Synthesis of the C1-C12-dihydropyran segment of the antitumor agent laulimalide by ring closing metathesis

Article abstract of DOI:10.1016/S0040-4039(99)02021-3

A stereocontrolled synthesis of the C1-C12 fragment 3 of laulimalide utilizing a ring closing metathesis with Grubbs' catalyst as the key step is described.

Full text of DOI:10.1016/S0040-4039(99)02021-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 33–36
Synthesis of the C1–C12-dihydropyran segment of the antitumor
agent laulimalide by ring closing metathesis
Johann Mulzer ∗ and Martin Hanbauer
Institut für Organische Chemie der Universität Wien, Währinger Str. 38, A-1090 Wien, Austria
Received 16 September 1999; accepted 19 October 1999
Abstract
A stereocontrolled synthesis of the C1–C12 fragment 3 of laulimalide utilizing a ring closing metathesis with
Grubbs’ catalyst as the key step is described. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: marine metabolites; antitumor compounds; metathesis; dihydropyran.
In the development of novel antitumor drugs recent attention has been focused on microtubule
stabilizing agents, the most popular ones being paclitaxel (Taxol™)1 and the epothilones.2 More recently
several other antitumor agents showing a similar mode of action have been identified, among which
laulimalide (1) is distinguished by a particularly high multidrug resistance (MDR).3 Compound 1, also
known as fijianolide B, has been isolated, together with isolaulimalide (2), from the marine sponges
Cacospongia mycofijiensis,4 Hyattella sp.,5 and Fasciospongia rimosa6 and shows a strong cytotoxicity
(IC50=15 ng/mL) against the KB cell line, whereas 2, which is easily obtained from 1 under acidic
conditions5 by nucleophilic attack of the C-20 hydroxyl group on the epoxide, shows much weaker
cytotoxicity (IC50>200 ng/mL).
So far no total synthesis of 1 has been reported, although major fragments have been prepared by
the groups of Ghosh7 and Nishiyama.8,9 Our retrosynthetic concept is shown in Scheme 1 and features
CC connections between C21 and C20 (Nozaki Kishi addition10) and between C13 and C12 (sulfone
∗
Corresponding author.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02021-3
tetl 15949

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anion–tosylate alkylation). In this letter we describe a novel approach to the C1–C12 fragment 3, which
is centered around a ring closing metathesis (RCM) reaction11 to form the crucial dihydropyran ring.
Scheme 1.
The known12 alcohol 6, readily prepared from commercially available ethyl (S)-2-methyl-3-
hydroxybutyrate, was tosylated and converted into cyanide 7, which, after reduction with DIBAH,
yielded aldehyde 8 (Scheme 2). Diastereocontrolled allylation was first attempted according to the
standard procedure by Brown13 via in situ formation of the allylborane. The homoallylic alcohol 9
was produced in reasonable yield but with unsatisfactory diastereoselectivity (5:1). Application of the
Duthaler Hafner reagent14 increased the diastereoselectivity to >98:2, but even with a large excess of
allyl titanium reagent (2 equiv.) the conversion was not complete. Finally, a modified Brown allylation15
under ‘salt-free conditions’ was applied and gave good diastereoselectivity (20:1) and excellent chemical
yield (90%). Transketalization of alcohol 9 with acrolein diethyl acetal, when carried out as described
by Crimmins,16 resulted in the formation of a 1:1 mixture of the diene 10 and starting material, which
had to be recycled twice to give 10 in a combined yield of 82%. In an improved modification, the
reaction was carried out in toluene under reduced pressure. Ethanol was removed azeotropically to
achieve full conversion and 84% yield of 10 after workup. The key step in our synthesis, a ring closing
metathesis (RCM) reaction,17 proceeded smoothly with a minimum amount (1–2%) of Grubbs’ catalyst
to produce the desired dihydropyran 11 from 10 in 94% yield. Introduction of the C-3–C-4 appendage
was first attempted with montmorillonite K-1018 and the commercially available vinyloxytrimethylsilane
to give aldehyde 12 in 65% yield. If the readily available19 vinyloxy-tert-butyldimethylsilane was
used the yield was increased to 81%. Application of other Lewis acids such as lithium perchlorate
21
(3 M in ethyl acetate)20 or TiCl2(OiPr)2 led to similar yields. Because of the simple handling and
the low cost montmorillonite K-10 was the reagent of choice. In all experiments only the desired
1,3-trans-disubstituted dihydropyran was observed, whose relative configuration was determined by
NOESY-NMR methods.22
The aldehyde 12 was submitted to a Still–Gennari–Horner olefination23 with bis(2,2,2-trifluoroethyl)-
phosphonoacetic acid methyl ester24 (Scheme 3). Enoate 13 was obtained with excellent chemical yield
(97%) but moderate Z:E selectivity (3:1). However, the two isomers could easily be separated by flash
chromatography to yield 73% of Z-13, whose reduction to the alcohol 14 proceeded smoothly with
DIBAH in 86% yield. After TBS protection of the 1-OH group the 12-PMB group was removed with
DDQ to give the alcohol 16, which was converted into the tosylate 3, which now is ready for coupling
with the C-13–C-20 fragment 5. No isomerization of the double bond was observed in this sequence.
In conclusion, we have described a novel and efficient approach to the laulimalide fragment 325 (12
steps, 8% overall yield). Further investigations towards the total synthesis of 1 are under way in our
laboratory.

