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A Functional Synthetic Model for the LanthanideDependent Quinoid Alcohol Dehydrogenase Active Site Alex McSkimming, Thibault Cheisson, Patrick J. Carroll, and Eric J. Schelter J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12318 • Publication Date (Web): 29 Dec 2017 Downloaded from http://pubs.acs.org on December 31, 2017
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Journal of the American Chemical Society
A Functional Synthetic Model for the LanthanideLanthanide-Dependent Quinoid Alcohol Dehydrogenase Active Site Alex McSkimming, Thibault Cheisson, Patrick J. Carroll and Eric J. Schelter* P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 S 34th St., Philadelphia, Pennsylvania 19104, United States Supporting Information Placeholder
ABSTRACT: The oxidation of methanol by dehydrogenase enzymes is an essential part of the bacterial methane metabolism cycle. The recent discovery of a lanthanide (Ln) cation in the active site of the XoxF dehydrogenase represents the only example of a rare-earth element in a physiological role. Herein, we report the first synthetic, functional model of Ln-dependent dehydrogenase and its stoichiometric and catalytic dehydrogenation of a benzyl alcohol. DFT calculations implicate a hydride transfer mechanism for these reactions.
Methanol dehydrogenase (MDH) enzymes play an important role in the global carbon cycle, namely through the bacterial methane metabolism pathway, by catalyzing the oxidation of methanol.1 The active site of MDH enzymes contains a pyrroloquinoline quinone (PQQ) cofactor bound to a Ca2+ ion, which accepts formally two electrons and two protons from an alcohol substrate to afford the corresponding aldehyde and catechol (H2PQQ, Scheme 1a).2 It was recently demonstrated that early lanthanide ions: La–Nd accelerated alcohol metabolism, and in one case were essential for cell growth of certain methanotrophic bacteria.3 An Xray structure of the XoxF-type MDH enzyme from Methylacidiphilum fumariolicum SoIV revealed a Ln3+ cation bound by the PQQ cofactor (Scheme 1b),3d the first example of a lanthanide (or rare-earth) element in a physiological role. Lanthanides evidently confer a competitive advantage over Ca2+, with XoxF-MDH displaying a 10-fold higher methanol affinity constant than Ca-MDHs.3d, 4 Furthermore, Ca-MDHs exhibit highest activities at pH ~9 whereas XoxF-MDH functions optimally at neutral pH and does not require ammonium ions for activation.3d, 4 Also, in contrast to Ca-MDHs, XoxF-MDH catalyzes the oxidation of formaldehyde to formate.3d, 4
The study of well-defined synthetic model compounds is essential for understanding the workings of enzyme active sites, which in turn may inspire novel catalysts.5 At present, however, reports of synthetic metal complexes of PQQ or analogues are scarce6 and only a handful of such compounds have been structurally characterized.7 Furthermore, their reactivity has typically not been reported, with a few exceptions.6a-e To date, there are no reports of a synthetic lanthanide complex of PQQ or its surrogates.
Scheme 1. a) Reaction between cofactor PQQ and alcohol substrates to give the catechol H2PQQ and b) the active site of Ln-dependent MDH from XRD data with bound EtOH ligand.
There are a number of challenges associated with synthesizing analogues of MDH active sites. First, PQQ derivatives may coordinate to a metal ion in non-natural binding modes, such as through the two quinone oxygen atoms7c, 7d or the distal pyrrole and carboxylic acid groups.7a Multiple quinoline quinones (QQs) may also bind a single metal center or otherwise exhibit complicated speciation.8 To overcome these potential problems we designed the ligand LQQ (Scheme 2), which incorporated a directing and sterically bulky chelator. An important goal of this design was the structural characterization of metal complexes of LQQ and the product(s) of their reaction with substrates. We report herein the synthesis of LQQ, its corresponding lanthanum complex [La(LQQ)(NO3)3] and its stoichiometric and catalytic dehydrogenation of a benzyl alcohol substrate.
