Synthesis and biological evaluation of a des-dihydropyran laulimalide analog

Article abstract of DOI:10.1016/j.tetlet.2009.07.122

The preparation of a novel simplified Laulimalide analog via a highly convergent and efficient route and its biological evaluation are presented. The outlined route enables the synthesis of C₅-C₉ modified analog 2 and uses Julia-Koci

Full text of DOI:10.1016/j.tetlet.2009.07.122

Tetrahedron Letters 50 (2009) 5790–5792
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Tetrahedron Letters
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Synthesis and biological evaluation of a des-dihydropyran laulimalide analog
b
c
a,
Andreas Gollner a, , Karl-Heinz Altmann , Jürg Gertsch , Johann Mulzer
*
*
a Institute of Organic Chemistry, University of Vienna, Währingerstrasse 38, 1090 Vienna, Austria
b Institute of Pharmaceutical Sciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland
c Institute of Biochemistry and Molecular Medicine, Universtiy of Bern, Bühlstrasse 28, 3012 Bern, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of a novel simplified Laulimalide analog via a highly convergent and efficient route and
its biological evaluation are presented. The outlined route enables the synthesis of C5–C9 modified analog
2 and uses Julia–Kocienski olefination for fragment assembly and a regioselective Yamaguchi macrolact-
onization for ring closure. This strategy should be suitable for the generation of various new C5–C9 des-
dihydropyran laulimalide derivatives for further SAR studies.
Received 16 June 2009
Revised 14 July 2009
Accepted 22 July 2009
Available online 26 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Antitumor drugs
Total synthesis
SAR studies
Evans alkylation
Macrolactonization
The marine macrolide laulimalide (1, Fig. 1) was contemporane-
ously isolated back in 1988 by two different groups from various
marine sources.1a,b It proved to be highly cytotoxic in the low
nanomolar range and induces microtubule polymerization similar
to the frontline antitumor drug paclitaxel.2
The outstanding biological properties were an incentive for to-
tal synthesis since natural sources are extremely limited. In fact,
different groups3 have achieved total syntheses of 1 and recently
also the total synthesis of its congeners isolaulimalide1 and neolau-
limalide1c was reported.3m,4 In recent years the search for simpli-
fied biologically active and more stable analogs of 1 has been
pursued with high intensity to identify an optimal clinical candi-
date.5 Unfortunately this endeavor has not proven successful so far.
Evaluation of previous results shows that the modification of
the C23–C27 side chain led to dramatically less active analogs.5e,g,i
Similarly, recently discovered natural members of the laulimalide
family with side chain variations exhibit significantly reduced
activity.1d Several other modifications led to inactive compounds
and so far, only des-epoxy laulimalide,3h,k,5a C20-OMe laulima-
lide,3k,5a C20-OAc laulimalide,3k C15-OAc laulimalide,3k and 11-
des-methyl laulimalide5b,f retain activity even though they are 10
to 40 times less active than 1.3,5
Figure 1. Structure of laulimalide (1) and the new analog 2.
fied analogs so far, we (as well as other groups)6 targeted our
efforts at this area. We now present a strategy for replacing the
C5–C9 trans-dihydropyran moiety by less complex motifs and illus-
trate this by the synthesis and biological evaluation of analog 2
(Fig. 1).
In Figure 2 it is shown which sections of 1 have been addressed
by various research groups in order to find active, simplified deriv-
atives. Since the C5–C9 region was not modified to generate simpli-
* Corresponding authors. Tel.: +43 4277 52190; fax: +43 1 42777 52189 (J.M.).
E-mail addresses: andreas.gollner@univie.ac.at (A. Gollner), johann.mulzer@
univie.ac.at (J. Mulzer).
Figure 2. Overview of previously modified areas of 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.122

