Total synthesis of (-)-laulimalide [12]

Full text of DOI:10.1021/ja0027416

J. Am. Chem. Soc. 2000, 122, 11027-11028
11027
Total Synthesis of (-)-Laulimalide
Arun K. Ghosh* and Yong Wang
Department of Chemistry
UniVersity of Illinois at Chicago
845 West Taylor Street
Chicago, Illinois 60607
ReceiVed July 25, 2000
Laulimalide (1), also known as figianolide B, a 20-membered
macrolide isolated from the Indonesian sponge Hyattella sp., has
shown remarkable antitumor activities.1 Recently, Laulimalide was
also isolated from an Okinawan sponge Fasciospongia rimosa.2
It displayed potent cytotoxicity against the KB cell line with an
IC50 value of 15 ng/mL.1 Furthermore, it has shown cytotoxicity
against P388, A549, HT29, and MEL28 cell lines in the range of
10-50 ng/mL (IC50 values).2b The structure of 1 was initially
established by NMR studies. Subsequently, its absolute config-
uration was established by X-ray analysis by Higa and co-
workers.2 The significant clinical potential of laulimalide has
stimulated considerable interest in its synthesis and structure-
function studies.3 Herein, we report the first synthesis of (-)-
laulimalide 1.
Figure 1.
Scheme 1a
As outlined in Figure 1, our synthetic strategy of laulimalide
is convergent and involves the assembly of C3-C16 segment 2
and C17-C28 segment 3 by Julia olefination, followed by an
intramolecular Horner-Emmons reaction between the C19 phospho-
noacetate and C3 aldehyde. The sensitive epoxide at C16-C17 was
selectively introduced at the final stage of the synthesis by
Sharpless epoxidation.4 The construction of both dihydropyran
rings of laulimalide was achieved by ring-closing olefin metathesis
utilizing Grubbs’ catalyst as the key step.5
The synthesis of C3-C16 segment is accomplished by modi-
fications of the previously published sequence.3a As outlined in
Scheme 1, diastereomerically pure δ-lactone 5 was prepared
efficiently by exposure of acryloyl ester 4 to Grubbs’ catalyst
(10 mol %) in CH2Cl2.3a DIBAL reduction of 5 at -78 °C in
CH2Cl2 followed by reaction with ethanol and CSA afforded the
ethyl glycoside.6 Reaction of this ethyl acetal with tert-butyldim-
ethylsilyl vinyl ether and Montmorillonite K-10 as the Lewis acid
in CH2Cl2 at 23 °C followed by NaBH4 reduction of the resulting
aldehyde afforded the corresponding dihydropyran as a single
a (a) Dibal-H, -78 °C then CSA, EtOH, 23 °C; (b) K-10, CH2
)
CHOTBS, 23 °C; (c) NaBH4, MeOH, 0 °C (54%); (d) TBSCl, imidazole,
DMF, 23 °C (75%); (e) Li, NH3 (95%); (f) I2, PPh3, Imidazole (96%);
(g) 8, NaH, DMF, 0°C then iodide 7, 60 °C (89%); (h) Red-Al, THF, 0
°C; (i) PhCOCl, Et3N, DMAP (cat.); (j) Na(Hg), Na2HPO4, MeOH, -20°
to 23 °C (72%); (k) MOMCl, i-Pr2NEt, 23 °C; (l) DDQ, pH 7 buffer, 23
°C (81%); (m) DMSO, (COCl)2, i-Pr2NEt, -60 °C (85%).
1
isomer (by H and 13C NMR). Protection of the alcohol with
TBSCl and imidazole furnished the TBS ether 6. Removal of the
benzyl group by lithium in liquid ammonia provided the alcohol
which was subsequently converted to iodide 7. To install the C13
methylene unit and the C15 hydroxyl group, alkylation of lactone
8 was carried out by treatment with NaH in DMF at 0 °C for 15
min followed by reaction with iodide 7 at 23 °C for 15 min and
then 60 °C for 12 h, which furnished lactone 9 as a mixture (4.2:1
by Red-Al provided the diol 10. Benzoylation of 10 afforded the
corresponding dibenzoate which was exposed to Na-Hg in
MeOH at -20 °C to provide the olefin 11.7 Protection of the C15
hydroxyl group as a MOM ether, removal of the PMB group and
Swern oxidation of the resulting alcohol furnished the C3-C16
segment, aldehyde 2.
