesis of Novel 11-Desmethyl
Analogues of Laulimalide by
Nozaki−Kishi Coupling
,†
Ian Paterson,* Hermann Bergmann,† Dirk Menche,† and Albrecht Berkessel‡
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K., and
Institut fu¨r Organische Chemie der UniVersita¨t zu Ko¨ln, Greinstrasse 4,
D-50939 Ko¨ln, Germany
ip100@cam.ac.uk
Received February 5, 2004
ABSTRACT
As a first entry into structurally simplified analogues of the anticancer agent laulimalide, 11-desmethyl compounds 2 and 3 were selected by
molecular modeling. The unfavorable diastereoselectivity in the key synthetic step, a Nozaki−Kishi coupling between macrocyclic aldehyde 4
and vinyl iodide 5, was overcome either by use of catalytic amounts of DIANANE-type ligands or L-Selectride reduction of the derived enone.
This methodology should allow modular introduction of other, unnatural, side chains.
By sharing the same microtubule-stabilizing mechanism as
Taxol and having nanomolar growth inhibitory activity
against cancer cell lines, including multidrug resistant cells,
laulimalide (1, Scheme 1) presents a promising lead structure
for development of new anticancer agents.1,2 However, in
comparison to Taxol and other known microtubule-stabilizing
agents, laulimalide appears to have a different (and as yet
undefined) binding site on tubulin.3
In contrast, a limited range of analogues, relying primarily
on modifying the hydroxyls, the (Z)-enoate, or removal of
the epoxide, have been reported to date for SAR studies.1a,3,6
Herein, we report the total synthesis of 11-desmethyl-
laulimalide (2) and its methyl ether 3 by a novel approach,
relying on an asymmetric Nozaki-Kishi coupling of the
macrocyclic aldehyde 4 with dihydropyran containing vinyl
This unique biological profile, together with the low
natural abundance from its sponge sources, has triggered
numerous synthetic efforts which have culminated in a
multitude of total syntheses, including one from our group.4-6
(4) For reviews, see: (a) Crimmins, M. T. Curr. Opin. Drug DiscoVery
DeV. 2002, 5, 944. (b) Mulzer, J.; O¨ hler, E. Chem. ReV. 2003, 103, 3753.
(5) (a) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122, 11027.
(b) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973. (c)
Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 42, 796. (d) Paterson,
I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149. (e) Mulzer, J.; O¨ hler,
E. Angew. Chem., Int. Ed. 2001, 40, 3843. (f) Evev, V. S.; Kaehlig, H.;
Mulzer, J. J. Am. Chem. Soc. 2001, 123, 10764. (g) Crimmins, M. T.;
Stanton, M. G.; Allwein, S. P. J. Am. Chem. Soc. 2002, 124, 5958. (h)
Williams, D. R.; Mi, L.; Mullins, R. J.; Stites, R. E. Tetrahedron Lett. 2002,
43, 4841. (i) Nelson, S. G.; Chueng, W. S.; Kassick, A. J.; Hilfiker, M. A.
J. Am. Chem. Soc. 2002, 124, 13654. (j) Wender, P. A.; Hegde, S. G.;
Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 4956.
(6) (a) Ahmed, A.; Hoegenauer, K.; Enev, V. S.; Hanbauer, M.; Kaehlig,
H.; O¨ hler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026. (b) Wender, P. A.;
Hegde, S. G.; Hubbard, R. D.; Zhang, L.; Mooberry, S. L. Org. Lett. 2003,
5, 3507. (c) Gallagher, B. M., Jr.; Fang, F. G.; Johannes, C. W.; Pesant,
M.; Tremblay, M. R.; Zhao, H.; Akasaka, K.; Li, X.-y.; Liu, J.; Littlefield,
B. A. Bioorg. Med. Chem. Lett. 2004, 14, 575.
† University of Cambridge.
‡ Universita¨t zu Ko¨ln.
(1) (a) Mooberry, S. L.; Tien, G.; Hernandez, A. H.; Plubrukarn, A.;
Davidson, B. S. Cancer Res. 1999, 59, 653. (b) Cragg, G. M.; Newman,
D. J. J. Nat. Prod. 2004, 67, 232.
(2) (a) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642.
(b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J. J.
