Tailoring metal-organic framework catalysts by click chemistry

We successively introduce new catalytic centers through click reaction into MOFs and modify their environment by addition of lipophilic groups. The resulting bifunctionalized MOF provides an optimized balance between basicity and lipophilicity and shows outstanding performance for the transesterification reaction.     

Multi component self-assembly: supramolecular organic frameworks containing metal-rotaxane subunits (RSOFs)

A facile, one-pot synthesis of rotaxanated supramolecular organic frameworks (RSOFs) is reported. These systems consist of bis-carboxylate anions threaded through the core of tetraimidazolium macrocycles. Trivalent metal cations, yttrium(III) and smaller lanthanides, are used to "lock" the threaded strut in place. This results in the formation of three-dimensional RSOFs.     

Cyclo[m]pyridine[n]pyrroles: hybrid macrocycles that display expanded π-conjugation upon protonation

Novel hybrid cyclo[m]pyridine[n]pyrroles have been synthesized using Suzuki coupling. Their NMR and optical spectroscopic features and solid state structural parameters provide support for the proposal that these species are best described as locally aromatic compounds devoid of long-range intersubunit conjugation. However, an extension of the π-conjugation in the macrocycles can be realized through protonation, as inferred from optical spectroscopic and X-ray diffraction-based structural studies.     

Development and mechanistic investigation of a highly efficient iridium(V) silyl complex for the reduction of tertiary amides to amines

The cationic Ir(III) acetone complex (POCOP)Ir(H)(2)(acetone)(+) (POCOP = 2,6-bis(di-tert-butylphosphinito)phenyl) was shown to catalyze the reduction of a variety of tertiary amides to amines using diethylsilane as reductant. Mechanistic studies established that a minor species generated in the reaction, the neutral silyl trihydride Ir(V) complex (POCOP)IrH(3)(SiEt(2)H), was the catalytically active species. High concentrations of this species could be conveniently generated by treatment of readily available (POCOP)IrHCl with tert-butoxide in the presence of Et(2)SiH(2) under H(2). Thus, using this mixture in the presence of a trialkylammonium salt, a wide array of tertiary amides, including extremely bulky substrates, are rapidly and quantitatively reduced to tertiary amines under mild conditions with low catalyst loading. A detailed mechanistic study has been carried out and intermediates identified. In brief, (POCOP)IrH(3)(SiEt(2)H) reduces the amide to the hemiaminal silyl ether that, in the presence of a trialkylammonium salt, is ionized to the iminium ion, which is then reduced to the tertiary amine by Et(2)SiH(2). Good functional group compatibility is demonstrated, and a high catalyst stability has provided turnover numbers as high as 10,000.     

Glycomimetic ligands for the human asialoglycoprotein receptor

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.     

In situ assembly of octahedral Fe(II) complexes for the enantiomeric excess determination of chiral amines using circular dichroism spectroscopy

A method for discriminating between α-chiral primary amine enantiomers is reported. The method utilizes circular dichroism (CD) spectroscopy and a sensing ensemble composed of 2-formyl-3-hydroxypyridine (4) and Fe(II)(TfO)(2). Aldehyde 4 reacts rapidly with chiral amines to form chiral imines, which complex Fe(II) to form a series of diastereomeric octahedral complexes that are CD-active in both the UV and visible regions of the spectrum. NMR studies showed that for enantiomerically pure imine complexes, the Δ-fac isomer is preferred. A statistical analysis of the distribution of stereoisomers accurately modeled the calibration curves for enantiomeric excess (ee). CD signals appearing in the UV region were bisignate, and the nulls of the CD signals were coincident with maxima in the UV spectrum, consistent with exciton coupling. Time-dependent density functional theory and semiempirical calculations confirmed that the CD signals in the UV region arise from coupling of the π-π* transitions in the imine chromophores and that they can be used to describe the signs and magnitudes of the curves accurately. The CD signals in the visible region arise from metal-to-ligand charge-transfer bands, and these signals can be used to determine the ee values of chiral amines with an average absolute error of ±5%. Overall, the strategy presented herein represents a facile in situ assembly process that uses commercially available simple reagents to create large optical signals indicative of ee values.     

