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Access to Resorcylic Acid Lactones via Phosphonate CHART 1. Selected RALs

Based Intramolecular Olefination

Carmela Napolitano, Patrick McArdle, and

Paul V. Murphy*
School of Chemistry, National University of Ireland,
Galway, University Road, Galway, Ireland

paul.v.murphy@nuigalway.ie
Received June 1, 2010
and L-783,2778).9 It can thus be argued that the RAL frame-
work is privileged10 and that analogues of these natural prod-
ucts should be of interest for screening in bioassays. Besides
their important biological properties, the RALs are of interest
from the synthetic point of view.11
Zearalenone, isolated in 1962 from the fungus Gibberella
zeae,12 was the first member of the RAL family to attract the
attention of both chemists and biologists due to its potent
agonism of the estrogen receptor. Zearalenone was shown to
adopt a conformation that mimics the steroid and competes
with estradiol binding to the estrogen receptor. As a result
of its interesting biological properties, several groups have
developed syntheses of this natural product,13 and it has served
as a testing ground for macrocyclization methodologies such as
the Corey-Nicolaou macrolactonization,14 Masamune’s thio-
An approach to resorcylic acid lactones is described, ex-
ester-lactonization,15 ring-closing metathesis (RCM),16 and
ploiting an intramolecular olefination reaction for the gen- more recently late stage aromatization-macrocyclization.17
eration of the 14-membered macrolactone. The synthetic
route gave zearalenone precursors, and the preparations of (8) Zhao, A.; Lee, S. H.; Mojena, M.; Jenkins, R. G.; Patrick, D. R.;
other RAL analogues, trans- and cis-resorcylides are in- Huber, H. E.; Goetz, M. A.; Hensens, O. D.; Zink, D. L.; Vilella, D.;
Dombrowski, A. W.; Lingham, R. B.; Huang, L. J. Antibiot. 1999, 52, 1086.
cluded, the latter being prepared by photoisomerization of (9) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22.
the trans-isomer. β-Haloketone derivatives were also pre- (10) (a) Hirschmann, R. Angew. Chem., Int. Ed. 1991, 30, 1278. (b) Koch,
M. A.; Waldmann, H. Drug Discovery Today 2005, 10, 471.
pared in a highly stereoselective manner by conjugate (11) For selected syntheses of aigialomycin D, see: (a) Yang, Z.-Q.; Geng, X;
addition of chloride or bromide to the E-enone using boron Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
trichloride and boron tribromide, respectively. 126, 7881. (b) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413. (c) Lu, J.; Ma,
J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymm. 2006, 17, 1066. (d)
Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11, 4910. For
hypothemycin and LL-Z1640-2, see: (e) Tatsuta, K.; Takano, S.; Sato, T.;
Nakano, S. Chem. Lett. 2001, 172. (f) Sell
