Predictable Selectivity in Remote C?H Oxidation of Steroids: Analysis of Substrate Binding Mode

Article abstract of DOI:10.1002/anie.202003078

Predictability is a key requirement to encompass late-stage C?H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp³)?H oxidation, as it requires distinguishing a specific C?H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C?H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host-guest adduct by NMR analysis. These analyses indicate which remote C?H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late-stage C(sp³)?H oxidation of amino-steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.

Full text of DOI:10.1002/anie.202003078

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Accepted Article
Title: Predictable selectivity in remote C-H Oxidation of steroids via
analysis of substrate binding mode
Authors: Miquel Costas, Giorgio Olivo, Giorgio Capocasa, Barbara
Ticconi, Osvaldo Lanzalunga, and Stefano Di Stefano
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003078
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Predictable selectivity in remote C-H Oxidation of steroids:
analysis of substrate binding mode
Giorgio Olivo,[a]‡* Giorgio Capocasa,[b]‡ Barbara Ticconi,[b] Osvaldo Lanzalunga,[b] Stefano Di Stefano[b]*
and Miquel Costas[a]*
[a]
[b]
Dr. G. Olivo, Dr. M. Costas
Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química
Universitat de Girona, Campus de Montilivi
C/ Pic de Peguera 15, 17003, Girona, Spain
E-mail: giorgio.olivo@udg.edu, miquel.costas@udg.edu
G. Capocasa, Dr. B. Ticconi, Prof. O. Lanzalunga, Prof. S. Di Stefano
Dipartimento di Chimica and Istituto CNR per i Sistemi Biologici (ISB-CNR), Sezione Meccanismi di Reazione
Sapienza Università di Roma
P.le A. Moro 5, I-00185 Rome, Italy
E-mail: stefano.distefano@uniroma1.it
‡These authors contributed equally
Supporting information for this article is given via a link at the end of the document.
Abstract: Predictability is a key requirement to encompass late-stage
C-H functionalization in synthetic routes. However, prediction (and
control) of reaction selectivity is usually challenging, especially for
complex substrate structures and elusive transformations such as
remote C(sp3)-H oxidation, as it requires to distinguish a specific C-H
bond from many others with similar reactivity. Herein, we develop a
strategy for predictable, remote C-H oxidation that entails substrate
binding to a supramolecular Mn or Fe catalyst followed by elucidation
of the conformation of the host-guest adduct via NMR analysis. These
analyses indicate which remote C-H bonds are suitably oriented for
the oxidation before carrying out the reaction, enabling prediction of
site-selectivity. We applied this strategy to late-stage C(sp3)-H
oxidation of aminosteroids at C15 (or C16) positions, with a selectivity
tunable by modification of catalyst chirality and metal.
The precise conformation adopted by the substrate in the active
site is key to the exceptional selectivity of C-H oxidizing enzymes.
Upon binding, the substrate is preorganized to expose only
targeted position(s) to the active unit, resulting in their selective
oxidation in front of far more reactive functions. On these bases,
elucidating how a substrate is bound and oriented inside the
active site (analysis of its binding mode) can enable prediction of
reaction selectivity, and even be a guide for its rational
modification. An elegant example of the above strategy begun
with the co-crystallization of PikC (a S. Venezuelae cytochrome
P450) with its natural macrolide substrate bound to the active site
(Figure 1A).[1,2] The X-ray structure showed the substrate binding
mode, clarified which C-H bonds are located close to the metal
catalyst and allowed prediction and rationalization of the
hydroxylation selectivity.[1,2] Moreover, it provided the basis to
modify the enzyme structure in order to host and predictably
hydroxylate exogenous substrates.[2,3]
Figure 1. : Prediction of selectivity via elucidation of substrate orientation bound to the catalytic moiety in enzymatic PiKC C-H hydroxylation (A),[1] stoichiometric
oxyfunctionalization of a triterpene (B)[27] and catalytic C-H oxidation of a steroid (C).
