Oxyfunctionalization of unactivated C-H bonds in triterpenoids with tert-butylhydroperoxide catalyzed by meso-5,10,15,20-tetramesitylporphyrinate osmium(II) carbonyl complex

Article abstract of DOI:10.1016/j.chemphyslip.2009.10.012

A system consisting of meso-5,10,15,20-tetramesitylporphyrinate osmium(II) carbonyl complex [Os(TMP)CO] as a precatalyst and tert-butylhydroperoxide (TBHP) as an oxygen donor is shown to be an efficient, regioselective oxidant system for the allylic oxidation, ketonization and hydroxylation of unactivated C-H bonds in a series of the peracetate derivatives of penta- and tetracyclic triterpenoids. Treatment of the substrates with this oxidant system afforded a variety of novel or scarce oxygenated derivatives in one-step. Structures of the isolated components, after chromatographic separation, were determined by spectroscopic methods including GC-MS and shift-correlated 2D-NMR techniques. Factors governing the regioselectivity and the possible mechanism for the oxyfunctionalization of the unactivated carbons are also discussed.

Full text of DOI:10.1016/j.chemphyslip.2009.10.012

Chemistry and Physics of Lipids 163 (2010) 165–171
Contents lists available at ScienceDirect
Chemistry and Physics of Lipids
journal homepage: www.elsevier.com/locate/chemphyslip
Oxyfunctionalization of unactivated C–H bonds in triterpenoids with
tert-butylhydroperoxide catalyzed by meso-5,10,15,20-tetramesitylporphyrinate
osmium(II) carbonyl complex
Shoujiro Ogawaa, Yasuo Wakatsukia, Mitsuko Makinob, Yasuo Fujimotob, Ken Yasukawac,
Takashi Kikuchid, Motohiko Ukiyad, Toshihiro Akihisad, Takashi Iidaa,∗
a Department of Chemistry, College of Humanities and Sciences, Nihon University, Sakurajousui, Setagaya-ku, Tokyo 156-8550, Japan
b Department of General Studies, College of Humanities and Sciences, Nihon University, Sakurajousui, Setagaya-ku, Tokyo 156-8550, Japan
c College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan
d Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, 1-8 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8301, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 August 2009
Received in revised form 29 October 2009
Accepted 29 October 2009
Available online 10 November 2009
A
system consisting of meso-5,10,15,20-tetramesitylporphyrinate osmium(II) carbonyl complex
[Os(TMP)CO] as a precatalyst and tert-butylhydroperoxide (TBHP) as an oxygen donor is shown to be
an efficient, regioselective oxidant system for the allylic oxidation, ketonization and hydroxylation of
unactivated C–H bonds in a series of the peracetate derivatives of penta- and tetracyclic triterpenoids.
Treatment of the substrates with this oxidant system afforded a variety of novel or scarce oxygenated
derivatives in one-step. Structures of the isolated components, after chromatographic separation, were
determined by spectroscopic methods including GC–MS and shift-correlated 2D-NMR techniques. Factors
governing the regioselectivity and the possible mechanism for the oxyfunctionalization of the unactivated
carbons are also discussed.
Keywords:
Allylic oxidation
Oxyfunctionalization
Cytochrome P-450
Hydroxylation
© 2009 Elsevier Ireland Ltd. All rights reserved.
Ketonization
Triterpenoid
Unactivated C–H bond
1. Introduction
osmium (II) carbonyl complex [Os(TMP)CO] as a precatalyst and
tert-butylhydroperoxide (TBHP) as an oxygen donor (Ogawa et al.,
In analogy with enzyme-controlled reactions in vivo, such as
cytochrome P-450 oxidase-dependent systems (Sono et al., 1996;
Makris et al., 2006), the oxyfunctionalization of unactivated car-
bon atoms is a key transformation in the efficient and convenient
synthesis of biologically active compounds, starting from abun-
dantly available, naturally occurring compounds such as steroids,
alkaloids, and bile acids. In particular, the combination of the
cytochrome P-450 analogs, metalloporphyrin precatalyst/oxygen-
donar systems (Breslow, 1990; Yang et al., 2000, 2002; Reese, 2001;
Meunier, 1992; Breslow et al., 1997; Ohtake et al., 1995; Shingaki et
al., 1997) and the smallest three-membered cyclic peroxide, dioxi-
ranes (Reese, 2001; Bovicelli et al., 1992; Iida et al., 2001), have
been shown to insert efficiently an oxygen atom into unactivated
methine and/or methylene C–H bonds in these substrates.
2007a; Iida et al., 2007). The oxidant system proceeds through
an active trans-dioxoosmiumporphyrin intermediate with a high
turnover rate (ca. 200:1) as a catalyst and oxidizes regioselectively
unactivated tertiary methine CH and/or secondary methylene CH2
protons to yield the corresponding hydroxy- and oxo-derivatives,
respectively. As a part of our ongoing program to produce bioactive
compounds from available natural products, we became interest
in the useful, efficient application of the Os(TMP)CO/TBHP system
to terpenoids. We describe here the regioselective oxyfunction-
alization of a series of penta- and tetracyclic triterpenoids using
this oxidant system. An additional aim of the study was to pre-
pare novel or scarece oxygenated derivatives of potential medicinal
significance.
We have recently developed a novel, powerful oxidant sys-
tem, which consists of meso-5,10,15,20-tetramesitylporphyrinate
2. Experimental
2.1. General
∗
Melting points (mp) were determined on an electric micro-
hot stage and are uncorrected. IR spectra were obtained on a
Corresponding author. Tel.: +81 3 3329 1151x5704; fax: +81 3 3303 9899.
E-mail address: takaiida@chs.nihon-u.ac.jp (T. Iida).
0009-3084/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.chemphyslip.2009.10.012

166
S. Ogawa et al. / Chemistry and Physics of Lipids 163 (2010) 165–171
JASCO FT-IR 4100 spectrometer (Tokyo, Japan) for samples in the
KBr tablets. 1H and 13C NMR spectra were measured on a JEOL
JNM-EX270 FT instrument (Tokyo, Japan) in CDCl3 containing 0.1%
Me4Si as an internal standard. Chemical shifts are expressed as
ı ppm relative to Me4Si and coupling constants as in Hz. 13C
NMR signals corresponding to methyl (CH3), methylene (CH2),
methine (CH), and quaternary (C) carbons were differentiated
by means of distortionless enhancement by polarization transfer
(DEPT) experiments. 2D-NMR spectra were measured on a JEOL
GSX-400 spectrometer or Verian Mercury 300BB (CA, USA). Low-
resolution electron-impact mass (LR-EI-MS) spectra were recorded
on a JEOL JMS-GCmate mass spectrometer at 70 eV using the posi-
tive ion mode (PIM). High-resolution electron-impact mass spectra
(HR-EI-MS) were measured on a JEOL GCmate mass spectrometer.
