Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time—and in contrast to earlier reports—the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the “rule of shielding” applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.

Natural products continue to be a robust source of novel therapeutics, with ~50% of currently approved anticancer drugs being natural products or their derivatives. 1 The luminacin family of natural products, discovered from the fermentation broth of the soil bacterium Streptomyces sp., 2 contains several members that have shown promising anticancer activity in multiple assays and cell lines. Two members of this family, luminacin D (1a), and luminacin C2 (1b, also known as UCS15A), have been shown to be potent inhibitors of angiogenesis in several in vitro assays. 3 Luminacin D was also shown to inhibit the proliferation of several cancer cell lines. 3 Additional studies with Luminacin C2 have shown it to be a protein-protein interaction inhibitor that targets Src signal transduction by inhibiting the SH3 domain-mediated interactions of Src kinase with its targets, thus preventing the src-specific tyrosine phosphorylation of numerous proteins. 4 Src kinases play a key role in the signaling and regulation of multiple processes associated with cancer, such as cell migration, cell adhesion, extracellular matrix sensing, cell cycle timing, as well as several poorly understood events necessary for angiogenesis.Luminacin C2 was further demonstrated to inhibit the invasion and metastasis of model breast cancer cell lines in vitro, by inhibition of the protein-protein interaction of the src-homology domain of cortactin with AMAP1. 5 The recent report that two structurally related compounds, named migracin A and B (1c), inhibit the migration of a breast cancer cell line, 6 provides further evidence for the anticancer potential of this molecule, or its derivatives.There is comparatively little information about the mode of action or biological function of luminacin D. Given that it is the most potent member of this family in several of the originally reported assays, 3 there is significant potential and need for an approach that enables the synthesis of sufficient quantities of this molecule to enable further research into its cellular mode of action.There are a few syntheses of the luminacins reported, 7 however each with shortcomings in terms of length and/or unselective reaction steps. A particular concern is the epoxide introduction, with three total syntheses featuring a late stage epoxidation step with very low, or undesired selectivity. 7b-d,8 Because of this, we sought to develop a synthetic approach in which an enantiopure epoxide intermediate is assembled first, to then utilise its stereochemistry for diastereoselective completion of the aliphatic portion, from which the luminacins and the migracins can be synthesised.Herein we report a successful total synthesis of (-)-luminacin D using this strategy, and report on the excellent diastereocontrol possible by allylation of aldehydes having α-oxygenated centres, including quaternary centres, under 1,3-chelation conditions. We also unambiguously show that this type of aldehyde addition is consistent with the Cornforth-Evans (CE) model of stereoinduction. Scheme 1....

The N-tosylcarboxamide group offers the possibility of directing the Pd-catalyzed C-H arylation of arenes providing a new entry to biarylcarboxamides. Moreover, its ability to react according to different reaction conditions including intramolecular reactions makes it a pivotal directing group for a divergent synthesis of biaryl-based compounds.

The N-tosylcarboxamide group can direct the room-temperature palladium-catalyzed C-H alkoxylation and halogenation of substituted arenes in a simple and mild procedure. The room-temperature stoichiometric cyclopalladation of N-tosylbenzamide was first studied, and the ability of the palladacycle to react with oxidants to form C-X and C-O bonds under mild conditions was demonstrated. The reaction conditions were then adapted to promote room-temperature ortho-alkoxylations and ortho-halogenations of N-tosylbenzamides using palladium as catalyst. The scope and limitation of both alkoxylations and halogenations was studied and the subsequent functional transformation of the N-tosylcarboxamide group through nucleophilic additions was evaluated. This methodology offers a simple and mild route to diversely functionalized arenes.