Regioselective fluorination of allenes enabled by I(I)/I(III) catalysis.

The prominence and versatility of propargylic fluorides in medicinal chemistry, coupled with the potency of F/H and F/OH bioisosterism, has created a powerful impetus to develop efficient methods to facilitate their construction. Motivated by the well-established conversion of propargylic alcohols to allenes, an operationally simple, organocatalysis-based strategy to process these abundant unsaturated precursors to propargylic fluorides would be highly enabling: this would consolidate the bioisosteric relationship that connects propargylic alcohols and fluorides. Herein, we describe a highly regioselective fluorination of unactivated allenes based on I(I)/I(III) catalysis in the presence of an inexpensive HF source that serves a dual role as both nucleophile and Brønsted acid activator. This strategy enables a variety of secondary and tertiary propargylic fluorides to be prepared: these motifs are prevalent across the bioactive small molecule spectrum. Facile product derivatisation, concise synthesis of multi-vicinal fluorinated products together with preliminary validation of enantioselective catalysis are disclosed. The expansive potential of this platform is also demonstrated through the highly regioselective organocatalytic oxidation, chlorination and arylation of allenes. It is envisaged that the transformation will find application in molecular design and accelerate the exploration of organofluorine chemical space.

A Fluorinated Sialic Acid Vaccine Lead Against Meningitis B and C.

Inspired by the specificity of α-(2,9)-sialyl epitopes in bacterial capsular polysaccharides (CPS), a doubly fluorinated disaccharide has been validated as a vaccine lead against Neisseria meningitidis serogroups C and/or B. Emulating the importance of fluorine in drug discovery, this molecular editing approach serves a multitude of purposes, which range from controlling α-selective chemical sialylation to mitigating competing elimination. Conjugation of the disialoside with two carrier proteins (CRM197 and PorA) enabled a semisynthetic vaccine to be generated; this was then investigated in six groups of six mice. The individual levels of antibodies formed were compared and classified as highly glycan-specific and protective. All glycoconjugates induced a stable and long-term IgG response and binding to the native CPS epitope was achieved. The generated antibodies were protective against MenC and/or MenB; this was validated in vitro by SBA and OPKA assays. By merging the fluorinated glycan epitope of MenC with an outer cell membrane protein of MenB, a bivalent vaccine against both serogroups was created. It is envisaged that validation of this synthetic, fluorinated disialoside bioisostere as a potent antigen will open new therapeutic avenues.

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access ß,ß-Difluorinated Carbocycles.

Cyclic ß,ß-difluoro-carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C-CF2-C>∠C-CH2-C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,ß-unsaturated esters and amides, and processes them to one-carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)-enabled O-activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r.) together with X-ray structural analyses and product derivatization.

Regio- and Stereo-Selective Isomerization of Borylated 1,3-Dienes Enabled by Selective Energy Transfer Catalysis.

Configurationally-defined dienes are pervasive across the bioactive natural product spectrum, where they typically manifest themselves as sorbic acid-based fragments. These C5 motifs reflect the biosynthesis algorithms that facilitate their construction. To complement established biosynthetic paradigms, a chemical platform to facilitate the construction of stereochemically defined, functionalizable dienes by light-enabled isomerization has been devised. Enabled by selective energy transfer catalysis, a variety of substituted ß-boryl sorbic acid derivatives can be isomerized in a regio- and stereo-selective manner (up to 97 : 3). Directionality is guided by a stabilizing nO→pB interaction in the product: this constitutes a formal anti-hydroboration of the starting alkyne. This operationally simple reaction employs low catalyst loadings (1 mol %) and is complete in 1 h. X-ray analysis supports the hypothesis that the nO→pB interaction leads to chromophore bifurcation: this provides a structural foundation for selective energy transfer.

para-Selective dearomatization of phenols by I(i)/I(iii) catalysis-based fluorination.

