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Organometallics 2009, 28, 1606–1609
Communications Synthesis of the First Ferrocenyl Derivatives of Curcuminoids Anusch Arezki, Emilie Brule´,* and Ge´rard Jaouen Ecole Nationale Supe´rieure de Chimie de Paris, Laboratoire Charles Friedel, UMR 7223, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France ReceiVed January 5, 2009 Summary: The synthesis of curcuminoids coValently bound to a ferrocenyl moiety was inVestigated using two strategies: a ferrocenyl unit was incorporated during the synthesis of 3,4dimethylcurcumin using a KnoeVenagel condensation, and the enolates of 3,5-dimethylcurcumin and curcumin, preViously protected, underwent a 1,4-addition on ferrocenyl propynone. Curcumin (1), extracted from the rhizome Curcuma longa, is the main component of the spice turmeric. This nontoxic dietary compound has been the subject of much attention, due to its known biological and pharmacological properties (Figure 1).1 This conjugated polyphenol, used in Asian traditional medicine for centuries, is an antioxidant2 and an anti-inflammatory3 and exhibits chemopreventive4 and antitumor activities.5 Indeed, two decades of clinical trials involving curcumin have been carried out on various cancers such as colon carcinoma. Other curcuminoids have also attracted attention, such as 3,4dimethylcurcumin6 (2) and 3,5-dimethylcurcumin7 (3), which also display biological properties. Our experience in bioorganometallic chemistry8 prompted us to investigate the synthesis of organometallic curcuminoids in order to potentially increase the cytotoxicity of the resulting new biomolecules. Several metal-curcumin complexes9 have been reported in the literature, but they all involve the * To whom correspondence should be addressed. E-mail: emilie-brule@ enscp.fr. (1) (a) Hatcher, H.; Planalp, R.; Cho, J.; Torti, F. M.; Torti, S. V. Cell. Mol. Life Sci. 2008, 65, 1631. (b) Goel, A.; Kunnumakkara, A. B.; Aggarwal, B. B. Biochem. Pharmacol. 2008, 75, 787. (c) Aggarwal, B. B.; Sundaram, C.; Malani, N.; Ichikawa, H. AdV. Exp. Med. Biol. 2007, 595, 1. (d) Sharma, R. A.; Gescher, A. J.; Steward, W. P. Eur. J. Cancer 2005, 41, 1955. (2) (a) Weber, W. M.; Hunsaker, L. A.; Abcouwer, S. F.; Deck, L. M.; Vander Jagt, D. L. Bioorg. Med. Chem. 2005, 13, 3811. (b) Ruby, A. J.; Kuttan, G.; Dinesh Babu, K.; Rajasekharan, K. N.; Kuttan, R. Cancer Lett. 1995, 94, 79. (c) Barclay, L. R. C.; Vinqvist, M. R.; Mukai, K.; Goto, H.; Hashimoto, Y.; Tokunaga, A.; Uno, H. Org. Lett. 2000, 2, 2841. (3) Weisberg, S. P.; Leibel, R.; Tortoriello, D. V. Endocrinology 2008, 149, 3449. (4) (a) Khan, N.; Afaq, F.; Mukhtar, H. Antiox. Redox Sign. 2008, 10, 475. (b) Ireson, C. R.; Jones, D. J. L.; Orr, S.; Coughtrie, M. W. H.; Boocock, D. J.; Williams, M. L.; Farmer, P. B.; Steward, W. P.; Gescher, A. J. Cancer Epidemiol. Biomarkers PreV. 2002, 11, 105. (5) (a) Aggarwal, B. B.; Kumar, A.; Bharti, A. C. Anticancer Res. 2003, 23, 363. (b) Anand, P.; Sundaram, C.; Jhurani, S.; Kunnumakkara, A. B.; Aggarwal, B. B. Cancer Lett. 2008, 267, 133. (6) Tamvakopolous, C.; Dimas, K.; Sofianos, Z. D.; Hatziantoniou, S.; Han, Z.; Liu, Z.-L.; Wyche, J. H.; Pantazis, P. Clin. Cancer Res. 2007, 13, 1269. (7) (a) Hahm, E.-R.; Cheon, G.; Lee, J.; Kim, B.; Park, C.; Yang, C.-H. Cancer Lett. 2002, 184, 89. (b) Park, C. H.; Lee, J. H.; Yang, C. H. J. Biochem. Mol. Biol. 2005, 38, 474. (8) Jaouen, G. Bioorganometallics. Biomolecules, Labelling, Medicine; Wiley-VCH: Weinheim, Germany, 2005.