A Shimadzu GC-2010 gas chromatograph equipped with a flame
ionization detector was used isothermally at 320 ◦C fitted with a
chemically bonded, fused silica capillary column (25QCC3/BPX5;
25 m × 0.32 mm i.d.; film thickness, 0.25 ␮m; SGE, Melbourne, Aus-
tralia). The preparative HPLC apparatus consisted of a Hitachi
(Tokyo, Japan) L-7100 pump equipped with a Shodex RI detector
(Tokyo, Japan) and a Pegasil Silica 60-5 column (250 mm × 10 mm
i.d., Tokyo, Japan); hexane-EtOAc mixtures (9:1–7:3,v/v) were used
as the eluent. Thin-layer chromatography (TLC) was performed
on precoated silica gel plates (0.25 mm layer thickness; E. Merck,
Darmstadt, Germany) using hexane-EtOAc mixtures as the devel-
oping solvent. 70% TBHP was purchased from Tokyo Kasei Kogyo
Co. (Tokyo, Japan); it was extracted with CH2Cl2 and the organic
layer was evaporated under reduced pressure prior to use.
(C-20), 33.9 (C-21), 30.9 (C-22), 28.0 (C-23) 16.7 (C-24), 16.5 (C-
25), 20.5 (C-26), 27.5 (C-27), 27.5 (C-28), 17.4 (C-29), 21.3 (C-30),
21.1 (CH3CO), 171.0 (CH3CO); LR-EI-MS (PIM) m/z 482 (M+, 18), 422
(M-CH3COOH, 7), 407 (M-CH3COOH-CH3 4), 273 (100), 232 (63).
20␣-Hydroxy-ursan-3␤,16␤-diyl diacetate (7). Colorless
amorphous solid, isolated from the oxidation product of 2, which
was crystallized from acetone, mp 222–224 ◦C; IR (KBr) cm−1 3492
(OH), 1726 (C O); 1H NMR (CDCl3, 400 MHz) ı 0.83 (3H, s, H-24),
0.85 (3H, s, H-23), 0.87 (3H, s, H-25), 0.90 (3H, s, H-28), 1.05 (3H,
s, H-26), 1.06 (3H, s, H-27), 1.08 (3H, d, J = 4.6 Hz, H-29), 1.18 (3H,
s, H-30), 2.00 and 2.04 (each 3H, s, CH3CO), 4.47 (1H, dd, J = 4.2,
11.2 Hz, H-3␣), 4.75 (1H, dd, J = 3.8, 11.5 Hz, H-16␣); 13C NMR
(CDCl3, 100 MHz) ı 38.4 (C-1), 23.7 (C-2), 80.9 (C-3), 36.8 (C-4),
55.2 (C-5), 18.1 (C-6), 34.4 (C-7), 41.5 (C-8), 49.1 (C-9), 37.8 (C-10)
21.6 (C-11), 29.1 (C-12), 38.6 (C-13), 42.7 (C-14), 32.8 (C-15), 79.4
(C-16), 39.5 (C-17), 46.1 (C-18), 38.1 (C-19), 72.7 (C-20), 34.9 (C-
21), 32.2 (C-22), 27.9 (C-23), 16.5 (C-24), 16.3 (C-25), 16.1 (C-26),
16.3 (C-27), 13.6 (C-28), 17.8 (C-29), 30.2 (C-30), 21.3 (CH3CO),
170.6 and 171.0 (CH3CO); LR-EI-MS (PIM) m/z 484 (M-CH3COOH,
53), 466 (M-CH3COOH-H2O, 69), 424 (M-2CH3COOH, 15), 406
(M-2CH3COOH-H2O, 15), 359 (30), 299 (65), 189 (100); HR-EI-MS
(PIM) m/z Calc. for C34H56O5 [M]+ 544.4128, Found m/z 544.4123.
21-Oxo-lupan-3␤,28-diyl diacetate (8). Colorless amorphous
solid, isolated from the oxidation product of 3, which was crystal-
lized from chloroform-methanol, mp 251–253 ◦C (lit., (Sejabel et
al., 1997) mp 250–254 ◦C); IR (KBr) cm−1 1725, 1736, 1750 (C O);
1H NMR (CDCl3, 300 MHz) ı 0.81 (3H, d, J = 6.9 Hz, H-29), 0.85 (3H,
s, H-24), 0.86 (3H, s, H-23), 0.87 (3H, s, H-25), 1.04 (3H, s, H-
27), 1.08 (3H, s, H-26), 1.15 (3H, d, J = 7.2 Hz, H-30), 1.80 (1H, d,
J = 14.7 Hz, H-22␣), 2.02 and 2.05 (each 3H, s, CH3CO), 2.36 (1H,
d, J = 16.8 Hz, H-22␤), 3.72 (1H, d, J = 11.4 Hz, H-28), 4.37 (1H, dd,
J = 1.2, 12.6 Hz, H-28), 4.47 (1H, dd, J = 6.6, 10.5 Hz, H-3␣); 13C NMR
(CDCl3, 75 MHz) ı 38.5 (C-1), 23.8 (C-2), 80.8 (C-3), 37.9 (C-4), 55.4
(C-5), 18.3 (C-6), 34.0 (C-7), 41.1 (C-8), 50.0 (C-9), 37.1 (C-10), 20.9
(C-11), 27.0 (C-12), 36.6 (C-13), 42.8 (C-14), 27.2 (C-15), 30.4 (C-
16), 41.7 (C-17), 46.9 (C-18), 54.2 (C-19), 30.0 (C-20), 218.1 (C-21),
52.3 (C-22), 28.1 (C-23), 16.5 (C-24), 16.2 (C-25), 16.3 (C-26), 14.9
(C-27), 64.4 (C-28), 22.4 (C-29), 16.7 (C-30), 21.1 and 22.5 (CH3CO),
170.7 (CH3CO); LR-EI-MS (PIM) m/z 542 (M+, 7), 482 (M-CH3COOH,
76), 467 (M-CH3-CH3COOH, 25), 439 (M-2CH3-CH2OCOCH3, 34),
379 (M-2CH3-CH3COOH-CH2OCOCH3, 4), 189 (100).
