Tetrahedron Letters 54 (2013) 1489–1490 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Total synthesis of (±)-mimosifoliol by lateral lithiation Iustina Slabu, Steven B. Rossington, Patrick M. Killoran, Nicholas Hirst, James A. Wilkinson ⇑ Centre for Drug Design, Biochemistry and Cancer Research, University of Salford, Salford M5 4WT, UK a r t i c l e i n f o a b s t r a c t Article history: Received 3 October 2012 Revised 19 December 2012 Accepted 10 January 2013 Available online 16 January 2013 A two-step protocol has been developed to allow the vinylation of diarylmethanes at the bridging CH2 using lateral lithiation and formylation followed by a Wittig reaction. This methodology has been applied in the racemic synthesis of the natural product mimosifoliol. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Organolithium chemistry Natural products Total synthesis (+)-R-Mimosifoliol (1) is a neoflavonoid extracted from the rootwood of Aeschynomene mimosifolia and has shown weak activity in a DNA-strand scission assay.1 Racemic (±)-mimosifoliol has been synthesized in five steps via an o-quinone methide intermediate and subsequently, (+)-mimosifoliol was obtained via cycloaddition of the same intermediate with a chiral enol ether (See Fig. 1).2 Our group has previously utilized lateral lithiation protocols for the asymmetric preparation of a range of diarylmethane derivatives.3 We now report the racemic synthesis of the natural product (±)-1 using a lateral lithiation approach. The study began with work on a simple model system bearing an ortho-methoxy substituent to allow coordination of lithium, but none of the other oxygenation required for the natural product. 2-Benzylanisole (2) was subjected to lithiation using sec-butyllithium in ether or THF and quenched with various formylating agents (Table 1).4 This gave, under our best conditions, the formylated product 3 in a 93% yield.5 The use of the chiral ligand ( )sparteine as an additive present in the reaction mixture before addition of 2 gave disappointing results with a considerably reduced yield and poor enantioselectivity as judged by the use of Table 1 Results of lithiation/formylation reactionsa Reagent Additive Yield of 3 (%) ee DMF N-Formylpiperidine N-Formylmorpholine N-Formylmorpholine None None None ( )-Sparteine 76 61 93 41 — — — ca. 8% a Conditions: sec-BuLi plus additive, Et2O, 78 °C to rt, 1 h. OMe OMe D Ph 3 OMe E-mail address: j.a.wilkinson@salford.ac.uk (J.A. Wilkinson). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.01.040 O 7 E OMe ⇑ Corresponding author. Tel.: +44 161 295 4046. OMe D MeO MeO Figure 1. Structure of (+)-mimosifoliol (1). Ph Scheme 1. Vinylation of 2-benzylanisole. Reagents and conditions: (a) sec-BuLi, Et2O, 20 °C, 1.5 h; N-formylmorpholine, 78 °C, 1 h, 93% (b) CH3PPh3Br, n-BuLi, THF, 20 °C, 3 h, 88%. 5 Ph 4 Ph OMe 1 (+) -1 OMe E O 2 MeO HO 20 °C, 1.5 h; formylating agent, MeO Ph OMe F MeO 8 Ph 6 Ph Scheme 2. Vinylation in the presence of a second methoxy group. Reagents and conditions: (a) AlCl3, CH2Cl2, C6H5COCl, 0–5 °C, 4 h, 71% (b) Et3SiH, TFA, CH2Cl2, reflux, 2 h, 80% (c) (i) sec-BuLi, Et2O, 78 °C, 2 h; N-formylmorpholine, 78 °C to rt, 3 h, 45%; (ii) CH3PPh3Br, THF, sec-BuLi, 15 °C, 3 h, 65%. 1490 I. Slabu et al. / Tetrahedron Letters 54 (2013) 1489–1490 HO OMe a) MeO b) MeO 9 OMe TBSO OMe TBSO O MeO 11 10 Ph c) HO OMe TBSO e) MeO 1 OMe d) TBSO MeO Ph OMe MeO 13 Ph 12 Ph Scheme 3. Total synthesis of (±)-mimosifoliol. Reagents and conditions: (a) DMAP, imidazole, DMF, TBSCl, 0 °C to rt, 16 h, 90% (b) AlCl3, CH2Cl2, C6H5COCl, 0–5 °C, 4 h, 74% (c) AlCl3, NaBH4, Et2O, reflux, 4 h, 90% (d) (i) sec-BuLi, THF, 78 °C, N-formylpiperidine, 16 h, 42% (ii) CH3PPh3Br, THF, n-BuLi, 20 °C, 50% (e) TBAF, THF, rt, 4 h, 90%. the chiral shift reagent TFAE in the 1H NMR. This will be optimized in future work. Conversion of 3 into the vinyl product 4 was effected in 88% yield using a Wittig protocol (Scheme 1).6 Carboxylation of the organolithium derived from 2 was also efficient, but the two-step conversion of the resulting carboxylate into aldehyde 3 was considered too clumsy. The next model study involved a second methoxy group para to the first (Scheme 2). 