The synthesis of the C17-C28 segment 3 has been achieved by
modification of reaction sequences published previously.3b Opti-
cally active dihydropyran derivative 12 was prepared in multigram
quantity by utilizing ring-closing olefin methathesis5 and Corey-
Fuchs’ homologation8 reactions as the key steps. The alkynyl
anion of 12 was readily obtained by treatment with n-BuLi at
-78 °C for 1 h followed by warming to 23 °C for 1 h (Scheme
2). Reaction of the resulting alkynyl anion with optically active
1
by H NMR) of isomers. Reduction of the mixture of lactone 9
(1) (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.
(2) (a) Jefford, C. W.; Bernardinelli, G.; Tanaka, J.-I.; Higa, T. Tetrahedron
Lett. 1996, 37, 159. (b) Tanaka, J.-I.; Higa, T.; Bernardinelli, G.; Jefford, C.
W. Chem. Lett. 1996, 255.
(3) (a) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 2319. (b)
Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 4705. (c) Mulzer, J.;
Hanbauer, M. Tetrahedron Lett. 2000, 41, 33. (d) Shimizu, A.; Nishiyama, S.
Synlett 1998, 1209. (e) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron
Lett. 1997, 38, 2427.
(4) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I.; Ed.; VCH Publishers: New York, 1993, p 103-158.
(5) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413 and references
therein.
(6) For a related method, see: Dahanukar, V. H.; Rychnovsky, S. D. J.
Org. Chem. 1996, 61, 8317.
(7) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S. Tetrahedron
Lett. 1995, 36, 5607.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
10.1021/ja0027416 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

11028 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Communications to the Editor
Scheme 2a
Scheme 3a
a (a) n-BuLi, -78 °C, 1 h and 23 °C, 1 h then 13, -78 °C (64%); (b)
Dess-Martin, CH2Cl2, 23 °C (81%); (c) L-Selectride, THF, -78 °C
(87%); (d) Red-Al, THF, -20 °C (81%); (e) CF3CO2H, CH2Cl2, 23 °C;
(f) p-MeO-Ph-CH(OMe)2, CSA, CH2Cl2, 23 °C (71%); (g) Dibal-H,
CH2Cl2, -78 °C (74%).
aldehyde 13 at -78 °C furnished a diastereomeric mixture (1.8:
1) of alcohols 14 and 15, which upon oxidation with Dess-Martin
periodinane9 gave the corresponding alkynyl ketone. L-Selectride
reduction of this ketone at -78 °C furnished the desired syn-
alkynyl alcohol 15 as a single diastereomer (by 1H NMR and 13
C
NMR). Red-Al reduction of 15 set the C21-C22 trans-olefin
geometry. Removal of the C19 PMB group by exposure to TFA10
and subsequent reaction of the resulting diol with p-methoxy-
benzylidene acetal and CSA provided acetal 16. DIBAL reduction
of 16 at -78 °C in CH2Cl2 afforded the C17-C28 segment 3 as a
a (a) n-BuLi, -78°C, 15 min, Then 2, -78 to -40 °C, 2 h; (b) Ac2O,
Et3N, DMAP (cat.); (c) Na(Hg), Na2HPO4, MeOH, -20 to 23 °C (34%);
(d) (CF3CH2O)2P(O)CH2CO2H, Cl3C6H2COCl, i-Pr2NEt, DMAP; (e)
AcOH-THF-H2O (3:1:1), 23 °C (99%); (f) Dess-Martin, CH2Cl2, 23
°C (79%); (g) K2CO3, 18-C-6, -20 to 0 °C (84%); (h) hν, Et2O, 50 min
(66%); (i) PPTS, t-BuOH, 84 °C (45%) (j) Ti(OiPr)4, (+)-DET, t-BuOOH,
-20 °C; (k) DDQ, pH 7, 23 °C (48%).
1
single regio isomer (by H and 13C NMR).
