Christof Sparr

Fluorine conformational effects in organocatalysis: an emerging strategy for molecular design.

Molecular design strategies that profit from the intrinsic stereoelectronic and electrostatic effects of fluorinated organic molecules have mainly been restricted to bio-organic chemistry. Indeed, many fluorine conformational effects remain academic curiosities with no immediate application. However, the renaissance of organocatalysis offers the possibility to exploit many of these well-described phenomena for molecular preorganization. In this minireview, we highlight examples of catalyst refinement by introduction of an aliphatic C-F bond which functions as a chemically inert steering group for conformational control.

The Fluorine-Iminium Ion Gauche Effect : Proof of Principle and Application to Asymmetric Organocatalysis

The gauche effect that is induced upon reversible formation of an iminium ion (see structure: green F, blue N) provides a powerful method for the preorganization of transient intermediates that are central to secondary amine catalyzed processes. This phenomenon has been exploited in the design of a novel organocatalyst and is showcased in the stereoselective epoxidation of alpha,beta-unsaturated aldehydes.

Organocatalytic Atroposelective Aldol Condensation: Synthesis of Axially Chiral Biaryls by Arene Formation

Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri-ortho-substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides.

Fluorinated quinine alkaloids: synthesis, X-ray structure analysis and antimalarial parasite chemotherapy.

Herein we report the synthesis of a series of C9-fluorinated quinine alkaloids by direct nucleophilic deoxyfluorination. This transformation gives rise to products bearing both S- and R-configured monofluoromethylene functionalities, consistent with an S(N)1-like mechanism. Furthermore, a series of ring-expanded 1-azabicyclo[3.2.2]nonane systems were generated by a skeletal rearrangement of the quinuclidine core. The modified alkaloids were converted to the corresponding hydrochloride salts and characterised by single-crystal X-ray diffraction analysis. The preference of the benzylic fluorine atom to adopt a gauche conformation relative to the protonated quinuclidine nitrogen atom was consistently observed throughout the cage-conserved compounds. Conversely, the molecular architecture of the 1-azabicyclo[3.2.2]nonane systems enforced an anti relationship between the fluorine atom and the protonated tertiary amine. This constitutes the first X-ray evidence of a vicinal fluorine atom at a stereogenic centre positioned anti to a substituted ammonium cation. The pharmacological efficacy of these compounds was assessed in vitro against the NF54 strain of Plasmodium falciparum (sensitive to all known antimalarial drugs). IC(50) values of as low as 267 nM were observed; this highlights the potential of these materials in developing novel agents for parasite chemotherapy.

Cyclopropyl Iminium Activation: Reactivity Umpolung in Enantioselective Organocatalytic Reaction Design

predisposed to react at the a (d) and g (d) donor positions, whereas nucleophiles add to the b (a) and d (a) acceptor positions. Direct inversion of this inherent selectivity is known as reactivity umpolung, and often provides a platform for the development of novel transformations. While various activation modes that allow for a (a/d), b (a), g (d), and e (d) functionalization have been reported through secondary amine organocatalysis, umpolung strategies remain elusive outwith the confines of SOMO activation and processes mediated by N-heterocyclic carbenes (NHCs). 4] Because pyrrolidineand imidazolidinone-based organocatalysts require carbonyl substrates to generate the transient intermediates that are central for catalysis, the substrate scope is limited to aldehydes and ketones with varying degrees of unsaturation. With a view to extending the substrate scope of secondary-amine-catalyzed processes, and providing an entry point into the design of homologous variants of addition reactions to a,b-unsaturated iminium ions, we began exploring the reactivity of cyclopropane carbaldehydes. Cyclopropane behaviour has striking parallels with that of olefins. In addition to their ability to interact with adjacent p systems, cyclopropanes function as effective donors when activated by adjacent low-lying empty orbitals: this can be rationalized by considering the Walsh orbitals. 7] Striking manifestations of the electron-donating aptitude of cyclopropanes include: 1) the unusual thermodynamic stability of the cyclopropylcarbinyl cation, and 2) the bond-length asymmetry of cyclopropanecarbonitirile (Dd(distal vicinal) = 0.033 ) as a consequence of hyperconjugation. 10] Of particular pertinence to this study is the latter observation. It was envisaged that the well described conjugation between a cyclopropane moiety and polar multiple bonds might form the basis of an activation strategy involving cyclopropyl iminium salts. Indeed, Wang and co-workers have described that the nucleophilic addition of benzenethiols to cyclopropanecarbaldehydes can be catalyzed by proline. The similarities in bonding between this species and that of conventional a,b-unsaturated iminium ions, together with the expected interaction of the cyclopropyl moiety with the conjugated iminium functionality, motivated us to investigate the reactivity of cyclopropane carbaldehydes upon unification with secondary amines (Scheme 2). Formally, nucleophilic addition to the transient cyclopropyl iminium species would constitute a formal umpolung of the g-position of a dienamine; d!a (Scheme 1). Moreover, by intercepting the transient enamine with an electrophile, this strategy would give an unprecedented method for the organocatalytic formation of 1,3-difunctionalized products in a single operation (Scheme 2). Herein, we report the first secondary-

Improved efficacy of fosmidomycin against Plasmodium and Mycobacterium species by combination with the cell penetrating peptide octaarginine

