Synthetic studies of antitumor macrolide laulimalide: A stereoselective synthesis of the C17-C28 segment

Article abstract of DOI:10.1016/S0040-4039(00)00715-2

A stereoselective synthesis of the C₁₇-C₂₈ segment of the potent antitumor macrolide, laulimalide has been accomplished. The key steps are a ring-closing olefin metathesis to construct the dihydropyran unit, nucleophilic addition of an alkynyl anion to the Weinreb amide, stereoselective reduction of the resulting ketone to set the C₂₀-hydroxyl stereochemistry, and elaboration of the C₂₁-C₂₂ trans-olefin geometry. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00715-2

Tetrahedron Letters 41 (2000) 4705±4708
Synthetic studies of antitumor macrolide laulimalide:
a stereoselective synthesis of the C17±C28 segment
Arun K. Ghosh* and Yong Wang
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA
Received 26 April 2000; accepted 2 May 2000
Abstract
A stereoselective synthesis of the C17±C28 segment of the potent antitumor macrolide, laulimalide has
been accomplished. The key steps are a ring-closing ole®n metathesis to construct the dihydropyran unit,
nucleophilic addition of an alkynyl anion to the Weinreb amide, stereoselective reduction of the resulting
ketone to set the C20-hydroxyl stereochemistry, and elaboration of the C21±C22 trans-ole®n geometry.
# 2000 Elsevier Science Ltd. All rights reserved.
Laulimalide (1) is a 20-membered macrolide isolated from the Indonesian sponge Hyattella sp.1
It has exhibited potent cytotoxicity in the range of 10±50 ng/mL (IC50 values) against numerous
human cancer cell lines.2 The remarkable antitumor activities as well as its unique structural
features have prompted considerable interest in the synthesis and structure±function studies of
laulimalide.3 An asymmetric synthesis of the C3±C14 segment of laulimalide has been previously
reported by us.4 More recently, we have reported an ecient enantioselective route to the C2±C16
segment.5 Our synthetic strategy of laulimalide is convergent and involves the assembly of fragments
2 (C2±C16 segment) and 3 (C17±C28) by Julia ole®nation and subsequent macrolactonization
between the C19-hydroxyl group and the C1-carboxylic acid. In continuation of our on-going
studies, we now report a stereocontrolled route to the C17±C28 segment (3) of laulimalide.
As depicted in Fig. 1, we planned to synthesize the fragment 3 by a nucleophilic addition of the
dibromo ole®n 5 derived alkynyl anion to the Weinreb amide 4 and subsequent stereoselective
reduction of the resulting ketone. The synthesis of both Weinreb amide 4 and dihydropyran
derivative 5 were planned from the readily available optically active glycidyl ether 6.6 Thus, the
synthesis of the dihydropyran derivative 5 was carried out as shown in Scheme 1. Opening of the
epoxide 6 with isopropenylmagnesium bromide in the presence of a catalytic amount of CuCN
(10 mol%) at ^78 to 23ꢀC for 2 h a€orded the homoallylic alcohol 7 in 94% yield after silica gel
chromatography. Allylation of alcohol 7 was carried out by treatment with potassium hydride
* Corresponding author. E-mail: arunghos@uic.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00715-2

