Access to resorcylic acid lactones via phosphonate based intramolecular olefination

Article abstract of DOI:10.1021/jo100998b

An approach to resorcylic acid lactones is described, exploiting an intramolecular olefination reaction for the generation of the 14-membered macrolactone. The synthetic route gave zearalenone precursors, and the preparations of other RAL analogues, trans

Full text of DOI:10.1021/jo100998b

pubs.acs.org/joc
CHART 1. Selected RALs
Access to Resorcylic Acid Lactones via Phosphonate
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-
ester-lactonization,15 ring-closing metathesis (RCM),16 and
more recently late stage aromatization-macrocyclization.17
An approach to resorcylic acid lactones is described, ex-
ploiting an intramolecular olefination reaction for the gen-
eration of the 14-membered macrolactone. The synthetic
route gave zearalenone precursors, and the preparations of
other RAL analogues, trans- and cis-resorcylides are in-
cluded, the latter being prepared by photoisomerization of
the trans-isomer. β-Haloketone derivatives were also pre-
pared in a highly stereoselective manner by conjugate
addition of chloride or bromide to the E-enone using boron
trichloride and boron tribromide, respectively.
(8) Zhao, A.; Lee, S. H.; Mojena, M.; Jenkins, R. G.; Patrick, D. R.;
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.
(9) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22.
(10) (a) Hirschmann, R. Angew. Chem., Int. Ed. 1991, 30, 1278. (b) Koch,
M. A.; Waldmann, H. Drug Discovery Today 2005, 10, 471.
(11) For selected syntheses of aigialomycin D, see: (a) Yang, Z.-Q.; Geng, X;
Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
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) Selles, P.; Lett, R. Tetrahedron Lett.
2002, 43, 4621. (g) Selles, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4627. (h) Dakas,
P.-Y.; Jogireddy, R.; Valot, G.; Barluenga, S.; Winssinger, N. Chem.;Eur. J.
2009, 15, 11490. For L-783,277, see: (i) Hofmann, T.; Altmann, K.-H. Synlett
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.
(12) Stob, M.; Baldwin, R. S.; Tuite, J.; Andrews, F. N.; Gillette, K. G.
Nature 1962, 196, 1318.
(13) For selected syntheses of zearalenone, see: (a) Taub, D; Girotra,
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.
Tetrahedron Lett. 1981, 22, 1363 and references therein. (c) Hitchcock, S. A.;
ꢀ
The resorcylic acid lactones (RALs, Chart 1) are endowed
with a breadth of biological activity. Compounds within this
class span from being transcription factor modulators (zearale-
none1 and zearalenol2) to HSP90 inhibitors (radicicol3 and
pochonin D4) and reversible (aigialomycin D5) as well as
irreversible kinase inhibitors (hypothemycin,6 LL-Z1640-2,7
(1) Miksicek, R. J. J. Steroid Biochem. Mol. Biol. 1994, 49, 153.
(2) Shier, W. T. Rev. Med. Vet. (Toulouse, Fr.) 1998, 149, 599.
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Toft, D.; Neckers, L. M. Cell Stress Chaperones 1998, 3, 100. (b) Sharma,
S. V.; Agatsuma, T.; Nakano, H. Oncogene 1998, 16, 2639.
(4) Moulin, E.; Zoete, V.; Barluenga, S.; Karplus, M.; Winssinger, N.
J. Am. Chem. Soc. 2005, 127, 6999.
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Pattenden, G. Tetrahedron Lett. 1990, 31, 3641. (d) Solladie, G.; Maestro,
M. C.; Rubio, A.; Pedregal, C.; Carreno, M. C.; Garcia Ruano, J. L. J. Org.
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Chem. 1991, 56, 2317. (e) Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org.
Chem. 1991, 56, 2883. (f) Wang, Z. Q.; Tian, S. K. Chin. Chem. Lett. 1997, 8,
591. (g) Nicolaou, K. C.; Wissinger, N.; Pastor, J.; Murphy, F. Angew.
Chem., Int. Ed. 1998, 37, 2534 and references therein.
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1999, 90, 1139. (b) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D. V.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4234.
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2003, 278, 18485.
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3515.
€
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2000, 65, 7990.
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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.
JOCNote
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
LL-Z1640-2 and L-783,277 are described herein.
