Short and efficient approach towards macrocyclic lactones based on a Sonogashira reaction

Article abstract of DOI:10.1002/ardp.200500132

Polyketide-derived macrolactones like zearalenone (1), zearalane (2) or curvularin (3) display a wide range of interesting pharmacological activities. Here, we present a short and efficient approach towards this class of natural products by a combination

Full text of DOI:10.1002/ardp.200500132

Arch. Pharm. Chem. Life Sci. 2005, 338, 605−608
DOI 10.1002/ardp.200500132
605
Short and Efficient Approach Towards Macrocyclic
Lactones Based on a Sonogashira Reaction*
Jürgen Krauss, Doris Unterreitmeier, Christine Neudert, Franz Bracher
Department of Pharmacy, Zentrum für Pharmaforschung, LMU Munich, Germany
Polyketide-derived macrolactones like zearalenone (1), zearalane (2) or curvularin (3) display a wide
range of interesting pharmacological activities. Here, we present a short and efficient approach towards
this class of natural products by a combination of the Sonogashira and Mitsunobu reactions. The
resulting lactone 9 was tested against human cancer cell lines at the NCI.
Keywords: Sonogashira reaction; Mitsunobu reaction; Macrolactones
Received: May 16, 2005; Accepted: July 27, 2005
Introduction
secondary alcohols. Other methods to build up macrolac-
tones are based on palladium-catalyzed cross-coupling
reactions like Suzuki and macrolactonizations by Corey,
Gerlach and Thalmann or a Wassermann protocol [6].
Polyketide-derived resorcyclic acid lactones like (S)-zeara-
lenone (1), (S)-zearalane (2) or (S)-curvularin (3) (Figure 1)
are a well-known group of natural products with interesting
pharmacological activities like cytotoxic, antibiotic, anti-
mycotic, anthelmintic, estrogenic, anabolic or immune-
modulating action [1Ϫ3]. Numerous total syntheses of re-
sorcyclic acid lactones have been described in the literature,
but most of these approaches are low-yielding procedures
using expensive starting materials.
Undec-10-yn-1-ol (5) was reacted in a Sonogashira reaction
with methyl 2-iodobenzoate (4) to the alkyne 6 [7] (Scheme
1). The best solvent for the Sonogashira coupling was ethyl-
dimethylamine (EDMA). After hydrogenation of the triple
bond with Pd-catalyst to the alkane 7, the methyl ester was
cleaved with methanolic aqueous KOH to give acid 8. This
acid was readily converted to the lactone 9 under Mitsu-
nobu conditions [8]. Cleavage of the methyl ester of 6 with-
out prior hydrogenation of the triple bond led to the couma-
rine derivative 10 [9]. In the course of this reaction, the ter-
minal hydroxy group was acetylated by the co-solvent ethyl
acetate (Scheme 1).
Results and discussion
In continuation of our work on total synthesis of naturally
occurring macrolactones [4, 5], we developed a new ap-
proach towards the class of benzolactones. Exemplarily, we
describe the synthesis of a simple 15-membered macrolac-
tone instead of the naturally occurring 14-membered lac-
tones and with a primary alcohol instead of the naturally
more common secondary alcohols, because these starting
materials are commercially available. The Sonogashira reac-
tion and the Mitsunobu reaction [4] are also possible with
In an alternative approach, we first prepared the acetylenic
ester 12 from 2-iodobenzoyl chloride (11) and the alkynol
5 (Scheme 2). The cyclization of 12 in an intramolecular
Sonogashira reaction to the acetylenic macrolactone 13 only
gave low yields.
The lactone 9 was tested at the NCI against the human
cancer cell lines NCI-H460, MCF7, and SF-268, but
showed no significant cytotoxic activities [10].
In summary, the preparation of lactone 9 is experimentally
very simple by using inexpensive starting materials. The de-
scribed method allows the preparation of macrolactones in
three steps. The total yield of lactone 9 was about 63%.
Figure 1. Naturally occurring resorcyclic lactones.
Acknowledgments
We wish to thank Tanja Höft for technical assistance.
Correspondence: Jürgen Krauss, Department of Pharmacy, Zentrum
für Pharmaforschung, LMU München, Butenandtstrasse 5Ϫ13, D-
81377 München, Germany. Phone: ϩ49-89-218077275, Fax: ϩ49-
89-218077171, e-mail: hjkra@cup.uni-muenchen.de
* Dedicated to Prof. Dr. K. Görlitzer on the occasion of his 65th
birthday.