4706
and allyl bromide in the presence of a catalytic amount of 18-Crown-6 in THF at 0 to 23ꢀC for 1
h to provide allyl ether 8 in quantitative yield. For ecient elaboration of the functionalized
dihydropyran ring, we relied upon a ring-closing metathesis protocol utilizing Grubbs' catalyst.7
Thus, exposure of the allyl ether 8 to Grubbs' catalyst (2 mol%) in CH2Cl2 at 23ꢀC for 2 h
furnished the dihydropyran derivative 9. Treatment of 9 with camphorsulfonic acid in methanol
at 23ꢀC for 1 h resulted in the deprotection of THP±ether providing the alcohol 10 in 81% yield
(two steps) after silica gel chromatography. Swern oxidation of 10 followed by subjection of the
resulting aldehyde to Corey±Fuchs' homologation conditions using carbon tetrabromide and
triphenylphosphine in CH2Cl2 at 0 to 23ꢀC for 30 min a€orded the dibromo ole®n 5 in 67% yield
(two steps).8 Dibromo ole®n 5 is the precursor for the alkynyl anion; thus, it set the stage for
coupling with Weinreb amide 4 which is also derived from the same glycidyl ether 6. Thus,
lithiation of phenyl methyl sulfone with 1 equiv. nBuLi in THF at 0ꢀC for 1 h followed by addition
of HMPA and reaction with epoxide 6 at ^78 to 23ꢀC for 2 h provided the alcohol 11 in 94%
isolated yield.9 Alcohol 11 was subsequently protected as the PMB ether 12 by treatment with
NaH and PMBCl in DMF at 0 to 23ꢀC for 12 h (85% yield).
Figure 1.
Scheme 1. (a) Isopropenyl magnesium bromide, CuCN (10 mol%), THF, ^78 to 23ꢀC (94%); (b) KH, 18-Crown-6
(cat.), allyl bromide, THF, 0 to 23ꢀC (quant); (c) Cl2(PCy3)2RuˆCHPh (2 mol%), CH2Cl2, 23ꢀC; (d) CSA, MeOH
(81%); (e) Swern oxidation; (f) CBr4, PPh3, CH2Cl2, 0 to 23ꢀC (67%); (g) PhSO2CH3, nBuLi, THF, 0ꢀC, 1 h then
HMPA, 6, ^78 to 23ꢀC (94%); (h) NaH, PMBCl, DMF, 0 to 23ꢀC (85%)

4707
Our next synthetic plan involved the conversion of 12 into its corresponding Weinreb amide 4.
As outlined in Scheme 2, the removal of the THP ether with CSA in methanol followed by Swern
oxidation of the resulting alcohol provided the aldehyde 13. Aldehyde 13 was subsequently
transformed into the Weinreb amide 4 in a two-step sequence involving: (1) oxidation of the
aldehyde with NaClO2 in the presence of 2-methyl-2-butene and NaH2PO4 in tBuOH; and (2)
reaction of the resulting acid with isobutyl chloroformate, N,O-dimethylhydroxylamine and
N-methylpiperidine in CH2Cl2 at 0 to 23ꢀC for 2 h.10 Weinreb amide 4 was obtained in 83%
isolated yield (from 12). Our initial attempt to install the C20-hydroxyl stereochemistry by addition
of the dihydropyran 5 derived alkynyl anion to the aldehyde 13 resulted in the formation of alkynyl
1
alcohol 14 in 64% yield. However, observed diastereoselectivity (syn:anti=1:1.8 by H NMR)
was far from satisfactory for our synthesis. To set the C20-hydroxyl stereochemistry, we therefore
relied upon the addition of the dihydropyran 5-derived alkynyl anion to the Weinreb amide 4 and
then diastereoselective reduction of the resulting alkynyl ketone. The coupling of Weinreb amide
4 and dibromo ole®n 5 was achieved by treatment of 5 with nBuLi at ^78ꢀC for 1 h followed by
warming to 23ꢀC for 1 h to form the corresponding alkynyl anion. The resulting anion was
cooled to ^78ꢀC and reacted with the Weinreb amide 4 at ^78ꢀC to 0ꢀC for 1 h to furnish the
alkynyl ketone 15 in 59% isolated yield.11 Diastereoselective reduction of 15 with L-Selectride in
THF at ^78ꢀC for 1 h a€orded the corresponding alkynyl alcohol as a single diastereomer (by 1H
NMR and 13C NMR analysis) in 87% yield.12 The C21±C22 trans-ole®n geometry was then set by
reduction of the alkynyl group by Red±Al in THF at ^20ꢀC for 1 h to a€ord the trans-allylic
alcohol 16 in 81% yield. The alcohol was subsequently protected as the TIPS-ether 3 by treat-
ment with TIPSOTf and 2,6-lutidine in CH2Cl2 at 0 to 23ꢀC for 2 h (92%). In order to establish
the C20-hydroxyl stereochemistry as well as the C21±C22 trans-ole®n geometry, the alcohol 16 was
converted to the isopropylidene derivative 17 by removal of the PMB±ether with tri¯uoroacetic
acid in CH2Cl2 followed by the exposure of the resulting diol with CSA and dimethoxypropane in
CH2Cl2 (70%).13 As shown in Scheme 2, an NOE was observed between the HA and HC. Also,
NOEs were detected between the b-sulfonyl hydrogens and the HB. Furthermore, a coupling
Scheme 2. (a) CSA, MeOH (91%); (b) Swern oxidation; (c) NaClO2, 2-meꢀthyl-2-butene, NaH2PO4, tBuOH; (d)
ꢀ
.
MeONHMe HCl, N-methylpiperidine, isobutyl chloroformate, CH2Cl2, 0 to 23 C (83%); (e) nBuLi, 5, ^78 C, 1 h and
23ꢀC, 1 h then 4, ^78 to 0ꢀC (59%); (f) l-Selectride, THF, ^78ꢀC (87%); (g) Red±Al, THF, ^20ꢀC (81%); (h) TIPSOTf,
2,6-lutidine, CH2Cl2, 0 to 23ꢀC (92%); (i) CF3CO2H, CH2Cl2, 23ꢀC; (j) Me2C(OMe)2, CSA, CH2Cl2, 23ꢀC (70%); (k)
nBuLi, 5, ^78 to 23ꢀC, 1 h then 13, ^78ꢀC (64%)

