Iron-catalysed, general and operationally simple formal hydrogenation using Fe(OTf)3 and NaBH4.

An operationally simple and environmentally benign formal hydrogenation protocol has been developed using highly abundant iron(iii) salts and an inexpensive, bench stable, stoichiometric reductant, NaBH4, in ethanol, under ambient conditions. This reaction has been applied to the reduction of terminal alkenes (22 examples, up to 95% yield) and nitro-groups (26 examples, up to 95% yield). Deuterium labelling studies indicate that this reaction proceeds via an ionic rather than radical mechanism.

Direct ortho-arylation of ortho-substituted benzoic acids: overriding Pd-catalyzed protodecarboxylation.

ortho-Arylation of ortho-substituted benzoic acids is a challenging process due to the tendency of the reaction products toward Pd-catalyzed protodecarboxylation. A simple method for preventing decarboxylation in sterically hindered benzoic acids is reported. The method described represents a reliable and broadly applicable entry to 2-aryl-6-substituted benzoic acids.

Scanning conformational space with a library of stereo- and regiochemically diverse aminoglycoside derivatives: the discovery of new ligands for RNA hairpin sequences.

A library of stereo- and regiochemically diverse aminoglycoside derivatives was screened at 1 microM using surface plasmon resonance (SPR) against RNA hairpin models of the bacterial A-site, and the HIV viral TAR and RRE sequences. In order to double the stereochemical diversity of the library, the compounds were screened against both enantiomers of each of these sequences. Remarkably, this initial screen suggested that the same four aminoglycoside derivatives bound most tightly to all three of the RNAs, suggesting that these compounds were good RNA binders which, nonetheless, discriminated poorly between the RNA sequences. The interactions between selected isomeric aminoglycoside derivatives and the RNA hairpins were then studied in more detail using an SPR assay. Three isomeric tight-binding aminoglycoside derivatives, which had been identified from the initial screen, were found to bind more tightly to the RNA hairpins (with K(D) values in the range 0.23 to 4.7 microM) than a fourth isomeric derivative (which had K(D) values in the range 6.0 to 30 microM). The magnitude of the tightest RNA-aminoglycoside interactions stemmed, in large part, from remarkably slow dissociation of the aminoglycosides from the RNA targets. The three tight-binding aminoglycoside derivatives were found, however, to discriminate rather poorly between alternative RNA sequences with, at best, around a twenty-fold difference in affinity for alternative RNA hairpin sequences. Within the aminoglycoside derivative library studied, high affinity for an RNA target was not accompanied by good discrimination between alternative RNA sequences.

Configurational stability of bisindolylmaleimide cyclophanes: from conformers to the first configurationally stable, atropisomeric bisindolylmaleimides.

The bisindolylmaleimides are selective protein kinase inhibitors that can adopt two limiting diastereomeric (syn and anti) conformations. The configurational stability of a range of substituted and macrocyclic bisindolylmaleimides was investigated by using appropriate techniques. With unconstrained bisindolylmaleimides, the size of the 2-indolyl substituents was found to affect configurational stability, though not sufficiently to allow atropisomeric bisindolylmaleimides to be obtained. However, with a tether between the two indole nitrogen atoms in place, the steric effect of 2-indolyl substituents was greatly exaggerated, leading to large differences in configurational stability. The rate of interconversion of the syn and anti conformers varied by over twenty orders of magnitude through substitution of a bisindolylmaleimide ring system, which was constrained within a macrocyclic ring. Indeed, the first examples of configurationally stable atropisomeric bisindolylmaleimides are reported; the half-life for epimerisation of these compounds at room temperature was estimated to be >10(7) years.

Synthesis of a library of stereo- and regiochemically diverse aminoglycoside derivatives.

A library of forty modified aminoglycosides was prepared in which the configuration and regiochemistry of two or three rings was widely varied. The library was based around three core ring systems: the 2-deoxystreptamine ring system found in the natural products, and both enantiomers of (1R*,2R*,4R*,5R*)-2,5-diamino-cyclohexane-1,4-diol and (1R*,3R*,4R*,6R*)-4,6-diaminocyclohexane-1,3-diol. In each case, the core was modified by glycosylation with one or two sugar rings. The absolute configuration of the sugar substituents (d or l), the configuration of the anomeric centres (alpha or beta), and the regiochemical arrangement of the amine(s) were varied.

Asymmetric double ring-opening of a C(2h)-symmetric bis-epoxide: improved enantiomeric excess of the product through enantioselective desymmetrisation and 'proof-reading' steps.

A new strategy in asymmetric synthesis is described in which the desymmetrisation of a C(2h)-symmetric molecule is followed by a subsequent enantioselective 'proof-reading' step. The double asymmetric ring-opening of the bis-epoxide (1R*,3R*,5S*,7S*)-4,8-dioxa-tricyclo[5.1.0.0(3,5)]octane with azidotrimethylsilane, catalysed by a chiral chromium Salen catalyst, was studied. The reaction involves the initial asymmetric ring-opening of the bis-epoxide to give the intermediate in moderate enantiomeric excess (ca. 50% ee); the second ring-opening step yields the required diazido diol, (1S,3S,4S,6S)-4,6-diazidocyclohexane-1,3-diol, in 72% yield and 70% ee. The origin of proof reading stems from the diversion of the minor enantiomer of the intermediate to a centrosymmetric by-product, a process which improves the enantiomeric excess of the required product. Using alternative conditions, the reaction was optimised to yield the required product in >98% ee.