(Scheme 3). Conversion of 9 to the TBS ether 1023 followed by
reduction of the ester afforded primary alcohol 11.24 Treatment
of 11 with NaH and 4-methoxybenzyl chloride (MPMCl) in
anhydrous DMF led in one pot to the protection of the primary
alcohol and simultaneous removal of the TBS group to give
alcohol 425 in 68% yield.
(S)-4-O-Methyl zearalenone 1 was approached initially. As
shown in Scheme 1, the initial disconnection of the C70-C80
bond in the upper side chain led to the proposal that key
precursor 2 would give 1 after intramolecular olefination
followed by chemoselective reduction of the resulting enone
and demethylation. The fully functionalized phosphonate
2 was envisaged to be obtained from fragments 3-5 via
Mitsunobu esterification19 and olefin cross metathesis (CM).20
While the order of coupling of 3-5 is conceptually possible in all
permutations, we were interested in investigating the Ando and
Still-Gennari variations of the HWE reaction for macrocyliza-
tion and whether either or both would lead to the cis-enone.
The synthesis of the aromatic fragment 3 is shown in
Scheme 2. Permethylation of 2,4,6-trihydroxybenzoic acid
6 using dimethyl sulfate was followed by a boron trichloride
induced demethylation of the o-methyl ether21 to give 7;
subsequent reaction of 7 with triflic anhydride provided
the aryl triflate 8 (51% yield over three steps). Hence,
Suzuki-Miyaura-type coupling of 8 with potassium vinyl
trifluoroborate catalyzed by Pd(dppf)Cl2 utilizing Molander’s
procedure22 and subsequent ester hydrolysis provided the
styrene 3 in good yield. Intermediate 4 was conveniently
obtained from methyl (R)-3-hydroxybutyrate 9 in three steps
Next the preparation of 14 was investigated (Scheme 4).
The Mitsunobu reaction of benzoic acid 3 with the ether 4,
promoted by triphenylphosphine in the presence of DIAD,
gave 12; subsequent oxidative removal of the 4-methoxy-
benzyl group from 12 using DDQ provided alcohol 13 (76%
over two steps). Oxidation to aldehyde 14 was then at-
tempted. While a number of widely used oxidizing conditions
(Swern conditions, pyridinium chlorochromate) were unsuc-
cessful, providing almost exclusively unreacted 13 together
with decomposition products, or were low yielding (DCC-
H3PO4-DMSO, 22%), the treatment of 13 with Dess-
Martin periodinane (DMP) in wet CH2Cl226 smoothly afforded
14 in excellent yield (96%). In order to access the envisaged
key intermediates 2a and 2b, the CM reactions of the aldehyde
14 with β-ketophosphonates 5a and 5b were then considered
(Scheme 4). Phosphonates 5a and 5b, which could respectively
be considered Still-Gennari27 and Ando28 reagents, were
(24) Moore, C. G.; Murphy, P. J.; Williams, H. L.; McGown, A. T.;
Smith, N. K. Tetrahedron 2007, 63, 11771.
(25) Sharma, G. V. M.; Veera Babua, K. Tetrahedron: Asymmetry 2007,
18, 2175.
(18) For recent papers from our own laboratory, see: (a) Rountree,
J. S. S.; Murphy, P. V. Org. Lett. 2009, 11, 871. (b) Matos, M. C.; Murphy,
P. V. J. Org. Chem. 2007, 72, 1803.
(19) Mitsunobu, O. Synthesis 1981, 1, 1.
(26) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(27) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(28) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105. (b) Ando, K. J. Org.
Chem. 1997, 62, 1934. (c) Ando, K. J. Org. Chem. 1998, 63, 8411. (d) Ando,
K. J. Org. Chem. 1999, 64, 8406. (e) Ando, K.; Oishi, T.; Hirama, M.; Ohno,
H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745. (f) Kokin, K.; Motoyoshiya, J.;
Hayashi, S.; Aoyama, H. Synth. Commun. 1997, 27, 2387. (g) Kokin, K.;
Iitake, K.; Takaguchi, Y.; Aoyama, H.; Hayashi, S.; Motoyoshiya, J.
Phosphorus, Sulfur Silicon 1998, 133, 21.
(20) For recent reviews concerning CM, see: (a) Connon, S. J.; Blechert,
S. Angew. Chem., Int. Ed. 2003, 42, 1900. (b) Chatterjee, A. K.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(21) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetra-
hedron 2003, 59, 2067.
(22) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107.