Figure 1. Selected curcuminoids.
coordination of the metal via the oxygen atoms of the β-diketone by deprotonation of the keto-enol tautomer form in most cases. Our previous work on the synthesis of organometallic biomolecules mainly involved the grafting of a ferrocenyl moiety. For instance, ferrocenyl derivatives of the commercial antiestrogen tamoxifen,10 polyphenol,11 steroidal androgens,12 and the commercial antiandrogen nilutamide13 were shown to display an increased cytotoxicity on breast and/or prostate cancer cells compared to their organic analogues. Ferrocene is known to be an interesting organometallic moiety, and reviews report its conjugation to other biomolecules.14 Literature and the results of our previous work encouraged us to investigate the challenging synthesis of the first examples of curcuminoids covalently bound to an organometallic moiety. As a result, we wish to report in this communication the preparation of such ferrocenyl curcuminoid derivatives. (9) (a) Ku¨hlwein, F.; Polborn, K.; Beck, W. Z. Anorg. Allg. Chem. 1997, 623, 1211. (b) Thompson, K. H.; Bo¨hmerle, K.; Polishchuk, E.; Martins, C.; Toleikis, P.; Tse, J.; Yuen, V.; McNeill, J. H.; Orvig, C. J. Inorg. Biochem. 2004, 98, 2063. (c) Mohammadi, K.; Thompson, K. H.; Patrick, B. O.; Storr, T.; Martins, C.; Polishchuk, E.; Yuen, V. G.; McNeill, J. H.; Orvig, C. J. Inorg. Biochem. 2005, 99, 2217. (d) Sumanont, Y.; Murakami, Y.; Tohda, M.; Vajragupta, O.; Watanabe, H.; Matsumoto, K. Biol. Pharm. Bull. 2007, 30, 1732. (e) John, V. D.; Krishnankutty, K. Transition Met. Chem. 2005, 30, 229. (f) John, V. D.; Krishnankutty, K. Appl. Organomet. Chem. 2006, 20, 477. (g) Zambre, A. P.; Kulkarni, V. M.; Padhye, S.; Sandur, S. K.; Aggarwal, B. B. Bioorg. Med. Chem. 2006, 14, 7196. (h) Pucci, D.; Bloise, R.; Bellusci, A.; Bernardini, S.; Ghedini, M.; Pirillo, S.; Valentini, A.; Crispini, A. J. Inorg. Biochem. 2007, 101, 1013. (10) Top, S.; Vessie`res, A.; Leclercq, G.; Quivy, J.; Tang, J.; Vaissermann, J.; Huche´, M.; Jaouen, G. Chem. Eur. J. 2003, 9, 5223. (11) Vessie`res, A.; Top, S.; Pigeon, P.; Hillard, E. A.; Boubeker, L.; Spera, D.; Jaouen, G. J. Med. Chem. 2005, 48, 3937. (12) Top, S.; Thibaudeau, C.; Vessie`res, A.; Brule´, E.; Le Bideau, F.; Joerger, J.-M.; Plamont, M.-A.; Samreth, S.; Edgar, A.; Marrot, J.; Herson, P.; Jaouen, G. Organometallics, 2009, DOI 10.1021/om800698y. (13) Payen, O.; Top, S.; Vessie`res, A.; Brule´, E.; Plamont, M.-A.; McGlinchey, M. J.; Mu¨ller-Bunz, H.; Jaouen, G. J. Med. Chem. 2008, 51, 1791. (14) (a) Metzler-Nolte, N.; Salmain, M. The bioorganometallic chemistry of ferrocene. In Ferrocenes: Ligands, Materials and Biomolecules; Stepnicka, P., Ed.; Wiley: Chichester, England, 2008; p 499. (b) Van Staveren, D. R.; Metzler-Nolte, N. Chem. ReV. 2004, 104, 5931.