2.2. Materials and reagents
meso-Tetraarylporphyrins were prepared by a slight modifi-
cation of the procedure of Lindsey et al. (1987). The Os(TMP)CO
complex was prepared from the meso-tetramesitylporphyrins and
Os3(CO)12 by the method reported by Che et al. (1985). ␣-Amyrin,
faradiol, betulin, cycloartenol, and euphol were from our laboratory
collection. Acetylation of the hydroxyl groups in these compounds
was carried out by the usual manner. Subsequent catalytic hydro-
genation of the resulting acetate derivatives with Pd/C catalyst
afforded the starting compounds (1–5) used in this study, except
for 1 and 5.
16-Oxo-lupan-3␤,28-diyl diacetate (9). Colorless amorphous
solid, isolated from the oxidation product of 3, which was crys-
tallized from chloroform-methanol, mp 226–228 ◦C; IR (KBr) cm−1
1699, 1740 (C O); 1H NMR (CDCl3, 300 MHz) ı 0.74 (3H, d, J = 6.3 Hz,
H-29), 0.85 (3H, s, H-24), 0.86 (3H, s, H-23), 0.86 (3H, d, J = 6.6 Hz, H-
30), 0.88 (3H, s, H-25), 0.90 (3H, s, H-27), 1.14 (3H, s, H-26), 1.87 (1H,
d, J = 13.5 Hz, H-15␣), 2.02 and 2.04 (each 3H, s, CH3CO), 2.77 (1H, d,
J = 13.8, H-15␤), 4.11 (1H, d, J = 11.4 Hz, H-28), 4.45 (1H, dd, J = 5.7,
10.5 Hz, H-3␣), 4.58 (1H, d, J = 11.4 Hz, H-28); 13C NMR (CDCl3,
75 MHz) ı 38.5 (C-1), 23.8 (C-2), 80.7 (C-3), 37.9 (C-4), 55.2 (C-5),
18.2 (C-6), 34.2 (C-7), 41.3 (C-8), 50.0 (C-9), 37.1 (C-10), 21.5 (C-11),
26.4 (C-12), 37.3 (C-13), 48.7 (C-14), 45.2 (C-15), 212.2 (C-16), 61.1
(C-17), 49.5 (C-18), 44.9 (C-19), 29.2 (C-20), 20.7 (C-21), 26.8 (C-
22), 28.1 (C-23), 16.7 (C-24), 16.2 (C-25), 16.7 (C-26), 15.6 (C-27),
64.3 (C-28), 14.8 (C-29), 22.8 (C-30), 21.0 (CH3CO), 170.6 and 170.7
(CH3CO); LR-EI-MS (PIM) m/z 542 (M+, 18), 482 (M-CH3COOH, 79),
467 (M-CH3-CH3COOH, 22), 439 (M-2CH3-CH2OCOCH3, 26), 379
(M-2CH3-CH3COOH-CH2OCOCH3, 12), 277 (22), 189 (100); HR-
EI-MS (PIM) m/z Calc. for C34H54O5 [M]+ 542.3971, Found m/z
542.3975.
2.3. General oxidation procedure with Os(TMP)CO/TBHP
To a solution of substrate (0.2 mmol) in benzene (500 ␮l), molec-
ular sieves (50 mg; 4 Å), Os(TMP)CO (1 mg, 1 ␮mol) and anhydrous
TBHP (360 mg, 4.0 mmol) were added, and the mixture was refluxed
for 48–96 h; the reaction was monitored by TLC; 48 h for 1, 96 h for
2-4, and 72 h for 5. After the reaction, each of the oxidation products
was isolated by a column chromatography on silica gel, followed by
preparative HPLC.
2.4. Physicochemical data for oxidation products
11-Oxo-urs-12-en-3␤-yl acetate (6). Colorless amorphous
solid, isolated from the oxidation product of 1, which was crys-
tallized from aqueous methanol, mp 279–281 ◦C (lit. (Dasgupta et
al., 1980), mp 276–278 ◦C); IR (KBr) cm−1 1655, 1734 (C O); 1H
NMR (CDCl3, 270 MHz) ı 0.80 (3H, d, J = 5.7 Hz, H-29), 0.82 (3H, s,
H-23), 0.88 (3H, s, H-24), 0.88 (3H, d, J = 1.2 Hz, H-30), 0.95 (3H, s,
H-28), 1.04 (3H, s, H-25), 1.17 (3H, s, H-26) 1.29 (3H, s, H-27), 2.05
(3H, s, CH3CO), 4.52 (1H, dd, J = 5.4, 11.6 Hz, H-3␣), 5.54 (1H, s, H-
12); 13C NMR (CDCl3, 67.5 MHz) ı 38.9 (C-1), 23.6 (C-2), 80.6 (C-3),
38.0 (C-4), 55.0 (C-5), 18.5 (C-6), 32.8 (C-7), 40.9 (C-8), 61.4 (C-9),
36.8 (C-10), 199.7 (C-11), 130.4 (C-12), 165.0 (C-13), 43.6 (C-14),
28.8 (C-15), 27.2 (C-16), 45.1 (C-17), 59.0 (C-18), 39.2 (C-19), 39.3
22-Oxo-lupan-3␤,28-diyl diacetate (10). Colorless amorphous
solid, isolated from the oxidation product of 3, which was crys-
tallized from chloroform-methanol, mp 228–230 ◦C; IR (KBr) cm−1
1728, 1741 (C O); 1H NMR (CDCl3, 300 MHz) ı 0.76 (3H, d, J = 6.9 Hz,
H-29), 0.84 (3H, s, H-24), 0.85 (3H, s, H-23), 0.86 (3H, d, J = 6.6 Hz,

S. Ogawa et al. / Chemistry and Physics of Lipids 163 (2010) 165–171
167
H-30), 0.87 (3H, s, H-25), 0.94 (3H, s, H-27), 1.05 (3H, s, H-26),
1.93 (1H, dd, J = 7.2, 19.2 Hz, H-21␤), 2.02 and 2.05 (each 3H, s,
CH3CO), 2.50 (1H, dd, J = 9.9, 19.2 Hz, H-21␣), 4.34 (2H, s, H-28),
4.46 (1H, dd, J = 5.7, 10.2 Hz, H-3␣); 13C NMR (CDCl3, 75 MHz) ı
38.4 (C-1), 23.8 (C-2), 80.7 (C-3), 37.8 (C-4), 55.2 (C-5), 18.3 (C-
6), 34.2 (C-7), 41.0 (C-8), 49.7 (C-9), 37.1 (C-10), 20.7 (C-11), 26.4
(C-12), 38.1 (C-13), 43.0 (C-14), 26.2 (C-15), 23.4 (C-16), 54.1 (C-
17), 45.1 (C-18), 41.0 (C-19), 28.7 (C-20), 35.9 (C-21), 216.0 (C-22),
28.0 (C-23), 16.7 (C-24), 16.2 (C-25), 16.3 (C-26), 14.4 (C-27), 60.7
(C-28), 14.8 (C-29), 22.8 (C-30), 21.0 and 21.5 (CH3CO), 170.7 and
170.8 (CH3CO); LR-EI-MS (PIM) m/z 542 (M+, 4), 482 (M-CH3COOH,
68), 469 (M-CH2OCOCH3, 13), 467 (M-CH3-CH3COOH, 19), 439
(M-2CH3-CH2OCOCH3, 25), 409 (M-CH3COOH-CH2OCOCH3, 6), 379
(M-2CH3-CH3COOH-CH2OCOCH3, 4), 189 (100); HR-EI-MS (PIM)
m/z Calc. for C34H54O5 [M]+ 542.3971, Found m/z 542.3980.
