Ryan Gilmour

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.

A Bio-Inspired, Catalytic E → Z Isomerization of Activated Olefins

Herein, Natures flavin-mediated activation of complex (poly)enes has been translated to a small molecule paradigm culminating in a highly (Z)-selective, catalytic isomerization of activated olefins using (-)-riboflavin (up to 99:1 Z/E). In contrast to the prominent Z → E isomerization of the natural system, it was possible to invert the directionality of the isomerization (E → Z) by simultaneously truncating the retinal scaffold, and introducing a third olefin substituent to augment A1,3-strain upon isomerization. Consequently, conjugation is reduced in the product chromophore leading to a substrate/product combination with discrete photophysical signatures. The operationally simple isomerization protocol has been applied to a variety of enone-derived substrates and showcased in the preparation of the medically relevant 4-substituted coumarin scaffold. A correlation of sensitizer triplet energy (ET) and reaction efficiency, together with the study of additive effects and mechanistic probes, is consistent with a triplet energy transfer mechanism.

Catalytic Difluorination of Olefins

Molecular editing with fluorine is a validated strategy for modulating the structure and function of organic systems. In the current arsenal of catalytic dihalogenation technologies, the direct generation of the vicinal difluoride moiety from simple olefins without a prefunctionalization step remains conspicuously absent. Herein we report a catalytic, vicinal difluorination of olefins displaying broad functional group tolerance, using inexpensive p-iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are also disclosed.

Fluorinated Organocatalysts for the Enantioselective Epoxidation of Enals: Molecular Preorganisation by the Fluorine‐Iminium Ion Gauche Effect

The fluorine-iminium ion gauche effect is triggered upon union of a secondary β-fluoroamine and an α,β-unsaturated aldehyde, providing a useful strategy for controlling the molecular topology of intermediates that are central to organocatalytic processes. The β-fluoroamine (S)-2-(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,β-unsaturated aldehydes. A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group when it is embedded in a β-fluoroiminium motif. Epoxidations of challenging cyclic α,β-disubstituted, β,β-disubstituted and α,β,β-trisubstituted enals catalysed by 1 proceed with excellent levels of enantiocontrol (up to 98% ee).

One Photocatalyst, n Activation Modes Strategy for Cascade Catalysis: Emulating Coumarin Biosynthesis with (−)-Riboflavin

Generating molecular complexity using a single catalyst, where the requisite activation modes are sequentially exploited as the reaction proceeds, is an attractive guiding principle in synthesis. This requires that each substrate transposition exposes a catalyst activation mode (AM) to which all preceding or future intermediates are resistant. While this concept is exemplified by MacMillans beautiful merger of enamine and iminium ion activation, examples in other fields of contemporary catalysis remain elusive. Herein, we extend this tactic to organic photochemistry. By harnessing the two discrete photochemical activation modes of (-)-riboflavin, it is possible to sequentially induce isomerization and cyclization by energy transfer (ET) and single-electron transfer (SET) activation pathways, respectively. This catalytic approach has been utilized to emulate the coumarin biosynthesis pathway, which features a key photochemical E → Z isomerization step. Since the ensuing SET-based cyclization eliminates the need for a prefunctionalized aryl ring, this constitutes a novel disconnection of a pharmaceutically important scaffold.

The crystal structure of D-ribose--at last!

Among the half-million or so chemical compounds whose crystal structures have been determined by X-ray or neutron diffraction, the crystal structure of d-ribose is conspicuously absent. Thus, although most modern chemistry textbooks and handbooks show the molecule of d-ribose in the bfuranose form, as present in countless biochemically important ribose derivatives, it has been known for more than forty years from early NMR observations that d-ribose exists in aqueous solution as a mixture of aand b-pyranoses and aand b-furanoses with the b-pyranose form predominating (Scheme 1).

Fluorination reactions in microreactors.

The DAST-mediated conversion of a range of alcohols to the corresponding fluorides in a microstructured device is described. This safe, practical fluorination method will facilitate reactions currently challenging on large scale.

Deconstructing Covalent Organocatalysis

Modern organocatalysis has rapidly evolved into an essential component of contemporary organic synthesis. One of the most distinctive aspects of organocatalytic processes is the biomimetic nature in which the catalyst engages the substrate, often forming covalently bound intermediates in a manner reminiscent of enzyme catalysis. Indeed, the process of intramolecularization is often accompanied by a conformational change of the catalyst scaffold, further accentuating this analogy with biological systems. The isolation and study of these catalytic intermediates facilitate the rapid generation of conformation and reactivity profiles to assist in organocatalytic reaction development and/or clarify reaction outcomes. Emulating the formative advances that have derived from studying reaction intermediates in mechanistic organometallic and enzymatic catalysis, the deconstruction of covalently bound organocatalysis intermediates is gaining momentum as a design strategy.

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.

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.