(23) Tartaglia, S.; Padula, D.; Scafato, P.; Chiummiento, L.; Rosini, C.
J. Org. Chem. 2008, 73, 4865.
J. Org. Chem. Vol. 75, No. 21, 2010 7405

Napolitano et al.
JOCNote
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
of intramolecular H-bonding between the macrolactone
carbonyl and the phenol hydroxyl group might facilitate
the photoisomerization to the cis-isomer by acting as
stereocontrolling element,33 we attempted the photoi-
somerization with the phenol 17, which was prepared
from 15 using the boron trichloride induced cleavage of
the o-methyl ether. Upon exposure to light (350 nm) 17
was readily isomerized, affording a 3:2 mixture of both the
cis-enones 18 and 19 (50% conversion, Scheme 5). Efforts
to achieve the selective photoisomerization of the enone
double bond by using different UV wavelengths (300 nm,
250 nm) were unsuccessful and gave complex mixtures of
products and/or degradation of the starting material.
Although the two isomers 18 and 19 were not, in our
hands, separable by chromatography, the success of the
trans-cis photoconversion represented an important
finding as together with the HWE type olefination reac-
tion it potentially allows the preparation of members of
both the trans- and cis-RAL subfamilies. It is also note-
worthy that the photoisomerization of the styryl alkene
could be of interest, as the cis-geometry at this position
occurs in aigialomycin E.34 Interestingly, the O-demethy-
lation of 15 afforded, besides the phenol 17, a small
amount (5%) of the 1,4-addition adduct33,4 20 as a single
diastereoisomer, the configuration at C80 being estab-
lished by X-ray crystallography. The β-haloketone 20
has been speculated to be a zearalenone metabolite.35
Evaluation of compounds as kinase inhibitors where the
cis-enone functionality is replaced with a β-haloketone
would be of interest. Like the cis-enone, the β-haloketone
could potentially react with a cysteine thiol group that is
conserved in some kinases.6b Thus, in order to generate
samples for biological evaluation, the halides 20 and 21
were obtained after treatment of 17 with boron trichloride
and boron tribromide, respectively. These reactions were
both highly stereoselective, leading to a single diastereoi-
somer. Steric factors in the transition state are the major
reason for the observed selectivity; the conformation of the
macrolide leaves one face of the enone open to, presumably,
Lewis acid facilitated nucleophilic attack of the halide.
Attempts to carry out a one-pot O-demethylation and
1,4-halide addition from 15 to give 20 and 21 were less
productive than the two-step process.
entry 2a/2b
conditions
T (°C) yield 15 (%)
1
2
3
4
5
2a
2a
2b
2b
2b
KHMDS, 18-crown-6, THF
NaH, THF
NaH, THF
DBU, NaI, THF
K2CO3, 18-crown-6, toluene
-83
0
0
-78
70
53
77
62
50
54
selected with a view to investigating whether the intramolecular
olefination reaction would lead to the cis-enone product, as
is generally the case for intermolecular reactions with these
types of reagents. This was necessary to clarify given that the
cis-enone is found in a number of important RALs such as
LL-Z1640-2 and L-783,277. The investigation of the reaction
of bis(2,2,2-trifluoroethyl) methylphosphonate and diphenyl
methylphosphonate with LDA in THF at -78 °C provided
5a and 5b in poor yield (16% and 14%, respectively). An
improvement was obtained by carrying out the reaction
at -95 °C and by replacing LDA with LHMDS as base; these
revised conditions led to the generation of 5a (57%) and 5b
(46%) in more respectable yields. Cross metathesis of aldehyde
14 with 5a and 5b using the Hoveyda-Grubbs’ generation II
catalyst provided 2a (65%) and 2b (69%), with the only
E-alkene products being obtained in each case.
