Angewandte
Communications
Chemie
Bioinspired Catalysis
Readily Accessible Bulky Iron Catalysts exhibiting Site Selectivity in
the Oxidation of Steroidal Substrates
David Font, Merc Canta, Michela Milan, Olaf Cussó, Xavi Ribas,
Abstract: Bulky iron complexes are described that catalyze the
with aminopyridine ligands have been recently shown to
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site-selective oxidation of alkyl C H bonds with hydrogen
promote preferential oxidation of 28 over 38 C H bonds
[5]
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peroxide under mild conditions. Steric bulk at the iron center is
introduced by appending trialkylsilyl groups at the meta-
position of the pyridines in tetradentate aminopyridine ligands,
and this effect translates into high product yields, an enhanced
because the 38 C H bonds are sterically more encumbered.
However, reagents that can override intrinsic relative reac-
tivities among not-activated methylene sites are very rare.[5c,6]
This remains a very relevant and challenging problem because
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preferential oxidation of secondary over tertiary C H bonds,
these strong and inert bonds are the most abundant C H sites
in organic molecules.
and the ability to perform site-selective oxidation of methylenic
sites in terpenoid and steroidal substrates. Unprecedented site
selective oxidation at C6 and C12 methylenic sites in steroidal
substrates is shown to be governed by the chirality of the
catalysts.
In the quest for iron catalysts that could regulate
regioselectivity, and that are synthetically accessible in
a straightforward manner, we considered installing bulky
trialkylsilyl moieties to tetradentate chiral aminopyridine
ligands. We envisioned that the bulky nature of the catalysts
will modulate their regioselectivity, and may also enhance
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S
elective alkyl C H functionalization is envisioned as a very
powerful reaction in organic synthesis.[1] Regioselectivity
exhibited by most oxidizing reagents is governed by the
stereoselectivity in C H oxidation reactions. Furthermore,
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from a practical point of view, the silyl derivatization offers
a simple synthetic strategy to obtain modular scaffolds
suitable for systematic tuning. Following these ideas, we
herein show chiral iron catalysts with sterically bulky centers
that mediate regioselective oxidation of alkane moieties. The
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innate reactivity of C H groups, and advances in under-
standing the factors that determine their relative reactivity
have introduced some degree of predictability in the site
selectivity of alkane oxidation reactions with non-enzymatic
reagents.[2] However, in enzymatic oxidations a combination
of directing elements can diverge site selectivity towards less-
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catalysts oxidize preferentially 28 over 38 C H bonds but most
remarkably, their chirality endows them with the ability to
determine site selectivity among distinct methylene sites in
the oxidation of complex molecules, as shown for steroids.
Chiral tetradentate ligands (L = tipsMCP and tipsPDP,
Scheme 1, giving the iron complexes 1 and 2, respectively)
in which the two pyridines are substituted with bulky tris-
(isopropyl)silyl (tips) moieties at the 5-position were targeted.
Silyl-substituted picolyl aldehyde precursors were obtained in
multigram scale in a one pot sequence of reactions (See
Supporting Information for details). The product yield and
simplicity of the procedure compare very favorably with
regard to methods required for preparing building blocks for
other bulky catalysts.[5a,7] Standard procedures served to
assemble the corresponding tetradentate ligands, which
were then used to prepare the corresponding iron complexes
of general formula (D or L)-[Fe(CF3SO3)2((R,R’ or S,S’)-L)],
L = tipsMCP or tipsPDP, (L = (S,S’)-MCP, L-tips1; L = (R,R’)-
MCP, D-tips1; L = (S,S’)- tipsPDP, L-tips2; L = (R,R’)-PDP, D-
tips2). For illustrative purposes, a schematic diagram of the
structure of the complexes is shown in Scheme 1, top.
Complexes are chiral at the metal (L or D), which in turn is
determined by the chirality of the diamine backbone (S,S’ and
R,R’, respectively). Space-filling diagrams corresponding to
(R,R’)-[Fe(CF3SO3)2(MCP)] (D-1),[8] [Fe(CF3SO3)2(PDP)]
(D-2),[9] L-tips1 and D-tips2 are also shown in Scheme 1,
bottom. Comparison of the silylated catalysts with that of
the parent 1[8] and 2,[9] indicates only minor differences
between their respective structural parameters of the first
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reactive C H bonds. Contributions towards producing selec-
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tive oxidations not governed by the innate reactivity of C H
bonds have started to appear, but are mainly restricted to
enzymes. For example, directed evolution of P450s can be
exploited to produce mutants that favor specific site selectiv-
ities.[3] Other recent approaches involve derivatization of
substrates with elements that can be precisely recognized by
enzymatic active sites, governing substrate positioning, so
[4]
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specific C H bonds are directed towards the reactive site.
Synthetic reagents and catalysts are highly desirable for
practical reasons but in the absence of the elaborate
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structures of enzymes, their ability to tune C H site selectivity
is still modest. Sterically bulky oxidants and iron catalysts
[*] Dr. D. Font, Dr. M. Canta, M. Milan, O. Cussó, Dr. X. Ribas,
Dr. M. Costas
Institut de Química Computacional I Catàlisi (IQCC)
Departament de Química, Universitat de Girona
Campus Montilivi, 17071 Girona (Catalonia, Spain)
E-mail: miquel.costas@udg.edu
Dr. R. J. M. Klein Gebbink
Organic Chemistry & Catalysis
Debye Institute for Nanomaterials Science, Utrecht University
Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)
E-mail: r.j.m.kleingebbink@uu.nl
Supporting information and the ORCID identification number(s) for
5776
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 5776 –5779