Synthesis of the C15-C27 fragment of the antitumor agent laulimalide

Article abstract of DOI:10.1016/S0040-4039(00)00961-8

A stereocontrolled synthesis of the C15-C27 fragment of laulimalide is described. Key features are a divergent-convergent synthesis from (R)-glycidol, an interesting formation of a trisubstituted double bond via ring closing metathesis with Grubbs' ruthen

Full text of DOI:10.1016/S0040-4039(00)00961-8

Tetrahedron Letters 41 (2000) 6323±6326
Synthesis of the C15±C27 fragment of the antitumor agent
laulimalide
E. Kate Dorling, Elisabeth Ohler and Johann Mulzer*
Institut fur Organische Chemie der Universitat Wien, Wahringer Str. 38, A-1090 Wien, Austria
È
È È
Received 6 June 2000; accepted 15 June 2000
Abstract
A stereocontrolled synthesis of the C15±C27 fragment of laulimalide is described. Key features are a
divergent±convergent synthesis from (R)-glycidol, an interesting formation of a trisubstituted double bond
via ring closing metathesis with Grubbs' ruthenium catalyst and a site selective protection of a syn-1,2-diol.
# 2000 Elsevier Science Ltd. All rights reserved.
Since the discovery of paclitaxel (TaxolTM) and the elucidation of its mode of action,1 a great
deal of e€ort has been focused on the discovery of new classes of compounds with similar
activity. Among recent advances have been the epothilones,2 discodermolide3 and eleutherobin.4
However, laulimalide (1) has been distinguished by an unusually high activity against multidrug
resistant cell lines.5 Laulimalide and isolaulimalide (2) have been isolated from the marine
sponges Cacospongia myco®jiensis,6 Hyatella sp.7 and Fasciospongia rimosa8 (Fig. 1). Laulimalide
shows strong cytotoxicity (IC50=15 ng/mL) against the KB cell line and a high level of activity
against the multidrug resistant cell line SKVLB-1 (IC50=1210 nM).5 In contrast, isolaulimalide
(2), which is easily obtained from 1 by treatment with acid,7 shows lower activity against both the
KB cell line (IC50>200 ng/mL) and the SKVLB-1 line (IC50=2650 nM).
Figure 1. Laulimalide and its isomer
* Corresponding author. Fax: +43-1-4277-9521; e-mail: johann.mulzer@univie.ac.at
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00961-8

6324
To date, there have been no reported total syntheses of 1, although major fragments have been
prepared by the groups of Ghosh9,10 and Nishiyama11 and we have recently published a synthesis
of the C1±C12 segment.12 Our current retrosynthetic concept is shown in Scheme 1 and features
CC connections between C14 and C15 (allylic transfer type reaction) and between C21 and C22
(HWE reaction). In this letter, we report a novel approach to the C15±C27 fragment, including
two methods of formation of the C22±C27 dihydropyran moiety 5 and a totally stereoselective
Luche reduction.13
Scheme 1. Retrosynthetic analysis
In the ®rst approach to aldehyde 5 (Scheme 2), (R)-glycidol was protected as the 4-methoxy-
benzyl ether14 and the epoxide opened with the lithium salt of ethyl propiolate to give alcohol 9
quantitatively. Treatment with lithium dimethyl cuprate and ring closure under acidic conditions
yielded the required lactone 10.15 DIBAL-H reduction followed by ionic hydrogenation16 gave
the dihydropyran in good yield. Removal of the PMB group with DDQ produced the highly
.
water soluble alcohol 11 and oxidation with SO3 pyr complex yielded aldehyde 5, which was used
without isolation.
Scheme 2. Reagents and conditions: (a) NaH, PMBCl (1.4 equiv.), Bu4NI, DMF, 5 h, ^20ꢀC to rt, 72%; (b) ethyl
n
n
ꢀ
.
propiolate, BuLi, BF3 OEt2 (each 3 equiv.), then 7, THF, 30 min, ^78 C, 100%; (c) (i) Me2CuLi (3 equiv.), then 9,
THF, ^78ꢀC; (ii) AcOH, PhMe, 80ꢀC, 12 h, 91%; (d) (i) DIBAL-H (1.2 equiv.), CH2Cl2, 1 h, ^78ꢀC; (ii) Et3SiH (1.5
equiv.), BF3 OEt2 (1.0 equiv.), CH2Cl2, 20 min, ^78ꢀC, 77%; (e) DDQ (1.2 equiv.), CH2Cl2:H2O (20:1), 85%; (f)
.
.
SO3 pyr, TEA, DMSO:CH2Cl2 (1:1)
The second, more convenient approach to aldehyde 5 included formation of the double bond
by RCM17 (Scheme 3). Thus, (R)-glycidol was protected to give trityl ether 12, the epoxide
opened with isopropenyl Grignard under copper(I) catalysis and the resulting alcohol allylated to
yield 14. When diene 14 (0.015 M in CH2Cl2) was exposed to 2.5±3% of the ruthenium-based
Scheme 3. Reagents and conditions: (a) TrCl, TEA, CH2Cl2, 0ꢀC to rt, 24 h, 88%; (b) isopropenyl magnesium bromide
(2 equiv.), copper(I) iodide (0.2 equiv.), THF, ^30ꢀC, 1 h, 99%; (c) (i) KOtBu, THF, rt to 45ꢀC; (ii) allyl bromide, rt, 1
h, 95%; (d) Cl2(Cy3P)2RuˆCHPh (3 mol%), CH2Cl2, 0.015 M, rt, 1±2 h, 99%; (e) HCl (g) in CH2Cl2 (5 equiv.), 0 to
5ꢀC, 30 min, 84%