The regio- and enantio-selective dearomatization of phenols has been achieved by I(i)/I(iii) catalysis enabled fluorination. The process is highly para-selective, guiding the fluoride nucleophile to the distal C4 position of the substrate to generate fluorinated cyclohexadienones in an operationally simple manner. Extensive optimization has revealed key parameters that orchestrate enantioselectivity in this historically challenging transformation. A range of diversely substituted substrates are disclosed (20 examples, up to 92 : 8 e.r.) and the reaction displays efficiency that is competitive with the current state of the art in hydroxylation chemistry: this provides a preparative platform to enable OH to F bioisosterism to be explored. Finally, the utility of the products in accessing densely functionalized cyclic scaffolds with five contiguous stereocenters is disclosed together with crystallographic analyses to unveil fluorine-carbonyl non-covalent interactions.

Regioselective, catalytic 1,1-difluorination of enynes.

Fluorinated small molecules are prevalent across the functional small-molecule spectrum, but the scarcity of naturally occurring sources creates an opportunity for creative endeavour in developing routes to access these important materials. Iodine(I)/iodine(III) catalysis has proven to be particularly well-suited to this task, enabling abundant alkene substrates to be readily intercepted by in situ-generated λ3-iodanes and processed to high-value (di)fluorinated products. These organocatalysis paradigms often emulate metal-based processes by engaging the π bond and, in the case of styrenes, facilitating fluorinative phenonium-ion rearrangements to generate difluoromethylene units. Here we demonstrate that enynes are competent proxies for styrenes, thereby mitigating the recurrent need for aryl substituents, and enabling highly versatile homopropargylic difluorides to be generated in an operationally simple manner. The scope of the method is disclosed, together with application in target synthesis (>30 examples, up to >90% yield).

Direct Observation of Triplet States in the Isomerization of Alkenylboronates by Energy Transfer Catalysis.

Alkenylboronates are versatile building blocks for stereocontrolled synthesis owing to the traceless nature of the boron group that can be leveraged to achieve highly selective geometric isomerization. Using thioxanthone as an inexpensive photocatalyst, the photoisomerization of these species continues to provide an expansive platform for stereodivergent synthesis, particularly in the construction of bioactive polyenes. Although mechanistic investigations are consistent with light-driven energy transfer, direct experimental evidence remains conspicuously absent. Herein, we report a rigorous mechanistic investigation using two widely used alkenylboronates alongside relevant reference compounds. Through the combination of irradiation experiments, transient absorption spectroscopic studies, kinetic modeling, and DFT calculations with all isomers of the model compounds, it has been possible to unequivocally detect and characterize the perpendicular triplet generated by energy transfer. Our results serve not only as a blueprint for mechanistic studies that are challenging with organic sensitizers, but these guidelines delineated have also enabled the development of more sustainable reaction conditions: for the first time, efficient organocatalytic isomerization under sunlight irradiation has become feasible.

Forging Medium Rings via I(I)/I(III)-Catalyzed Diene Carbofunctionalization.

A main-group catalysis-based strategy to access 8-membered carbocycles via the direct carbofunctionalization of 2-phenethyl-substituted 1,3-dienes is disclosed. Through the intervention of an I(I)/I(III) catalysis cycle, the synthesis of densely functionalized, fluorinated benzocyclooctenes can be achieved in an operationally simple manner. Modulating the oxidation/activation regime, and the external nucleophile, the process has been extended to unify the challenging cyclization with formation of allylic C-O, C-N, and C-C bonds (>30 examples). Derivatization of the product benzocyclooctenes is demonstrated together with X-ray conformational analysis, preliminary validation of enantioselective catalysis and a scalable resolution protocol.

Light-enabled deracemization of cyclopropanes by Al-salen photocatalysis.

Privileged chiral catalysts-those that share common structural features and are enantioselective across a range of reactions-continue to transform the chemical-research landscape1. In recent years, new reactivity modes have been achieved through excited-state catalysis, processes activated by light, but it is unclear if the selectivity of ground-state privileged catalysts can be matched. Although the interception of photogenerated intermediates by ground-state cycles has partially addressed this challenge2, single, chiral photocatalysts that simultaneously regulate reactivity and selectivity are conspicuously scarce3. So far, precision donor-acceptor recognition motifs remain crucial in enantioselective photocatalyst design4. Here we show that chiral Al-salen complexes, which have well-defined photophysical properties, can be used for the efficient photochemical deracemization5 of cyclopropyl ketones (up to 98:2 enantiomeric ratio (e.r.)). Irradiation at λ = 400 nm (violet light) augments the reactivity of the commercial catalyst to enable reactivity and enantioselectivity to be regulated simultaneously. This circumvents the need for tailored catalyst-substrate recognition motifs. It is predicted that this study will stimulate a re-evaluation of many venerable (ground-state) chiral catalysts in excited-state processes, ultimately leading to the identification of candidates that may be considered 'privileged' in both reactivity models.

Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols.

Partially saturated, fluorine-containing rings are ubiquitous across the drug discovery spectrum. This capitalises upon the biological significance of the native structure and the physicochemical advantages conferred by fluorination. Motivated by the significance of aryl tetralins in bioactive small molecules, a reaction cascade has been validated to generate novel gem-difluorinated isosteres from 1,3-diaryl cyclobutanols in a single operation. Under the Brønsted acidity of the catalysis conditions, an acid-catalysed unmasking/fluorination sequence generates a homoallylic fluoride in situ. This species serves as the substrate for an I(I)/I(III) cycle and is processed, via a phenonium ion rearrangement, to an (isolable) 1,3,3-trifluoride. A final C(sp3)-F bond activation event, enabled by HFIP, forges the difluorinated tetralin scaffold. The cascade is highly modular, enabling the intermediates to be intercepted: this provides an expansive platform for the generation of structural diversity.

Fluorinated carbohydrates for 18F-positron emission tomography (PET).

Carbohydrate diversity is foundational in the molecular literacy that regulates cellular function and communication. Consequently, delineating and leveraging this structure-function interplay continues to be a core research objective in the development of candidates for biomedical diagnostics. A totemic example is the ubiquity of 2-deoxy-2-[18F]-fluoro-D-glucose (2-[18F]-FDG) as a radiotracer for positron emission tomography (PET), in which metabolic trapping is harnessed. Building on this clinical success, more complex sugars with unique selectivities are gaining momentum in molecular recognition and personalised medicine: this reflects the opportunities that carbohydrate-specific targeting affords in a broader sense. In this Tutorial Review, key milestones in the development of 2-[18F]-FDG and related glycan-based radiotracers for PET are described, with their diagnostic functions, to assist in navigating this rapidly expanding field of interdisciplinary research.

Geometric Isomerisation of Bifunctional Alkenyl Fluoride Linchpins: Stereodivergence in Amide and Polyene Bioisostere Synthesis.

Amide groups are pervasive across the chemical space continuum, where their structural and pharmacological importance, juxtaposed with the hydrolytic vulnerabilities, continues to fuel bioisostere development. Alkenyl fluorides have a venerable history as effective mimics (Ψ[CF=CH]) owing to the planarity of the motif and intrinsic polarity of the C(sp2 )-F bond. However, emulating the s-cis to the s-trans isomerisation of a peptide bond with fluoro-alkene surrogates remains challenging, and current synthetic solutions only enable access to a single configuration. Through the design of an ambiphilic linchpin based on a fluorinated ß-borylacrylate, it has been possible to leverage energy transfer catalysis to affect this unprecedented isomerisation process: this provides geometrically-programmable building blocks that can be functionalised at either terminus. Irradiation at λmax =402 nm with inexpensive thioxanthone as a photocatalyst enables rapid, effective isomerisation of tri- and tetra-substituted species (up to E/Z 98 : 2 in 1 h), providing a stereodivergent platform for small molecule amide and polyene isostere discovery. Application of the methodology in target synthesis and initial laser spectroscopic studies are disclosed together with crystallographic analyses of representative products.

Fluorine-Directed Automated Mannoside Assembly.