4708
constant (JCD) of 15.5 Hz was measured between the HC and HD protons of 17 which correponds
to trans-ole®n geometry.
Thus, a stereocontrolled synthesis of the C17±C28 fragment of laulimalide has been achieved.
The key steps are the ring-closing ole®n metathesis to construct the dihydropyran side chain,
nucleophilic addition of an alkynyl anion to the Weinreb amide and subsequent reduction to set
the stereochemistry of C20. Further work toward the total synthesis of laulimalide is in progress.
Acknowledgements
Financial support of this work by the National Institutes of Health (GM 53386) is gratefully
acknowledged.
References
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23
D
13. All new compounds gave satisfactory spectral data. Compound 3: ‰ꢀŠ ^66 (c 1.21, CHCl3); 1H NMR (400 MHz,
CDCl3) ꢁ 7.85 (d, J=7.4 Hz, 2H), 7.62 (t, J=7.4 Hz, 1H), 7.52 (t, J=7.4 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 6.85 (d,
J=8.6 Hz, 2H), 5.78±5.68 (m, 2H), 5.40 (s, 1H), 4.47 (AB q, 2H, ÁꢂAB=51.2 Hz, JAB=11.4 Hz), 4.44 (m, 1H),
4.15 (br s, 2H), 4.00 (m, 1H), 3.79 (s, 3H), 3.48 (m, 1H), 3.20 (m, 1H), 3.02 (m, 1H), 1.99±1.91 (m, 2H), 1.85 (d,
J=14.5 Hz, 1H), 1.73 (m, 1H), 1.70 (s, 3H), 0.98 (s, 21H); 13C NMR (100 MHz, CDCl3) ꢁ 159.4, 139.1, 133.5,
132.4, 131.3, 130.1, 129.6, 129.1, 128.7, 128.0, 119.8, 113.8, 79.6, 73.3, 72.1, 72.0, 65.5, 55.3, 53.1, 35.6, 23.0, 22.8,
23
1
18.1, 12.2. Compound 17: ‰ꢀŠ ^69 (c 0.32, CHCl3); H NMR (400 MHz, CDCl3) ꢁ 7.92 (d, J=7.9 Hz, 2H), 7.67
D
(t, J=7.0 Hz, 1H), 7.58 (t, J=7.6 Hz, 2H), 5.87 (dd, J=15.5, 5.0 Hz, 1H), 5.66 (dd, J=15.5, 7.6 Hz, 1H), 5.42 (s,
1H), 4.18 (s, 2H), 4.03 (m, 1H), 3.99 (t, J=8.1 Hz, 1H), 3.67 (m, 1H), 3.32 (m, 1H), 3.15 (m, 1H), 2.10±1.99 (m,
2H), 1.93±1.88 (m, 2H), 1.70 (s, 3H), 1.34 (s, 6H); 13C NMR (125 MHz, CDCl3) ꢁ 139.5, 136.6, 134.2, 131.7, 129.8,
128.5, 126.8, 120.1, 109.6, 82.1, 79.0, 73.2, 66.1, 53.6, 36.0, 27.5, 27.3, 25.3, 23.3.