A heteroatom-tethered regioselective ring-closing metathesis reaction was used for the C-19 functionalization of 1alpha-hydroxy-5,6-trans-vitamin D(2) analogues. Applications of the reaction to form a range of analogues by manipulation of the tether using both organolithium reagents and Diels-Alder cycloadditions are described.
A binding site optimisation protocol for the design of artificial enzymes based on "small molecule-small molecule" binding studies by diffusion NMR is presented. Since the reaction chosen was the hydrolysis of ester 1 ([4-(4-carboxy-1-oxobutyl)-aminobenzyl]-phenethyl ester), an analogous phosphonate ester 2 ([4-(4-carboxy-1-oxobutyl)-aminobenzyl]-phosphonic phenethyl ester) was selected as a suitable transition state analogue (TSA). The key objective of the NMR studies was to find a unit with functional groups capable of binding to the acidic sites of the TSA. Nine dipeptides, mainly with basic and hydroxyl groups, were used and their affinity to the TSA was studied by measuring the change in the diffusion coefficient, D(pep), upon binding by pulse field gradient NMR. The value of D(pep) at 298 K in D(2)O at pD 5, 7 and 10 was measured both in free solution, and mixtures containing one dipeptide and the TSA. As both components are low molecular weight species with M < 500, a TSA-to-dipeptide ratio of 10:1 was used to detect significant changes in D(pep). The results revealed that dipeptides with basic residues show higher affinity to the TSA than those with hydroxyl or aliphatic side chains in aqueous solutions. The dipeptide showing the most significant relative change in D(pep) was H-Arg-Arg-OH, and the binding constant was estimated to be 86 L M(-1) by measuring D(pep) at varying concentrations of the TSA. In addition, binding of the TSA to a new water-soluble polymer with a polyallylamine backbone and randomly distributed Arg-Arg binding sites was examined, and the binding constant was estimated to be > or =1500 L M(-1). As confirmed by further catalytic activity tests, polymers containing Arg-Arg as a binding site are capable of significant rate accelerations in the hydrolysis of ester 1.
Dynamic properties of the hydroxyl groups in a selectively deuterated polycrystalline sample of triphenylsilanol (Ph3SiOD) have been studied using variable-temperature solid-state 2H NMR spectroscopy. The crystal structure of triphenylsilanol contains eight crystallographically independent molecules, which are arranged in two tetrameric building units. Within each of these tetrameric units, the four silicon atoms are arranged in the form of a slightly distorted square, with the O atoms of the four hydroxyl groups involved in O−H···O hydrogen bonding. The temperature dependence of the quadrupole echo 2H NMR line shape in the temperature range 213−358 K and 2H NMR spin−lattice relaxation time measurements at 368 K demonstrate that the hydrogen-bonding arrangement is dynamic. From the 2H NMR line-shape analysis, the dynamic process is interpreted as interconversion between “clockwise” and “anticlockwise” hydrogen-bonding arrangements within each tetrameric unit, via a two-site jump motion of each hydroxyl deuteron about the Si−OD bond. It is assumed that the motions of the hydroxyl groups in each hydrogen-bonded tetramer are highly correlated. The temperature dependence of the jump frequency exhibits Arrhenius behavior, with the activation energy for the dynamic process estimated to be 35 ± 2 kJ mol-1. High-resolution solid-state 29Si NMR spectroscopy has also been used to identify crystallographically inequivalent silicon sites.
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