Automated glycan assembly (AGA) on solid support has become invaluable in reconciling the biological importance of complex carbohydrates with the persistent challenges associated with reproducible synthesis. Whilst AGA platforms have transformed the construction of many natural sugars, validation in the construction of well-defined (site-selectively modified) glycomimetics is in its infancy. Motivated by the importance of fluorination in drug discovery, the biomedical prominence of 2-fluoro sugars and the remarkable selectivities observed in fluorine-directed glycosylation, fluorine-directed automated glycan assembly (FDAGA) is disclosed. This strategy leverages the fluorine atom for stereocontrolled glycosylation on solid support, thereby eliminating the reliance on O-based directing groups. The logical design of C2-fluorinated mannose building blocks, and their application in the fully (α-)stereocontrolled automated assembly of linear and branched fluorinated oligomannosides, is disclosed. This operationally simple strategy can be integrated into existing AGA and post-AGA protocols to augment the scope of programmed carbohydrate synthesis.

Catalytic, Regioselective 1,4-Fluorodifunctionalization of Dienes.

A catalysis-based regioselective 1,4-fluorofunctionalization of trifluoromethyl substituted 1,3-dienes has been developed to access compact, highly functionalized products. The process allows E,Z-mixed dienes to be processed to a single E-alkene isomer, and leverages an inexpensive and operationally convenient I(I)/I(III) catalysis platform. The first example of catalytic 1,4-difluorination is disclosed and subsequently evolved to enable 1,4-hetero-difunctionalization, which allows δ-fluoro-alcohol and amine derivatives to be forged in a single operation. The protocol is compatible with a variety of nucleophiles including fluoride, nitriles, carboxylic acids, alcohols and even water thereby allowing highly functionalized products, with a stereocenter bearing both C(sp3 )-F and C(sp3 )-CF3 groups, to be generated rapidly. Scalability (up to 3 mmol), and facile post-reaction modifications are demonstrated to underscore the utility of the method in expanding organofluorine chemical space.

Skeletal Ring Contractions via I(I)/I(III) Catalysis: Stereoselective Synthesis of cis-α,α-Difluorocyclopropanes.

The clinical success of α,α-difluorocyclopropanes, combined with limitations in the existing synthesis portfolio, inspired the development of an operationally simple, organocatalysis-based strategy to access cis-configured derivatives with high levels of stereoselectivity (up to >20:1 cis:trans). Leveraging an I(I)/I(III)-catalysis platform in the presence of an inexpensive HF source, it has been possible to exploit disubstituted bicyclobutanes (BCBs) as masked cyclobutene equivalents for this purpose. In situ generation of this strained alkene, enabled by Brønsted acid activation, facilitates an unprecedented 4 → 3 fluorinative ring contraction, to furnish cis-α,α-difluorinated cyclopropanes in a highly stereoselective manner (up to 88% yield). Mechanistic studies are disclosed together with conformational analysis (X-ray crystallography and NMR) to validate cis-α,α-difluorocyclopropanes as isosteres of the 1,4-dicarbonyl moiety. Given the importance of this unit in biology and the foundational no → π* interactions that manifest themselves in this conformation (e.g., collagen), it is envisaged that the title motif will find application in focused molecular design.

Regio- and Enantioselective Intermolecular Aminofluorination of Alkenes via Iodine(I)/Iodine(III) Catalysis.

The regio- and enantio-selective, intermolecular vicinal fluoroamination of α-trifluoromethyl styrenes has been achieved by enantioselective II /IIII catalysis. Leveraging C2 -symmetric resorcinol-based aryl iodide catalysts, it has been possible to intercept the transient iodonium intermediate using simple nitriles, which function as both the solvent and nucleophile. In situ Ritter reaction provides direct access to the corresponding amides (up to 89 % yield, e.r. 93 : 7). This main group catalysis paradigm inverts the intrinsic regioselectivity of the uncatalyzed process, thereby providing facile access to tertiary, benzylic stereocenters bearing both CF3 and F groups. Privileged phenethylamine pharmacophores can be generated in which there is complete local partial charge inversion (CF3δ- /Fδ- versus CH3δ+ /Hδ+ ). Crystallographic analyses of representative ß-fluoroamide products reveal highly pre-organized conformations that manifest the stereoelectronic gauche effect.

Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis.