25-Hydroxy-5␣-cycloartan-3␤-yl acetate (11). Colorless
amorphous solid, isolated from the oxidation product of 4, which
was crystallized from aqueous methanol, mp 134–136 ◦C (lit.
(Anjaneyulu et al., 1989), mp 136–138 ◦C); IR (KBr) cm−1 3449
(OH), 1736 (C O); 1H NMR (CDCl3, 270 MHz) ı 0.34 and 0.58 (each
1H, d, J = 5.4 Hz, H-19), 0.85 (3H, s, H-29), 0.86 (3H, d, J = 5.4 Hz,
H-21), 0.89 (6H, s, H-28 and H-30), 0.96 (3H, s, H-18), 1.22 (6H, s,
H-26 and H-27), 2.05 (3H, s, CH3CO), 4.55 (1H, dd, J = 5.2, 10.5 Hz,
H-3␣); 13C NMR (CDCl3, 67.5 MHz) ı 31.6 (C-1), 26.8 (C-2), 80.7
(C-3), 39.4 (C-4), 47.2 (C-5), 20.9 (C-6), 28.2 (C-7), 47.8 (C-8), 20.1
(C-9), 25.9 (C-10), 25.8 (C-11), 36.1 (C-12), 45.3 (C-13), 48.8 (C-14),
32.8 (C-15), 26.5 (C-16), 52.3 (C-17), 18.0 (C-18), 29.8 (C-19),
35.5 (C-20), 18.3 (C-21), 36.7 (C-22), 21.1 (C-23), 44.4 (C-24),
71.1 (C-25), 29.2 (C-26), 29.3 (C-27), 25.4 (C-28), 15.1 (C-29), 19.3
(C-30), 21.3 (CH3CO), 171.0 (CH3CO); LR-EI-MS (PIM) m/z 486 (M+,
7), 468 (M-H2O, 19), 453 (M-CH3-H2O, 12), 426 (M-CH3COOH, 63),
408 (M-CH3COOH-H2O, 38), 393 (M-CH3-CH3COOH-H2O, 34), 357
(M-side chain (S.C.), 22), 297 (M-CH3COOH-S.C., 43), 203 (54), 95
(100).
25-Hydroxy-7,11-dioxo-euph-8-en-3␤-yl acetate (12). Non-
crystalline substance which isolated from the oxidation product
of 5. IR (KBr) cm−1 3449 (OH) 1672, 1735 (C O); 1H NMR (CDCl3,
270 MHz) ı 0.89 (3H, d, J = 5.4 Hz, H-21), 0.91 (3H, s, H-18), 0.92 (3H,
s, H-30), 0.98 (3H, s, H-29), 1.08 (3H, s, H-28), 1.23 (6H, s, H-26 and
H-27), 1.26 (3H, s, H-19), 2.08 (3H, s, CH3CO), 4.56 (1H, dd, J = 5.4,
10.8 Hz, H-3␣); 13C NMR (CDCl3, 67.5 MHz) ı 35.4 (C-1), 23.8 (C-2),
79.5 (C-3), 37.5 (C-4), 48.6 (C-5), 33.6 (C-6), 202.0 (C-7), 149.8 (C-8),
154.6 (C-9), 37.8 (C-10), 199.5 (C-11), 51.4 (C-12), 45.1 (C-13), 47.9
(C-14), 31.7 (C-15), 29.7 (C-16), 49.3 (C-17), 17.8 (C-18), 18.4 (C-
19), 35.9 (C-20), 18.4 (C-21), 35.5 (C-22), 21.1 (C-23), 44.2 (C-24),
71.0 (C-25), 29.2 (C-26), 29.4 (C-27), 24.0 (C-28), 27.5 (C-29), 16.1
(C-30), 21.2 (CH3CO), 170.9 (CH3CO); LR-EI-MS (PIM) m/z 514 (M+,
28), 496 (M-H2O, 100), 481 (M-CH3-H2O, 9), 436 (M-CH3COOH-
H2O, 12), 385 (M-S.C., 10), 318 (24), 292 (29); HR-EI-MS (PIM) m/z
Calc. for C32H50O5 [M]+ 514.3658, Found m/z 514.3663.
euphol were transformed into the respective ␣-amyrin acetate
(1), dihydrofaradiol diacetate (2), dihydrobetulin diacetate (3),
cycloartanyl acetate (4), and dihydroeuphol acetate (5) (Fig. 1). The
ꢀ
12(13)-bond in 1 resisted hydrogenation attempts, probably owing
to steric hindrance of the axially-oriented methyl groups at C-8 (26-
CH3) andC-14(27-CH3) andthe equatorialmethylatC-19 (29-CH3).
