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Synlett 2008(14): 2172-2174  
DOI: 10.1055/s-2008-1078248
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

cis-Dihydroxylation of Alkenes by a Non-Heme Iron Enzyme Mimic

Sarah M. Barry, Peter J. Rutledge*
School of Chemistry F11, University of Sydney, NSW 2006, Australia
Fax: +61(2)93513329; e-Mail: p.rutledge@chem.usyd.edu.au;
Further Information

Publication History

Received 2 June 2008
Publication Date:
05 August 2008 (online)

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Abstract

Using the non-heme iron oxidase active site as a template, a peptidomimetic ligand has been designed, synthesized, and used to effect the dihydroxylation of alkene substrates. Fenton-type radical pathways are also observed.

Key words

alkenes - bioorganic chemistry - dihydroxylations - iron - oxygenations

15

Conversion of 5 into 9 was achieved as detailed in ref. 12. Then a solution of ethylaniline 4 (0.19 mL, 1.49 mmol) in THF (10 mL) was cooled to 0 ˚C and n-BuLi (1.5 M, 1.19 mL) added via syringe. The yellow solution was stirred at 0 ˚C for 20 min, then DMPU (0.22 mL, 1.78 mmol) was added and the solution stirred for a further 20 min. The mixture was cooled to -40 ˚C and added via cannula to a solution of 9 (500 mg, 1.24 mmol) in THF (10 mL) also at -40 ˚C. The reaction was stirred at -40 ˚C for 5 h, then left to warm to r.t. overnight, The mixture was poured onto half-saturated NH4Cl solution (4 mL), and the aqueous phase was extracted with Et2O (3 × 8 mL). The organic extracts were combined, dried, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10:1 cyclohexane-EtOAc) to give 10 as a yellow oil (470 mg, 85%).
Compound 10 (150 mg, 0.34 mmol) was dissolved in THF (0.30 mL); aq LiOH (1 M, 0.44 mL) was added. The mixture was heated at reflux for 17 h, then cooled to r.t., adjusted to pH 7 with 1 M HCl and extracted with CH2Cl2 (3 × 1 mL). The organic phases were combined, dried, and evaporated to a yellow oil which solidified under vacuum. Trituration with Et2O (3 × 2 mL) gave 3 as an off-white solid (120 mg, 95%).
Characterization Data for (S)-3-{6-[(Ethyl-phenyl-amino)-methyl]-pyridin-2-yl}-2-hydroxy-2-phenyl-propionic Acid 3
R f = 0.2 (CH2Cl2-MeOH, 10:1); [α]D ²0 -92.6 (CHCl3, c 0.38); mp 110-112 ˚C. IR (KBr): νmax = 3355 (w, OH str), 1612 (s, C=O str), 1505 (m, C=C str), 1575 (m, C=C str), 807, 745 cm-¹. ¹H NMR (300 MHz, CD3OD): δ = 1.24 (3 H, t, J = 7.0 Hz, NCH2CH 3), 3.56 (2 H, q, J = 7.0 Hz, NCH 2CH3), 3.64 (1 H, d, J = 14.5 Hz, 1 of CH 2CC6H5), 3.53 (1 H, d, J = 14.5 Hz, 1 of CH 2CC6H5), 4.57 (2 H, s, CH2N), 6.65 (3 H, m, 3 NC6H5), 7.05 (1 H, d, J = 7.5 Hz, py-Hδ), 7.12-7.29 (6 H, m, 3 of CC6H5, 2 of NC6H5, py-Hβ), 7.54 (1 H, t, J = 7.0 Hz, py-Hγ), 7.76 (2 H, m, 2 of CC6H5). ¹³C NMR (75 MHz, CDCl3): δ = 11.26 (NCH2 CH3), 44.82 (CH2CC6H5), 48.85 (NCH2CH3), 55.11 (CH2N), 79.64 (CC6H5), 111.09 (CH of C6H5), 115.25 (py-Cβ), 117.43 (py-Cδ), 121.94, 125.17, 125.35, 126.35, 128.15 (CH of C6H5), 136.61 (py-Cγ), 141.97 (Cipso of CC6H5), 146.55 (Cipso of NC6H5), 157.02 (py-Cα), 158.21 (py-Cε), 176.53 (C=O). MS (ES+): m/z (%) = 377 (100) [MH]+, 359 (45) [MH -H2O]+. HRMS (ES+): m/z calcd for C23H24N2O3: 377.1865; found: 377.1860 (100%) [MH]+.

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Turnover Procedure
Methanol was distilled over CaH2 and degassed in three freeze-thaw cycles before use. All substrates were distilled over CaH2 and passed through activated alumina before use to remove any peroxides. All reactions were carried out under an atmosphere of argon. Ligand 3 (50 mg, 0.13 mmol) was dissolved in anhyd CH2Cl2 (0.75 mL) and treated with NaH (12 mg, 0.53 mmol). After stirring for 45 min at r.t. the solvent was removed in vacuo to give the sodium salt of 3 as a white powder. To a suspension of this salt (4.0 mg, 10 µmol) in MeOH (0.20 mL) was added Fe(OAc)2 (1.7 mg, 10 µmol) in MeOH giving a yellow solution which was stirred at r.t. for 45 min. The solution was diluted with MeOH (15 mL), and the substrate alkene (10 mmol) was added. Hydrogen peroxide (100 µmol, 30% aq) diluted in MeOH (1 mL) was added to the stirring solution over 4 h, and the solution was stirred at r.t. for a further 12 h. The reaction was reduced in vacuo, diluted with EtOAc and filtered through SiO2. n-Decane was added as an internal standard. Products 12-16 were analyzed by gas chromatography and GC-MS and identified unambiguously by comparison with authentic samples.
Gas chromatography was carried out on a Hewlett-Packard 5890 Series II gas chromatograph fitted with an HP-1ms column (30 m × 0.25 mm ID, 0.25 µm;S/N US2469051H), and (to distinguish cis- and trans-diols) a Hewlett-Packard 5890A gas chromatograph fitted with a BP-20 column (25 m × 0.22 mm ID, 0.25 µm) and ChemStation software. Both chromatographs were equipped with split/splitless capillary inlets and flame-ionisation detectors (FID).