The success of saturated, fluorinated heterocycles in contemporary drug discovery provides a stimulus for creative endeavor in main group catalysis. Motivated by the ubiquity of isochromans across the bioactive small molecule spectrum, the prominence of the anomeric effect in regulating conformation, and the metabolic lability of the benzylic position, iodine(I)/iodine(III) catalysis has been leveraged for the stereocontrolled generation of selectively fluorinated analogs. To augment the current arsenal of fluorocyclization reactions involving carboxylic acid derivatives, the reaction of readily accessible 2-vinyl benzaldehydes is disclosed (up to >95 : 05 d.r. and 97 : 03 e.r.). Key stereoelectronic interactions manifest themselves in the X-ray crystal structures of the products, thereby validating the [CH2 -CHF] fragment as a stereoelectronic mimic of the [O-CH(OR)] acetal motif.

Leveraging the n→π* Interaction in Alkene Isomerization by Selective Energy Transfer Catalysis.

Examples of geometric alkene isomerization in nature are often limited to the net exergonic direction (ΔG°<0), with the antipodal net endergonic processes (ΔG°>0) comparatively under-represented. Inspired by the expansiveness of the maleate to fumarate (Z→E) isomerization in biochemistry, we investigated the inverse E→Z variant to validate nO →πC=O * interactions as a driving force for contra-thermodynamic isomerization. A general protocol involving selective energy transfer catalysis with inexpensive thioxanthone as a sensitizer (λmax =402 nm) is disclosed. Whilst in the enzymatic process nO →πC=O * interactions commonly manifest themselves in the substrate, these same interactions are shown to underpin directionality in the antipodal reaction by shortening the product alkene chromophore. The process was validated with diverse fumarate derivatives (>30 examples, up to Z:E>99:1), including the first examples of tetrasubstituted alkenes, and the involvement of nO →πC=O * interactions was confirmed by X-ray crystallography.

Advances in the E → Z Isomerization of Alkenes Using Small Molecule Photocatalysts.

Geometrical E → Z alkene isomerization is intimately entwined in the historical fabric of organic photochemistry and is enjoying a renaissance (Roth et al. Angew. Chem., Int. Ed. Engl. 1989 28, 1193-1207). This is a consequence of the fundamental stereochemical importance of Z-alkenes, juxtaposed with frustrations in thermal reactivity that are rooted in microscopic reversibility. Accessing excited state reactivity paradigms allow this latter obstacle to be circumnavigated by exploiting subtle differences in the photophysical behavior of the substrate and product chromophores: this provides a molecular basis for directionality. While direct irradiation is operationally simple, photosensitization via selective energy transfer enables augmentation of the alkene repertoire to include substrates that are not directly excited by photons. Through sustained innovation, an impressive portfolio of tailored small molecule catalysts with a range of triplet energies are now widely available to facilitate contra-thermodynamic and thermo-neutral isomerization reactions to generate Z-alkene fragments. This review is intended to serve as a practical guide covering the geometric isomerization of alkenes enabled by energy transfer catalysis from 2000 to 2020, and as a logical sequel to the excellent treatment by Dugave and Demange (Chem. Rev. 2003 103, 2475-2532). The mechanistic foundations underpinning isomerization selectivity are discussed together with induction models and rationales to explain the counterintuitive directionality of these processes in which very small energy differences distinguish substrate from product. Implications for subsequent stereospecific transformations, application in total synthesis, regioselective polyene isomerization, and spatiotemporal control of pre-existing alkene configuration in a broader sense are discussed.

Expanding organofluorine chemical space: the design of chiral fluorinated isosteres enabled by I(i)/I(iii) catalysis.

Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena. Delineating their biological origins and significance have resulted in landmark developments in synthetic organic chemistry: Arigoni's venerable synthesis of the chiral methyl group is a personal favourite. Whilst radioisotopes allow the steric footprint of the native group to be preserved, this strategy was never intended for therapeutic chemotype development. In contrast, leveraging H → F bioisosterism provides scope to complement the chiral, radioactive bioisostere portfolio and to reach unexplored areas of chiral chemical space for small molecule drug discovery. Accelerated by advances in I(i)/I(iii) catalysis, the current arsenal of achiral 2D and 3D drug discovery modules is rapidly expanding to include chiral units with unprecedented topologies and van der Waals volumes. This Perspective surveys key developments in the design and synthesis of short multivicinal fluoroalkanes under the auspices of main group catalysis paradigms.