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.


Introduction
Fluorinated architectures traverse the functional small molecule landscape, 1 where they manifest themselves in blockbuster drugs (1-3), 2 essential agrochemicals (4-6) 3 (Fig. 1) and highperformance materials such as Teon®. 4 Ubiquitous in modern society, uorinated motifs continue to feature in the vanguard of focussed molecular design strategies 5 with short peruoroalkyl groups such as CF 3 and CF(CF 3 ) 2 now enjoying "privileged" status. 6,7 In a reductionist sense, the functional diversity of uorinated materials can be attributed to the physicochemical consequences of C(sp 2 /sp 3 )-H d+ / C(sp 2 /sp 3 )-F dÀ structural editing 8 and the new regions of chemical space that result. 9 The (stereo)electronic impact of this (bio)isosterism appears subtle but, when appropriately leveraged, can induce counterintuitive conformational behaviour, 10 elicit novel molecular recognition modes 11 and augment stability. 1,2,5 Whilst this latter consequence of uorination has been widely lauded as a triumph in bioactive Stephanie Meyer was born in Sögel (Germany) in 1995. She completed her Bachelors degree in chemistry at the WWU Münster, which included an internship with Prof. Ian Fairlamb at the University of York (UK, 2016). She obtained her BSc degree in 2017 and, aer an industrial stay at Beiersdorf AG in Hamburg, joined Prof. Andrei Yudin's group at the University of Toronto as a visiting student (Canada, 2018). Stephanie completed her Masters degree working with Prof. Ryan Gilmour (2019) and remained in the group as a doctoral student working on I(I)/I(III) catalysis.
small molecule discovery, it has obvious environmental consequences. 12 This is unsurprising given the conspicuous dearth of uorinated natural products 13 and, by extension, regulatory enzymes to facilitate the construction and degradation of this class of organohalogens. 14 Reconciling the benets of short, uorinated motifs as essential modulators of health and development, with environmental considerations, continues to aggravate this complex relationship. This juxtaposition provides a powerful impetus to explore new areas of organouorine chemical space to expand the current portfolio of drug and agrochemical discovery modules. Augmenting the current arsenal of achiral 2D and 3D motifs to include chiral 3D topologies will open up a wealth of opportunities, 15 and simultaneously reduce dependence on peruorocarbon moieties: this may allow existing degradative enzymes to be harnessed and thus mitigate environmental accumulation. 16 This personal Perspective reects on the possible motivating factors that have led to a surge of interest in the generation of short, chiral uorinated groups and highlights the important role of I(I)/I(III) catalysis as an enabling technology in this arena.
2. Short aliphatic groups in (bio)organic chemistry

Radioisotopes to stable isotopes
The frequency with which simple methyl groups are encountered in the natural product repertoire mirrors the success of its electronic antipode (CF 3 ) in contemporary drug discovery. However, striking disparities in the stability of the respective isotopes of H and F render the development of a chiral CF 3 group improbable. In the case of the parent methyl group, it is possible to exploit the three natural isotopes of hydrogen ( 1 H, 2 H and 3 H) to generate a stereogenic center and this has been instrumental in the course of mechanistic enzymology (Fig. 2, le, the chiral methyl group). 17 In addition, deuterium is regularly leveraged in drug discovery to delineate pharmacokinetic parameters 18 and is now a key feature of deutetrabenazine (Austedo®) to treat Huntington's disease. 19 Although uorine has a plethora of known isotopes, it is practically and synthetically implausible to translate this into a "chiral" CF 3 group. This provides an opportunity for creative endeavour in conceiving and evaluating new chemical entities based on short aliphatic groups (C 1 -C 10 ). Inspiration can be gleaned in abundance from the bioactive small molecule repository (vide infra), where both linear and branched groups (e.g. t Bu in ginkgolide B) are well represented. This will ultimately result in an array of new chiral entities with distinct properties that will complement the aliphatic series.

