A macrolactonization-based strategy to obtain microtuble-stabilizing agent (-)-laulimalide

Article abstract of DOI:10.1016/S0040-4039(01)00436-1

An alternative synthesis of anti-tumor macrolide (-)-laulimalide is described. The synthesis was achieved utilizing Yamaguchi macrolactonization as the key step. The sensitive C₂-C₃ cis-olefin functionality has been installed by a ma

Full text of DOI:10.1016/S0040-4039(01)00436-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3399–3401
A macrolactonization-based strategy to obtain
microtuble-stabilizing agent (−)-laulimalide
Arun K. Ghosh* and Yong Wang†
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 8 March 2001; accepted 15 March 2001
Abstract—An alternative synthesis of anti-tumor macrolide (−)-laulimalide is described. The synthesis was achieved utilizing
Yamaguchi macrolactonization as the key step. The sensitive C2–C3 cis-olefin functionality has been installed by a macrolactoniza-
tion of hydroxy alkynic acid and subsequent hydrogenation over Lindlar’s catalyst. © 2001 Elsevier Science Ltd. All rights
reserved.
Anti-tumor macrolide laulimalide (1), also known as
figanolide B, has been isolated from both the Indone-
sian sponge Hyattella sp. and the Okinawan sponge
Fasciospongia rimosa.1 It displays remarkable anti-
tumor activity against numerous NCI cell lines. It
displayed cytotoxicity against the KB cell line with an
IC50 value of 15 ng/mL. Furthermore, it has shown
cytotoxicity against P388, A549, HT29, and MEL28
cell lines in the range of 10–50 ng/mL (IC50 values).2
Laulimalide exhibits microtubule-stabilizing properties
similar to paclitaxel (Taxol™).3 One of the intriguing
properties of laulimalide is that it inhibits the P-glyco-
protein that is responsible for multiple-drug resistance
in tumor cells. Recently, it has been shown that it is as
much as 100-fold more potent than Taxol in multidrug-
resistant cell lines.3 Thus, laulimalide represents a new
class of microtubule-stabilizing agents with significant
clinical potential. The remarkable anti-tumor activity as
well as its unique structural features has stimulated
considerable interest in its synthesis and structure–func-
tion studies. Several synthetic approaches toward frag-
ments of laulimalide have been reported by us4 and
others.5 Recently we reported the first total synthesis of
(−)-laulimalide (1).6 The key macrocyclization step in
this synthesis involved an intramolecular Horner–
Emmons reaction of the C-19 bis-(trifluoroethyl) phos-
phonoacetate and C-3 aldehyde which provided a 1:2
mixture of C2–C3 cis/trans macrolactones (Fig. 1). The
isomers were separated and the major trans-isomer was
photoisomerized to the cis-isomer.6 In an effort to
install the C2–C3 cis-olefin geometry selectively, we now
have investigated an alternative macrolactonization
strategy. Herein, we wish to report a macrolactoniza-
tion route to laulimalide in which the sensitive C2–C3
cis-olefin functionality has been incorporated by
macrolactonization of a hydroxy alkynic acid followed
by hydrogenation of the resulting alkyne derivative.
First, we explored the possibility of macrolactonization
between the C-19 hydroxyl group and the C-1 alkenyl
acid utilizing Yamaguchi protocol.7 Selective prepara-
tion of this type of sensitive cis-alkenyl acid was previ-
Figure 1.
* Corresponding author.
† University Fellow (2000–2001), University of Illinois at Chicago.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00436-1

