Victor W. Day

A Series of Peroxomanganese(III) Complexes Supported by Tetradentate Aminopyridyl Ligands: Detailed Spectroscopic and Computational Studies

A set of four [Mn(II)(L(7)py(2)(R))](2+) complexes, supported by the tetradentate 1,4-bis(2-pyridylmethyl)-1,4-diazepane ligand and derivatives with pyridine substituents in the 5 (R = Br) and 6 positions (R = Me and MeO), are reported. X-ray crystal structures of these complexes all show the L(7)py(2)(R) ligands bound to give a trans complex. Treatment of these Mn(II) precursors with either H(2)O(2)/Et(3)N or KO(2) in MeCN at -40 degrees C results in the formation of peroxomanganese complexes [Mn(III)(O(2))(L(7)py(2)(R))](+) differing only in the identity of the pyridine ring substituent. The electronic structures of two of these complexes, [Mn(III)(O(2))(L(7)py(2)(H))](+) and [Mn(III)(O(2))(L(7)py(2)(Me))](+), were examined in detail using electronic absorption, low-temperature magnetic circular dichroism (MCD) and variable-temperature variable-field (VTVH) MCD spectroscopies to determine ground-state zero-field splitting (ZFS) parameters and electronic transition energies, intensities, and polarizations. DFT and TD-DFT computations were used to validate the structures of [Mn(III)(O(2))(L(7)py(2)(H))](+) and [Mn(III)(O(2))(L(7)py(2)(Me))](+), further corroborating their assignment as peroxomanganese(III) species. While these complexes exhibit similar ZFS parameters, their low-temperature MCD spectra reveal significant shifts in electronic transition energies that are correlated to differences in Mn-O(2) interactions among these complexes. Taken together, these results indicate that, while the [Mn(III)(O(2))(L(7)py(2)(H))](+) complex exhibits symmetric Mn-O(peroxo) bond lengths, consistent with a side-on bound peroxo ligand, the peroxo ligand of the [Mn(III)(O(2))(L(7)py(2)(Me))](+) complex is bound in a more end-on fashion, with asymmetric Mn-O(peroxo) distances. This difference in binding mode is rationalized in terms of the greater electron-donating abilities of the methyl-appended pyridines and suggests a simple way to modulate Mn(III)-O(2) bonding through ligand perturbations.

Highly Stereoselective Ring Expansion Reactions Mediated by Attractive Cation–n Interactions