35
Scheme 2. Reagents and conditions: (a) (i) TsCl, pyridine, rt; (ii) NaCN, DMSO, 80°C (80%); (b) DIBAH, THF, −78°C to rt
(80%); (c) (−)-Ipc2BCH2CH_CH2, Et2O, −100°C (90%); (d) CH2_CHCH(OEt)2, PPTS, toluene, 80 mbar, 35°C (84%); (e)
Cl2(Cy3P)2Ru_CHPh, CH2Cl2, reflux (94%); (f) CH2_CHOTBS, montmorillonite K-10, CH2Cl2, rt (81%)
Scheme 3. Reagents and conditions: (a) (CF3CH2O)2P(O)CH2COOMe, KHMDS, 18-crown-6, THF, −78°C, then 12 (73%);
(b) DIBAH, THF, −78°C to rt (86%); (c) TBSCl, imidazole, DMF, rt (78%); (d) DDQ, CH2Cl2:H2O (10:1), rt (81%); (e) pTsCl,
pyridine, rt (60%)
Acknowledgements
Technical advice by Dr. Elisabeth Öhler is gratefully acknowledged.
References
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36
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Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192–194
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25. Compound 3: 1H NMR (250 MHz, CDCl3): δ=0.06 (s, 6H); 0.89 (s, 9H); 0.92 (d, J=6.7 Hz, 3H); 1.16 (m, 1H); 1.51 (m,
1H); 1.89 (m, 2H); 2.04 (m, 1H); 2.28 (bt, J=7.0 Hz, 2H); 2.44 (s, 3H); 3.69 (m, 1H); 3.83 (dd, J=6.4 Hz, J=9.1 Hz, 1H);
3.96 (dd, J=5.1 Hz, J=9.1 Hz, 1H); 4.09 (m, 1H); 4.20 (d, J=5.7 Hz, 2H); 5.46 (m, 1H); 5.58 (m, 1H); 5.63 (m, 1H); 5.79
(m, 1H); 7.34 (d, J=8.1 Hz, 2H); 7.78 (d, J=8.1 Hz, 2H); 13C NMR (63 MHz, CDCl3): δ=−4.7; 16.6; 22.1; 23.3; 26.4; 29.8;
31.5; 32.9; 38.8; 59.9; 65.5; 72.6; 76.2; 124.7; 126.8; 128.4; 129.4; 129.6; 130.2; 131.9; 132.1.