10.1021/om900003g CCC: $40.75 2009 American Chemical Society Publication on Web 02/25/2009
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Organometallics, Vol. 28, No. 6, 2009 1607
Scheme 1. Synthesis of Ferrocenyl 3,4-Dimethylcurcumin Derivatives
Scheme 2. Synthesis of Ferrocenyl 3,5-Dimethylcurcumin Figure 2. Molecular structure of 7. Selected bond lengths (Å) and angles (deg): O(1)-C(5) ) 1.313(3), O(2)-C(3) ) 1.298(3), C(3)-C(4) ) 1.435(3), C(4)-C(5) ) 1.428 (3), C(4)-C(20) ) 1.482(3); C(3)-C(4)-C(5) ) 117.8(2), C(3)-C(4)-C(20) ) 119.61(19), C(4)-C(20)-C(21) ) 125.9(2), C(21)-C(22)-C(23) ) 118.03(9).
Our first synthetic strategy consisted of replacing one of the aromatic rings of 3,4-dimethylcurcumin (2) by a ferrocene unit. Monophenyl-3,4-dimethylcurcumin (4), synthesized using Pederson’s conditions,15 was reacted with ferrocenecarboxaldehyde in a Knoevenagel condensation with piperidine (Scheme 1). In the presence of boric anhydride and tributylborate, used for the preparation of both symmetrical and unsymmetrical curcuminoids,16 the condensation takes place on the terminal carbon, since a boron complex of the β-diketone is formed and prevents the condensation on the central carbon position. The unsymmetrical ferrocenyl curcuminoid 5 was thus obtained in 60% yield (Scheme 1). The role of boric anhydride and tributylborate was confirmed by reiterating the reaction in their absence, which led to the condensation of ferrocenecarboxaldehyde on the central carbon of the β-diketone to yield the ferrocenyl monophenyl-3,4-dimethylcurcumin 6 in 48% yield after 24 h at room temperature. The lower yield may be due to an increased steric hindrance compared to the condensation on the terminal position. The Z configuration of the double bond of compound 6 was determined by NOESY analysis, which showed NOE correlations between the ethylene proton of the side chain and the methyl group of the terminal ketone and between a ferrocenyl proton and an ethylene proton of the curcuminoid backbone. It is also noteworthy that in this case the β-diketone is obliged to be in its diketo form instead of as the keto-enol tautomer, confirmed by the presence of two peaks at 194.8 and 198.4 ppm corresponding to the two carbonyl units in the 13C NMR spectrum. In order to retain the symmetry of the curcuminoid skeleton, a second strategy was investigated with the grafting of the ferrocenyl unit on the central carbon atom of the β-diketone. This substitution has already been studied by Lin and co-
(15) Pederson, U.; Rasmussen, P. B.; Lawesson, S.-O. Liebigs Ann. Chem. 1985, 1557. (16) Lin, L.; Shi, Q.; Nyarko, A. K.; Bastow, K. F.; Wu, C.-C.; Su, C.-Y.; Shih, C. C.-Y.; Lee, K.-H. J. Med. Chem. 2006, 49, 3963.