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Arch. Pharm. Chem. Life Sci. 2005, 338, 605−608
Scheme 1. Synthesis of macrolactone 9 and coumarine derivative 10. (a) EDMA, CuI, PdCl2(PPh3)2; (b) H2/Pd (C), methanol;
(c) KOH, methanol, H2O; (d) P(Ph)3, DEAD, toluene; (e) KOH, methanol, H2O, EtOAc.
Palo Alto, CA, USA); Shimadzu GC-MS (GC 17A GCMS OP 500)
(Shimadzu Deutschland GmbH, Duisburg, Germany), NMR: Jeol
GSX 400 (1H: 400 MHz, 13C: 100 MHz) (Jeol (Germany) GmbH,
Eching/München, Germany); flash column chromatography (FCC):
silica gel 60 (230Ϫ400 mesh, E. Merck, Darmstadt, Germany).
HR-MS: Heraeus CHN-Rapid (Heraeus Holding GmbH, Hanau,
Germany).
Chemistry
Methyl (2-(11-hydroxyundec-1-ynyl)benzoate (6)
Methyl-2-iodobenzoate (4) (1.0 g, 3.8 mmol) and 640 mg (3.8 mmol)
undec-10-yn-1-ol (5) were dissolved in 30 mL of a suspension of
Scheme 2. Alternative synthesis route of cumarine derivative
200 mg (1.1 mmol) CuI and 200 mg (0.29 mmol) PdCl2(PPh3)2 in
10. (a) Toluene, EDMA; (b) EDMA, CuI, PdCl2(PPh3)2.
EDMA. The suspension was stirred for 12 h, the solvent was evapo-
rated and the residue dissolved in 10% Na2S2O3 solution. After
extraction with diethylether (3 ϫ 30 mL) the combined organic
layers were dried over Na2SO4 and the solvent was evaporated. The
Experimental
residue was purified with FCC (n-hexane/ethyl acetate 5:1) to give
1.1 g (96%) of 6. 1H-NMR (CDCl3) δ (ppm) ϭ 1.32 (m, 8H,
General
4 ϫ CH2), 1.39 (s, 1H, OH), 1.46 (m, 2H, CH2), 1.54 (m, 2H, CH2),
IR-Spectra: Jasco FT-IR 410 (Jasco, Groß-Umstadt, Germany);
MS: Hewlett Packard MS-Engine, electron ionisation (EI) 70 eV,
chemical ionisation (CI) with CH4 (300 eV) (Agilent Technologies,
1.62 (m, 2H, CH2), 2.46 (t, J ϭ 7.2 Hz, 2H, CH2), 3.61 (t, J ϭ 7.3
Hz, 2H, CH2), 3.90 (s, 3H, OCH3), 7.29 (ddd, J ϭ 1.3 Hz, J ϭ 7.5
Hz, J ϭ 7.5 Hz, 1H, aromat. CH), 7.40 (ddd, J ϭ 1.3 Hz, J ϭ 7.5
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Arch. Pharm. Chem. Life Sci. 2005, 338, 605−608
Macrocyclic Lactones Based on Sonogashira Reaction
607
Hz, J ϭ 7.5 Hz, 1H, aromat. CH), 7.49 (dd, J ϭ 1.3 Hz, J ϭ 7.5
Hz, 1H, aromat. CH), 7.89 (dd, J ϭ 1.3 Hz, J ϭ 7.5 Hz, 1H, 6-H).
13C-NMR (CDCl3) δ (ppm) ϭ 19.64 (CH2), 25.66 (CH2), 28.59
(CH2), 28.86 (CH2), 29.10 (CH2), 29.33 (CH2), 29.41 (CH2), 32.73
(CH2), 52.01 (OCH3), 62.99 (CH2O), 79.17 (quart. C), 95.99 (quart.
C), 124.45 (quart. C), 127.07 (aromat. CH), 130.07 (aromat. CH),
131.42 (aromat. CH), 131.88 (quart. C), 134.16 (aromat. CH),
166.99 (COO). Calcd.: C: 75.46, H: 9.15. Found: C: 75.09, H: 8.74.
10 h. The solution was neutralized with 10% HCl solution and ex-
tracted with diethyl ether (3 ϫ 30 mL). The combined organic layers
were dried over Na2SO4 and evaporated. The residue was purified
by FCC (n-hexane/ethyl acetate 5:1) to give 120 mg (56%) of 10.
