2174
S. M. Barry, P. J. Rutledge
LETTER
–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
the reaction is far from catalytic. This is due primarily to
competing oxidative chemistry mediated by hydroxyl rad-
icals, which diverts a significant amount of the oxidizing
power and gives rise to C–H abstraction and allylic oxida-
tion. Hydroxyl radical intermediates are generated from
the hydrogen peroxide oxidant either by reaction with un-
complexed iron(II) in solution (the traditional Fenton re-
action) or by reaction with an iron-ligand species on a
‘Fenton-type’ path. Either way, the ligand 3 does not af-
ford sufficient control over the chemistry of iron(II) and
hydrogen peroxide. Work is under way to prepare im-
proved ligand architectures which combine more effec-
tively with iron(II) to suppress these competing Fenton
pathways.
Rf = 0.2 (CH2Cl2–MeOH, 10:1); [a]D20 –92.6 (CHCl3, c
0.38); mp 110–112 °C. IR (KBr): nmax = 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): d = 1.24 (3 H,
t, J = 7.0 Hz, NCH2CH3), 3.56 (2 H, q, J = 7.0 Hz,
NCH2CH3), 3.64 (1 H, d, J = 14.5 Hz, 1 of CH2CC6H5), 3.53
(1 H, d, J = 14.5 Hz, 1 of CH2CC6H5), 4.57 (2 H, s, CH2N),
6.65 (3 H, m, 3 NC6H5), 7.05 (1 H, d, J = 7.5 Hz, py-Hd),
7.12–7.29 (6 H, m, 3 of CC6H5, 2 of NC6H5, py-Hb), 7.54 (1
H, t, J = 7.0 Hz, py-Hg), 7.76 (2 H, m, 2 of CC6H5). 13C NMR
(75 MHz, CDCl3): d = 11.26 (NCH2CH3), 44.82
Acknowledgment
We wish to thank the Irish Research Council for Science, Enginee-
ring, and Technology for an Embark Award to SMB. This work was
further supported in Ireland by the Centre for Synthesis & Chemical
Biology at University College Dublin under the Programme for Re-
search in Third Level Institutions (PRTLI) administered by the
HEA, and in Australia by the University of Sydney.
References and Notes
(1) Ortiz de Montellano, P. R. Cytochrome P-450 Structure,
Mechanism and Biochemistry; Plenum: New York, 1995.
(2) (a) Que, L.; Ho, R. Y. N. Chem. Rev. 1996, 96, 2607.
(b) Kappock, T. J.; Caradonna, J. P. Chem. Rev. 1996, 96,
2659.
(3) Wallar, B. J.; Lipscomb, J. D. Chem. Rev. 1996, 96, 2625.
(4) Karlsson, A.; Parales, J. V.; Parales, R. E.; Gibson, D. T.;
Eklund, H.; Ramaswamy, S. Science 2003, 299, 1039.
(5) Burzlaff, N. I.; Rutledge, P. J.; Clifton, I. J.; Hensgens, C. M.
H.; Pickford, M.; Adlington, R. M.; Roach, P. L.; Baldwin,
J. E. Nature (London) 1999, 401, 721.
(6) Barton, D. H. R. Tetrahedron 1998, 54, 5805.
(7) Chen, K.; Que, L. Angew. Chem. Int. Ed. 1999, 38, 2227.
(8) (a) Bugg, T. D. H. Tetrahedron 2003, 59, 7075. (b) Costas,
M.; Mehn, M. P.; Jensen, M. P.; Que, L. Chem. Rev. 2004,
104, 939. (c) Shan, X. P.; Que, L. J. Inorg. Biochem. 2006,
100, 421.
(9) Oldenburg, P. D.; Que, L. Catal. Today 2006, 117, 15.
(10) (a) Rohde, J.-U.; In, J.-H.; Lim, M. H.; Brennessel, W. W.;
Bukowski, M. R.; Stubna, A.; Munck, E.; Nam, W.; Que, L.
Science 2003, 299, 1037. (b) Oldenburg, P. D.; Shteinman,
A. A.; Que, L. J. Am. Chem. Soc. 2005, 127, 15672.
(c) Oldenburg, P. D.; Ke, C. Y.; Tipton, A. A.; Shteinman,
A. A.; Que, L. Angew. Chem. Int. Ed. 2006, 45, 7975.
(11) Chen, M. S.; White, M. C. Science 2007, 318, 783.
(12) Krall, J. A.; Rutledge, P. J.; Baldwin, J. E. Tetrahedron
2005, 61, 137.
(13) Hegg, E. L.; Que, L. Eur. J. Biochem. 1997, 250, 625.
(14) (a) Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704.
(b) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313.
(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
(CH2CC6H5), 48.85 (NCH2CH3), 55.11 (CH2N), 79.64
(CC6H5), 111.09 (CH of C6H5), 115.25 (py-Cb), 117.43 (py-
Cd), 121.94, 125.17, 125.35, 126.35, 128.15 (CH of C6H5),
136.61 (py-Cg), 141.97 (Cipso of CC6H5), 146.55 (Cipso of
NC6H5), 157.02 (py-Ca), 158.21 (py-Ce), 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]+.
(16) 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
mmol) in MeOH (0.20 mL) was added Fe(OAc)2 (1.7 mg, 10
mmol) 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 mmol, 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 mm;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 mm) and ChemStation software.
Both chromatographs were equipped with split/splitless
capillary inlets and flame-ionisation detectors (FID).
(17) Walling, C. Acc. Chem. Res. 1975, 8, 125.
Synlett 2008, No. 14, 2172–2174 © Thieme Stuttgart · New York