workers17 with the addition of organic chains, by deprotonation of the enol moiety followed by a reaction with an appropriate electrophile. Lin and co-workers have also shown that the presence of a conjugated side chain in that position is important for the biological and pharmacological properties of the new curcuminoid.16 The electrophilic ferrocenyl derivative chosen for our study was therefore ferrocenyl propynone, which could undergo a 1,4-addition to form a R,β-unsaturated ketone. Initially, 3,5dimethylcurcumin (3) was the selected curcuminoid, as no hydroxy group, which could compete with the enol during its deprotonation, is present on the aromatic rings. Curcuminoid 3 was deprotonated by sodium hydride to yield the corresponding carbanion after 2 h at room temperature. Ferrocenyl propynone (obtained in two steps from ferrocenecarboxaldehyde)18 dissolved in dry THF was then added dropwise to form the desired ferrocenyl curcumin derivative 7 in 30% yield after 1 h at 20 °C (Scheme 2). A modest yield was obtained, as it was not possible to achieve total consumption of the curcuminoid even after a prolonged time, which mainly induced degradation of the starting material 3. The conserved symmetry of 7 was evident by its 1H NMR spectrum, where only half of the proton peaks, that is, only the unique protons of the curcuminoid backbone, were observed. The disappearance of the peak at 5.85 ppm, corresponding to the central proton of the β-diketone in its keto-enol form, showed that the substitution took place at the desired C-4 position. The structure of 7 was confirmed by X-ray diffraction analysis (Figure 2). The compound crystallized from dichloromethane/ hexane as red crystals in the triclinic space group P1j. A statistical distribution of the hydrogen atoms at the two positions of the β-diketone was observed. This geometry is in accordance with the crystal structure of curcumin19 and confirms the keto-enol tautomer form. Distances C(3)-C(4) and C(4)-C(5) are almost identical and the two C-O bonds have a similar length of 1.3 Å, intermediate between a single and double bond, indicating a conjugation with the curcuminoid backbone. The (17) Lin, L.; Shi, Q.; Su, C.-Y.; Shih, C. C.-Y.; Lee, K.-H. J. Med. Chem. 2006, 14, 2527. (18) Barriga, S.; Marcos, C. F.; Riant, O.; Torroba, T. Tetrahedron 2002, 58, 9785. (19) Tønnesen, H. H.; Karlsen, J.; Mostad, A. Acta Chem. Scand. 1982, 36B, 475.
1608 Organometallics, Vol. 28, No. 6, 2009 Scheme 3. Synthesis of Ferrocenyl THP-curcumin
ferrocenyl unit tilts parallel to the conjugated chain of the curcuminoid but is shifted out of the plane formed by the keto-enol moiety because of the presence of the spacer chain. A deviation from planarity of the conjugated backbone is also observed. Following the successful synthesis of the ferrocenyl curcuminoid 7, we decided to incorporate a ferrocenyl unit onto curcumin itself using the same strategy. However, prior to the deprotonation of the enol, protection of the phenols was necessary. The protecting group tetrahydropyranyl (THP) was first chosen by following the synthesis of bis-THP curcumin 8 reported by Lin et al.17 The protection was carried out in dry dichloromethane in the presence of 6 equiv of dihydropyran and a catalytic amount of pyridinium p-toluenesulfonate (PPTS) (Scheme 3). In our case, the formation of the desired product was not total, giving a mixture of mono-THP- and bis-THPcurcumins 9 and 8, respectively, obtained in the ratio 1:2. To our knowledge, mono-THP-curcumin 9 has not been described yet and appears to be an interesting compound which could be used in monosubstitution reactions on the remaining free phenol group. Bis-THP-curcumin 8 was then deprotonated under the same conditions as above, followed by 1,4-addition on ferrocenyl propynone to form the ferrocenyl bis-THP-curcumin 10 in a moderate yield of 46%. The deprotection was then attempted in EtOH in the presence of a catalytic amount of PPTS. However, the presence of a conjugated ferrocenyl side chain rendered the curcuminoid very sensitive to acid and only degradation was observed. As a result, it appeared essential to use a protecting group that can be removed without the use of acid or base and tertbutyldimethylsilyl (TBDMS) seemed appropriate. The literature only reports the preparation of mono-TBDMS-curcumin,20 and its preparation was adapted for the synthesis of bis-TBDMScurcumin 11 by using 2 equiv of tert-butydimethylsilyl chloride in the presence of imidazole in dry DMF (Scheme 4). However the bis-protection was not total even by increasing the reaction time, and a mixture of bis-TBDMS- and mono-TBDMScurcumins 11 and 12, respectively, was obtained in a ratio of 3.5:1. The deprotonated bis-protected curcumin 11 subsequently underwent the 1,4-addition on ferrocenylpropynone to yield ferrocenyl bis-TBDMS-curcumin 13 in 26% yield. The modest yield was once again due to the incomplete consumption of the curcuminoid. The deprotection of 13 consisted of the addition of an excess of tetrabutylammonium fluoride in dry THF, and ferrocenyl curcumin 14 was successfully obtained after 10 min of reaction in 64% yield. This ferrocenyl compound 14 was fully characterized, and 1H NMR spectroscopy showed only the (20) Takeuchi, T.; Ishidoh, T.; Iijima, H.; Kuriyama, I.; Shimazaki, N.; Koiwai, O.; Kuramochi, K.; Kobayashi, S.; Sugawara, F.; Sakaguchi, K.; Yoshida, H.; Mizushina, Y. Genes Cells 2005, 11, 223.
