Modular Ligands for Dirhodium Complexes Facilitate Catalyst Customization

Article abstract of DOI:10.1002/adsc.201500050

Although stereoselectivity is often the focus of ligand optimizations in catalysis, ligand modularity can be used to control many other properties of catalysts. For example, solubility, amenability to purification, and steric shielding of sensitive catalytic intermediates are all important, but seldom appreciated, functions of ligands. We describe a brief and modular approach to various homo- and heteroleptic lantern-type rhodium(II) complexes and perform benchmarking studies with the new catalysts in common rhodium(II)-catalyzed reactions. We demonstrate the power of ligand modularity by creating catalysts customized for aqueous catalysis or for applications in chemical biology.

Full text of DOI:10.1002/adsc.201500050

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DOI: 10.1002/adsc.201500050
Modular Ligands for Dirhodium Complexes Facilitate Catalyst
Customization
Daniel G. Bachmann,a Pascal J. Schmidt,a Stefanie N. Geigle,a
Antoinette Chougnet,a Wolf-Dietrich Woggon,a and Dennis G. Gillinghama,*
a
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: (+41)-61-267-0976; phone: (+41)-61-267-1148; e-mail: dennis.gillingham@unibas.ch
Received: January 20, 2015; Revised: April 1, 2015; Published online: May 1, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500050.
Abstract: Although stereoselectivity is often the
focus of ligand optimizations in catalysis, ligand
modularity can be used to control many other prop-
erties of catalysts. For example, solubility, amenabil-
ity to purification, and steric shielding of sensitive
catalytic intermediates are all important, but
seldom appreciated, functions of ligands. We de-
scribe a brief and modular approach to various
homo- and heteroleptic lantern-type rhodium(II)
complexes and perform benchmarking studies with
the new catalysts in common rhodium(II)-catalyzed
reactions. We demonstrate the power of ligand
modularity by creating catalysts customized for
aqueous catalysis or for applications in chemical
biology.
rhodium carboxylates was unpredictable. Inspired by
previous work from Bonar-Law in creating dirhodi-
um-based metal-organic architectures,[6] we examined
dicarboxylate ligands derived from 1,3-benzenediols
(see Scheme 1). This construct maintains the essential
À
Keywords: carboxylate ligands; C H activation; flu-
orescent probes; rhodium; water chemistry
We became interested in tethered bis-dicarboxylate
rhodium(II) complexes in the context of our recent
studies on metal carbenoid-based nucleic acid alkyla-
tion.[1] To further develop this technology we needed
a set of rhodium(II) complexes with stable and modu-
lar ligands that still performed well in typical rhodi-
um(II)-catalyzed reactions, particularly in water. Most
rhodium complexes are highly insoluble in water and
not readily amenable to modification.[2] We settled on
the tethered bis-carboxylate structure because we
thought its increased stability,[3] as well as its potential
to intercalate DNA,[4] could deliver performance im-
provements in comparison with Rh2(OAc)4. The
ligand introduced by Du Bois and co-workers[5] was
chosen as a starting scaffold but two major problems
prompted us to change tack: first, creating a library of
ligands proved synthetically cumbersome and second,
Scheme 1. Modular approach towards mono- and bis-substi-
tuted rhodium(II) complexes. See the Supporting Informa-
controlling mono- versus double-substitution in the tion, pages S2–S6 and S14–S19 for detailed protocols.
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Daniel G. Bachmann et al.
structural features of the espino ligand, but has the
advantage of modularity since numerous 1,3-benzene-
diol derivatives are commercially available. Moreover,
since Bonar-Law used these dicarboxylates to create
well-defined supramolecular objects the coordination
of each ligand needed to be precisely controlled, pro-
viding valuable information for our own studies.
The syntheses of the various homo- and heterolep-
tic rhodium(II) complexes we use are shown in
Scheme 1. Using the conditions developed by Bonar-
Law the monobiscarboxylate complex 1 is obtained in
60% yield after three hours in N,N-dimethylaniline.