3400
A. K. Ghosh, Y. Wang / Tetrahedron Letters 42 (2001) 3399–3401
ously reported by Roush during the synthesis of verru-
carin B.8 Therefore, we elected to use a 2-(trimethyl-
silyl)ethyl ester as the blocking group for the C-1
carboxylic acid as it can be removed under mild condi-
tions. The corresponding precursor 5 for the synthesis
was prepared by Julia reaction of sulphone 4 with
aldehyde 2 as described previously (46% yield).6 Protec-
tion of the C-20 alcohol as a THP ether with dihy-
dropyran and a catalytic amount of PPTS in CH2Cl2,
followed by removal of the TBS group by treatment
with nBu4N+F− in THF afforded primary alcohol 6 in
76% yield (Scheme 1). Dess–Martin oxidation9 of the
alcohol, followed by Ando’s modified Horner–Emmons
F− in THF provided the hydroxy acid, the key macrolac-
tonization precursor, in 60% yield. Yamaguchi
lactonization7 of the hydroxy acid at 23°C, however,
resulted in a mixture of macrolactones 8 and 9 (65%,
E:Z ratio 2:1). Evidently, olefin isomerization occurred
during the macrolactonization reaction. Attempted
cyclization under a variety of reaction conditions (base,
acylating agent) did not improve the ratio of desired
Z-isomer. Roush previously reasoned that such olefin
isomerization is due to the reversible Michael addition
of the acylating catalyst (DMAP) to the active acylating
agent.8
reaction10
of
the
resulting
aldehyde
with
We then turned our attention to the macrolactonization
of the C-19 alcohol and C-1 alkynyl acid (Scheme 2).
Thus, protection of alcohol 106 as a THP ether, fol-
lowed by removal of TBS by reaction with nBu4N+F−
in THF furnished the alcohol 11. Dess–Martin oxida-
tion of the alcohol provided the aldehyde which was
(PhO)2P(O)CH2CO2SEM, KN(TMS)2 and 18-crown-6
at −78°C for 30 min provided the cis-a,b-unsaturated
1
ester 7 as a single isomer in 64% yield (by H NMR).11
Removal of the PMB-ether by DDQ and subsequent
deprotection of the SEM ester by exposure to nBu4N+
THP
O
OH
OH
MOM-O
MOM-O
H2C
O
O
PhO2S
O
b, c
a
H2C
Me
H
H
H
O
O
O
PMB
PMB
PMB
Me
Me
Me
5
Me
4
6
H
H
H
H
O
OTBS
O
OH
d, e
THP
THP
O
THP
O
O
MOM-O
H2C
O
MOM-O
H2C
O
O
MOM
H2C
Me
f - h
O
H
H
+
O
O
O
H
PMB
O
O
O
Me
Me
Me
SEM O
Me
Me
H
H
H
O
H
H
H
O
O
8
9
7
Scheme 1. (a) Ref. 6; (b) dihydropyran, PPTS, CH2Cl2; (c) TBAF, THF (76%); (d) Dess–Martin, CH2Cl2; (e) KN(TMS)2,
18-crown-6, (PhO)2P(O)CH2CO2SEM, THF, −78°C (64%); (f) DDQ, CH2Cl2, pH 7 buffer; (g) TBAF, THF (60%); (h)
Cl3PhCOCl, iPr2NEt, THF then DMAP, benzene (65%).
Scheme 2. (a) Dihydropyran, PPTS, CH2Cl2; (b) TBAF, THF (87%); (c) Dess–Martin, CH2Cl2; (d) CBr4, PPh3, CH2Cl2, 0°C; (e)
nBuLi, THF, −78°C then ClCO2Me, −78°C (59%); (f) CSA, MeOH; (g) LiOH, THF, H2O (74%); (h) Cl3PhCOCl, iPr2NEt, THF
then DMAP, benzene (68%); (i) H2, Lindlar’s catalyst, 1-hexene, EtOAc (94%).