Communications Scheme 4. Synthesis of Ferrocenyl Curcumin
keto-enol tautomer, as no peak other than the phenolic protons was observed in the 5-6 ppm region. In summary, we have shown the successful synthesis of the first ferrocenyl curcuminoid derivatives, which appeared to be challenging due to the high conjugation of these new compounds. The only other example of an organometallic curcuminoid reported in the literature involves a cyclopalladated ligand coordinated to the β-diketone’s oxygen atoms. Our strategy developed to yield these ferrocenyl derivatives is now generally applicable to other curcuminoids, ferrocenyl, and organometallic moieties. The ferrocenylpropenone unit generated during the synthesis of the curcuminoids 7 and 14 has already been used in various biomolecules.21 These new ferrocenyl compounds thus may have potential biological properties, and particularly, their antiproliferative activity on prostatic cancer cells is currently under investigation. Experimental Section. For handling techniques, reagents, instruments, experimental details for compounds 5, 6, 8, 9, 11, 12 and detailed analytical data for all compounds, see the Supporting Information. High-resolution mass spectroscopy molecular weights are provided instead of elemental analysis as curcuminoid compounds tenaciously retain fractional amounts of solvents. X-ray data of 7: C36H34FeO7, Mr ) 634.51, triclinic, space group P1j, a ) 10.3827(14) Å, b ) 10.428(2) Å, c ) 15.760(4) Å, V ) 1548.3(6) Å3, T ) 200 K, Z ) 2, µ ) 0.536 mm-1, Dc ) 1.361 Mg m-3, λ ) 0.710 73 Å, θmax ) 27.50°, 13 367 reflections measured, 7001 unique reflections, Rint ) 0.04. General Procedure for the Preparation of Ferrocenyl Curcuminoids 7, 10, and 13. An anhydrous THF solution of the appropriate curcuminoid (1 equiv) was added dropwise to an oil-free suspension of NaH (1.7 equiv) in anhydrous THF at 0 °C. After it was stirred for 30 min at 0 °C, the reaction mixture was warmed to room temperature and stirring was continued for a further 2 h to allow the sodium salt of the curcuminoid to precipitate. A solution of 1-ferrocenyl-2-propyn-1-one (2 equiv) in anhydrous THF was added dropwise, and the reaction mixture (21) (a) Wu, X.; Wilairatb, P.; Go, M.-L. Bioorg. Med. Chem. Lett. 2002, 12, 2299. (b) Wu, X.; Tiekink, E. R. T.; Kostetski, I.; Kocherginsky, N.; Tan, A. L. C.; Khoo, B. S.; Wilairat, P.; Go, M.-L. Eur. J. Pharm. Sci. 2006, 27, 175.