Most stereoselective reactions are ruled by steric effects. In particular, kinetically controlled asymmetric transformations utilizing chiral reagent, auxiliaries, or catalysts succeed due to energy differences in transition states that most often arise by the minimization of repulsive, non-bonded interactions. Stereoelectronic considerations, which arise when the alignment of particular orbitals are necessary for a successful reaction, can also play a role.[1] An iconic stereoelectronic effect in organic chemistry is the anomeric effect.[2] Reactions controlled by the anomeric effect, such as glycosidations, largely depend on the relative orientation of the non-bonding or n electrons of a nearby alkoxy group. In recent years, alkoxy group control of stereoselective reactions via electrostatic interactions has received renewed scrutiny, led by the Woerpel group.[3] In this communication, we report an alternative and highly effective approach to stereocontrol through the maximization of attractive non-bonded interactions between an alkoxy or alkylthio group and a positively charged leaving group. The Lewis acid-promoted reaction of a symmetrically substituted cyclic ketone with a chiral hydroxyalkyl azide provides a stereoselective route to lactams (Scheme 1).[4] In this reaction, initial formation of a spirocyclic intermediate sets up the selective migration of one of the alkyl groups originally adjacent to the ketone carbonyl. Migration of a C–C bond antiperiplanar to the N2+ leaving group (only possible when the latter is in an axial position as shown) affords an iminium ether that is converted into lactam by workup with aqueous base. For 1- or 3-substituted azidopropanols (not shown), 10:1 selectivities are obtained, corresponding to preferential reaction through the most stable chairlike heterocyclic ring (A or B) resulting from equatorial addition of azide relative to the tert-butyl group. Intermediates A and B can interconvert through conformational reorganization or by reversion to the initially formed oxonium ion followed by reclosure. In this scenario, selectivity is attained by stabilization of A over B due to traditional minimization of 1,3-diaxial interactions by placement of the R1 or R3 into equatorial positions in the former. Scheme 1 Origin of selectivity in asymmetric Schmidt reactions. 2-Substituted 1,3-azidopropanols present a special case that is unusually susceptible to stereoelectronic control due to three factors: (1) the methylene groups near the spiro linkage are locally isoelectronic, so the reaction cannot be controlled by “migratory aptitude”, (2) the presence of either an oxygen ether or an N–N2+ group in a 1,3 relationship to the R group means that 1,3-diaxial steric interactions will be minimized, and (3) the 1,3 relationship between axial R and N2+ groups provides a strong opportunity for attractive electrostatic interactions to occur between these groups in intermediate B. In previous work, it was demonstrated that unusually low selectivities obtained in this system when R = aryl could be ascribed to preferential stabilization of intermediate B by attractive, non-bonded cation–π interactions between the aromatic group and the N2+ leaving group (Table 1).[5] Although such interactions are commonly proposed in biological systems,[6] they are rarely invoked as stereocontrolling features of small-molecule stereoselective reactions.[7] Table 1 Selectivity of reactions of substituted 1,3-hydroxyalkyl azides. A computational study[8] and analogy to the well-known ability of ether groups to bind cations suggested that intermediates like B should be even more enhanced in compounds where R = alkoxy. As shown in Figure 1, isomer B containing a diaxial relationship between methoxy group and leaving group was calculated to be ca. 3.8 kcal/mol more stable than the equatorial isomer for which no interaction between methoxy and N2+ groups are possible. To test this, 1-azido-2-methoxypropanol 3 was prepared and reacted with 4-tert-butylcyclohexanone using BF3•OEt2 as Lewis acid promoter. A striking 24:1 selectivity in favor of the isomer emanating from an axially disposed methoxy group was obtained in high yield (Table 1, entry 3). Figure 1 Calculations for proposed intermediates A and B performed at the MP2/6-311+G**//MP2/6-31G* level of theory.[8] This result suggests that the methoxy cation–n interaction is considerably stronger than the previously reported cation–π effect, due to the fact that the highest 3:2 ratio observed to date was 57:43 for the electron-rich 3,4,5-trimethoxyphenyl group (not shown).[5] The fact that the small MeO group (A value = 0.6[9]) pays a relatively small steric penalty in the axial orientation is a likely contributor to the high selectivity of this reaction as well. However, the much higher selectivity and opposite direction of stereocontrol obtained for the smaller MeO group as compared to alkyl or aryl substituents (Table 1, entries 1 and 2) is strong evidence for the proposed role of electrostatics in this reaction. We proposed that a similar effect might be observed with a more polarizable heteroatom.[3m] Accordingly, 1d where R = SMe, was prepared and submitted to the asymmetric Schmidt reaction protocol. Remarkably, a >98:2 dr was obtained for this system, favoring 3d. The selectivities obtained with both methoxy and methylthio, which depend mainly on electrostatics and feature axially disposed substituents, are higher than any previously reported, sterically-based, example of this ring-expansion reaction.[4,5] Although the first example of an asymmetric azido-Schmidt reaction reported utilized an azidoethanol reagent, that series has typically provided lower selectivities relative to the three-carbon-containing reagents like 1 and has more recently been shown to occur via predominant steric control, even when a phenyl group is in a position to participate in a cation–π interaction.[5] In sharp contrast to these previous results, the reaction using reagent 4 afforded a high 97:3 ratio of 5 over 6, in which the major product goes through an intermediate in which a syn relationship between the methoxy group and the leaving N2+ substituent is possible (Scheme 2). A computational investigation showed that the cation–n intermediate C is stabilized by 3.9 kcal/mol. Notably, the O–N2+ distances, energy differences, and ratios are similar between systems B and C. Previous work in the reactions of substituted 1,2-azidoethanols has shown the predominant steric feature affecting stereochemistry to exist between the migrating carbon and substituents on the five-membered heterocyclic ring.[4,5b] In cases where the alkyl group is adjacent to oxygen (i.e., across the ring from the migrating methylene group and the N2+ leaving group), steric effects do not play an important role in determining reaction stereochemistry, as clearly demonstrated by the non-selective cyclohexyl case shown in Scheme 2b. Scheme 2 (a) Electrostatically controlled reaction of 1-azidoethanol derivative 4 with 4-tert-butylcyclohexanone (including calculated energies of proposed, minimized intermediates C and D[8]) and (b) a cyclohexyl-containing control.[5b] The model systems used ... The opposite situation occurs when the methoxymethyl group is placed adjacent to the azido group. In this case, there is no substantial difference in distance between the methoxy group and either isomeric intermediate, so electrostatic considerations cannot play a role and the preference for syn E over anti F drops to 0.6 kcal/mol computationally. Instead, the usual steric course of the reaction leads to the same product observed for the analogous example to 14 (Scheme 3). Scheme 3 Sterically controlled reactions of (a) 10 and (b) a previously reported cyclohexanyl example.[5] The model systems used for the calculations are given in the Supporting Information (Figure S1). The most interesting elements of this approach are that: (1) intermediates are subject to non-bonded, attractive interactions that are able to strongly favor one stereoisomeric form over the other, (2) these intermediates lead to the corresponding products in a process entirely controlled by stereoelectronic considerations, and (3) the overall stereoselectivity ultimately depends on the control of leaving group stereoslectivity at an epimerizable nitrogen atom. The high yields of these reactions combined with the utility of the lactam products suggests a high level of utility of the present reaction. Of perhaps greater long-term interest will be the attempted utilization of cation nonbonding electron stabilization in other stereoselective processes.[10]