Org. Chem. 1988, 53, 3644. (c) Jefford, C. W.; Bernardinelli, G.; Tanaka,
J.; Higa, T. Tetrahedron Lett. 1996, 37, 159.
(3) Pryor, D. E.; O’Brate, A.; Bilcer, G.; Diaz, J. F.; Wang, Yu.; Wang,
Yo.; Kabaki, M.; Jung, M. K.; Andreu, J. M.; Ghosh, A. K.; Gianna-kakou,
P.; Hamel, E. Biochemistry 2002, 41, 9109.
10.1021/ol049791q CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/19/2004

Scheme 1
Scheme 2a
a Conditions: (a) [CuHPPh3]6, benzene (wet), rt; (b) Zn, TMSCl,
CH2I2, TiCl4, PbI2, THF; (c) TBAF/AcOH (pH 7), THF, 0 °C to
rt, 72 h, 82%; (d) (COCl)2 (15 equiv), DMSO (30 equiv), NEt3 (70
equiv), CH2Cl2, -78 to -10 °C.
Following our earlier route,5d the dihydropyran unit of the
authentic side chain of laulimalide was conveniently prepared
by application of the Jacobsen HDA reaction10 of aldehyde
10 and diene 11 (Scheme 3).5d After homologation of
iodide 5. Notably, this synthesis design should enable the
modular construction of a wide range of laulimalide ana-
logues with unnatural side chains.
Scheme 3a
Based on molecular modeling, 11-desmethyl analogues of
laulimalide were chosen as a first, promising series of
simplified structures.7 In particular, these were expected to
adopt conformations closely related to 1 in the presumably
crucial C1-C4 and C15-C20 regions.1a,6
To allow for a high degree of convergence, our synthesis
of the macrocyclic ring 4 (Scheme 2) was based on
previously established5c diastereoselective aldol coupling
using chiral boron enolate methodology of the C1-C14
subunit 7 with C15-C19 subunit 6, followed by a Mitsunobu-
type macrolactonization. Conjugate reduction of enone 8
using Stryker’s reagent8 and Takai methylenation9 of the
ketone group proceeded smoothly (77%) and allowed the
preparation of building block 9 in a reliable and scalable
process. This was transformed into aldehyde 4 by selective
deprotection to reveal the primary hydroxyl (TBAF/AcOH)
followed by Swern oxidation (60%).
a Conditions: (a) K2CO3, MeOH; (b) Cp2ZrHCl, CH2Cl2; I2.
aldehyde 12 with the Ohira-Bestmann reagent 13,11 hy-
drozirconation of the derived alkyne 14, and trapping of the
organometallic species with iodine,12 the vinyl iodide 5 was
obtained.
For the pivotal coupling of 5 with aldehyde 4, we chose
an asymmetric variant of the Nozaki-Kishi reaction,13
(7) The 3-dimensional structures of 1 and 2 were obtained by 10 000-
step Monte Carlo conformational searches with MacroModel 8.0 using the
MM2*-force field and the generalized Born/surface area (CB/SA) solvent
model and the crystal structure data of 12c as input geometries: (a)
Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Kiskamp, R.; Lipton, M.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440. (b) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson,
J. Am. Chem. Soc. 1990, 112, 6127. A series of closely related conformers
of 1 and 2 were found within 3.00 kcal/mol of the global minima both in
water and chloroform.
(8) Mahoney, W. S.; Brestensky, D. M., Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291.
(9) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668.
(10) Jacobsen, E. N.; Dossetter, A. G.; Jamison, T. F. Angew. Chem.,
Int. Ed. 1999, 38, 2398.
(11) (a) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
1996, 521. (b) Ohira, S. Synth. Commun. 1989, 19, 561.
(12) Schwartz, J.; Carr, D. B. J. Am. Chem. Soc. 1979, 101, 2927.
(13) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. (b)
Fu¨rstner, A. Chem. ReV. 1999, 99, 991. (c) Choi, H.-W.; Nakajima, K.;
Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett. 2002,
4, 4435.