1
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Analogous rational prediction of selectivity is attractive also in
artificial catalysis, and especially in late-stage C(sp3)-H
functionalization, where a specific site has to be reliably singled
out from many others with comparable reactivities.[4–8]
Predictability is possible only if substrate orientation is well-
defined and known, and is thus limited to proximal sites via
intramolecular processes[9,10] or activated C-H bonds in
intermolecular reactions[4–8] (although the latter may be
same intensity. In particular, some C-H bonds in the α face (C9,
C7α, C5, C14) experience an upfield shift (0.5-1 ppm) far higher
than the average, while the ones of the lateral chain remain
untouched (Figure 3B; see SI for full signal assignment and
differences in chemical shift). NOESY experiments showed
proximity between these C-H bonds and the benzocrown ring, as
well as between the D-ring and the pyridine moiety (Figure 3C).
challenging to discern
a priori). Predictable remote (or
intermolecular) functionalization demands a supramolecular,
biomimetic strategy, where binding of a substrate to a receptor
controls its orientation.[11–14] This pioneering approach has
already unlocked elusive transformations, such as remote[15–19] or
enantioselective C(sp3)-H oxidations,[20,21] meta[22,23] and ortho[24]
C-H borylations or selective olefin hydroformylation.[25–27] The
selectivity in these systems can be rationalized and somehow
predicted by computational methods, design of catalyst and
substrate structure and analysis of product distribution. However,
in spite of its potential, prediction of site-selectivity via
experimental elucidation of the substrate-catalyst relative
orientation remains highly underexplored. Proof-of-concept has
been recently provided for stoichiometric monofunctionalization of
1,ω-dihaloalkanes inside a cavitand[28,29] or of a triterpene
encapsulated into a metal-organic cage (Figure 1B).[30] In the
latter case, site-selectivity can be predicted via crystal structure
and NMR analysis of the adduct. To the best of our knowledge,
application of this strategy to catalytic processes and C-H
functionalization is unprecedented.
Herein, we combined analysis of substrate binding mode and
recognition-driven oxidation to achieve predictable, remote
C(sp3)-H oxidation of amino-steroids, a class of compounds with
promising antiviral and angiogenetic activity.[31–33] We used
supramolecular catalysts (CRpdp)Mn and Fe (Figure 1C and 2),
that were previously shown to promote remote and substrate-
selective oxidation of protonated linear alkyl amines.[18,34] These
catalysts rely on crown ether receptors to bind primary ammonium
ions and expose C8 and C9 C-H bonds[18] to the oxidizing species,
Figure 2. Structures of the complexes used in this work. ORTEP Plot (50%
probability) of the crystal structure of (S,S)-(CR,TMSpdp)Mn (hydrogen atoms
omitted for clarity).
a
high-valent metal-oxo intermediate generated by H2O2
activation at a Fe or Mn center and competent for C(sp3)-H
hydroxylation
(Figure 2).[35–38] In order to investigate the
Both the shifts and the NOESY correlations are lost upon addition
of Ba(OTf)2, which displaces the ammoniums from the crown
ethers (Figure S10). All these observations suggest that 12·(R,R)-
orientation of the bound substrate via 1H-NMR analysis we
prepared complex (R,R)-(CRpdp)Zn which features the same
topology of the corresponding Fe and Mn complexes (Figure S1)
but contains a diamagnetic metal center.
(
CRpdp)Zn adopts the geometry depicted in Figure 3B, with the α-
face oriented towards the aromatic rings, the B ring on top of the
benzocrown and the D-ring above the pyridine. Such analysis
places the D-ring C-H bonds, and in particular C15, close to the
metal center, suggesting their selective hydroxylation. Oxidation
of proximal C16-H bond cannot be fully excluded, and other factors,
such as catalyst chirality or the relative reactivity of these C-H
bonds, may play a role in modulating this preference. Since these
sites are located 8 or 9 carbons away from the anchoring α -C3-
1H-NMR monitoring of the binding of aminosteroid 1 to (R,R)-
(
CRpdp)Zn suggests a 2:1 stoichiometry (Figures S2-S5), akin to
[18,39]
that previously observed for linear ammonium ions,
with
each crown ether hosting one guest to form a symmetric adduct
(Figure 3A and S2, S3). Further evidence for such 2:1
stoichiometry comes from the loss and subsequent recovery of
the fine structure of the benzocrown NMR signals along the
titration, consistent with initial 1:1 adducts with lower symmetry
(loss of signal definition) that eventually form symmetric 2:1
structures after the equivalence (Figure S4).[40] The signals of 1
experience a generalized upfield shift upon binding (~0.1 ppm)
due to partial transfer of the positive charge from the guest to the
host (Figure 3B). They remain defined up to a 2:1 stoichiometry,
after which their upfield shift and fine structure are eroded (Figure
S5), consistent with a rapid exchange between bound and
unbound 1 that occurs on NMR timescale and allows catalytic
turnover. Interestingly, not all the signals of 1 are shifted with the
+
NH3 function, such prediction would be fully in line with the C8
and C9 selectivity previously observed with alkyl chains.[18] The
same prediction can be reinforced by simple and rough docking
of the crystal structures to provide a rapid yet surprisingly
accurate way to confirm the predicted selectivity (Figure S12).