However, for ligands with electron-withdrawing
groups at C-5 (10b–d) milder conditions were necessa-
ry: Rh2(OAc)2(TFA)2 in DCE at 60–708C with small
amounts of EtOAc as co-solvent led to acceptable
yields (31% for 2, 27% for 3, and 35% for 4). The
yields are low to moderate, but this is a typical fea-
Scheme 2. Compounds 8a–e are commercially available. i)
Ethyl-2-bromoisobutyrate, K2CO3, Cs2CO3, DMF, 808C,
12 h, 47–82% ii) LiOH·H2O, MeOH/H2O 2:1, 608C, 3 h, 79–
99% or THF/H2O 1:1, 608C, 20 h, 77–84% for 10b and 10e,
ture in the syntheses of rhodium(II) complexes; in respectively.
many cases substantial amounts of starting material
can be recovered and recycled. Unfortunately, at-
tempts to perform a second substitution to access the basic additives since our primary goals are for aque-
heteroleptic complexes using Bonar-Lawꢁs conditions ous catalysis. Although methanol and acetic acid both
led to low yields and mixtures of products. We there- attenuate the reactivity of 7, complete conversions
fore turned to Taberꢁs original procedure involving were still achieved in reasonable reaction times (en-
a portion-wise addition of the ligand.[7] Through the tries 6 and 7). The powerful Lewis base trimethyl-
combination of these protocols we have been able to amine, however, inhibited the reaction (entry 8). The
synthesize new rhodium(II) complexes containing superiority of catalyst 7 in nitrene insertion may be
a variety of functional groups (Scheme 1).
a result of the more electron-deficient character of
Shown in Scheme 2 is the full collection of dicar- the ligand, which would make the catalyst difficult to
boxylate ligands 10a–e we have synthesized thus far oxidize. Du Bois has shown that oxidative damage to
starting from commercial C-5 substituted 1,3-benzene- catalysts is the primary mode of catalyst deactivation
diols 8a–e. Diesters 9a–e were synthesized by double in nitrene insertion.[9]
O-alkylation with ethyl-2-bromoisobutyrate and a mix-
ture of K2CO3 and Cs2CO3 in yields between 77 and
99%. Final hydrolysis was accomplished with LiOH
Table 1. Benchmarking of catalysts in a nitrene insertion.
to afford the desired dicarboxylate ligands 10a–e in
excellent yield, bearing a variety of functional groups
poised for further modification such as amide bond
formation (2 or 6), Pd-catalyzed cross coupling (3) or
condensation reactions (4, 6, 7).
To probe the impact of the ligand on catalysis, di-
Entry Catalyst
Additive Temp. [8C] Time [min][a]
rhodium(II) catalysts 5, 6, and 7 were tested in a typi-
cal intramolecular nitrene insertion reaction of sulfa-
mate ester 11 (Table 1). Catalyst 5 leads to reaction at
a similar rate as the Du Bois catalyst (see entries 1
and 2); only at 0.1 mol% loading does the Du Bois
system prove superior,[5] still delivering complete con-
version while 5 stalls at 35% (data not shown). For
operational simplicity and to allow comparisons at
early time points, reactions with catalysts 5–7 were
also run at 258C. At 258C 5 reached complete conver-
sion in 2 h (entry 3), while 6 required 4 h (entry 4).
Catalyst 7 performed best of all, giving complete con-
versions at 60 min (entry 5). Catalyst 7 was further
tested with some potential interfering additives to de-
termine its robustness.[8] We chose protic or Lewis
1
2
3
4
5
6
7
8
5
–
40
40
25
25
25
25
25
25
45[b]
45
Rh2(esp)2
–
–
–
–
5
6
7
7
7
7
120[c]
240[c]
60[c]
MeOH
AcOH
NEt3
120[c]
240[c]
n.r.[c]
[a]
Time to reach ꢀ95% conversion; for a complete tabula-
tion of time-point measurements see the Supporting In-
formation, pages S7 and S8.
98% isolated yield after chromatography.
Determined by H NMR monitoring of the reactions in
[b]
[c]
1
CD2Cl2.
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Modular Ligands for Dirhodium Complexes
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Table 2. Benchmarking of catalysts in C H insertion reactions.