1H-NMR (CDCl3) δ (ppm) ϭ 1.30 (m, 10H, 5 ϫ CH2), 1.60 (m, 2
H, CH2), 1.69 (m, 2H, CH2), 2.03 (s, 3H, CH3), 2.51 (t, J ϭ 7.2 Hz,
2H, CH2), 4.03 (t, J ϭ 7.1 Hz, 2H, CH2), 6.24 (s, 1H, aromat. CH),
7.34 (d, J ϭ 7.7 Hz, 1H, aromat. CH), 7.43 (ddd, J ϭ 7.4 Hz, J ϭ
7.5 Hz, J ϭ 1.4 Hz, 1H, aromat. CH), 7.66 (ddd, J ϭ 7.5 Hz, J ϭ
7.9 Hz, J ϭ 7.9 Hz, 1H, aromat. CH), 8.24 (d, J ϭ 7.7 Hz, 1H, 8Љ-
H). 13C-NMR (CDCl3) δ (ppm) ϭ 20.98 (CH3), 25.85 (CH2), 26.87
(CH2), 28.55 (CH2), 28.94 (CH2), 29.15 (CH2), 29.19 (CH2), 29.31
(CH2), 33.51 (CH2), 64.58 (OCH3), 102.85 (aromat. CH), 120.14
(quart. C), 124.98 (aromat. CH), 127.51 (aromat. CH), 129.49 (aro-
mat. CH), 134.67 (aromat. CH), 137.62 (quart. C), 158.28 (quart.
C), 163.06 (quart. C), 171.19 (quart. C). MS (EI): m/z (%) ϭ 330
(Mϩ, 30), 288 (20), 172 (100), 118 (80), 89 45). MS (CI): m/z (%) ϭ
331 (100, Mϩϩ1), 289 (25), 271 (20).
Methyl (2-(11-hydroxyundecyl)benzoate (7)
Of 6, 500 mg (1.6 mmol) was dissolved in 50 mL methanol, and
100 mg Pd (C) (10%) was added. The suspension was stirred under
H2 atmosphere for 12 h. The catalyst was filtered off and the solvent
was evaporated to give 450 mg (92%) of 7. 1H-NMR (CDCl3) δ
(ppm) ϭ 1.28 (m, 14H, 7 ϫ CH2), 1.47 (s, 1H, OH), 1.57 (m, 4H,
2 ϫ CH2), 2.93 (t, J ϭ 7.8 Hz, 2H, CH2), 3.63 (t, J ϭ 6.6 Hz, 2H,
CH2), 3.89 (s, 3H, CH3), 7.23 (m, 2H, 2 aromat. CH), 7.40 (ddd,
J ϭ 7.5 Hz, J ϭ 7.5 Hz, J ϭ 1.4 Hz, 1H, aromat. CH), 7.84 (dd,
J ϭ 7.7 Hz, J ϭ 1.4 Hz, 1H, 6-H).
Undec-10-yn-1-yl-2-iodobenzoate (12)
2-(11-Hydroxyundecyl)benzoic acid (8)
Of 2-iodobenzoyl chloride (11), 2.6 g (10.0 mmol) and 1.68 g (10.0
mmol) undec-10-yn-1-ol (5) were dissolved in toluene, 5 mL EDMA
were added and the mixture was stirred for 12 h. The solvent was
evaporated, the residue dissolved in 50 mL water and extracted with
diethyl ether (3 ϫ 50 mL). The combined organic layers were dried
over MgSO4 and the the solvent was evaporated. The residue was
purified by FCC (n-hexane/ethyl acetate 5:1) to give 3.5 g (88%) of
12. 1H-NMR (CDCl3) δ (ppm) ϭ 1.31 (m, 14H, CH2), 1.53 (m, 2H,
CH2), 1.78 (m, 2H, CH2), 1.94 (t, J ϭ 2.5 Hz, 1H, CH), 2.18 (dt,
J ϭ 2.5 Hz, J ϭ 7.2 Hz, 2H, CH2), 4.33 (t, J ϭ 6.7 Hz, 2H, CH2),
7.15 (ddd, J ϭ 1.8 Hz, J ϭ 7.5 Hz, J ϭ 7.9 Hz, 1H, aromat. CH),
7.40 (ddd, J ϭ 1.2 Hz, J ϭ 7.9 Hz, J ϭ 7.5 Hz, 1H, aromat. CH),
7.78 (dd, J ϭ 1.7 Hz, J ϭ 7.9 Hz, 1H, aromat. CH), 7.99 (dd, J ϭ
1.2 Hz, J ϭ 7.9 Hz, 1H, aromat. CH). 13C-NMR (CDCl3) δ
(ppm) ϭ 25.72 (CH2), 28.48 (CH2), 28.72 (CH2), 29.03 (CH2), 29.36
(CH2), 29.44 (CH2), 32.80 (CH2), 38.93 (CH2), 42.79 (CH2), 63.05
(CH2O), 84.77 (CH), 92.90 (quart. C), 126.88 (aromat. CH), 128.22
(aromat. CH), 129.87 (aromat. CH), 139.16 (aromat. CH), 142.92
(quart. C), 170.07 (CO). MS (EI): m/z (%) ϭ 398 (Mϩ, 6), 248 (100),
231 (63), 203 (18). HR-MS: Calcd.: 398.0743. Found: 38.0739.