Control of the evolution of iron peroxide intermediate in superoxide reductase from Desulfoarculus baarsii. Involvement of lysine 48 in protonation

Superoxide reductase is a nonheme iron metalloenzyme that detoxifies superoxide anion radicals O(2)(?-) in some microorganisms. Its catalytic mechanism was previously proposed to involve a single ferric iron (hydro)peroxo intermediate, which is protonated to form the reaction product H(2)O(2). Here, we show by pulse radiolysis that the mutation of the well-conserved lysine 48 into isoleucine in the SOR from Desulfoarculus baarsii dramatically affects its reaction with O(2)(?-). Although the first reaction intermediate and its decay are not affected by the mutation, H(2)O(2) is no longer the reaction product. In addition, in contrast to the wild-type SOR, the lysine mutant catalyzes a two-electron oxidation of an olefin into epoxide in the presence of H(2)O(2), suggesting the formation of iron-oxo intermediate species in this mutant. In agreement with the recent X-ray structures of the peroxide intermediates trapped in a SOR crystal, these data support the involvement of lysine 48 in the specific protonation of the proximal oxygen of the peroxide intermediate to generate H(2)O(2), thus avoiding formation of iron-oxo species, as is observed in cytochrome P450. In addition, we proposed that the first reaction intermediate observed by pulse radiolysis is a ferrous-iron superoxo species, in agreement with TD-DFT calculations of the absorption spectrum of this intermediate. A new reaction scheme for the catalytical mechanism of SOR with O(2)(?-) is presented in which ferrous iron-superoxo and ferric hydroperoxide species are reaction intermediates, and the lysine 48 plays a key role in the control of the evolution of iron peroxide intermediate to form H(2)O(2).     

Coupled motion in proteins revealed by pressure perturbation

The cooperative nature of protein substructure and internal motion is a critical aspect of their functional competence about which little is known experimentally. NMR relaxation is used here to monitor the effects of high pressure on fast internal motion in the protein ubiquitin. In contrast to the main chain, the motions of the methyl-bearing side chains have a large and variable pressure dependence. Within the core, this pressure sensitivity correlates with the magnitude of motion at ambient pressure. Spatial clustering of the dynamic response to applied hydrostatic pressure is also seen, indicating localized cooperativity of motion on the sub-nanosecond time scale and suggesting regions of variable compressibility. These and other features indicate that the native ensemble contains a significant fraction of members with characteristics ascribed to the recently postulated "dry molten globule". The accompanying variable side-chain conformational entropy helps complete our view of the thermodynamic architecture underlying protein stability, folding, and function.     

Development of Zn–ProPhenol‐Catalyzed Asymmetric Alkyne Addition: Synthesis of Chiral Propargylic Alcohols

The development of a general and practical zinc‐catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand ( 1 ) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,β‐unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products.     

Lithium Choreography: Intramolecular Arylations of Carbamate‐Stabilised Carbanions and Their Mechanisms Probed by In Situ IR Spectroscopy and DFT Calculations

Deprotonation of O‐allyl, O‐propargyl or O‐benzyl carbamates in the presence of a lithium counterion leads to carbamate‐stabilised organolithium compounds that may be quenched with electrophiles. We now report that when the allylic, propargylic or benzylic carbamate bears an N‐aryl substituent, an aryl migration takes place, leading to stereochemical inversion and C‐arylation of the carbamate α to oxygen. The aryl migration is an intramolecular S_NAr reaction, despite the lack of anion‐stabilising aryl substituents. Our in situ IR studies reveal a number of intermediates along the rearrangement pathway, including a “pre‐lithiation complex,” the deprotonated carbamate, the rearranged anion, and the final arylated carbamate. No evidence was obtained for a dearomatised intermediate during the aryl migration. DFT calculations predict that during the reaction the solvated Li cation moves from the carbanion centre, thus freeing its lone pair for nucleophilic attack on the remote phenyl ring. This charge separation leads to several alternative conformations. The one having Li⁺ bound to the carbamate oxygen gives rise to the lowest‐energy transition structure, and also leads to inversion of the configuration. In agreement with the IR studies, the DFT calculations fail to locate a dearomatised intermediate.