Similarly, the ꢀ8(9)-bond in 5 did not hydrogenate at all, because
of the presence of the axial methyls at C-10 (19-CH3), C-13 (18-
CH3), and C-14 (28-CH3). All of the compounds 1–5 are the same
3␤-acetoxy derivatives of penta- and tetracyclic triterpenoids with
the trans A/B-ring juncture (5␣-H).
Oxidation of 1–5 with Os(TMP)CO/TBHP was carried out in
refluxing benzene for 48–96 h under the conditions employed (see
Section 2); the reaction was monitored by TLC. The use of anhy-
drous TBHP as an oxygen donor is essential (Iida et al., 2007). After
chromatographic separation of each of the reaction products, the
structures of the isolated components (6–12) were determined on
the basis of the MS and the 1H and 13C NMR data.
The Os(TMP)CO/TBHP oxidation of ␣-amyrin acetate (1), hav-
ing a ꢀ12(13)-bond in the 5␣-pentacyclic triterpenoid nucleus,
produced a single component, which was identified as 11-oxo-␣-
amyrin acetate (6, 80% isolated yield after 48 h); no 12,13-epoxy
derivative was detected at all. An oxygen atom in the oxidant
was inserted preferentially into the C-11 allylic position in 1 to
give the ␣,␤-unsaturated ketones 6 exclusively within a relatively
short reaction time. The result can be rationalized in terms of
electronic effect of the ꢀ12(13)-bond, suggesting the oxidant sys-
tem is electrophilic in nature (Iida et al., 2004). The enone 6
has been isolated as a minor component from the fruits of an
Indian Ayurvedic plant (Dendrophthoe falcate) (Mallavadhani et al.,
2006) and also prepared by reaction of 1 with N-bromosuccinimide
(Finucane and Thomson, 1969). According to the previous find-
ing (Ogawa et al., 2007b), when ursolic acid acetate and oleanolic
acid acetate, both of which have the same ꢀ12(13)-bond in the
5␣-pentacyclic triterpenoid nucleus, were oxidized with dimethyl-
dioxirane, the major products were the respective 11-oxo-ꢀ12(13)
analogs.
When dihydrofaradiol diacetate (2), which has the equatorially-
oriented ␣-methyl (29-CH3) at C-19 and ␤-methyl (30-CH3)
at C-20, was subjected to the Os(TMP)CO/TBHP oxidation, the
corresponding 20␣-hydroxy-ursan-3␤,16␤-diyl diacetate (7, 50%
isolated yield after 96 h) was obtained as a new compound. The
result indicates that the electron-enriched methine carbon at C-
20 in 2 is more easily oxyfunctionalized than methylene carbons.
The stereochemistry of the 20␣-hydroxylation in 7 was completely
retained to that of 20␣-H in 2, supporting the hypothesis that a
direct O-insertion into the C–H bond took place (see below). In addi-
tion, the sterically less hindered 20␣-H was attacked in preference
to the more crowded 19␤-H.
On the other hand, the Os(TMP)CO/TBHP treatment of dihy-
drobetulin 3,28-diacetate (3), which has the equatorially-oriented
␣-isopropyl group at C-19 and the axial ␤-CH2OCOCH3 group at
C-17, afforded the three major oxo-derivatives. After chromato-
graphic separation of the individual compounds, their structures
were identified as 21-oxo- (8; 10% isolated yield after 96 h) (Sejbal
et al., 1997), 16-oxo- (9; 10%), and 22-oxo-lupan-3␤,28-diyl diac-
etates (10; 17%). A similar result was also obtained by oxidation of
lupanol acetate with methyl(trifluoromethyl)dioxirane as an oxi-
dant (unpublished data). Since 3 has the two methine protons at
C-19 and C-20 (isopropyl moiety) in the E-ring, these carbon atoms
would be expected to be oxidized most preferentially as compared
to the methylene carbons at C-16, C-21, and C-22. However, such
methine oxidized products were not isolated at all. Although the
reason is unclear, the ketonization on the D- and E-rings presum-
ably occurred by a combined steric and inductive effect of the C-17
substituent.
3. Results and discussion
The five variants of 5␣-penta- and 5␣-tetracyclic triterpenoids
(␣-amyrin, faradiol, betulin, cycloartenol, and euphol) used as sub-
strates in this study occur naturally in many plant species. The
oxyfunctionalization of the triterpenoids with the oxidant system
afforded a variety of scarce and/or novel oxygenated derivatives in
one-step with good isolated yields.
Prior to Os(TMP)CO/TBHP oxidation, all of the hydroxyl groups
present in each of the substrates were acetylated by the usual man-
ner with acetic anhydride/pyridine and then the double bonds were
hydrogenated in the presence of Pd/C catalyst, in order to pre-
vent simultaneous oxidation of the functional groups. As a result of
the pre-treatments, ␣-amyrin, faradiol, betulin, cycloartenol, and

168
S. Ogawa et al. / Chemistry and Physics of Lipids 163 (2010) 165–171
Fig. 1. Oxidation products of penta- and tetracyclic triterpenoids with Os(TMP)CO/TBHP system.
When cycloartanyl acetate (4) having the iso-octyl (C8H17) side
dized derivatives, which would be expected as the initial reaction
intermediates, were not isolated at all under the experimental
conditions employed. The predominant formation of 12 from 5 is
consistent with the results of compounds 1 and 4 mentioned above:
the allylic methylene carbons at C-7 and C-11 and the unhindered
methine carbon at C-25 were oxidized preferentially. A similar
regioselectivity has also been observed, when dihydrolanosteryl
acetate (trans C/D-ring juncture with the axial 18␤-CH3 at C-13
and the axial 28␣-CH3 at C-14), which is the stereoisomer of 5,
was subjected to (5,10,15,20-tetramesitylporphyrinate) ruthenium
(II) carbonyl complex/2,6-dichloropyridine N-oxide/HBr oxidation,
yielding the corresponding 25-hydroxy-7,11-dioxo analog as a
minor reaction product (Iida et al., 2004).
