Bioorganic & Medicinal Chemistry Letters 15 (2005) 5463–5466
A thiolate ligand on a cytochrome P-450 mimic permits the use
of simple environmentally benign oxidants for biomimetic
steroid hydroxylation in water
Zhenglai Fang and Ronald Breslow*
Department of Chemistry, Columbia University, New York, NY 10027, USA
Received 16 August 2005; revised 25 August 2005; accepted 29 August 2005
Available online 23 September 2005
Abstract—Manganese porphyrin systems carrying cyclodextrin binding groups can regioselectively and stereoselectively hydroxylate
bound steroid substrates, using iodosobenzene as oxidant, but hydrogen peroxide and other simple oxidants such as sodium hypo-
chlorite are not effective in water. Thiol ligands were then added to the catalyst, both covalently attached and hydrophobically
bound, and with these ligands hydrogen peroxide was now an effective oxidant.
Ó 2005 Elsevier Ltd. All rights reserved.
We have described the hydroxylations of steroids direct-
ed by geometric control, in complexes of the substrates
with cytochrome P-450 mimics that are based on man-
ganese porphyrins carrying cyclodextrin binding
groups.1 In the earliest version, we saw that catalyst 1
could bind and hydroxylate substrate 2—with two ester
groups attached at C-3 and C-17 of the steroid—in
water with iodosobenzene as the oxidant. The product
was exclusively the diester of the 6a hydroxy steroid 3,
which was not further oxidized to a ketone because of
the inaccessibility of the product 6b hydrogen in the
complex. However, there were only eight turnovers be-
fore the catalyst was oxidatively destroyed. In a later
version, catalyst 4, the fluorines stabilized the catalyst
against oxidative destruction and 187 catalytic turnovers
were seen before the catalyst was destroyed (Fig. 1).1c
pler oxidants, such as hydrogen peroxide, sodium hypo-
chlorite, sodium chlorite, oxone (potassium persulfate),
or peracetic acid, but they failed. These oxidants have
been used previously in oxidations by metalloporphy-
rins,2 but not in an aqueous system. Such oxidants are
attractively convenient and cheap, and in many cases
environmentally benign (ÔGreenÕ) but in our system only
the stronger oxidant iodosobenzene was successful.
The mechanism of the catalyzed reactions ordinarily in-
volves an oxygen atom transfer to the metal atom of the
metalloporphyrins, followed by hydroxylation of the
bound substrate by the metal oxo species, so the prob-
lem is apparently that the other oxidants tried were
not strong enough to oxidize the metal to the oxo state
in water. One solution is to find even stronger benign
oxidants; the other is to make the metal oxidation easier.
An electron donor ligand should accomplish this.
With the same catalyst 4, we saw that oxidation of sub-
strate with three binding ester groups attached to car-
bons 3, 6, and 17 led to hydroxylation at C-9 of the
steroid.1d This selectivity reflected the new geometry in
the complex of the substrate with three cyclodextrins
of catalyst 4. With a different catalyst we were also able
to hydroxylate C-9 in a substrate carrying two binding
ester groups at carbons 3 and 6, with only two binding
interactions between substrate and catalyst.1f However,
in all these cases we looked for the possible use of sim-
In the natural P-450 enzymes the iron porphyrin has a
cysteine thiolate sulfur as the fifth ligand, while we
had used imidazole as a fifth ligand (the oxygen is
added to the sixth position), either simply in solution
or covalently attached to the porphyrin system. We
had used this imidazole as a way to block one face
of the porphyrin, so that both the substrate and the
added oxygen atom would be on the same porphyrin
face for reaction. However, Woggon,3 Battersby
et al.,4 Collman and Groh,5 and Traylor et al.6 have
prepared some porphyrins with thiolates as the fifth
ligand, and it was clear that the oxidation of the metal
Keywords: Cyclodextrin; Hydrophobic binding; Porphyrins.
*
Corresponding author. Tel.: +1 212 854 2170; fax: +1 212 854
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.08.090