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Org. Lett., Vol. 6, No. 8, 2004

Scheme 4a
a Conditions: (a) (R,R)-15 (10 mol %), CrCl2 (10 mol %), NiCl2 (2 mol %), NEt3 (20 mol %), Mn, TMSCl, THF; (b) TBAF/AcOH (pH
7), THF, 0 °C to rt; (c) CrCl2, NiCl2, THF/DMF; (d) (COCl)2, DMSO, NEt3, CH2Cl2, -78 to -10 °C; (e) L-Selectride, THF, -78 °C; (f)
HF/pyridine, THF; 0 °C to rt; (g) L-(+)-DIPT, Ti(OiPr)4, TBHP, 4 Å MS, CH2Cl2, -20 °C; (h) Me3O+BF4-, Proton Sponge, CH2Cl2.
developed by our groups using C2-symmetric DIANANE-
type salen ligands (Scheme 4).14 Employing catalytic amounts
of the chromium(II) complex of (R,R)-15, preformed in situ
using our previously reported protocol,14a overcame the
substrate selectivity in this coupling and gave allylic alcohol
16 with the desired configuration and useful levels of
stereoinduction (dr 78:22). In contrast, the matched reaction,
using (S,S)-15, almost exclusively gave the undesired 20-
epi-16 (dr 94:6, not shown). Notably, these addition reactions
represent one of the first examples of synthetically useful
levels of asymmetric induction being realized for catalytic,
enantioselective Nozaki-Kishi couplings in complex cou-
pling partners.13c With the recently developed14b efficient
large-scale enantioselective synthesis of the diamine back-
bone of 15 it is very promising to now develop and also
evaluate structural analogues of these novel salen-type
ligands. For preparative purposes, it proved convenient to
enhance the diastereomeric ratio in favor of 16 by a two-
step oxidation-reduction sequence via enone 17. Among the
reagents screened, L-Selectride gave optimal results with
respect to both chemo- and stereoselectivity.15,16 Subsequent
TBS deprotection followed by a highly selective Sharpless
epoxidation5d,e completed the synthesis of 11-desmethyl-
laulimalide (2). Its methyl ether 317 was prepared by utilizing
the same sequence after methylation of the C20-hydroxyl in
16. This derivative was selected to mitigate the inherent
intramolecular nucleophilicity of the C20-hydroxyl group
toward the epoxide (leading to isolaulimalide), which will
be crucial to transform laulimalide into a true drug candi-
date.18
In summary, based on conformational analysis, we have
prepared 11-desmethyl analogues of laulimalide representing
a structural simplification of this antimitotic macrolide. Our
convergent approach relies on separate construction of the
macrocyclic core and the side chain and assembly of these
two units by a Nozaki-Kishi reaction. For this coupling,
use of DIANANE-based salen ligands succeeded in over-
coming the undesired substrate facial bias in a mismatched
situation. This approach established herein should enable the
introduction of a variety of different side chains.
Acknowledgment. We thank the EC (HPRN-CT-2000-
00014 Research Training Network and Marie Curie Post-
doctoral Fellowship for H.B.), EPSRC (GR/N08520), and
Merck for support and Dr. Maria Silva (Cambridge) for
helpful discussions over the modeling studies.
Supporting Information Available: Full characterization
of all new compounds and copies of NMR spectra for 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Berkessel, A.; Menche, D.; Sklorz, C.; Schro¨der, M.; Paterson,
I. Angew. Chem., Int. Ed. 2003, 42, 1032. (b) Berkessel, A.; Schro¨der, M.;
Sklorz, C. A.; Tabanella, S.; Vogl, N.; Lex, J.; Neudo¨rfl, J. M. J. Org.
Chem. 2004, 69, in press.
OL049791Q
(15) Use of oxazaborolidine mediated borane reduction with (S)-18 gave
better diastereoselectivity but proceeded with only moderate yields.
(16) The configuration of 16 was deduced from model studies and is in
agreement with the expected selectivity of the Nozaki-Kishi reaction14a
and was further confirmed by the close similarity of the NMR data for 2
and 1 and their precursors.5d
(17) During the course of our studies, the Wender group disclosed the
synthesis and biological evaluation of the corresponding methyl ether of
laulimalide; see ref 6b.
(18) First, biological evaluation suggests 2 to be of very similar potency
to laulimalide, while 3 is less active. Full details will be reported elsewhere.
Org. Lett., Vol. 6, No. 8, 2004
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