Probing Chemical Space with Alkaloid-Inspired Libraries

Screening of small molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries, due to their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin, and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

Cyclophane Capsule Motifs with Side Pockets

Neutral and charged multitopic cyclophane-capped anion hosts connected by three or four diamide/monoamine chains and a decomposition product with two chains have been synthesized and characterized. The chains in the two former hosts fold together to form one or two binding pockets, respectively, and FHF(-) and several phosphate complexes have been obtained with the anions nestled in these pockets. The decomposition product also shows propensity for binding dicarboxylates, as evidenced by an isophthalate crystal structure.

Cytotoxic withanolide constituents of Physalis longifolia.

Fourteen new withanolides, 1-14, named withalongolides A-N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15-22). The structures of compounds 1-14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC₅₀ values in the range between 0.067 and 9.3 μM.

Structure Based Design, Synthesis, Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Novel Cyclophilin D Inhibitors

Cyclophilin D (CypD) is a peptidyl prolyl isomerase F that resides in the mitochondrial matrix and associates with the inner mitochondrial membrane during the mitochondrial membrane permeability transition. CypD plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death and has been linked to Alzheimer’s disease (AD). Because CypD interacts with amyloid beta (Aβ) to exacerbate mitochondrial and neuronal stress, it is a potential target for drugs to treat AD. Since appropriately designed small organic molecules might bind to CypD and block its interaction with Aβ, 20 trial compounds were designed using known procedures that started with fundamental pyrimidine and sulfonamide scaffolds know to have useful therapeutic effects. Two-dimensional (2D) quantitative structure–activity relationship (QSAR) methods were applied to 40 compounds with known IC50 values. These formed a training set and were followed by a trial set of 20 designed compounds. A correlation analysis was carried out comparing the statistics of the measured IC50 with predicted values for both sets. Selectivity-determining descriptors were interpreted graphically in terms of principle component analyses. These descriptors can be very useful for predicting activity enhancement for lead compounds. A 3D pharmacophore model was also created. Molecular dynamics simulations were carried out for the 20 trial compounds with known IC50 values, and molecular descriptors were determined by 2D QSAR studies using the Lipinski rule-of-five. Fifteen of the 20 molecules satisfied all 5 Lipinski rules, and the remaining 5 satisfied 4 of the 5 Lipinski criteria and nearly satisfied the fifth. Our previous use of 2D QSAR, 3D pharmacophore models, and molecular docking experiments to successfully predict activity indicates that this can be a very powerful technique for screening large numbers of new compounds as active drug candidates. These studies will hopefully provide a basis for efficiently designing and screening large numbers of more potent and selective inhibitors for CypD treatment of AD.

