An enantioselective synthesis of the C2-C16 segment of antitumor macrolide laulimalide

Article abstract of DOI:10.1016/S0040-4039(00)00158-1

An enantioselective synthesis of the C₂-C₁₆ segment of the novel antitumor agent laulimalide is described. The key steps involve a highly diastereoselective allylation, ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester, a stereoselective anomeric alkylation and an elaboration of an exo-methylene unit by a Julia olefination reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00158-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2319–2322
An enantioselective synthesis of the C2–C16 segment of antitumor
macrolide laulimalide1
Arun K. Ghosh ∗ and Yong Wang
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA
Received 5 January 2000; accepted 19 January 2000
Abstract
An enantioselective synthesis of the C2–C16 segment of the novel antitumor agent laulimalide is described. The
key steps involve a highly diastereoselective allylation, ring-closing olefin metathesis of a homoallylic alcohol
derived acrylate ester, a stereoselective anomeric alkylation and an elaboration of an exo-methylene unit by a Julia
olefination reaction. © 2000 Elsevier Science Ltd. All rights reserved.
Marine natural products containing macrocyclic features have been shown to exhibit anticancer
properties with significant clinical potential.2 One such compound is laulimalide (1), a 20-membered
macrolide isolated from the Indonesian sponge Hyattella sp.3 More recently, laulimalide, also known
as figianolide B, has been isolated from an Okinawan sponge Fasciospongia rimosa.4 Laulimalide
represents a novel class of macrolide with remarkably potent antitumor activities. It has displayed potent
cytotoxicity against the KB cell line with an IC50 value of 15 ng/mL.3b Furthermore, laulimalide has
shown cytotoxicity against P388, A549, HT29 and MEL28 cell lines in the range of 10–50 ng/mL (IC50
values).4b Initially, the gross structure of laulimalide was established by NMR studies and its absolute
configuration has now been elucidated by X-ray crystallographic analysis.4a The unique structural
features coupled with its significant antitumor activities have stimulated much interest in its synthesis
and structure–function studies. We have earlier reported an asymmetric synthesis of the C3–C14 segment
of laulimalide.5 More recently, Nishiyama and Mulzer have also constructed various fragments of
laulimalide.6 As part of our continuing interest in the chemistry and biology of laulimalide, we have now
constructed the C2–C16 segment of 1 in which the key steps involve a highly diastereoselective Brown’s
asymmetric allylboration, a ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester,
a stereoselective anomeric alkylation with allyltrimethylsilane, and a novel Julia olefination reaction for
the elaboration of the C13 exo-methylene unit.
As shown in Fig. 1, we plan to synthesize laulimalide in a convergent manner from the fragment 2 and
3. The fragments will be connected by Julia olefination followed by macrolactonization between the C19
∗
Corresponding author. E-mail: arunghos@uic.edu (A. K. Ghosh)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00158-1
tetl 16438

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hydroxyl group and the C1 carboxylic acid group. We plan to introduce the sensitive epoxide between
C16 and C17 at the final stage of the synthesis. The synthesis of the C2–C16 segment commenced with
the known optically active alcohol 4 (Scheme 1).7 The alcohol 4 was mesylated with mesyl chloride and
triethylamine in CH2Cl2 at 0°C for 30 min. Displacement of the resulting mesylate with sodium cyanide
furnished the cyanide 5 in 95% yield. DIBAL reduction of the cyanide afforded the aldehyde 6 which was
subjected to Brown’s asymmetric allylboration protocol to provide the homoallylic alcohol 7 (ratio 96:4)
in 75% yield.8 Alternatively, the alcohol 7 has been prepared by utilizing Keck’s allylation of 6 employing
a catalytic amount (10 mol%) of (S)-BINOL and titanium isopropoxide to furnish 7 diastereoselectively
(de 92%) in 46% yield.9 For the elaboration of the dihydropyran ring, we plan to form an α,β-unsaturated
δ-lactone and then introduce the side chain functionality stereoselectively. For efficient elaboration of
the corresponding δ-lactone, we relied on ring-closing metathesis protocol utilizing Grubbs’ catalyst
as described recently.10,11 Thus, reaction of the alcohol 7 with acryloyl chloride and Et3N in CH2Cl2
provided the acrylate ester 8 in 76% isolated yield. Exposure of the acrylate ester to Grubbs’ catalyst (10
mol%) in CH2Cl2 in the presence of a catalytic amount (30 mol%) of Ti(OiPr)4 at 40°C for 5 h furnished
the δ-lactone 9 in 72% yield after silica gel chromatography.
Fig. 1.
Scheme 1. (a) MsCl, Et3N, CH2Cl2, 0°C; (b) NaCN, DMSO, 60°C (95%); (c) DIBAL-H, CH2Cl2, 0°C (93%); (d)
CH2_CHCH2B[(−)-Ipc]2, THF, −100°C (75%); (e) CH2_CHCOCl, Et3N, 0 to 23°C, CH2Cl2 (76%); (f) Cl2(PCy3)2Ru=CHPh
(10 mol%), Ti(OiPr)4 (30 mol%), CH2Cl2, 40°C (72%); (g) DIBAL-H, CH2Cl2, −78°C then Ac2O, pyridine, DMAP, −78 to
23°C; (h) BF3·OEt2, CH2Cl2, CH2_CHCH2SiMe3, −78°C (82%); (i) Li, NH3, (78%); (j) I2, PPh3, imidazole, MeCN–Et2O
(97%)
To append the side chain, the unsaturated δ-lactone was reduced by reaction with DIBAL at −78°C
in CH2Cl2. The resulting lactol was subjected to in situ acylation by reaction with acetic anhydride,
pyridine and DMAP as described by Dahanukar and Rychnovsky.12 Exposure of the resulting acetate to
allyltrimethylsilane in the presence of BF3·OEt2 in CH2Cl2 at −78°C, afforded the anomeric allylation