Entry
1
Catalyst
Additive
–
Product
Ratio of 14:15[a]
Time [min][b]
270[b]
Rh2(OAc)4
19:1
2
3
4
5
6
7
5
6
7
5
5
5
–
–
–
14a
14a
14a
14a
14a
14a
>49:1
>49:1
>49:1
>49:1
>49:1
–
20[c]
120[b]
60[b]
30[b]
150[b]
n.r.
MeOH
AcOH
NEt3
8
Rh2(OAc)4
–
4:1
60[b]
9
10
11
5
6
7
–
–
–
14b
14b
14b
9:1
8:1
9:1
10[d]
60[b]
10[b]
[a]
1
Ratio measured by H NMR analysis of crude reaction mixtures.
[b]
1
Time to reach ꢀ95% conversion according to H NMR monitoring of the reactions in CD2Cl2; for a complete tabulation
of intermediate time-points see the Supporting Information, pages S8 and S9.
76% isolated yield after silica gel chromatography.
[c]
[d]
80% isolated yield after silica gel chromatography.
In a second set of benchmarking experiments the that more efficient water-soluble systems be devel-
new set of catalysts was tested in C H insertion reac- oped.[14] The heteroleptic dirhodium(II) complex 6
tions to make b- or g-lactams (see 14a and 14b in bearing a ketone functionalized ligand (10c) and a car-
Table 2).[10] Comparison of entries 1–4 indicates that 5 boxylate functionalized ligand (10b) was found to be
À
À
performed best for b-lactam formation by C H inser- completely water soluble above the pKa of the car-
tion. This trend was also seen in the formation of a g-
lactam (cf. entries 8–11), although with this substrate
7 also worked well. The reaction times of 20 and
10 min for the reactions in entries 2 and 9, respective-
ly, are rapid for this reaction class. As a point of com-
parison the conditions in entry 8 are the previous best
results for this transformation; here higher loading
(3 mol%), higher temperature (708C in toluene), and
a longer reaction time were needed (60 min).
The modularity of the catalyst system opens new
vistas in controlling rhodium-carbene chemistry. For
example, although aqueous rhodium(II) catalysis is
well established, moderate water solubility limits the
scope of most catalysts. Catalysis in water has there-
fore been limited to soluble variants,[11] systems that
contain cosolvents or detergents,[12] or for catalysts
bearing peptide ligands.[13] The emerging importance
À
of rhodium catalysis in chemical biology demands Scheme 3. Aqueous intramolecular C H insertion with 6.
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Table 3. Conjugation of complex 4 with a variety of useful
small molecules.
a good candidate for future development in aqueous
catalysis (an additional example of the potential of 6
in aqueous catalysis is provided in the Supporting In-
formation, page S11).
We designed the ligand to combine structural flexi-
bility without perturbing rhodiumꢁs primary ligand
sphere, thus facilitating sophisticated modifications of
the rhodium complexes (Table 3). Aldehyde-bearing
complex 4 was condensed with a variety of hydrazide
derivatives of small molecules that are important in
chemical biology to create dirhodium(II) complexes
with tailored properties. In particular, conjugates with
biotin, folic acid, maleimide, and Hoechst dye were
all prepared without event. The maleimide and biotin
complexes could be used in metalloenzyme develop-
ment;[15] while biotin could also be used for directing
the catalyst to histones,[16] potentially offering a way
to modify them.
Many dirhodium(II) complexes have been shown to
have DNA binding properties comparable with cispla-
tin;[4] and the folate receptor is known to be overex-
pressed on cancer cells due to increased nutrient re-
quirements.[17] By combining these properties, folate-
rhodium conjugates might therefore provide cancer-
selective cytotoxins. The g-acid of folate has previous-
ly been shown to be amenable to modification with-
out interfering with receptor binding[18] and we were
pleased to find that a hydrazide installed at this posi-
tion led to smooth and selective condensation with
complex 4 (51% yield, entry 2, Table 3).