Our subsequent synthetic strategy calls for the assembly of
fragments 2 and 3 by Julia olefination (Scheme 3). Thus, lithiation
of sulfone derivative 3 with 2.1 equiv of n-BuLi in THF at -78
°C for 15 min followed by reaction of the resulting dianion with
the aldehyde 2 at -78 °C to -40 °C for 2 h furnished the expected
R-hydroxy sulfone derivatives. The hydroxy sulfone was trans-
formed into the corresponding C16-C17 olefin in a two step
sequence involving (1) acylation of the hydroxy sulfone deriva-
tives with Ac2O, Et3N and DMAP (cat.) and (2) exposure of the
resulting acetates to Na(Hg) in methanol at -20 °C for 2 h
followed by warming the reaction to 23 °C for 30 min. The C16-
C17 trans olefin 17 was obtained in 34% yield along with 10%
cis-olefin, which was readily separated by silica gel chromatog-
raphy.
Subsequent elaboration to the macrolactone possessing C2-
C3 cis-olefin geometry proved to be a formidable task. We finally
relied upon an intramolecular Horner-Emmons reaction of C19
phosphonoacetate and C3 aldehyde using Still’s protocol.11 Thus,
acylation of C19 hydroxyl group with bis-(2,2,2-trifluoroethyl)-
phosphonoacetic acid followed by removal of the TBS group by
exposure to aqueous acetic acid in THF at 23 °C furnished the
acetate derivative 18 in near quantitative yield.12 Oxidation of
18 with Dess-Martin periodinane provided the C3 aldehyde which
upon treatment with K2CO3 in the presence of 18-C-6 at -20 °C
for 30 min and then at 0 °C for 2.5 h furnished a mixture (2:1)
of macrolactones 19 and 20 in 84% yield (Scheme 3). Both cis-
and trans-lactones were separated by silica gel chromatography.
Horner-Emmons reaction of the corresponding (diphenylphospho-
no)acetate derivative provided slight improvement of the cis-
selectivity (cis:trans ) 1:1.7, 69% isolated yield).13 Further
attempts to improve the ratio for 20 by changing reaction
conditions or C20 protecting group have been unsuccessful. The
overall yield of the desired cis-macrolactone 20 was however
improved to 47% after photoisomerization of the trans-macro-
lactone 19.14 Thus, irradiation of 19 in ether under UV in a
Rayonet photochemical reactor for 50 min afforded a mixture of
trans-lactone 19 (33%) and the cis-lactone 20 (33%) which were
separated by chromatography. The identity of the cis-olefin
geometry of 20 was established by its observed coupling constant
(J ) 11.6 Hz). Macrolactone 20 was converted to synthetic (-)-
laulimalide 1 as follows: removal of the MOM group by refluxing
with PPTS in t-BuOH,15 exposure of the resulting alcohol to
Sharpless epoxidation4 with (+)-DET and removal of the C20
PMB ether by exposure to DDQ. Spectral data (1H and 13C NMR)
of synthetic 1 ([R]23 -196 c 0.23, CHCl3) are identical to that
D
from a sample of natural laulimalide (lit.2a [R]29 -200 c 1.03,
D
CHCl3) kindly provided by Professor Higa.
Thus, a stereocontrolled synthesis of (-)-laulimalide has been
achieved. Considering its clinical potential as an antitumor agent,
the present synthesis will enable important structure-function
studies as well as synthesis of structural variants of laulimalide.
Further improvement in synthesis and biological studies are
currently in progress.
Acknowledgment. Financial support by the National Institutes of
Health (GM 55600) is gratefully acknowledged. We also thank Professor
Higa for providing a sample of natural laulimalide and Professor Forsyth
for the experimental details of bis-(2,2,2-trifluoroethyl)phosphonoacetic
acid.
Supporting Information Available: Experimental procedures and
1
spectral data for compounds 1-3, 6-11, 15-20; H NMR spectra for
compounds 1, 3, 11, 15-17, 19, 20; and 13C NMR for compounds 1, 3,
11, 17, and 19 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) Meger, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(10) Yan, L.; Kahne, D. Synlett 1995, 523.
JA0027416
(11) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(12) This protocol was recently employed in the synthesis of phorboxazole
A. See: Forsyth, C. J.; Ajmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc.
1998, 120, 5597.
(14) Smith, A. B.; Lupo, A. T.; Ohba, M.; Chen, K. J. Am. Chem. Soc.
1989, 111, 6648 and references therein.
(15) Monti, H.; Leandri, G.; Klos-Ringquet, M.; Corriol, C. Synth. Commun.
1983, 13, 1021.
(13) Ando, K. J. Org. Chem. 1999, 64, 8406 and references therein.