Confirmation of the structures of the new compounds 7, 9, and
10 was made by 1H-13C shift-correlated 2D-NMR (heteronuclear
multiple quantum coherence (HMQC) and heteronuclear multiple-
bond connectivity (HMBC)) and nuclear Overhauser effect (NOE)
techniques; differentiation among CH3, CH2, CH, and C was attained
by the DEPT experiments (Fig. 2). In the 1H NMR spectrum of
20␣-hydroxy-ursan-3␤,16␤-diyl diacetate (7), a singlet peak at
1.18 ppm and a doublet signal at 1.08 ppm were shown to arise from
chain at C-17 in the 5␣-tetracyclic terpenoid nucleus was subjected
to the Os(TMP)CO/TBHP system, the sole reaction product was 25-
hydroxy-cycloartanyl acetate (11, 50% isolated yield after 96 h).
The result implies that the oxidant attacks preferentially at a ster-
ically less hindered, electron-enriched methine carbon (C-25 in 4).
Although the chemical synthesis of 11 has not yet been reported, it
was isolated in nature from Indian fruits (Mango, Mangifera indica
L.) (Anjaneyulu et al., 1989) and natural wheat straw (Triticum aes-
tivum) (Gaspar and das Neves, 1993) as a minor component. The 1
H
NMR spectral data of 11 was in good agreement with those reported
in a literature (Gaspar and das Neves, 1993). It is also noted that the
compound 11 was proposed as a treatment of Alzheimers’s disease
(Saito et al., 1990).
We then examined the Os(TMP)CO/TBHP oxidation of dihy-
droeuphol acetate (5), which has a ꢀ8(9)-bond and an iso-octyl
side chain at C-17 in the trans C/D-ring juncture nucleus (axial
18␣-CH3 at C-13 and axial 28␤-CH3 at C-14). Treatment of 5
with the oxidant afforded exclusively 25-hydroxy-7,11-dioxo-
euph-8-en-3␤-yl acetate (12, 48% isolated yield after 72 h) as
a novel compound. Any 7-, 11-, and/or 25-mono- and dioxi-

S. Ogawa et al. / Chemistry and Physics of Lipids 163 (2010) 165–171
169
Fig. 2. 1H–13C long-range correlations observed for the HMBC spectra of compounds 7, 9, and 10.
methyl groups. On the other hand, a quaternary 13C signal appeared
at 72.7 ppm and a tertiary carbon at 38.1 ppm. These results suggest
that a hydroxyl group was inserted in a methine carbon at C-19 or
C-20 of the substrate 2. In the HMBC spectrum of 7, distinct correla-
tion peaks were observed for the singlet 1H signal at 1.18 ppm with
13C signals at C-19 (38.1 ppm), C-20 (72.7), and C-21 (34.9). Fur-
thermore, the doublet 1H signal at 1.08 ppm was correlated with
the 13C signals at C-18 (46.1 ppm), C-19 (38.1), and C-20 (72.7). The
hydroxylation position was therefore assigned to the methine car-
bon at C-20. To elucidate the stereochemical configuration of the
hydroxyl group, the difference NOE was then measured. Since the
NOE was observed between the axial 19␤-H (1.43 ppm) and the
equatorial 30␤-H3 (1.18 ppm), the stereochemistry of the hydroxyl
group at C-20 was determined to be the axial ␣-configuration.
In 16-oxo-lupan-3␤,28-diyl diacetate (9), correlation peaks
were observed between 1H signals at 28-H2 (4.11 and 4.58 ppm)
and 13C signals at C-16 (212.2 ppm) and C-22 (26.8 ppm) in the
HMBC spectrum. Both the 28-H2 signals (3.82 and 4.24 ppm)
appearing in the substrate 3, were largely deshielded by ca. 0.3 ppm
in 9, probably owing to the ketonization at C-16. In support of this
view, the 13C signal at 212.2 ppm correlates with 1H signals occur-
ring at 2.77 and 1.87 ppm, which are also correlated with a 13C
signal appearing at 45.2 ppm in the HMQC spectrum. In addition, a
13C signal at 45.2 ppm has a correlation peak with the 27-H3 signal
that occurs at 0.90 ppm in the HMBC. The 13C signal at 45.2 ppm
and the 1H signals at 2.77, and 1.87 ppm were, therefore, assigned
to the C-15, 15␤-H, and 15␣-H, respectively.
22-Oxo-lupan-3␤,28-diyl diacetate (10) showed the following
characteristic correlation peaks in the HMBC spectrum: a singlet
1H signal occurring at 4.34 ppm (28-H2) correlates that with the
13C signal at 23.4 ppm (C-16) and 216 ppm. The carbonyl signal
at 216 ppm also correlated with 1H signals at 2.50 and 1.93 ppm.
Furthermore, the 1H signals at 2.50 and 1.93 ppm exhibited a corre-
lation with the 13C signals at C-20 (28.7 ppm) and C-19 (41.0 ppm),
indicating that the two 1H signals arise from the 21␣-H and 21␤-H,
respectively.
In 25-hydroxy-7,11-dioxo-euph-8-en-3␤-yl acetate (12), a 1H
signal (singlet, 6H) appearing at 1.23 ppm and a 13C signal occurring
at 71.0 ppm (quaternary carbon) showed the presence of a hydroxyl
group at C-25. Furthermore, 13C signals observed at 149.8 ppm (C-
8) and 155.0 ppm (C-9) as olefinic carbons and at 202.0 ppm (C-7)
and 199.5 ppm (C-11) as carbonyl carbons are additional evidences
that 12 has the allylic 7,11-dioxo-ꢀ8(9) structure.
As shown in Fig. 3, the mass spectrum of the ursane type of 7
exhibited two characteristic peaks at m/z 359 (M-CH3COOH-2CH3-
C2H5-ring E + 2H, 30%) and 299 (M-2CH3COOH-2CH3-C2H5-ring
E + 2H, 65%), which appear to originate from fragmentation through
rings D/E by the onium cleavage, together with the loss of CH3COOH
from the acetoxyl groups at C-3 and C-16 (Anjaneyulu et al., 1985).
An additional intense peak appearing at m/z 189 (100%) was formed
by the rupture of ring C with the loss of two hydrogen. In the
mass spectra of the lupane type of triterpenes 9 and 10, highly
intense ions were observed for at m/z 482 (M-CH3COOH, 79 and
68%) and at m/z 189 (100%) originating from fragmentation of ring
Fig. 3. Characteristic fragment ions observed for the mass spectra of compounds 7, 9, 10, and 11.

170
S. Ogawa et al. / Chemistry and Physics of Lipids 163 (2010) 165–171
Fig. 4. Possible mechanism of Os(TMP)CO-catalyzed ketonization of unactivated methylene carbons by TBHP.