C15 oxidation is very attractive, since C15 oxygenated steroids are
known to inhibit natural sterol biosynthesis[41,42] and some of these
derivatives have found application as anti-hypertensive and anti
cholesterol drugs.[41] However, D-ring oxidation is elusive, and the
only reported methodology requires several steps, the key one
2
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10.1002/anie.202003078
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COMMUNICATION
being
Breslow’s
templated,
stoichiometric
remote
generally low (23-35%), testifying the low propensity of 1 to
undergo oxidation.
functionalization.[43–49]
At this point, we tested our predictions in the oxidation of 1 with
catalytically active Mn and Fe catalysts (Figure 4 and Table 1).
Non-directed oxidation with (pdp)Fe and Mn complexes afford a
mixture of 6 products (see SI), the main one being 1a (Figure 4
and Table 1, entries 1-4, 12-14% yield), irrespective of the catalyst
chirality or the nature of the metal center (Fe or Mn). 1a derives
from hydroxylation of the most accessible tertiary C25-H bond on
the lateral chain, which is the preferential reaction site in related
transformations with dioxiranes or radical reactants.[47] Bulkier
To our delight, supramolecular catalysts completely suppressed
oxidation at C25 and furnished ketones 1b and 1c as the main
products (entries 7-13 and S4-S6), with a selectivity for C15 and
C16 sites fully in line with our predictions. Catalyst chirality and the
nature of the metal center[50] now exert a great impact over
selectivity, likely as a result of the limited flexibility of the bound
substrate, and modulate the C15/C16 preference. Under catalytic
conditions (Table 1), (S,S)-(CRpdp)Mn delivered oxidation on C16
(with alcohol as the main product) in 13% yield and 86%
selectivity (entry 7-8), (R,R)-(CRpdp)Mn and (S,S)-(CRpdp)Fe yield
1:1 mixture of 1b:1c (entries 9-10), while (R,R)-(CRpdp)Fe inverts
this preference and mainly furnishes 1c (14%, 82% selectivity,
(
TIPSpdp) catalysts increase the selectivity for the sterically
accessible C25-H oxidation up to 60% (entries 5-6), but yields are
A) Binding of 1 to (R,R)-(CRpdp)Zn
B) Shift of the signals of 1 upon binding
Free 1
14
7α
7β
9
12·(CRpdp)Zn
7β
9
14
7α
C) Intermolecular NOESY between (R,R)-(CRpdp)Zn and bound 1
17
5
7α
14
9
Intramolecular NOESY
+
-NH3
ζ
β
γ
Figure 3. Analysis of the binding mode of 1 to (R,R)-(CRpdp)Zn (A). B) Upfield shift of the signals of 1 upon binding (full assignation, spectra and shifts shown in the
SI). C) Intermolecular NOESY correlations between 1 and (R,R)-(CRpdp)Zn (full spectrum in the SI).
3
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10.1002/anie.202003078
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COMMUNICATION
Figure 4. Oxidation of 1 with the structures of the oxidation products.[51] Selectivity calculated as product yield/total yield.
Table 1. Oxidation of 1.[a]
Entry
Catalyst
Conv/tot yield
(%)
1a
(sel)
1b
(sel)
1c
(sel)
1
2
(S,S)-(pdp)Mn
(R,R)-(pdp)Mn
(S,S)-(pdp)Fe
(R,R)-(pdp)Fe
(S,S)-(TIPSpdp)Mn
(S,S)-(TIPSpdp)Fe
(S,S)-(CRpdp)Mn
(S,S)-(CRmcp)Mn
(R,R)-(CRpdp)Mn
(S,S)-(CRpdp)Fe
(R,R)-(CRpdp)Fe
“
26/23
61/31
56/28
63/27
62/35
34/32
16/15
40/16
32/21
27/18
28/17
82/48
45/15
12
14
12
12
21 (60)
14
tr.
7
4
9
6
3
8
8
4
7
8
5
8
4
6
9
7
7[b]
8
13[c] (87)
2
tr.
10[c]
10[c]
6
3
9
tr.
11
6
10
11
12[d]
13
tr.
tr.
3
14 (82)
41[e] (85)
3
tr.