es, P.; Lett, R. Tetrahedron Lett.
2002, 43, 4621. (g) Sell
es, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4627. (h) Dakas,
The resorcylic acid lactones (RALs, Chart 1) are endowed P.-Y.; Jogireddy, R.; Valot, G.; Barluenga, S.; Winssinger, N. Chem.;Eur. J.
with a breadth of biological activity. Compounds within this 2009, 15, 11490. For L-783,277, see: (i) Hofmann, T.; Altmann, K.-H. Synlett
class span from being transcription factor modulators (zearale- 2008, 10, 1500. (j) Choi, H. G.; Son, J. B.; Park, D.-S.; Ham, Y. J.; Hah, J.-M.;
Sim, T. Tetrahedron Lett. 2010, 51, 4942–4946.
none1 and zearalenol2) to HSP90 inhibitors (radicicol3 and (12) Stob, M.; Baldwin, R. S.; Tuite, J.; Andrews, F. N.; Gillette, K. G.
pochonin D4) and reversible (aigialomycin D5) as well as Nature 1962, 196, 1318.
(13) For selected syntheses of zearalenone, see: (a) Taub, D; Girotra,
irreversible kinase inhibitors (hypothemycin,6 LL-Z1640-2,7 N. N.; Hoffsommer, R. D.; Kuo, C. H.; Slates, H. L.; Weber, S.; Wendler,
N. L. Tetrahedron 1968, 24, 2443. (b) Takahashi, T.; Ikeda, H.; Tsuji, J.
(1) Miksicek, R. J. J. Steroid Biochem. Mol. Biol. 1994, 49, 153. Tetrahedron Lett. 1981, 22, 1363 and references therein. (c) Hitchcock, S. A.;
(2) Shier, W. T. Rev. Med. Vet. (Toulouse, Fr.) 1998, 149, 599. Pattenden, G. Tetrahedron Lett. 1990, 31, 3641. (d) Solladie, G.; Maestro,
(3) (a) Schulte, T. W.; Akinaga, S.; Soga, S.; Sullivan, W.; Stensgard, B.; M. C.; Rubio, A.; Pedregal, C.; Carre~ no, M. C.; Garcia Ruano, J. L. J. Org.
Toft, D.; Neckers, L. M. Cell Stress Chaperones 1998, 3, 100. (b) Sharma, Chem. 1991, 56, 2317. (e) Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org.
S. V.; Agatsuma, T.; Nakano, H. Oncogene 1998, 16, 2639. Chem. 1991, 56, 2883. (f) Wang, Z. Q.; Tian, S. K. Chin. Chem. Lett. 1997, 8,
(4) Moulin, E.; Zoete, V.; Barluenga, S.; Karplus, M.; Winssinger, N. 591. (g) Nicolaou, K. C.; Wissinger, N.; Pastor, J.; Murphy, F. Angew.
J. Am. Chem. Soc. 2005, 127, 6999. Chem., Int. Ed. 1998, 37, 2534 and references therein.
(5) Barluenga, S.; Dakas, P.-Y.; Ferandi, Y.; Meijer, L.; Winssinger, N. (14) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
Angew. Chem., Int. Ed. 2006, 118, 4055. (15) Masamune, S.; Kamata, S.; Schilling, W. J. Am. Chem. Soc. 1975, 97,
(6) Tanaka, H.; Nishida, K.; Sugita, K.; Yoshioka, T. Jpn. J. Cancer Res. 3515.
1999, 90, 1139. (b) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D. V. (16) F€urstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4234. 2000, 65, 7990.
(7) Ninomiya-Tsuji, J.; Kajino, T.; Ono, K.; Ohtomo, T.; Matsumoto, (17) Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.;
M.; Shiina, M.; Mihara, M.; Tsuchiya, M; Matsumoto, K. J. Biol. Chem. Howsham, C.; Br€ ackow, J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008, 130,
2003, 278, 18485. 10293.