Of 7, 400 mg (1.4 mmol) was dissolved in 40 mL 5% KOH solution
(methanol/H2O 1:1) and refluxed for 10 h. The solution was neu-
tralized with 10% HCl solution and extracted with diethyl ether
(3 ϫ 40 mL). The combined organic layers were dried over Na2SO4
and the solvent was evaporated. The residue was purified by FCC
(n-hexane/ethyl acetate 1:1) to give 370 mg (91%) of 8. 1H-NMR
(CDCl3) δ (ppm) ϭ 1.29 (m, 14H, 7 ϫ CH2), 1.58 (m, 4H, 2 ϫ
CH2), 3.01 (t, J ϭ 7.7 Hz, 2H, CH2), 3.67 (t, J ϭ 6.7 Hz, 2H, CH2),
7.26 (m, 2H, 2 aromat. CH), 7.45 (ddd, J ϭ 7.7 Hz, J ϭ 7.7 Hz,
J ϭ 1.5 Hz, 1H, aromat. CH), 8.00 (d, J ϭ 7.2 Hz, 1H, 6-H). 13C-
NMR (CDCl3) δ (ppm) ϭ 25.63 (CH2), 29.22 (CH2), 29.23 (CH2),
29.24 (2 ϫ CH2), 29.30 (CH2), 34.59 (CH2), 34.61 (CH2), 34.64
(CH2), 34.65 (CH2), 63.21 (CH2O), 125.83 (aromat. CH), 128.28
(quart. C), 131.23 (aromat. CH), 131.54 (aromat. CH), 132.68 (aro-
mat. CH), 145.79 (quart. C), 171.98 (COOH). MS (EI): m/z (%) ϭ
274 (MϩϪ18, 20), 131 (100), 55 (44). MS (CI): m/z (%) ϭ 293
(Mϩϩ1, 4), 275 (100). Calcd.: C: 73.93, H: 9.65. Found: C: 73.81,
H: 9.63.
8,9,10,12,13,14,15,16,17ϪDecahydro-7H-6-oxabenzo-cyclopenta-
decen-5-one (9)
8,9,10,11,12,13,14,15-Octahydro-7H-6-oxa-benzo-cyclopentadecen-
16-in-5-one (13)
Of 8, 200 mg (0.7 mmol) was dissolved in 10 mL toluene and
dropped over a period of 4 h to a solution of 520 mg (2.0 mmol)
triphenyl phosphine and 400 mg (2.3 mmol) DEAD in 100 mL dry
toluene. The mixture was stirred for 12 h. The solvent was evapo-
rated and the residue purified by FCC (n-hexane/ethyl acetate 10:1)
to give 150 mg (78%) of 9 as a colourless oil. 1H-NMR (CDCl3) δ
(ppm) ϭ 1.27 (m, 6H, 3 ϫ CH2), 1.37 (m, 4H, 2 ϫ CH2), 1.52 (m,
2H, CH2), 1.73 (m, 2H, CH2), 2.96 (t, J ϭ 8.1 Hz, 2H, CH2), 4.42
(t, J ϭ 5.2 Hz, 2H, CH2O), 7.22 (m, 2H, 2 aromat. CH), 7.37 (ddd,
J ϭ 7.5 Hz, J ϭ 7.5 Hz, J ϭ 1.4 Hz, 1H, aromat. CH), 7.69 (dd,
J ϭ 1.6 Hz, J ϭ 7.5 Hz, 1H, aromat. CH). 13C-NMR (CDCl3) δ
(ppm) ϭ 23.78 (CH2), 24.46 (CH2), 24.58 (CH2), 25.64 (CH2), 26.64
(CH2), 26.93 (2 ϫ CH2), 28.89(CH2), 30.64 (CH2), 34.15 (CH2),
64.33 (CH2), 125.64 (aromat. CH), 129.95 (aromat. CH), 130.82
(aromat. CH), 131.28 (aromat. CH), 143.39 (quart. C), 150.07
(quart. C), 169.11 (COO). MS (EI): m/z (%) ϭ 274 (Mϩ, 35), 148
(100), 55 (95). MS (CI): m/z (%) ϭ 275 (Mϩϩ1, 100). HR-MS:
Calcd.: 274.1933. Found: 274.1919.