6
Figure 5. Oxidation of 2 and 3.
(S,S)-(CR,TMSpdp)Mn
<1
8[c]
ments (1:cat ratio 2:1, Table S4) show a similar change in
selectivity, albeit to a lower extent.[53]
[a] Reaction conditions: cat 1 μmol, 1 mol% (5 mol% for Fe complexes), 1 0.1
mmol (1 eq, 2.5 mM in CH3CN), H2O2 2.5 eq (added over 30 min. by syringe
pump), AcOH 22 eq (11 eq for Fe complexes). Workup described in the SI. All
reactions have been carried out in triplicate, analysed by GC (error ±5%) and
referred to an internal standard. Total yield includes unidentified, detected
products. Further optimizations are reported in the SI. [b] cat 5mol%, propanoic
acid (22 eq), -40°C (optimization in Table S6). [c] The main product of the
mixture is the alcohol in C16, which has the same retention time (see SI). [d]Cat
(5 mol%), H2O2 (2.5 eq) and AcOH (22 eq) added three times.[36] [e] 37%
isolated yield.
To test the generality of our strategy, we extended our study to
other aminosteroid substrates with the same androstane skeleton,
+
bearing an α-C3-NH3 anchoring group (Figure 5, compounds 2
and 3). We were pleased to observe that the selectivity for remote
D-ring oxidation, rationally tunable by manipulation of catalyst
chirality and nature, is retained also with these substrates. 2b is
the main product (25% yield, 57% sel.) in the oxidation of 2 with
(S,S)-(CRpdp)Mn, and derives from oxidation of C16.[54] 3c is the
main product (28% yield, 70% sel.) in the oxidation of 3 catalyzed
by (R,R)-(CRpdp)Fe, with the same C15 selectivity observed for 1.
Also in these cases, undirected oxidations furnished mixtures of
products with low yield (Tables S7-S8).
In summary, we have designed a supramolecular strategy for
predictable, late-stage C-H oxidation at remote sites. This
strategy relies on a biomimetic Mn or Fe catalyst equipped with
crown ether receptors to bind and orient ammonium substrates.
Orientation of the bound substrate inside the catalytic moiety can
be inferred by NMR analysis, enabling prediction of the oxidation
entry 11). In the latter case, yield of 1c can be improved up to 41%
without erosion of selectivity (entry 12), providing the first catalytic,
direct C15 functionalization of steroids. The enhancement in
selectivity going from linear amines to aminosteroid 1 (from 61-
81% combined C8+C9 selectivity up to 85% C15 selectivity) is likely
due to the increased rigidity of the latter. A catalyst bearing a
single receptor, (S,S)-(CR,TMSpdpMn) (Figure 2[52] and entry 13),
affords essentially the same selectivity of (S,S)-(CRpdp)Mn,
indicating that only even a single receptor can effectively control
substrate orientation. Control experiments run under
stoichiometric conditions similar to those of the binding experi-
4
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10.1002/anie.202003078
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site. The potential of this method was tested in the late-stage
oxidation of aminosteroids to disclose a selectivity which is fully in
line with predictions. Remarkably, this strategy enables elusive D-
ring oxygenation in three steroidal substrates, and represents one
of the very few methodologies for remote steroid functionalization.
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Keywords: Molecular Recognition • Supramolecular Catalysis •
Oxidation • Predictability • Hydrogen Bonds
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The origin of the difference in selectivity between Fe and Mn (CRpdp)
catalysts with the same chirality is not clear at the present stage.
X-Ray structures of 1a and 1c can be found at CCDC with numbers
1999035 and 1999034, respectively
[51]
[52]
[53]
CCDC number 1999033.
The erosion of selectivity in stoichiometric oxidations (cat:1: H2O2
1:2:2.5) might be due to the greater relevance of the initial one-
electron oxidation of the metal by H2O2 leading to homolytic
cleavage of the peroxide bond and free radical induced unselective
oxidation.
[54]
Acetylation of C16 alcohol is more efficient in 2b than in 1b likely as
a result of the lower steric hindrance of the former, making
acetylated α-C16-alcohol 2b the main product in the oxidation of 2.
6
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10.1002/anie.202003078
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Analysis of substrate binding mode to a supramolecular catalyst enables rational prediction of site-selectivity in late-stage C(sp3)-H
oxidation of aminosteroids.
Institute and/or researcher Twitter usernames: @QBIScat_UdG, @MIquelCostas, @olivo_giorgio
7
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