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product 10 as a single isomer in 82% yield from lactone 9.13 The next step in our synthetic plan was to
convert the benzyl ether functionality into its corresponding iodide 11. The removal of benzyl group was
effected by exposure of 10 to lithium in liquid ammonia at −78°C for 10 min. Treatment of the resulting
primary alcohol with iodine, triphenylphosphine and imidazole in a mixture (1:1) of Et2O and CH3CN
at 23°C for 30 min furnished the iodide 11 in 76% yield (two steps) after silica gel chromatography.
For installation of the C13 methylene unit and the C15 hydroxyl group, we relied upon alkylation
of α-sulphonyl-γ-lactone 13 with the iodide 11, reduction of the resulting lactone followed by a Julia
olefination reaction. For the synthesis of the lactone 13, commercial (R)-(+)-glycidol was first protected
as the p-methoxybenzyl ether 12 as described by Smith and co-workers.14 Reaction of the epoxide 12
with the sodium enolate of methyl phenylsulphonylacetate in EtOH at 23°C for 12 h afforded the α-
sulphonyl-γ-lactone 13 as a 2.4:1 diastereomeric mixture in 83% yield after silica gel chromatography.
Alkylation of lactone 13 with iodide 11 was carried out by treatment of 13 (1.7 equiv.) with NaH (1.7
equiv.) in DMF at 23°C for 15 min followed by reaction of the iodide 11 (1 equiv.) at 23°C for 15 min
and then 60°C for 12 h. The alkylated sulfone 14 was isolated in 91% yield as a single diastereomer with
stereochemistry as depicted in Scheme 2. For elaboration of the C13 exo-methylene unit, the sulphonyl
lactone 14 was treated with LiBH4 in THF at 23°C for 12 h to provide the diol 15. Treatment of the
diol 15 with benzoyl chloride and Et3N in the presence of a catalytic amount of DMAP in CH2Cl2
afforded the dibenzoate derivative. Exposure of the resulting dibenzoate to magnesium amalgam in
ethanol as described by Pak and co-workers, furnished the olefin 16 with concomitant hydrolysis of
the C-15 benzoate derivative in 44% overall yield (from 14).15,16 The alkylation of α-sulfonyl-γ-lactone
and Julia olefination sequence may provide a convenient access to other exo-methylene units inherent to
other biologically important macrolides.2
Scheme 2. (a) NaH, PhSO2CH2CO2Me, EtOH (83%); (b) NaH, DMF, iodide 11, 60°C (91%); (c) LiBH4, THF, 0 to 23°C; (d)
PhCOCl, Et3N, DMAP (cat), CH2Cl2; (e) Mg, HgCl2 (cat), EtOH (44%)
In conclusion, the asymmetric synthesis of the C2–C16 fragment of laulimalide has been achieved
stereoselectively. The synthesis involved a number of important steps including a Brown’s asymmetric
allylboration, ring-closing olefin metathesis to form a δ-lactone, a highly stereoselective anomeric
alkylation reaction to a functionalized dihydropyran and development of protocol for installation of the
C13 exo-methylene unit. Further work toward the total synthesis of laulimalide is in progress.

2322
Acknowledgements
Financial support of this work by the National Institutes of Health (GM 55600) is gratefully acknow-
ledged.
References
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23
1
16. All new compounds gave satisfactory spectral data. Compound 16: [α]D −35 (c 0.23, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.25 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.87–5.80 (m, 2H), 5.68 (d, J=10.5 Hz, 1H), 5.08 (d, J=19.0 Hz,
1H), 5.04 (d, J=11.4 Hz, 1H), 4.86 (s, 1H), 4.84 (s, 1H), 4.47 (s, 2H), 4.18 (brs, 1H), 3.94 (m, 1H), 3.78 (s, 3H), 3.75 (m,
1H), 3.46 (dd, J=9.3, 3.4 Hz, 1H), 3.34 (dd, J=9.3, 7.1 Hz, 1H), 2.49 (brs, 1H), 2.40 (m, 1H), 2.24 (m, 1H), 2.16 (d, J=6.7
Hz, 2H), 2.05 (m, 1H), 1.96–1.83 (m, 4H), 1.60 (m, 1H), 1.08 (m, 1H), 0.86 (d, J=6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 159.2, 144.4, 135.2, 130.1, 129.4, 129.4, 129.2, 124.6, 116.7, 113.9, 113.9, 113.8, 74.0, 73.0, 72.2, 68.2, 65.2, 55.2, 44.6,
42.6, 39.9, 38.8, 31.4, 26.7, 19.2.