Intermediate 2a was found to be unstable to chromatog-
raphy; efforts to purify 2a using silica gel, which had been
pretreated with 1% triethylamine or using florisil led to the
spontaneous conversion to the E-enone 15 in 20% and 35%
yield, respectively, over two steps. Chromatography using
nontreated silica gel afforded a sample of 2a contaminated
with small amount (5-10%) of enone E-15. The intramo-
lecular olefination was subsequently investigated (Table 1)
under a range of conditions. When reacting 2a with NaH in
THF at 0 °C (entry 2), the E-isomer 15 was obtained in 77%
isolated yield. The phosphonate 2b gave E-15 in lower yield
(62%, entry 3) under the same conditions. The conversion of
15 to 1 was next accomplished (Scheme 5). Thus, chemose-
lective hydride-mediated conjugate reduction of 15 using
29
the copper(I) hydride cluster [(Ph3P)CuH]6 followed by
cleavage of the o-methyl ether from 16 readily gave (S)-4-
O-methyl zearalenone (1, 72% over two steps). The full de-
O-methylation of 16 to give zearalenone was described
previously.30
Although attempts to use the Still-Gennari or Ando
phosphonates to promote Z-selective intramolecular ole-
fination were unsuccessful, the strategy was efficient for
generating trans-resorcylides (i.e., 15), allowing the direct
access to the aigialomycin A31 framework, for example. A
Finally, the reduced compounds 22-25 (Scheme 6) were
prepared, where the styryl double bond was converted
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.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
(32) (a) Jogireddy, R.; Dakas, P.-Y.; Valot, G.; Barluenga, S.; Winssinger, N.
Chem.;Eur. J. 2009, 15, 11498 and references therein. (b) Barluenga, S.; Dakas,
P.-Y.; Boulifa, M.; Moulin, E.; Winssinger, N. C. R. Chim. 2008, 11, 1306.
(c) Hofmann, T.; Altmann, K.-H. C. R. Chim. 2008, 11, 1318.
977.
(34) Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M. J. Org. Chem.
2002, 67, 1561.
(35) (a) Bolliger, G.; Tamm, C. Helv. Chim. Acta 1972, 55, 3030. (b)
Jackson, R. A.; Fenton, S. W.; Mirocha, C. J.; Davis, G. J. Agric. Food Chem.
1974, 22, 1015.
7406 J. Org. Chem. Vol. 75, No. 21, 2010

Napolitano et al.
JOCNote
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
mmol) afforded, after common workup and purification proce-
hydrogenation of 20 led to 22 in good yield (76%). The
bromide 21 was over-reduced under the same conditions and
gave 23 (85%) as the only product. Under basic conditions
(Et3N, CH2Cl2) the chloride 22 readily transformed to trans-
enone 24, which was then converted to the cis-enone 25
photochemically (97% yield, 83% conversion). The efficiency
of the latter reaction demonstrated the potential of the photo-
isomerization in preparing cis-RALs after masking or remov-
ing the alkene adjacent to the aromatic ring.
The synthesis of a series of simple RAL analogues via an
efficient intramolecular phosphonate olefination for the
generation of the 14-membered lactone ring has been
described. Although the olefination gave the E-enone prod-
uct, routes to a Z-enone were established by photoisom-
erization of the initially formed E-isomer. Also 1,4-halide
addition to the E-enone was achieved in a highly stereo-
selective manner to give β-haloketone derivatives. The
biological properties of these RALs as kinase inhibitors
are currently under investigation and will be reported
shortly.
20
dures, 15 (5.6 mg, 62%) as a pale yellow oil; [R]D þ17.0 (c 0.17,
CHCl3);1H NMR (500 MHz, CDCl3) δ1.44 (d, J6.5 Hz, 3H, CH3),
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-
2.86 (m, 1H), 3.80 (s, 3H), 3.83 (s, 3H), 5.18-5.27 (m, 1H),
6.04-6.13 (m, 1H), 6.09 (d, J 16.0 Hz, 1H), 6.28 (d, J 15.0 Hz,
1H), 6.36 (d, J 2.0 Hz, 1H), 6.62 (d, J 2.0 Hz, 1H), 6.85 (dt, J 7.5 Hz,
16.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 20.7 (CH3), 23.4
(CH2), 31.5 (CH2), 35.0 (CH2), 38.8 (CH2), 55.4 (CH3), 56.0 (CH3),
70.7 (CH), 97.8 (CH), 101.1 (CH), 116.3 (C), 128.6 (CH), 132.6
(CH), 135.0 (CH), 136.6 (C), 142.8 (CH), 157.6 (C), 161.3 (C), 167.5
(C), 192.3 (C). HRMS (ESI): found 367.1433 [M þ Na]þ, C20H24-
O5Na requires 367.1521.
Acknowledgment. The material described herein was
funded by Science Foundation Ireland (PI/IN1/B966).
Supporting Information Available: General and experimen-
tal procedures, 1H and 13C NMR spectra, and X-ray structure of
20 in CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 21, 2010 7407