Fluoride: Solution- and Solid-State Structural Binding Probe

Solid-state and solution studies were performed to determine if F(-) is encapsulated by anion hosts in both media. X-ray crystal structure determinations were compared with both (1)H and (19)F solution NMR data. Three hosts were studied: (1) two polyamide hosts, one with isophthaloyl spacers and the other with pyridine spacers, and (2) a polythioamide host with pyridine spacers. Binding studies showed that the pyridine-containing amide cryptand shows the highest affinity (K(a) > 10(5) in DMSO-d(6)), with the other hosts at least a factor of 10 lower. All of the cryptands appear to encapsulate F(-) in solution, where a deuterium-exchange reaction with DMSO-d(6) can be monitored by (19)F NMR. Four crystal structures are reported and compared: two for the pyridine-containing free base hosts and two for encapsulated F(-) complexes of the two amide-based cryptands.

The Influence of Amine Functionalities on Anion Binding in Polyamide-Containing Macrocycles

Mixed amide/amine macrocyclic anion hosts of varying sizes and with different amine substituents have been synthesized and characterized. Host 2, containing a 28-membered ring and secondary amines, has shown selective binding for HSO(4)(-) over other oxo anions and halides in DMSO-d(6) using NMR titrations. Crystal structures of SO(4)(2-), HPO(4)(2-), H(2)PO(4)(-), and H(2)P(2)O(7)(2-) with the 28-membered ring hosts indicate different macrocyclic conformations depending on the N-substituent. Anion affinities appear to be correlated with macrocycle conformation.

Encapsulation and selective recognition of sulfate anion in an azamacrocycle in water

Structural characterization of a sulfate complex with an azamacrocycle suggests that one sulfate is encapsulated in the macrocyclic cavity with eight hydrogen bonds; a significant selectivity of the host was observed for sulfate over halides, nitrate and perchlorate as evaluated by (1)H NMR studies in water.

Synthesis, Structure, and Physical Properties for a Series of Monomeric Iron(III) Hydroxo Complexes with Varying Hydrogen-Bond Networks

Mononuclear iron(III) complexes with terminal hydroxo ligands are proposed to be important species in several metalloproteins, but they have been difficult to isolate in synthetic systems. Using a series of amidate/ureido tripodal ligands, we have prepared and characterized monomeric Fe (III)OH complexes with similar trigonal-bipyramidal primary coordination spheres. Three anionic nitrogen donors define the trigonal plane, and the hydroxo oxygen atom is trans to an apical amine nitrogen atom. The complexes have varied secondary coordination spheres that are defined by intramolecular hydrogen bonds between the Fe (III)OH unit and the urea NH groups. Structural trends were observed between the number of hydrogen bonds and the Fe-O hydroxo bond distances: the more intramolecular hydrogen bonds there were, the longer the Fe-O bond became. Spectroscopic trends were also found, including an increase in the energy of the O-H vibrations with a decrease in the number of hydrogen bonds. However, the Fe (III/II) reduction potentials were constant throughout the series ( approximately 2.0 V vs [Cp 2Fe] (0/+1)), which is ascribed to a balancing of the primary and secondary coordination-sphere effects.