6325
Grubbs' catalyst for only 1±2 h at room temperature, the corresponding dihydropyran was
obtained in nearly quantitative yield.
This result is particularly remarkable as literature precedent indicates that RCM of dienes
bearing one gem-disubstituted double bond, when performed with Grubbs' catalyst, is not
possible18 or requires careful optimization of the reaction conditions.19,20 Acidic removal of the
trityl group in the absence of water yielded alcohol 11.
The synthesis of the C15±C21 segment 6 was perceived as being derived from the epoxide-
opened alkyne 9 (Scheme 4). Alcohol 15, formed by standard transformations, was converted to
the ester and treated with the lithium salt of dimethyl methylphosphonate, yielding phosphonate
6 in good yield.
Scheme 4. Reagents and conditions: (a) TBDPSCl (1.3 equiv.), imidazole, DMF, 5 h, 100%: (b) DIBAL-H (2.2
equiv.), CH2Cl2, 1 h, ^78ꢀC, 91%; (c) dihydropyran, TsOH, 20 min, 96%; (d) DDQ (1.2 equiv.), CH2Cl2:H2O (20:1),
.
30 min, 97%; (e) (i) SO3 pyr, TEA, CH2Cl2:DCM (1:1), 30 min; (ii) NaClO2, (3 equiv.), KH2PO4, 2,3-dimethylbut-2-
ene:tBuOH (1:1), 1 h; (iii) CH2N2, Et2O, 80%; (f) dimethyl methylphosphonate (2.5 equiv.), nBuLi, then 17, THF, 3 h,
^78ꢀC, 91%; (g) nBuLi then H2O, 6 then 5, THF:Et2O (1:1), 0ꢀC to rt, 2 h, 80%; (h) NaBH4 (1.0 equiv.), CeCl3,
MeOH, 5 min, 67% (plus 20% mixed regioisomers); (i) MOMCl (20 equiv.), DIPEA, DMF, 3 h, 90%; (j) 2.5% HCl
(aq.), MeOH, 0ꢀC to rt, 30 min, 100%; (k) Red-Al1 (1.2 equiv.), Et2O, rt, 24 h, 84%; (l) (+)-DET, Ti(OiPr)4, TBHP, 4
A MS, CH2Cl2, ^20ꢀC, 9 h, 55%, dr 94:6.
The Horner±Wadsworth±Emmons coupling was achieved with lithium hydroxide, which was
prepared in situ from n-butyllithium and water21 and gave better results than commercial lithium
hydroxide. Reduction of the C20 ketone with L-Selectride1 yielded a single diastereomer, which
was assigned as syn by analogy.22 However, a signi®cant proportion of migration of the silyl
group from C19 to C20 was observed. It was believed that a cerium(III) counterion would result
in lower nucleophilicity of the alkoxide, limiting the migration to a great extent and hence a
Luche reduction14 was performed. Under these conditions, less than 10% migration was observed
and to our surprise, only a single diastereomer was isolated, which was identical in all respects to
the single product of the L-Selectride reduction. Protection of the newly formed alcohol as the
MOM ether proceeded well and the THP group could be selectively cleaved with 2.5% HCl in
MeOH. Reduction of the triple bond with Red-Al1 gave a single double bond isomer, assigned as
E by the vicinal coupling constant of 15.3 Hz. We envisage that aldehydes derived from 18 and 19
are both possible coupling partners with fragment 4. Finally, Sharpless epoxidation with (+)-DET
1
gave epoxide 2023 in 55% yield and diastereomeric ratio of 94:6 (by H NMR). Current work
focuses both on methodology for the removal of the C20 protecting group in the presence of the
sensitive g,d-epoxide functionality and on coupling of the two fragments.

6326
In conclusion, we have described a novel and ecient approach to the C15±C27 fragment of
laulimalide. Further investigations towards the total synthesis of 1 are currently underway in our
laboratories.
Acknowledgements
We thank the Austrian Science Fund (FWF) for ®nancial support.
References
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1
23. Data for compound 20. H NMR (400 MHz, C6D6) 1.22 (9H, s), 1.41 (1H, bm), 1.52 (3H, bs), 1.69 (1H, bd,
J=16.7), 1.86 (1H, dt, J=13.6, 6.7), 2.02 (2H, m), 2.56 (2H, m), 3.04 (3H, s), 3.13 (1H, m), 3.30 (1H, m), 3.46 (1H,
m), 3.97 (1H, dt, J=9.8, 4.7), 4.03 (1H, bd, J=15.4), 4.15 (1H, bd, J=15.9), 4.24 (1H, t, J=5.4), 4.30 (1H, m),
4.35 (1H, m), 4.50 (1H, m), 5.16 (0.96H, bs), 5.22 (0.04H, bs), 5.94 (1H, dd, J=4.7, 15.7), 6.07 (1H, dd, J=6.3,
15.7), 7.24 (6H, m) and 7.86 (4H, m); 13C NMR (100 MHz, C6D6) 19.8, 23.0, 27.4, 35.8, 36.6, 53.2, 55.3, 59.4, 51.8,
65.8, 73.5 (two signals) 78.8, 81.4, 94.8, 120.5, 126.4, 128.1, 128.6, 130.1, 131.3, 134.3, 134.4, 135.4 and 136.5 (two
signals); HRMS (EI, 160ꢀC, 70 eV) found: 495.2223. C18H35O6Si requires: 495.2203.