A. K. Ghosh, Y. Wang / Tetrahedron Letters 42 (2001) 3399–3401
3401
subjected to Corey–Fuches homologation conditions12
using carbon tetrabromide and triphenylphosphine in
CH2Cl2 at 0°C for 30 min to afford the dibromo olfefin.
Treatment of the resulting dibromo olefin with nBuLi
at −78°C for 10 min afforded the alkynyl anion, which
upon treatment with methyl chloroformate at −78°C
for 30 minutes afforded alkynyl ester 12 in 59% yield
for the three-step sequence. Removal of the THP ether
by treatment with CSA in methanol, followed by
saponification of the methyl ester by exposure to
aqueous lithium hydroxide provided the precursor
hydroxy acid 13 in 74% yield. Yamaguchi macro-
lactonization7 of hydroxy acid 13 afforded lactone
14 in 68% isolated yield.13 Hydrogenation of lactone
14 over Lindlar’s catalyst in a mixture (1:1) of 1-hexene
and EtOAc for 1.5 h afforded the cis-macrolactone
15 as a single isomer (94% yield).14 The spectral proper-
ties of macrolactone 15 are in full agreement with
reported values.6 Macrolactone 15 was previously conver-
ted to synthetic (−)-laulimalide (1) by us.6
4. (a) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41,
4705; (b) Ghosh, A. K.; Wang, Y. Tetrahedron Lett.
2000, 41, 2319; (c) Ghosh, A. K.; Mathivanan, P.; Cap-
piello, J. Tetrahedron Lett. 1997, 38, 2427.
5. (a) Shimizu, A.; Nishiyama, S. Synlett 1998, 1209; (b)
Shimizu, A.; Nishiyama, S. Tetrahedron Lett. 1997, 38,
6011; (c) Mulzer, J.; Hanbauer, M. Tetrahedron Lett.
2000, 41, 33; (d) Mulzer, J.; Ohler, E.; Dorling, K. E.
Tetrahedron Lett. 2000, 41, 6323; (e) Paterson, I.; Savi, C.
D.; Tudge, M. Org. Lett. 2001, 3, 213; (f) Messenger, B.
T.; Davidson, B. Tetrahedron Lett. 2001, 42, 797; (g)
Nadolskir, G. T.; Davidson, B. Tetrahedron Lett. 2001,
42, 801.
6. Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122,
11027.
7. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 53, 1989.
8. (a) Roush, W. R.; Spada, A. P. Tetrahedron Lett. 1983,
24, 3693; (b) Roush, W. R.; Blizzard, T. A. J. Org. Chem.
1984, 49, 4332.
9. Meger, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59,
7549.
10. Ando, K. J. Org. Chem. 1999, 64, 8406 and references
cited therein.
11. The reagent, (PhO)2P(O)CH2CO2SEM was derived from
benzyl (diphenylphosphono)acetate which was prepared
by following the procedure of Ando.10 Catalytic hydro-
genation followed by esterification of the resulting acid
with trimethylsilylethyl alcohol in the presence of DCC
and DMAP in CH2Cl2 provided the (diphenylphos-
phono)acetate derivative in near quantitative yield from
the benzyl ester.
In conclusion, a stereoselective synthesis of (−)-lauli-
malide via a macrolactonization strategy has been
achieved. The key steps are alkylation of the dibromo
olefin derived alkynyl anion with methyl chloroformate
and Yamaguchi macrolactonization. Considering its
clinical potential as an anti-tumor agent, the present
synthesis will provide convenient access to the synthesis
of analogues of laulimalide for biological evaluation.
Acknowledgements
12. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
13. All new compounds gave satisfactory spectral data. Com-
pound 14: [h]2D3 −46 (c 0.92, CHCl3); 1H NMR (400 MHz,
CDCl3) l 7.23 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz,
2H), 5.89 (m, 1H), 5.86 (dd, J=15.6, 5.6 Hz, 1H),
5.63–5.57 (m, 3H), 5.51 (dd, J=15.6, 6.8 Hz, 1H), 5.43 (s,
1H), 5.10 (m, 1H), 4.85 (s, 1H), 4.78 (s, 1H), 4.63 (d,
J=6.9 Hz, 1H), 4.59 (d, J=11.8 Hz, 1H), 4.47 (d, J=6.8
Hz, 1H), 4.43 (brd, J=11.0 Hz, 1H), 4.32 (d, J=11.8 Hz,
1H), 4.20 (brs, 2H), 4.08 (m, 1H), 3.85 (t, J=6.4 Hz, 1H),
3.80 (s, 3H), 3.69 (m, 1H), 3.30 (s, 3H), 2.71 (dd, J=17.4,
11.1 Hz, 1H), 2.37 (dd, J=17.4, 2.7 Hz, 1H), 2.34–1.79
(m, 12H), 1.71 (s, 3H), 1.58 (m, 1H), 1.08 (m, 1H), 0.82
(d, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) l
165.2, 159.1, 153.1, 144.7, 135.8, 134.9, 131.3, 130.1,
129.3, 127.6, 126.9, 126.7, 126.2, 119.7, 113.7, 113.5, 94.0,
86.8, 79.2, 76.2, 73.9, 73.2, 71.1, 70.1, 65.6, 65.1, 55.4,
55.2, 45.0, 43.2, 41.1, 35.7, 32.2, 31.3, 26.0, 24.0, 23.0,
18.5.
Financial support of this work by the National Insti-
tutes of Health (GM 55600) is gratefully acknowledged.
We would also like to express our gratitude to Profes-
sor Higa for sending us a sample and NMR spectra of
natural laulimalide.
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