ABSTRACT Cellular drug delivery can improve efficacy and render intracellular pathogens susceptible to compounds that cannot permeate cells. The transport of physiologically active compounds across membranes into target cells can be facilitated by cell-penetrating peptides (CPPs), such as oligoarginines. Here, we investigated whether intracellular delivery of the drug fosmidomycin can be improved by combination with the CPP octaarginine. Fosmidomycin is an antibiotic that inhibits the second reaction in the nonmevalonate pathway of isoprenoid biosynthesis, an essential pathway for many obligate intracellular pathogens, including mycobacteria and apicomplexan parasites. We observed a strict correlation between octaarginine host cell permeability and its ability to improve the efficacy of fosmidomycin. Plasmodium berghei liver-stage parasites were only partially susceptible to an octaarginine-fosmidomycin complex. Similarly, Toxoplasma gondii was only susceptible during the brief extracellular stages. In marked contrast, a salt complex of octaarginine and fosmidomycin greatly enhanced efficacy against blood-stage Plasmodium falciparum. This complex and a covalently linked conjugate of octaarginine and fosmidomycin also reverted resistance of Mycobacteria to fosmidomycin. These findings provide chemical genetic evidence for vital roles of the nonmevalonate pathway of isoprenoid biosynthesis in a number of medically relevant pathogens. Our results warrant further investigation of octaarginine as a delivery vehicle and alternative fosmidomycin formulations for malaria and tuberculosis drug development.

Theoretical and X‐ray Crystallographic Evidence of a Fluorine‐Imine Gauche Effect: An Addendum to Dunathan’s Stereoelectronic Hypothesis

The preference of β-fluoroimines to adopt a gauche conformation has been studied by single-crystal X-ray diffraction analysis and DFT methods. Empirical and theoretical evidence for a preferential gauche arrangement around the NCCF torsion angle (φ) is presented ((E)-2-fluoro-N-(4-nitrobenzylidene)ethanamine: φ(NCCF) =70.0°). In the context of this study, the analysis of a pyridoxal-derived β-fluoroaldimine was performed, a species that is implicated in the inhibition of pyridoxal phosphate (PLP)-dependent enzymes by β-fluoroamine derivatives. The gauche preference of the internal aldimine (=NCH(2)CH(2)F) that can be rationalized by stereoelectronic arguments does not hold for the corresponding external system (N=CHCH(2)F) (E(min) when φ(NCCF) =120°). Moreover, the C-F bond is lengthened by more than 0.02 Å at φ(NCCF) =±90°, when it is exactly antiperiplanar to the conjugated imine. This activation of the C-F σ bond by an adjacent π system constitutes an addendum to Dunathans stereoelectronic hypothesis.

Stereoselective Arene-Forming Aldol Condensation: Synthesis of Configurationally Stable Oligo-1,2-naphthylenes.

Structurally well-defined oligomers are fundamental for the functionality of natural molecular systems and key for the design of synthetic counterparts. Herein, we describe a strategy for the efficient synthesis of individual stereoisomers of 1,2-naphthylene oligomers by iterative building block additions and consecutive stereoselective arene-forming aldol condensation reactions. The catalyst-controlled atropoenantioselective and the substrate-controlled atropodiastereoselective aldol condensation reaction provide structurally distinct ter- and quaternaphthalene stereoisomers, which represent configurationally stable analogues of otherwise stereodynamic, helically shaped ortho-phenylenes.

Syntheses, Receptor Bindings, in vitro and in vivo Stabilities and Biodistributions of DOTA‐Neurotensin(8–13) Derivatives Containing β‐Amino Acid Residues – A Lesson about the Importance of Animal Experiments

Neurotensin(8–13) (NTS(8–13)) analogs with C‐ and/or N‐terminal β‐amino acid residues and three DOTA derivatives thereof have been synthesized (i.e., 1–6). A virtual docking experiment showed almost perfect fit of one of the 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) derivatives, 6a, into a crystallographically identified receptor NTSR1 (Fig. 1). The affinities for the receptors of the NTS analogs and derivatives are low, when determined with cell‐membrane homogenates, while, with NTSR1‐exhibiting cancer tissues, affinities in the single‐digit nanomolar range can be observed (Table 2). Most of the β‐amino acid‐containing NTS(8–13) analogs (Table 1 and Fig. 2), including the 68Ga complexes of the DOTA‐substituted ones (6; Figs. 2 and 5), are stable for ca. 1 h in human serum and plasma, and in murine plasma. The biodistributions of two 68Ga complexes (of 6a and 6b) in HT29 tumor‐bearing nude mice, in the absence and in the presence of a blocking compound, after 10, 30, and 60 min (Figs. 3 and 4) lead to the conclusion that the amount of specifically bound radioligand is rather low. This was confirmed by PET‐imaging experiments with the tumor‐bearing mice (Fig. 6). Comparison of the in vitro plasma stability (after 1 h) with the ex vivo blood content (after 10–15 min) of the two 68Ga complexes shows that they are rapidly cleaved in the animals (Fig. 5).

Stereoselective Arene‐Forming Aldol Condensation: Synthesis of Axially Chiral Aromatic Amides

The increasing awareness of the importance of amide atropisomers prompts the development of novel strategies for their selective preparation. Described herein is a method for the enantioselective synthesis of atropisomeric aromatic amides by an amine-catalyzed arene-forming aldol condensation. The high reactivity of the glyoxylic amide substrates enables a remarkably efficient construction of a new aromatic ring, which proceeds within minutes at ambient temperature to afford products with excellent stereoselectivity. The high rotational barriers of the reduced products highlight the utility of this stable, spatially organized chiral scaffold.