Communications
was monitored by TLC and stirred for 1-2 h. After hydrolysis with water, the mixture was extracted with ethyl acetate, and the organic phases were dried on magnesium sulfate, filtered, and evaporated under reduced pressure. The ferrocenyl curcuminoid was purified by flash chromatography on silica gel using hexane/ethyl acetate as eluent. (1E,4Z,6E)-1,7-Bis(3,4-dimethoxyphenyl)-4-[(E)-1-ferrocenylprop-2-en-1-one]-3-hydroxyhepta-1,4,6-trien-5-one (7). Red solid, 30% yield. Mp: 170-171 °C. 1H NMR (400 MHz, CD2Cl2): δ 7.89 (d, J ) 15.2 Hz, 1H, Hvinyl), 7.76 (d, J ) 15.5 Hz, 2H, H1/H7), 7.20 (d, J ) 15.5 Hz, 2H, H2/H6), 6.75 (d, J ) 2.2 Hz, 4H, H13/H15/H9/H19), 6.65 (d, J ) 15.2 Hz, 1H, Hvinyl), 6.50 (t, J ) 2.2 Hz, 2H, H11/H17), 4.80 (t, J ) 1.9 Hz, 2H, C5H4), 4.55 (t, J ) 1.8 Hz, 2H, C5H4), 4.17 (s, 5H, C5H5), 3.78 (s, 12H, OCH3). 13C NMR (100 MHz, CD2Cl2): δ 191.4 (CO), 183.5 (C3/C5), 160.8 (C12/C16/C10/C18), 142.2 (C1/C7), 136.5 (C8/C14), 133.6 (Cvinyl), 128.8 (Cvinyl), 121.5 (C2/C6), 111.4 (C4), 105.9 (C13/C15/C9/C19), 102.5 (C11/C17), 80.3 (C5H4, Cip), 72.5 (C5H4), 69.7 (C5H5), 69.2 (C5H4), 55.1 (OCH3). MS (APCI): m/z 635.5 [M + H]+, 633.6 [M - H]-. HRMS (ESI): m/z calcd for C36H34FeO7Na+ 657.154 68, found 657.153 53. (1E,4Z,6E)-1,7-Bis[3-methoxy-4-(tetrahydro-2H-pyran2-yloxy)phenyl]-4-[(E)-1-ferrocenylprop-2-en-1-one]-3-hydroxyhepta-1,4,6-trien-5-one (10). Red solid, 46% yield. Mp: 108 °C. 1H NMR (400 MHz, CD2Cl2): δ 7.93 (d, J ) 15.2 Hz, 1H, Hvinyl), 7.79 (d, J ) 15.4 Hz, 2H, H1/H7), 7.20 (dd, J ) 8.3 Hz, J ) 1.5 Hz, 2H, H9/H19), 7.14 (s, 2H, H13/H15), 7.14 (d, J ) 7.1 Hz, 2H, H10/H18), 7.13 (d, J ) 15.4 Hz, 2H, H2/ H6), 6.67 (d, J ) 15.2 Hz, 1H, Hvinyl), 5.43 (t, J ) 3.1 Hz, 1H, CH), 4.80 (t, J ) 1.9 Hz, 2H, C5H4), 4.57 (t, J ) 1.9 Hz, 2H, C5H4), 4.18 (s, 5H, C5H5), 3.84 (s, 6H, OCH3), 3.58-3.55 (m, 2H, CH2), 2.03-1.91 (m, 2H, CH2), 1.89-1.87 (m, 4H, CH2), 1.67-1.58 (m, 8H, CH2). 13C NMR (100 MHz, CD2Cl2): δ 192.0 (CO), 184.0 (C3/C5), 150.4 (C11/C17), 148.9 (C12/C16), 142.6 (C1/C7), 134.5 (Cvinyl), 129.3 (C8/C14), 128.6 (Cvinyl), 122.7 (C9/C19), 119.6 (C2/C6), 117.0 (C10/C18), 111.7 (C13/C15), 111.3 (C4), 97.3 (CH), 80.8 (C5H4, Cip), 72.9 (C5H4), 70.1 (C5H5), 69.6 (C5H4), 62.3 (CH2), 56.2 (OCH3), 30.3 (CH2), 25.2 (CH2), 18.9 (CH2). MS (APCI): m/z 775.8 [M + H]+, 773.7 [M - H]-. HRMS (ESI): m/z calcd for C44H46FeO9Na+ 797.238 40, found 797.239 03. (1E,4Z,6E)-1,7-Bis[3-methoxy-4-((tert-butyldimethylsilyl)oxy)phenyl]-4-[(E)-1-ferrocenylprop-2-en-1-one]-3-hydroxyhepta-1,4,6trien-5-one (13). Orange-red solid, 26% yield. Mp: 62 °C. 1H NMR (300 MHz, CDCl3): δ 7.98 (d, J ) 14.9 Hz, 1H, Hvinyl), 7.80 (d, J ) 15.3 Hz, 2H, H1/H7), 7.12 (d, J ) 11.8 Hz, 2H, H9/H19), 7.09 (d, J ) 15.7 Hz, 2H, H2/H6), 7.06 (s, 2H, H13/ H15), 6.85 (d, 2H, J ) 8.1 Hz, H10/H18), 6.63 (d, J ) 15.2 Hz, 1H, Hvinyl), 4.82 (bs, 4H, C5H4), 4.54 (bs, 4H, C5H4), 4.17 (s, 5H, C5H5), 3.80 (s, 6H, OCH3), 0.98 (s, 18H, tBu-Si), 0.16