1,4-Dimethoxybenzene (5) was ortho-lithiated under a variety of conditions, but quenching of the organolithium with benzyl bromide failed to produce any of the desired diarylmethane 6. An alkylation catalysed by bismuth acetate according to the method of Rueping was also unsuccessful in our hands.7 Access to 6 was provided by a two-step route using Friedel–Crafts acylation followed by reduction of the resulting ketone 7.8 This provided 6 in a 57% yield over two steps. Lithiation of 6 proceeded smoothly giving high levels of deuterium incorporation when quenched with deuterium oxide. Formylation was more difficult, but by using N-formylmorpholine, we were able to isolate the product in 45% yield.9 Conversion into the vinylated product 8 was more efficient giving a 65% yield. Completion of the total synthesis of (±)-mimosifoliol required a masked hydroxyl group to be carried through the synthesis. To this end, compound 9 was protected with a tert-butyldimethylsilyl group giving 10 (Scheme 3).10 This was acylated and the resulting ketone 11 reduced to give lithiation precursor 12. Careful control of the temperature of the Friedel–Crafts reaction was required to avoid accidental deprotection. The vinylation protocol gave just a 21% yield for the two steps. This reflects the difficulty in clean lateral lithiation of highly oxygenated substrates which we have observed in the past.11 This provided 13 which was deprotected to give the natural product in six steps from starting material 9. Our sample of (±)-mimosifoliol gave data identical to those reported other than for optical rotation. In conclusion, a method has been developed which allows efficient vinylation of diarylmethane precursors using organolithium chemistry and the racemic synthesis of a natural product has resulted. Future work will be directed towards the asymmetric synthesis of this natural product either by using chiral ligands or a chiral auxiliary. Acknowledgment We acknowledge financial support from Kidscan for I.S. References and notes 1. Fullas, F.; Kornberg, L. J.; Wani, M. C.; Mall, M. E.; Farnsworth, N. R.; Chagwedera, T. E.; Kinghorn, A. D. J. Nat. Prod. 1996, 59, 190–192. 2. (a) Tuttle, K.; Rodriguez, A. A.; Pettus, T. R. R. Synlett 2003, 2234–2236; (b) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196–9203. 3. Wilkinson, J. A.; Rossington, S. B.; Ducki, S.; Leonard, J.; Hussain, N. Tetrahedron 2006, 62, 1833. and references cited therein. 4. Typical procedure for formylation reaction: 2-Benzylanisole (1 equiv) was dissolved in dry Et2O (10 mL) and cooled to 20 °C, when sec-BuLi 1.4 M in cyclohexane (1.5 equiv) was added dropwise. The reaction was stirred at 20 °C for 2 h under an inert atmosphere. The mixture was cooled to 78 °C and the formylating agent (2 equiv) in dry Et2O (5 mL) was added dropwise. The reaction was allowed to warm to room temperature, and monitored by TLC (petroleum ether/EtOAc, 9:1). The reaction was quenched with saturated aqueous NH4Cl (10 mL), diluted with Et2O (10 mL), separated and the aqueous layer extracted with Et2O (3  20 mL). The combined organics were washed with 10% HCl (20 mL), H2O (2  30 mL) and brine (2  30 mL), dried and the solvent removed to afford the crude product. The pure aldehyde was separated by flash column chromatography. 5. Hill, G.; Harris, F. L. J. Org. Chem. 1977, 42, 3306–3307. 6. (a) Alexakis, A.; El Hajjaji, S.; Polet, D.; Rathgeb, X. Org. Lett. 2007, 9, 3393– 3395; (b) Polet, D.; Rathgeb, X.; Falciola, C. A.; Langlois, J.-B.; El Hajjaji, S.; Alexakis, A. Chem. Eur. J. 2009, 15, 1205–1216; (c) Selim, K. B.; Matsumoto, Y.; Yamada, K.-I.; Tomioka, K. Angew. Chem., Int. Ed. 2009, 48, 8733–8735. 7. Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal. 2006, 348, 1033–1037. 8. Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 1066–1069. 9. All new compounds gave satisfactory spectral data. 10. 2,5-Dimethoxyphenol (9) is commercially available but at an extremely high price. It was therefore prepared by a Baeyer–Villiger reaction from the corresponding aldehyde according to the procedure of Meiji Dairies Corporation, EP1854777A, 2007; Chem. Abstr. 2006, 145, 314653. 11. Rossington, S. B. Ph.D. Dissertation, University of Salford, 2004.