A. Gollner et al. / Tetrahedron Letters 50 (2009) 5790–5792
5791
Scheme 3. Synthesis of analog 2. Reagents and conditions. (a) KHMDS, THF, ꢁ78 °C,
then 5 (78%); (b) nBuLi, CO2, then 7% HFꢀpyridine, THF, ꢁ78 °C to rt (82%); (c) 2,4,6-
Cl3C6H3C(O)Cl, NEt3, DMAP, benzene, rt (68%); (d) 35% HFꢀpyridine, THF, 0 °C to rt
(93%); (e) H2, Lindlar cat., quinoline, EtOAc/cyclohexene, rt (87%); (f) Ti(OiPr)4, (+)
DIPT, tBuOOH, 4 Å MS, CH2Cl2, ꢁ20 °C (67%). Abbreviations: DIPT, diisopropyl
tartrate; KHMDS, potassium bis(trimethylsilyl)amide; MS = molecular sieves.
Table 1
Inhibition of proliferationa
Cell line compound
MCF-7
PC-3 M IC50 (nM)
HCT-116
Laulimalide (1)
Analog 2
11.6 0.5
>10,000
5.9 0.3
>10,000
7.8 0.8
>10,000
a
Cells were treated with varying concentrations of the compounds for 72 h. The
values represent the means of three experiments SD.
Scheme 1. Retrosynthesis. Abbreviations: HWE, Horner–Wadsworth–Emmons olef-
ination; PT, 1-phenyl-1H-terazol; TBDPS, tert-butyldiphenylsilyl; TBS, tert-butyldi-
methylsilyl; TES, triethylsilyl.
iodide 14. Selective cleavage of the primary TBS-ether with NH4F
and final oxidation with IBX delivered fragment 5 in only six steps
from 8.
Fragment 5 was coupled with sulfone fragment 4 by a com-
pletely E-selective Julia–Kocienski8 olefination (no Z-product was
observed) to deliver the key fragment 3 in 78% yield (Scheme 3).
Seco acid 16 was prepared in a one pot-reaction: first the terminal
alkyne was converted to the acid by treatment of 3 with nBuLi and
quenching the anion with CO2; then HFꢀpyridine was added to
cleave both TES-ethers selectively. Macrolactonization under Yam-
aguchi conditions9 gave the 20-membered macrolide exclusively
and in good yields.3f Cleavage of the remaining TBS-protecting
group furnished compound 17. Finally Lindlar reduction to the la-
bile Z-enoate was followed by selective Sharpless epoxidation
(>20:1 dr) employing the established protocol to deliver the de-
sired analog 2.10,3c,h
Scheme 2. Synthesis of aldehyde fragment 5. Reagents and conditions: (a) NaI,
acetone, reflux, 2 h (98%); (b) NaHMDS, THF, ꢁ78 to ꢁ30 °C (85%); (c) LiBH4, H2O,
Et2O, 0 °C (97%); (d) NaH (2 equiv), DMF, 0 °C, then 14 (2 equiv), rt, 14 h (55%); (e)
NH4F, MeOH, rt, 30 h (90%, 68% conversion); (f) IBX, MeCN, reflux, 15 min (98%).
Abbreviations: Bn, benzyl; DMF, dimethylformamide; IBX, 2-iodoxybenzoic acid;
NaHMDS, sodium bis(trimethylsilyl)amide; THF, tetrahydrofuran.
Compound 2 was tested for its effect on the proliferation of se-
lected tumor cell lines using laulimalide (1) as a standard. Unfortu-
nately, 2 showed no cytotoxic activity (Table 1) and had no effect
in a tubulin polymerization assay as well.
In summary we described an effective, convergent, and com-
pletely stereoselective route to the simplified laulimalide analog 2.
This route in principle can be extended to a variety of related
C5–C9 modified compounds for further SAR studies. A first biological
evaluationof 2showedthattheactivityis lostwhentheC5–C9 dihyd-
ropyran moiety is removed, which suggests that it is part of the
pharmacophore region. Nevertheless more analogs have to be syn-
thesized to clarify the role of this specific region of laulimalide (1).
Compound 2 was selected, because it fits nicely into our estab-
lished approach.3m In fact, compared to our recent synthesis of 1,3m
the number of steps can be reduced by five including the costly
RCM and Brown allylation steps.7 In Scheme 1 we present our ret-
rosynthesis which utilizes our sulfone 4.3m,4 Aldehyde 5 is new and
should be available from allylic bromide 83m,4 or iodine 9.
The synthesis of 5 (Scheme 2) started from allylic bromide 8
which was obtained from the commercially available diol 10 in
four steps via a Kulinkovich reaction and subsequent cyclopro-
pyl-allyl rearrangement.3m,4 Evans alkylation of oxazolidinone 11
with bromide 8 gave a yield of 77% at 79% (>20:1 dr) conversion.
The yield was increased to 85% by using iodide 9, obtained from
8 by a Finkelstein reaction in almost quantitative yield. Reductive
cleavage of the auxiliary delivered alcohol 13. The ether formation
to form fragment 15 was accomplished in acceptable yields of 55%
by treatment of alcohol 13 with an excess of NaH and reaction with
Acknowledgments
Financial support from the Austrian Science Fund (FWF project
L202-N19) is gratefully acknowledged. We thank Dr. H. Kählig,
Dr. L. Brecker and S. Felsinger, Universität Wien, for NMR spectra
and M. Wartmann, Novartis AG, Switzerland, for providing the cell
lines for the cytotoxicity assays.

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A. Gollner et al. / Tetrahedron Letters 50 (2009) 5790–5792
Zhang, L., ; Wender, P. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8803–8804; (d)
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5.89 (ddd, J = 15.7, 5.4, 1.3 Hz, 1H), 5.85–5.82 (m, 1H), 5.75 (ddd, J = 15.6, 5.9,
1.4 Hz, 1H), 5.42 (br s, 1H), 5.16 (ddd, J = 11.0, 5.4, 2.1 Hz, 1H), 4.89 (br s, 1H),
4.88 (br s, 1H), 4.23–4.20 (m, 1H), 4.19–4.16 (m, 2H), 4.06–4.02 (m, 1H), 3.76–
3.72 (m, 1H), 3.45–3.40 (m, 2H), 3.34 (dd, J = 9.9, 4.1 Hz, 1H), 3.15–3.06 (m,
2H), 2.97 (ddd, J = 7.3, 5.1, 2.3 Hz, 1H), 2.84 (dd, J = 4.3, 2.2 Hz, 1H), 2.43–2.37
(m, 2H), 2.26 (dd, J = 14.4, 2.6 Hz, 1H), 2.20–2.17 (m, 1H), 2.15–2.10 (m, 2H),
2.07–2.00 (m, 2H); 1.95–1.86 (m, 3H), 1.85–1.78 (m, 1H), 1.69 (br s, 3H), 1.67–
1.58 (m, 2H), 0.79 (d, J = 6.7 Hz, 3H); 13C NMR: (125 MHz, CDCl3) d = 167.5,
151.8, 144.4, 134.2, 131.3, 128.7, 119.8, 119.1, 114.9, 76.2, 73.6, 73.1, 72.6,
69.8, 68.1, 65.6, 60.7, 54.1, 41.1, 38.4, 35.7, 33.9, 31.2, 26.6, 23.0, 16.3, 16.0; IR
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(cmꢁ1): 2925, 2852, 1717, 1261, 1020, 875; ½a D
ꢂ ꢁ51.2 (c 0.08, CHCl3); HR-MS
(ESI) calcd for C27H40O7Na [M+Na]+: 499.2672, found: 499.2684.