It has recently been shown that fluorescently la-
belled dirhodium(II) complexes are taken up by cells
and accumulate in lysosomes and mitochondria.[19] No
dirhodium(II) could be detected in the nucleus, an un-
fortunate reality given that dirhodium(II)ꢁs antiproli-
ferative activity is likely a consequence of its interac-
tion with DNA.[20] We envisioned reprogramming the
cellular fate of rhodium by attaching a traceable mol-
ecule known to target DNA and we selected the
common nuclear staining dye Hoechst 33258 for
proof-of-concept (entry 4, Table 3). Indeed we were
very pleased to find that after 30 min of incubation
with a 100 mM solution, fluorescence microscopy re-
vealed the accumulation of 19 in cell nuclei of live
U87 brain tumor cells (Figure 1).
[a]
Please see the Supporting Information for detailed reac-
tion conditions.
Refers to isolated yield after preparative reverse-phase
HPLC.
[b]
The strapped bidentate ligands were an important
development for dirhodium(II) chemistry;[3,5,7] here
boxylate. This simple feature of complex 6 demon- we add the innovation of a modular handle to this
strates the power of modularity in controlling the class of catalysts. The modularity facilitates rapid be-
bulk properties of a catalyst. As a proof-of-concept spoke customization, as demonstrated by the reac-
for the potential of 6 in aqueous catalysis, we tested tions in Scheme 3 and the new catalysts in Table 3.
the b-lactam formation under aqueous conditions We are currently exploring the potential biological
À
(Scheme 3). In the intramolecular C H insertion, cat- applications of the catalysts described in Table 3. But
alyst 6 required lower loading (0.5% vs. 1–2%) and the ability to redirect dirhodium catalysts to the cell
less time (10 min vs. 0.5–24 h) than the previous best nucleus through simple Hoechst conjugation is al-
catalyst.[11] Dirhodium(II) catalysts with high TOF in ready indicative of the enabling power of modular li-
water are rare and therefore catalyst 6 represents gands. Now that we can localize rhodium to DNA the
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Modular Ligands for Dirhodium Complexes
À
Representative C H Insertion (14a) Procedure
To a solution of diazo compound 13a (20.8 mg, 68.3 mmol) in
CH2Cl2 (405.4 mL), a stock solution of 5 (278.8 mL, 4.91 mM
in CH2Cl2, 2 mol%) was added and the reaction mixture was
stirred at room temperature. Analysis of the mixture via
1H NMR spectroscopy after 10 min showed full conversion
of the starting material to the single cis b-lactam 14a. The
solvent was removed under reduced pressure and the resi-
due was purified by flash chromatography (10 g C18 reverse
phase silica, MeCN/0.1% TFA in H2O). The corresponding
fractions were combined, the solvent removed under re-
duced pressure to obtain b-lactams 14a and 15a as a white
solid; yield: 14.3 mg, (51.7 mmol, 76%). These could be fur-
ther separated by preparative reverse phase HPLC.
Characterization for 14a: 1H NMR (400 MHz, CDCl3):
d=7.47–7.31 (m, 5H), 4.90 (d, J=6.3 Hz, 1H), 4.21 (d, J=
6.2 Hz, 1H), 3.76 (q, J=7.1 Hz, 2H), 1.31 (s, 9H), 0.84 (t,
J=7.1 Hz, 3H, 14a); 13C NMR (101 MHz, CD2Cl2): d=
166.6, 163.3, 137.6, 129.1, 128.8, 127.8, 61.3, 59.6, 57.0, 55.3
28.3.
For complete experimental details please see the Support-
ing Information.
Figure 1. Selective Rh(II) complex uptake into cell nuclei of
live U87 cells: (a) cells under white light, (b) cell nuclei
stained by complex 19b, (c) overlay. See the Supporting In-
formation, page S24 for a full description of the staining
protocol and control experiments.
Acknowledgements
We gratefully acknowledge Mr. Martin Nussbaumer for assis-
tance with cell culture and live-cell imaging, Dr. Daniel
Häussinger for measuring and interpreting high-field 2D
NMR spectra, and Dr. Heinz Nadig for recording high reso-
lution ESI mass spectra.
next step is to understand whether this specificity im-
pacts rhodiumꢁs anti-cancer properties.
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