Organometallics, Vol. 28, No. 6, 2009 1609
(s, 12H, CH3-Si). 13C NMR (100 MHz, CD2Cl2): δ 191.7 (CO), 183.6 (C3/C5), 151.0 (C11/C17), 147.5 (C12/C16), 142.3 (C1/ C7), 134.2 (Cvinyl), 130.6 (Cvinyl), 128.7 (C8/C14), 122.2 (C10/ C18), 120.8 (C9/C19), 119.0 (C2/C6), 111.2 (C13/C15), 110.8 (C4), 80.6 (C5H4, Cip), 70.5 (C5H4), 69.6 (C5H5), 69.2 (C5H4), 55.1 (OCH3), 25.1 (tBu-Si), 18.0 (CMe3-Si), -5.3 (CH3-Si). MS (APCI): m/z 835.5 [M + H]+, 833.7 [M - H]-. HRMS (ESI): m/z calcd for C46H59FeO7Si2+ 835.314 33, found 835.314 75. (1E,4Z,6E)-1,7-Bis(3-methoxy-4-hydroxyphenyl)-4-[(E)-1-ferrocenylprop-2-en-1-one]-3-hydroxyhepta-1,4,6-trien-5-one (14). TBAF (290 µL, 2.90 mmol, 1.0 M in THF) was added dropwise to a stirred solution of 13 (93 mg, 0.11 mmol) in anhydrous THF (2.5 mL) at 0 °C. The reaction mixture was stirred for 8 min at room temperature and was then quenched with a phosphate buffer pH 6 (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried on magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography on silica gel using 1:1 hexane/ ethyl acetate as eluent, yielding 14 as a red solid (70 mg, 64% yield). Mp: 139 °C. 1H NMR (300 MHz, CDCl3): δ 7.99 (d, J ) 15.2 Hz, 1H, Hvinyl), 7.79 (d, J ) 15.5 Hz, 2H, H1/H7), 7.18 (d, J ) 7.5 Hz, 2H, Har), 7.07 (s, 2H, H13/H15), 7.06 (d, J ) 15.4 Hz, 2H, H2/H6), 6.93 (d, J ) 8.20 Hz, 2H, Har), 6.63 (d, J ) 15.2 Hz, 1H, Hvinyl), 5.98 (bs, 2H, OH), 4.83 (t, J ) 1.8 Hz, 4H, C5H4), 4.55 (t, J ) 1.8 Hz, 4H, C5H4), 4.18 (s, 5H, C5H5), 3.89 (s, 6H, OCH3). 13C NMR (100 MHz, CD2Cl2): δ 192.9 (CO), 183.6 (C3/C5), 148.1 (C11/C17), 146.7 (C12/C16), 142.3 (C1/C7), 134.3 (Cvinyl), 133.6 (Cvinyl), 127.4 (C8/C14), 123.1 (C9/C19), 118.5 (C2/C6), 114.4 (C10/C18), 110.7 (C4), 109.8 (C13/C15), 79.7 (C5H4, Cip), 72.6 (C5H4), 69.7 (C5H5), 69.2 (C5H4), 55.8 (OCH3),. MS (APCI): m/z 607.5 [M + H]+, 605.4 [M - H]-. HRMS (ESI): calcd for C34H31FeO7+ 607.141 37, found 607.140 58.
Acknowledgment. Financial support is acknowledged from the Centre National de la Recherche Scientifique, the French Ministry of Research and Technology, and Gottlieb Daimler- and Karl Benz-Foundation (Ph.D. grant). We also thank P. Herson for X-ray analysis and E. A. Hillard and F. Le Bideau for helpful discussions. Supporting Information Available: Text and figures giving experimental procedures, analytical and spectral characterization data, and NMR spectra for all compounds prepared in this paper and a CIF file giving crystal data for 7. This material is available free of charge via the Internet at http://pubs.acs.org. OM900003G