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Proligand LQQ was synthesized in 11 steps from commercially available starting materials (Scheme 2). Metallation of LQQ proceeded smoothly using [La(NO3)3(THF)4] to obtain [La(LQQ)(NO3)3] in 90% yield as a moisturesensitive orange solid (Scheme 2). [La(LQQ)(NO3)3] is a TBSCl, imidazole
SeO2
6M HCl-PhMe, 100 °C 24%
DMF 91%
dioxane, 100 °C 40%
N 1
OH
TBS =
THF-MeOH 91%
N O
H
OTBS
3
N
SiMe 2tBu
2
N O
4
H
OH
N O
5
N
O
N 1-N(CH2CONCy2)22-NH2-C 6H4 (8)
DCM-MeCN 80%
H
OTBS
IBX
HCl
H
rare example of a metal complex of a quinoline quinone7 and is the first such lanthanide complex. The Xray crystal structure of [La(LQQ)(NO3)3] revealed La(1) to bound to the pyridyl nitrogen atom N(1) and a single quinone oxygen O(1) of the
crotonaldehyde
NH2 OH
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O
DCM 94%
O O
N O
NCy2 NCy2
O
LQQ
[La(THF)4(NO3)3] MeCN, 1h 90%
N(4)
N(4)
4MePhCHO
+ 2 DBUHNO3
O(3) N(3)
La(1)
O(1)
N(2)
O(4) N(1) N(5)
O(2)
4MeBnOH
+
2 DBU 67%
N(3)
N(2)
N(1)
O(3)
or 2 [Cp2Co] 91%
La(1)
C(2)
O(4) O(1) O(2)
N(5)
[La(LQQ2–)(NO3)]2
C(3)
[La(LQQ)(NO3)3] 2–
Scheme 2. The synthesis of LQQ, [La(LQQ)(NO3)3] and [La(LQQ )(NO3)]2 with 50% thermal ellipsoid plots. H-atoms have been – omitted, cyclohexyl groups have been truncated and NO3 ligands are displayed in wireframe for clarity.
QQ moiety (Scheme 2 and S1), analogous to the coordination environment of the XoxF enzyme active site (Scheme 1).3d, 4 Cyclic voltammograms (CVs) performed on LQQ revealed a largely reversible process at E½ = – 0.95 V vs. Fc/Fc+ for the quinone-semiquinone (QQ/QQ•–) couple (Figure 1, dotted line) followed by an irreversible process at Ec = –1.76 V assigned as formation of the catecholate dianion (Q2–).9 For [La(LQQ)(NO3)3], the QQ/QQ•– couple was observed at +0.61 V higher potential (E½ = –0.34 V; ia/ic ≈ 0.8 at 100 mV s–1, Figure 1, solid line.) Two poorly reversible, overlapping reduction events were revealed on further cathodic sweeps at –0.68 V and –0.77 V, which showed return waves at –0.66 V and –0.52 V. Overall, the CV of [La(LQQ)(NO3)3] was complicated by loss of NO3– ligand(s) and dimerization equilibria (vide infra); the waves were not definitively assigned (Figures S31-36). Importantly, the anodic shift of the QQ/QQ•– couple for [La(LQQ)(NO3)3] compared to LQQ reflected stabilization of the QQ•– anion by the bound metal ion.9a, 10
We expected that the relative ease of reduction of the QQ moiety upon coordination to La would be reflected in the ability of [La(LQQ)(NO3)3] to oxidize an alcohol substrate. A CD2Cl2 solution of free ligand LQQ with a 4-fold 4Me 11 excess of BnOH gave no detectable aldehyde product 1 by H NMR spectroscopy, upon mixing, even after 3 days. 4Me In contrast, [La(LQQ)(NO3)3] reacted with 2.5 equiv BnOH in CD2Cl2 to produce
0
-0.3
-0.6
-0.9 -1.2 E (V vs. Fc/Fc+)
-1.5
-1.8
-2.1
Figure 1. Cyclic voltammograms of [La(LQQ)(NO3)3] (solid
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Journal of the American Chemical Society line) and LQQ (dashed line) in CH2Cl2 with 0.1 M n F –1 [ Pr4N][BAr 4] at a scan rate of 100 mV s . 4Me
PhCHO in 30% yield in 24 h (67% yield in 3 days, Table S3). As observed by Itoh and Fukuzumi in a related system,6b, 6c addition of 2.2 equiv DBU accelerated the dehydrogenation of 4MeBnOH by [La(LQQ)(NO3)3] with 4Me PhCHO produced in 63±3% yield (1H NMR spectroscopy) in