7404 J. Org. Chem. 2010, 75, 7404–7407 Published on Web 10/12/2010 DOI: 10.1021/jo100998b
r 2010 American Chemical Society
Napolitano et al.
JOC Note
SCHEME 1. Retrosynthetic Analysis of 1 SCHEME 3. Synthesis of 4

SCHEME 4. Synthesis of 2a and 2b

SCHEME 2. Synthesis of 3

Herein we report an approach to the RAL core scaffold, which

exploits cross metathesis followed by modified Horner-
Wadsworth-Emmons (HWE) olefination. This was motivated
by a desire to generate new analogues of the RAL family18 for
biological evaluation. The syntheses of 4-O-methyl zearalenone,
trans- and cis-enone, and β-haloketone containing analogues of (Scheme 3). Conversion of 9 to the TBS ether 1023 followed by
LL-Z1640-2 and L-783,277 are described herein. reduction of the ester afforded primary alcohol 11.24 Treatment
(S)-4-O-Methyl zearalenone 1 was approached initially. As of 11 with NaH and 4-methoxybenzyl chloride (MPMCl) in
shown in Scheme 1, the initial disconnection of the C70 -C80 anhydrous DMF led in one pot to the protection of the primary
bond in the upper side chain led to the proposal that key alcohol and simultaneous removal of the TBS group to give
precursor 2 would give 1 after intramolecular olefination alcohol 425 in 68% yield.
followed by chemoselective reduction of the resulting enone Next the preparation of 14 was investigated (Scheme 4).
and demethylation. The fully functionalized phosphonate The Mitsunobu reaction of benzoic acid 3 with the ether 4,
2 was envisaged to be obtained from fragments 3-5 via promoted by triphenylphosphine in the presence of DIAD,
Mitsunobu esterification19 and olefin cross metathesis (CM).20 gave 12; subsequent oxidative removal of the 4-methoxy-
While the order of coupling of 3-5 is conceptually possible in all benzyl group from 12 using DDQ provided alcohol 13 (76%
permutations, we were interested in investigating the Ando and over two steps). Oxidation to aldehyde 14 was then at-
Still-Gennari variations of the HWE reaction for macrocyliza- tempted. While a number of widely used oxidizing conditions
tion and whether either or both would lead to the cis-enone. (Swern conditions, pyridinium chlorochromate) were unsuc-
The synthesis of the aromatic fragment 3 is shown in cessful, providing almost exclusively unreacted 13 together
Scheme 2. Permethylation of 2,4,6-trihydroxybenzoic acid with decomposition products, or were low yielding (DCC-
6 using dimethyl sulfate was followed by a boron trichloride H3PO4-DMSO, 22%), the treatment of 13 with Dess-
induced demethylation of the o-methyl ether21 to give 7; Martin periodinane (DMP) in wet CH2Cl226 smoothly afforded
subsequent reaction of 7 with triflic anhydride provided 14 in excellent yield (96%). In order to access the envisaged
the aryl triflate 8 (51% yield over three steps). Hence, key intermediates 2a and 2b, the CM reactions of the aldehyde
Suzuki-Miyaura-type coupling of 8 with potassium vinyl 14 with β-ketophosphonates 5a and 5b were then considered
trifluoroborate catalyzed by Pd(dppf)Cl2 utilizing Molander’s (Scheme 4). Phosphonates 5a and 5b, which could respectively
procedure22 and subsequent ester hydrolysis provided the be considered Still-Gennari27 and Ando28 reagents, were
styrene 3 in good yield. Intermediate 4 was conveniently
obtained from methyl (R)-3-hydroxybutyrate 9 in three steps
(24) Moore, C. G.; Murphy, P. J.; Williams, H. L.; McGown, A. T.;
(18) For recent papers from our own laboratory, see: (a) Rountree, Smith, N. K. Tetrahedron 2007, 63, 11771.
J. S. S.; Murphy, P. V. Org. Lett. 2009, 11, 871. (b) Matos, M. C.; Murphy, (25) Sharma, G. V. M.; Veera Babua, K. Tetrahedron: Asymmetry 2007,
P. V. J. Org. Chem. 2007, 72, 1803. 18, 2175.
(19) Mitsunobu, O. Synthesis 1981, 1, 1. (26) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(20) For recent reviews concerning CM, see: (a) Connon, S. J.; Blechert, (27) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
S. Angew. Chem., Int. Ed. 2003, 42, 1900. (b) Chatterjee, A. K.; Choi, T.-L.; (28) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105. (b) Ando, K. J. Org.
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360. Chem. 1997, 62, 1934. (c) Ando, K. J. Org. Chem. 1998, 63, 8411. (d) Ando,
(21) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetra- K. J. Org. Chem. 1999, 64, 8406. (e) Ando, K.; Oishi, T.; Hirama, M.; Ohno,
hedron 2003, 59, 2067. H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745. (f) Kokin, K.; Motoyoshiya, J.;
(22) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107. Hayashi, S.; Aoyama, H. Synth. Commun. 1997, 27, 2387. (g) Kokin, K.;
(23) Tartaglia, S.; Padula, D.; Scafato, P.; Chiummiento, L.; Rosini, C. Iitake, K.; Takaguchi, Y.; Aoyama, H.; Hayashi, S.; Motoyoshiya, J.
J. Org. Chem. 2008, 73, 4865. Phosphorus, Sulfur Silicon 1998, 133, 21.

J. Org. Chem. Vol. 75, No. 21, 2010 7405

JOC Note Napolitano et al.

