Model systems for flavoenzyme activity: relationships between cofactor structure, binding and redox properties

A series of flavins were synthesized bearing electron-withdrawing and -donating substituents. The electrochemical properties of these flavins in a nonpolar solvent were determined. The recognition of these flavins by a diamidopyridine (DAP) receptor and the effect this receptor has on flavin redox potential was also quantified. It was found that the DAP-flavin binding affinity and the reduction potentials (E(1/2)) for both the DAP-bound and unbound flavins correlated well with functions derived from linear free energy relationships (LFERs). These results provide insight and predictive capability for the interplay of electronics and redox state-specific interactions for both abiotic and enzymatic systems.     

Inert site in a protein zinc cluster: isotope exchange by high resolution mass spectrometry

Using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry, we show that one Zn2+ ion in the Zn4 cluster of cyanobacterial metallothionein is inert to exchange with 67Zn2+. We suggest that this is zinc in site A, which together with the surrounding alpha and beta secondary structure forms a zinc-finger fold.     

Studies on the Lewis acid mediated cleavage of alpha-aminoacetals: synthesis of novel 1,2-aminoethers,and evidence for alpha-alkoxy aziridinium ion intermediates

The nucleophilic cleavage of alpha-amino acetals induced by TMSOTf can be used to prepare a wide range of substituted 1,2-aminoethers. In particular, organometallic reagents, N-heterocycles, and enamines all react efficiently to give products in good yield. In appropriate cases, good levels of stereocontrol are possible, but this is very dependent on the nature of the nucleophile and the substrate, with diethylzinc proving particularly effective across a range of substrates. The degree of stereocontrol can be used to infer the nature of the reactive intermediates involved in the reaction. With diethylzinc, it is most likely that the reaction proceeds by coordination of the nucleophile to the amino group followed by transfer of an ethyl group to an alpha-oxocarbenium ion. With non-coordinating nucleophiles, the stereochemical outcome can be rationalised in terms of addition to the possible alpha-alkoxy aziridinium ion intermediates.     

Chiral base-mediated benzylic functionalisation of tricarbonylchromium(0) complexes of benzylamine derivatives

The novel complex (eta 6-benzylamine)tricarbonylchromium(0) 11 was prepared in up to 66% yield by direct complexation with Cr(CO)6 in refluxing 1,4-dioxane. Imine derivatives of this complex were readily deprotonated at the benzylic position by diamide 5, and the resultant anions reacted regioselectively with electrophiles (Me3SiCl or MeI) to give fairly good yields of products substituted at the benzylic carbon. Products of up to 87% e.e. were obtained in these reactions, with the highest enantioselectivity being derived from the tert-butyl-substituted imine complex 25.     

High-throughput manual parallel synthesis using SynPhase crowns and lanterns

The high-throughput manual solid-phase parallel synthesis of libraries comprising thousands of discrete samples using pellicular supports (i.e. SynPhase crowns and lanterns) and a suite of novel tools and techniques is described. Key aspects of this approach include the combination of a split-split-split synthesis strategy with spatial encoding to differentiate thousands of crowns, the rapid washing and filtration of up to 48 reaction vessels in parallel, the application of an inexpensive and environmentally friendly technique to remove trifluoroacetic acid from sixteen 96-well plates in parallel, and a high-throughput method for removing cleaved crowns from reusable pin racks. Tens of thousands of discrete samples have been produced in-house using this conceptually and operationally straightforward strategy.     

Palladium-catalyzed sequential alkylation-alkenylation reactions: new three-component coupling leading to oxacycles

A new three-component domino reaction catalyzed by palladium was devised, producing polysubstituted bicyclic molecules in good yields from readily available substrates. The reaction conditions and the scope of the process were examined, and a possible mechanism is proposed. [reaction: see text]     

Redox modulation of benzene triimides and diimides via noncovalent interactions

[reaction: see text] Mellitic triimides undergo three sequential one-electron reduction processes whose potentials are significantly lowered in the presence of alkyl thioureas. The two sequential reductions of benzene diimides are similarly stabilized. Calculation of the relative free energy change between the different electronic states of the imide acceptors and their corresponding alkyl thiourea complexes indicates dramatic increases in hydrogen bond strength with increasing acceptor charge density.     

Efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921

[reaction: see text] An efficient asymmetric synthesis of the vasopeptidase inhibitor BMS-189921 was accomplished. Two short enantioselective syntheses of the common key intermediate (S)-alpha-aminoazepinone 6b were developed. Olefin 3 was converted to 6b via asymmetric hydrogenation. Alternatively, enyne 12 was converted to racemic alpha-aminoazepinone 15b, which was transformed to 6b by a practical dynamic resolution.     

Synthesis of muscothiazoles A and B: Critical role of methyl group substitution in RCM-based syntheses of macrocycles

[reaction: see text] Muscothiazoles A (2b) and B (2c) have been prepared by two approaches that differ in the order of assembly of the rings. Comparative studies show that substitution of the carbon chains in substrate 5 or 12 (respective precursors to 13-membered and 14-membered rings by RCM), even by a single methyl group, can have a profound effect on increasing the efficiency of the macrocyclization.     

Fluxional behavior of a cadmium zwitterion complex: proton transport and tautomerism in methylene chloride solution

The synthesis and structure of the tautomeric Cd(II) isoindoline zwitterion coordination compound [Cd(4'-MeLH)(NO(3))(2)].CH(3)OH (4'-MeLH = 1,3-bis[2-(4-methylpyridyl)imino]isoindoline) are reported. In methylene chloride solution, tautomer interconversion occurs as the N-H proton moves between the identical imine nitrogen atoms. We report the kinetics of proton transfer as followed by variable temperature (1)H NMR spectroscopy and demonstrate that methanol of solvation and adventitious water facilitate rapid proton transfer.