C. On the other hand, the mass spectrum of the euphane type of
12 showed highly diagnostic ions at m/z 318 (24%) and 292 (29%),
which must have originated from fragmentation through ring C and
a part of rings C/D, respectively, accompanied by the movement of
one and/or two hydrogen atoms to the unsaturated system result-
ing in scission and charge retention on the fragment possessing
rings A and B. Based on the previous finding of a lanostane series
of triterpenoids (Dias, 1976), the ion at m/z 292 is probably arising
from transfer of two hydrogen atoms from the 18-methyl to the
11-oxo group by the McLafferty rearrangement.
alkoxy radical (ii), accompanied by the regeneration of (b). The
homogenic formation of (ii) and H· produces the secondary alcohol
(iii) (Amadelli et al., 1992; Murahashi et al., 1995), which is then
immediately oxidized by (b) and/or TBHP to give the correspond-
ing ketone (iv). Thus, the ketonization of the methylene carbon
would go through a two-step mechanism, via the secondary alcohol
intermediate (iii). On the other hand, hydroxylation of the methine
carbon in a substrate to the corresponding tertiary alcohol (i) would
proceed in a one-step mechanism from (c), via the carbon radical
intermediate (d-1) and/or the alkylperoxy intermediate (d-2) (Iida
et al., 2007).
The regioselectivity of the O-insertion reaction induced by
metalloporphyrin/oxygen-donor systems depends significantly
upon the steric and electronic effects of the electron-withdrawing
substituents situated in the vicinity of the methine and methy-
lene carbons under consideration (Iida et al., 2004, 2007).
Electron-withdrawing substituents (e.g., acetoxyl group) probably
destabilize the transition state for the oxidant complex insertion in
the nearby carbons through unfavorable electrostatic interactions.
In this connection, the electrophilic metalloporphyrin/oxygen-
donor systems usually attack the electron-enriched methine
carbons in a substrate, rather than methylene and methyl carbons,
to produce the corresponding tertiary alcohols predominately.
The product profile strongly suggests that an active trans-
dioxoosmium porphyrin intermediate formed from Os(TMP)CO
complex has an unambiguous radical center (Ogawa et al., 2007a;
Gross and Mahammed, 1999) and that the oxyfunctionalization
proceeds in radical chain reaction by thermal, homolytic scission of
TBHP. An ion intermediate is not involved (Barr et al., 1996; Trotta et
al., 1983). In this study, particularly noteworthy was the predomi-
nant formation of oxo-derivatives by ketonization of an unactivated
methylene C–H bond in the substrates 1, 3, and 5. Fig. 4 shows
the possible mechanism of Os(TMP)CO-catalyzed ketonization of
a unactivated methylene carbon with TBHP, along with hydrox-
ylation of a methine carbon. Assuming that oxyfunctionalization
of 1–5 proceeds by the homolysis induced by Os(TMP)CO (a) as a
precatalyst, (a) is at first transformed into the trans-dioxoosmium
porphyrin (b) (Gross and Mahammed, 1999) as an active catalyst by
subtracting an oxygen atom from TBHP. An additional acceptance
of an oxygen radical from TBHP to (b) results in the formation of
Os-porphyrin peroxy radical (c), which in turn is converted to the
Os-porphyrin alkylperoxy intermediate (e) with a specific methy-
lene carbon in substrates (Arasasingham et al., 1989; Maldotti
et al., 1991). Subsequent homolytic cleavage of (e) affords the
In conclusion, a variety of oxyfunctionalization products, which
include novel and scarce compounds, were obtained by the
Os(TMP)CO/TBHP system in one-step from penta- and tetracyclic
triterpenoids 1–5. The oxidant caused effective allylic oxidation,
hydroxylation, and ketonization of the unactivated C–H bonds in
the substrates, which provides a useful tool for the facile synthesis
of hydrophilic oxygenated derivatives from natural triterpenoids.
A further study on biological activity of the oxygenated derivatives
is now progress in our laboratory and the results will be reported
elsewhere.
Acknowledgements
We thank Dr. Alan F. Hofmann, University of California, San
Diego for help in manuscript preparation. This work was supported
in part by a Nihon University Multidisciplinary Research Grant for
2007–2008 and Research Project of The Institute of Natural Sciences
Nihon University in 2009 and a Grant-in-Aid for Scientific Research
from the Ministry of Education, Sciences, Sports, and Culture of
Japan for 2007–2008 (to T.I.).
References
Amadelli, R., Bregola, M., Polo, E., Carassiti, V., Maldotti, A., 1992. Photooxidation of
hydrocarbons on porphyrin-modified titanium dioxide powders. J. Chem. Soc.
Chem. Commun., 1355–1357.
Anjaneyulu, V., Harischandra Prasad, K., Ravi, K., Connolly, J.D., 1985. Triterpenoids
from Mangifera indica. Phytochemistry 24, 2359–2367.
Anjaneyulu, V., Ravi, K., Harischandra Prasad, K., Connolly, J.D., 1989. Triterpenoids
from Mangiferaindica. Phytochemistry 28, 1471–1477.
Arasasingham, R.D., Balch, A.L., Cornman, C.R., Latos-Grazynski, L., 1989. Dioxygen
insertion into iron(III)-carbon bonds. NMR studies of the formation and reac-
tivity of alkylperoxo complexes of iron(III) porphyrins. J. Am. Chem. Soc. 111,
4357–4363.

S. Ogawa et al. / Chemistry and Physics of Lipids 163 (2010) 165–171
171
Barr, D.P., Martin, M.V., Guengerich, F.P., Mason, R.P., 1996. Reaction of cytochrome
P450 with cumene hydroperoxide: ESR spin-trapping evidence for the
homolytic scission of the peroxide O–O bond by ferric cytochrome P450 1A2.
Chem. Res. Toxicol. 9, 318–325.
Bovicelli, P., Lupattelli, P., Mincione, E., Prencipe, T., Curci, R., 1992. Oxidation of
natural targets by dioxiranes. Oxyfunctionalization of steroids. J. Org. Chem. 57,
2182–2184.
Mallavadhani, U.V., Narasimhan, K., Sudhakar, A.V.S., Mahapatra, A., Li, W.,
van Breemen, R.B., 2006. Three new pentacyclic triterpenes and some
flavonoids from the fruits of an Indian ayurvedic plant Dendrophthoe falcate
and their estrogen receptor binding activity. Chem. Pharm. Bull. 54, 740–
744.