TABLE 1. Intramolecular Olefination challenge was to extend the route to the preparation of cis-
enone containing resorcylides, which have recently
emerged as lead compounds for kinase inhibition.32 The
photoinduced isomerization of the trans-enone to the
thermodynamically less stable cis-isomer was thus inves-
tigated. When exposed to light, 15 gave an intractable
mixture of products. Hypothesizing that the introduction
entry 2a/2b conditions T (°C) yield 15 (%) of intramolecular H-bonding between the macrolactone
1 2a KHMDS, 18-crown-6, THF -83 53 carbonyl and the phenol hydroxyl group might facilitate
2 2a NaH, THF 0 77 the photoisomerization to the cis-isomer by acting as
3 2b NaH, THF 0 62 stereocontrolling element,33 we attempted the photoi-
4 2b DBU, NaI, THF -78 50 somerization with the phenol 17, which was prepared
5 2b K2CO3, 18-crown-6, toluene 70 54
from 15 using the boron trichloride induced cleavage of
selected with a view to investigating whether the intramolecular the o-methyl ether. Upon exposure to light (350 nm) 17
olefination reaction would lead to the cis-enone product, as was readily isomerized, affording a 3:2 mixture of both the
is generally the case for intermolecular reactions with these cis-enones 18 and 19 (50% conversion, Scheme 5). Efforts
types of reagents. This was necessary to clarify given that the to achieve the selective photoisomerization of the enone
cis-enone is found in a number of important RALs such as double bond by using different UV wavelengths (300 nm,
LL-Z1640-2 and L-783,277. The investigation of the reaction 250 nm) were unsuccessful and gave complex mixtures of
of bis(2,2,2-trifluoroethyl) methylphosphonate and diphenyl products and/or degradation of the starting material.
methylphosphonate with LDA in THF at -78 °C provided Although the two isomers 18 and 19 were not, in our
5a and 5b in poor yield (16% and 14%, respectively). An hands, separable by chromatography, the success of the
improvement was obtained by carrying out the reaction trans-cis photoconversion represented an important
at -95 °C and by replacing LDA with LHMDS as base; these finding as together with the HWE type olefination reac-
revised conditions led to the generation of 5a (57%) and 5b tion it potentially allows the preparation of members of
(46%) in more respectable yields. Cross metathesis of aldehyde both the trans- and cis-RAL subfamilies. It is also note-
14 with 5a and 5b using the Hoveyda-Grubbs’ generation II worthy that the photoisomerization of the styryl alkene
catalyst provided 2a (65%) and 2b (69%), with the only could be of interest, as the cis-geometry at this position
E-alkene products being obtained in each case. occurs in aigialomycin E.34 Interestingly, the O-demethy-
Intermediate 2a was found to be unstable to chromatog- lation of 15 afforded, besides the phenol 17, a small
raphy; efforts to purify 2a using silica gel, which had been amount (5%) of the 1,4-addition adduct33,4 20 as a single
pretreated with 1% triethylamine or using florisil led to the diastereoisomer, the configuration at C80 being estab-
spontaneous conversion to the E-enone 15 in 20% and 35% lished by X-ray crystallography. The β-haloketone 20
yield, respectively, over two steps. Chromatography using has been speculated to be a zearalenone metabolite. 35
nontreated silica gel afforded a sample of 2a contaminated Evaluation of compounds as kinase inhibitors where the
with small amount (5-10%) of enone E-15. The intramo- cis-enone functionality is replaced with a β-haloketone
lecular olefination was subsequently investigated (Table 1) would be of interest. Like the cis-enone, the β-haloketone
under a range of conditions. When reacting 2a with NaH in could potentially react with a cysteine thiol group that is
THF at 0 °C (entry 2), the E-isomer 15 was obtained in 77% conserved in some kinases.6b Thus, in order to generate
isolated yield. The phosphonate 2b gave E-15 in lower yield samples for biological evaluation, the halides 20 and 21
(62%, entry 3) under the same conditions. The conversion of were obtained after treatment of 17 with boron trichloride
15 to 1 was next accomplished (Scheme 5). Thus, chemose- and boron tribromide, respectively. These reactions were
lective hydride-mediated conjugate reduction of 15 using both highly stereoselective, leading to a single diastereoi-
the copper(I) hydride cluster [(Ph3P)CuH]629 followed by somer. Steric factors in the transition state are the major
cleavage of the o-methyl ether from 16 readily gave (S)-4- reason for the observed selectivity; the conformation of the
O-methyl zearalenone (1, 72% over two steps). The full de- macrolide leaves one face of the enone open to, presumably,
O-methylation of 16 to give zearalenone was described Lewis acid facilitated nucleophilic attack of the halide.
previously.30 Attempts to carry out a one-pot O-demethylation and
Although attempts to use the Still-Gennari or Ando 1,4-halide addition from 15 to give 20 and 21 were less
phosphonates to promote Z-selective intramolecular ole- productive than the two-step process.
fination were unsuccessful, the strategy was efficient for Finally, the reduced compounds 22-25 (Scheme 6) were
generating trans-resorcylides (i.e., 15), allowing the direct prepared, where the styryl double bond was converted
access to the aigialomycin A 31 framework, for example. A to an alkane. While this modification may seem modest,
the structural change can alter the macrocycle conformation
and consequently the selectivity of RALs.32a Thus, catalytic
(29) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. J. Am. Chem. Soc.
1988, 110, 291.
(30) Hitchcock, S. A.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1992,
1323. (33) Couladouros, E. A.; Mihou, A. P.; Bouzas, E. A. Org. Lett. 2004, 6,
(31) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; 977.
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561. (34) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M. J. Org. Chem.
(32) (a) Jogireddy, R.; Dakas, P.-Y.; Valot, G.; Barluenga, S.; Winssinger, N. 2002, 67, 1561.
Chem.;Eur. J. 2009, 15, 11498 and references therein. (b) Barluenga, S.; Dakas, (35) (a) Bolliger, G.; Tamm, C. Helv. Chim. Acta 1972, 55, 3030. (b)
P.-Y.; Boulifa, M.; Moulin, E.; Winssinger, N. C. R. Chim. 2008, 11, 1306. Jackson, R. A.; Fenton, S. W.; Mirocha, C. J.; Davis, G. J. Agric. Food Chem.
(c) Hofmann, T.; Altmann, K.-H. C. R. Chim. 2008, 11, 1318. 1974, 22, 1015.