Of 12, 680 mg (1.7 mmol) were dissolved in 10 mL EDMA and
added dropwise to a stirred suspension of 500 mg (2.6 mmol) CuI
and 400 mg (0.6 mmol) PdCl2(PPh3)2 in 250 mL dry EDMA and
stirred for 12 h. Then, the solvent was evaporated and the residue
was dissolved in 30 mL water. The aqueous layer was extracted with
diethylether (3 Ϯ 30 mL) and the combined organic layers were
dried over MgSO4 and the solvent was evaporated. The residue was
purified by FCC (n-hexane/ethyl acetate 10:1) to give 70 mg (15%)
1
of 13. H-NMR (CDCl3) δ (ppm) ϭ 1.42 (m, 12H, 6 ϫ CH2), 1.75
(m, 2H, CH2), 2.51 (dd, J ϭ 5.8 Hz, J ϭ 5.8 Hz, 2H, CH2), 4.49
(dd, J ϭ 5.3 Hz, J ϭ 5.3 Hz, 2H, CH2O), 7.29 (ddd, J ϭ 0.9 Hz,
J ϭ 7.5 Hz, J ϭ 7.6 Hz, 1H, aromat. CH), 7.38 (ddd, J ϭ 1.1 Hz,
J ϭ 7.5 Hz, J ϭ 7.5 Hz, 1H, aromat. CH), 7.50 (dd, J ϭ 1.1 Hz,
J ϭ 7.6 Hz, 1H, aromat. CH), 7.69 (dd, J ϭ 0.9 Hz, J ϭ 7.7 Hz,
1H, aromat. CH). 13C-NMR (CDCl3) d (ppm) ϭ 23.56 (CH2), 25.55
(CH2), 25.76 (CH2), 25.86 (CH2), 27.25 (CH2), 27.64 (CH2), 29.52
(CH2), 33.79 (CH2), 63.78 (CH2O), 79.06 (quart. C), 95.27 (quart.
C), 123.71 (quart. C), 126.99 (aromat. CH), 129.35 (aromat. CH),
130.76 (aromat. CH), 133.81 (aromat. CH), 167.65 (CO). MS (EI):
m/z (%) ϭ 270 (Mϩ, 6), 199 (100), 159 (72).
(9-(1-Oxo-1H-isochromen-3-yl)-nonyl) acetate (10)
Of 3, 200 mg (0.65 mmol) and 0.5 mL ethylacetate were dissolved
in 20 mL 5% KOH solution (methanol/H2O 1:1) and refluxed for
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Arch. Pharm. Chem. Life Sci. 2005, 338, 605−608
[4] F. Bracher, J. Krauss, Monatsh. Chem. 2001, 132, 805Ϫ811.
[5] F. Bracher, J. Krauss, Eur. J. Org. Chem. 2001, 24, 4701Ϫ4704.
[6] Q. Meng, M. Hesse, Top. Curr. Chem. 1991, 161, 107Ϫ176.
[7] J. Krauss, F. Bracher, Arch. Pharm. Pharm. Med. Chem. 2004,
337, 371Ϫ375.
References
[1] D. T. Kiang, B. J. Kennedy, S. V. Pathre, C. J. Mirocha, Cancer
Res. 1978, 38, 3611Ϫ3615.
[2] C. K, Edwards, M. J. Jacobs, P. Myers-Keith, L. M. Yunger,
Immunopharmacol. 1989, 17, 107Ϫ118.
[8] O. Mitsunobu, Synthesis 1981, 1Ϫ28.
[9] D. Villemin, D. Goussu, Heterocycles 1989, 29, 1255Ϫ1261.
[10] http://dtp.nci.nih.gov
[3] A. Kobayashi, T. Hino, S. Yata, T. J. Itoh, H. Sato, A. Kawazu,
Agric. Biol. Chem. 1988, 52, 3119.
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