Meunier, B., 1992. Metalloporphyrins as versatile catalysts for oxidation reactions
and oxidative DNA cleavage. Chem. Rev. 92, 1411–1456.
Breslow, R., 1990. Enzyme mimics. Pure Appl. Chem. 62, 1859–1866.
Breslow, R., Zhang, X., Huang, Y., 1997. Selective catalytic hydroxylation of a steroid
by an artificial cytochrome P-450 enzyme. J. Am. Chem. Soc. 119, 4535–4536.
Che, C.-M., Poon, C.-K., Chung, W.-C., Gray, H.B., 1985. Synthesis and characterization
of osmium porphyrins. Inorg. Chem. 24, 1277–1278.
Dasgupta, A., Goswami, A., Ray, T.K., Nath, A., Khastgir, H.N., 1980. Reactions of some
triterpenes with mercuric acetate: an unusual reaction with taraxeryl acetate.
Indian J. Chem. 19B, 165–168.
Murahashi, S., Naota, T., Komiya, N., 1995. Metalloporphyrin-catalyzed oxidation of
alkanes with molecular oxygen in the presence of acetaldehyde. Tetrahedron
Lett. 36, 8059–8062.
Ogawa, S., Hosoi, K., Iida, T., Wakatsuki, Y., Makino, M., Fujimoto, Y., Hofmann,
A.F., 2007a. Osmiumporphyrin-catalyzed oxyfunctionalization and isomeriza-
tion of natural (5␤)-bile acids with tert-butylhydroperoxide. Eur. J. Org. Chem.,
3555–3563.
Ogawa, S., Hosoi, K., Ikeda, N., Makino, M., Fujimoto, Y., Iida, T., 2007b. Oxyfunction-
alization products of terpenoids with dimethyldioxirane and their biological
activity. Chem. Pharm. Bull. 55, 247–250.
Dias, J.R., 1976. Mass spectral fragmentation of functionalized lanostanes -1. Mass
Spectro. 11, 333–346.
Finucane, B.W., Thomson, J.B., 1969. Direct oxidation of allylic methylene to car-
bonyl. J. Chem. Soc. D: Chem. Commun., 1220.
Gaspar, E.M.M., das Neves, H.J.C., 1993. Steroidal constituents from mature wheat
straw. Phytochemistry 34, 523–527.
Gross, Z., Mahammed, A., 1999. Novel reactivities of iodosylbenzene in the catalytic
oxygenation of olefins. J. Mol. Catal. A 142, 367–372.
Ohtake, H., Higuchi, T., Hirobe, M., 1995. The highly efficient oxidation of olefins,
alcohols, sulfides and alkanes with heteroaromatic N-oxides catalyzed by ruthe-
nium porphyrins. Heterocycles 40, 867–903.
Reese, P.B., 2001. Remote functionalization reactions in steroids. Steroids 66,
481–497.
Saito, S., Matsumoto, T., Tokunaga, Y. Brain function improvers containing steroids.
Iida, T., Ogawa, S., Hosoi, K., Makino, M., Fujimoto, Y., Goto, T., Mano, N., Goto, J.,
Hofmann, A.F., 2007. Regioselective oxyfunctionalization of unactivated carbons
in steroids by a model of cytochrome P-450: osmiumporphyrin complex/tert-
butylhydroperoxide system. J. Org. Chem. 72, 823–830.
Jpn. Kokai Tokkyo Koho JP 02032022 A (1990).
Sejbal, J., Klinot, J., Bude˘sˇínsky´, M., Protiva, J., 1997. Functionalization of lupane-
3␤,28-diyl diacetate with chromium(VI) oxide part 2. Collect. Czech. Chem.
Commun. 62, 1905–1918.
Iida, T., Ogawa, S., Miyata, S., Goto, T., Mano, N., Goto, J., Nambara, T., 2004.
Shingaki, T., Miura, K., Higuchi, T., Hirobe, M., Nagano, T., 1997. Regio- and stereo-
selective oxidation of steroids using 2,6-dichloropyridine N-oxide catalysed by
ruthenium porphyrins. Chem. Commun., 861–862.
Sono, M., Roach, M.P., Coulter, E.D., Dawson, J.H., 1996. Heme-containing oxyge-
nases. Chem. Rev. 96, 2841–2887.
Trotta, R.J., Sullivan, S.G., Stern, A., 1983. Lipid peroxidation and haemoglobin degra-
dation in red blood cells exposed to t-butylhydroperoxide. Biochem. J. 212,
759–772.
Yang, J., Gabriele, B., Belvedere, S., Huang, Y., Breslow, R., 2002. Catalytic oxidations
of steroid substrates by artificial cytochrome P-450 enzymes. J. Org. Chem. 67,
5057–5067.
Biomimetic oxidation of unactivated carbons in steroids by
a model of
cytochrome P-450, oxorutheniumporphyrinate complex. Lipids 39, 873–880.
Iida, T., Yamaguchi, T., Nakamori, R., Hikosaka, M., Mano, N., Goto, J., Nambara,
T., 2001. A highly efficient, stereoselective oxyfunctionalization of unactivated
carbons in steroids with dimethyldioxirane. J. Chem. Soc., Perkin Trans. 1,
2229–2236.
Lindsey, J.S., Schreiman, I.C., Hsu, H.C., Kearney, P.C., Marguerettaz, A.M., 1987.
Rothemund and Adler-Longo reactions revisited: synthesis of tetraphenylpor-
phyrins under equilibrium conditions. J. Org. Chem. 52, 827–836.
Makris, T.M., von Koenig, K., Schlichting, I., Sligar, S.G., 2006. The status of high-
valent metal oxo complexes in the P450 cytochromes. J. Inorg. Biochem. 100,
507–518.
Yang, J., Weinberg, R., Breslow, R., 2000. The hydroxylation and amidation of
equilenin acetate catalyzed by chloro[5,10,15,20-tetrakis(pentafluorophenyl)
porphyrinato]manganese(III). Chem. Commun., 531–532.
Maldotti, A., Bartocci, C., Amadelli, R., Polo, E., Battioni, P., Mansuy, D., 1991. Oxi-
dation of alkanes by dioxygen catalysed by photoactivated iron porphyrins. J.
Chem. Soc. Chem. Commun., 1487–1489.