7406 J. Org. Chem. Vol. 75, No. 21, 2010

Napolitano et al.
JOC Note
SCHEME 5. Synthesis of Various RALs from 15

SCHEME 6. Synthesis of 22-25 Experimental Section

(7S,9E,15E)-2,4-Dimethoxy-7-methyl-7,8,13,14-tetrahydro-12H-
6-oxa-benzocyclotetradecene-5,11-dionelenone 15. Sodium hydride
(60% oil dispersion, 6.5 mg, 0.16 mmol) was added to a stirred
solution of 2a (50 mg, 0.081 mmol) in dry THF (5 mL) that had been
precooled to 0 °C. The resulting mixture was stirred at 0 °C for 2 h,
and then H2O and EtOAc were added. The layers were separated,
and the aqueous phase was extracted with EtOAc. The combined
organic portions were dried (Na2SO4) and filtered, and the solvent
was removed under diminished pressure. Chromatography of the
residue (silica gel, CH2Cl2-acetone, 100:0 to 95:5) gave 15 (21.5 mg,
77%) as a pale yellow oil. Under similar conditions reported above,
treatment of 2b (20.0 mg, 0.034 mmol) with an excess of NaH (0.047
hydrogenation of 20 led to 22 in good yield (76%). The mmol) afforded, after common workup and purification proce-
bromide 21 was over-reduced under the same conditions and dures, 15 (5.6 mg, 62%) as a pale yellow oil; [R]D20 þ17.0 (c 0.17,
gave 23 (85%) as the only product. Under basic conditions CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.44 (d, J 6.5 Hz, 3H, CH3),
(Et3N, CH2Cl2) the chloride 22 readily transformed to trans- 1.68-1.79 (m, 1H), 2.09-2.16 (m, 2H), 2.22 (ddd, J 3.5 Hz, J 5.5
Hz, J 15.0 Hz, 1H), 2.26-2.35 (m, 1H), 2.40-2.55 (m, 2H), 2.77-
enone 24, which was then converted to the cis-enone 25
2.86 (m, 1H), 3.80 (s, 3H), 3.83 (s, 3H), 5.18-5.27 (m, 1H),
photochemically (97% yield, 83% conversion). The efficiency 6.04-6.13 (m, 1H), 6.09 (d, J 16.0 Hz, 1H), 6.28 (d, J 15.0 Hz,
of the latter reaction demonstrated the potential of the photo- 1H), 6.36 (d, J 2.0 Hz, 1H), 6.62 (d, J 2.0 Hz, 1H), 6.85 (dt, J 7.5 Hz,
isomerization in preparing cis-RALs after masking or remov- 16.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 20.7 (CH3), 23.4
ing the alkene adjacent to the aromatic ring. (CH2), 31.5 (CH2), 35.0 (CH2), 38.8 (CH2), 55.4 (CH3), 56.0 (CH3),
The synthesis of a series of simple RAL analogues via an 70.7 (CH), 97.8 (CH), 101.1 (CH), 116.3 (C), 128.6 (CH), 132.6
efficient intramolecular phosphonate olefination for the (CH), 135.0 (CH), 136.6 (C), 142.8 (CH), 157.6 (C), 161.3 (C), 167.5
generation of the 14-membered lactone ring has been (C), 192.3 (C). HRMS (ESI): found 367.1433 [M þ Na]þ, C20H24-
described. Although the olefination gave the E-enone prod- O5Na requires 367.1521.
uct, routes to a Z-enone were established by photoisom- Acknowledgment. The material described herein was
erization of the initially formed E-isomer. Also 1,4-halide funded by Science Foundation Ireland (PI/IN1/B966).
addition to the E-enone was achieved in a highly stereo-
selective manner to give β-haloketone derivatives. The Supporting Information Available: General and experimen-
biological properties of these RALs as kinase inhibitors tal procedures, 1H and 13C NMR spectra, and X-ray structure of
are currently under investigation and will be reported 20 in CIF format. This material is available free of charge via the
shortly. Internet at http://pubs.acs.org.

J. Org. Chem. Vol. 75, No. 21, 2010 7407