Expanding organouorine chemistry beyond achiral 2D and 3D chemical space
In our quest to design short, chiral uorine-containing groups, and having disregarded isotope discrimination blueprints from  the outset, the formal oxidation of a C 2 fragment was an appealing starting point. Vicinal oxidation is pervasive across the bioactive small molecule spectrum and is intimately involved in orchestrating structure-function interplay. 20 Examples abound and include the immunosuppressant Rapamycin (Sirolimus) (7), the anti-tumour agents Taxol (Paclitaxel) (8) and Vinblastine (Velban) (9), and the serine palmitoyltransferase inhibitor Myriocin (Thermozymocidin) (10) (Fig. 3). It is pertinent to note that this natural product provided the inspiration for Fingolimod (Gilenya®) (11) to treat relapsing remitting multiple sclerosis. 21 A conspicuous feature of these bioactive molecules is the presence of both short alkyl fragments and vicinal oxidation patterns. Indeed, this latter feature commonly occurs in the low molecular weight APIs such as the bronchodilator Salbutamol (Ventolin®) (12). 22 It was envisaged that integrating these two common structural features in the development of a short, chiral uorinated group would also provide a much-needed solution to generating a bioisostere of the vicinal diol motif. Whilst OH / F bioisosterism is well established, 6 vicinal diuorination strategies are comparatively underdeveloped. This is noteworthy given the interest in halogenated natural products containing contiguous halogen centres, 23 including the prominent synthesis of a uorinated analogue of the sulfolid danicalipin A by Carreira and coworkers. 24 The conspicuous absence of selective vicinal diuorination protocols is in stark contrast with the prominence of uorination patterns in the drug discovery process. This may reect a limitation in synthetic organic chemistry as opposed to a lack of suitability as drug discovery modules. This echoes the sentiments expressed by former NIH Director Zerhouni that "One interesting result of the NIH Roadmap development process came when we surveyed scientists to nd out what the stumbling blocks for biological sciences were. The number one stumbling block turned out to be synthetic organic chemistry." 25 As Seebach commented in his celebrated essay "Organic Chemistry: Where Next?", 26 "molecular function and activity now occupy centre stage": realising this objective will require practitioners of organic chemistry to address deciencies in the synthesis arsenal, such as the fundamental task of adding molecular uorine across an alkene in a mild and selective manner. Achieving parity with vicinal chlorination and bromination, and expanding the protocol to enable the synthesis of telescoped multivicinal uoroalkanes requires innovative solutions. This latter aspect is particularly urgent given the potential of these materials in the life sciences and materials elds (vide infra).

Multivicinal uoroalkanes (C 2 -C 6 )
Multivicinal uoroalkanes are an evolving class of hydrocarbon/ polyuorocarbon hybrids that are composed of repeating CHF units. The simplest member of this organohalogen class may be accessed by the programmed addition of uorine across an alkene unit (Fig. 4). 27 Although uorine has a small van der Waals radius, it is highly electronegative and therefore the inclusion of multiple C (sp 3 )-F bonds along a carbon chain regulates conformation and physicochemistry. The relative conguration of the system gives rise to distinct topologies that manifest stabilising, secondorder hyperconjugative interactions (s CH / s CF *; the venerable stereoelectronic gauche effect in 1,2-diuoroethane 13) 1,10 and mitigate 1,3-repulsion. 28,29 The latter acyclic conformational control aspect becomes particularly dominant in systems where n $3 due to formation of the venerable Leonard Link. 28,30 Since each carbon homologation enables the generation of 2 n stereoisomers (for n homologated carbons), these materials have the potential to signicantly expand organouorine chemical space (13): this necessarily requires the development of effective, stereocontrolled methods to facilitate synthesis. Pioneering studies, most notably by O'Hagan and co-workers, 27b have culminated in the synthesis and physicochemical evaluation of several multivicinal uoroalkane scaffolds. These elegant routes leverage (asymmetric) oxidation/stereospecic uorodeoxygenation protocols to efficiently access the target scaffolds of interest. Applications range from the design of peptide mimics to regulate conformation (Fig. 5)  compare the erythro-and threo-diastereoisomers of 1,2-diuorodiphenylethanes and 2,3-diuorosuccinic acid derivatives, 33 and to regulate the conformation of simple peptides. [34][35][36][37] Augmentation to the vicinal a,b,g-triuoro array has been achieved and applied to the synthesis of peptides, 38-40 liquid crystals 41 and unnatural monosaccharides (e.g. 19 and 20). 42 More recently, the (terminal) tetrauoro structural unit has been explored in analogues of the multiple sclerosis drug Gilenya® (11 - Fig. 3, 21 and 22). 43 Remarkably, the O'Hagan laboratory have also reported synthesis routes to (internal) vicinal tetra-uoro-, 44-46 pentauoro-(23) 47 and hexauoro-48 motifs (24).
These advances in the stereocontrolled synthesis of linear multivicinal uoroalkanes have been complemented by equally impressive synthesis campaigns to generate cyclic motifs (Fig. 6). Many of these materials, in which the uorine atoms are in an all-syn relationship, display signicantly lower log P values than the parent hydrocarbon. Examples of these facially polarised "Janus" motifs include the all-cis 1,2,3-tri-uorocyclopropane 25 (cf. 26) 49 and the tetrauorocyclohexane 27 (cf. 28). 50 It is interesting to note that the all-cis hexa-uorocyclohexane 29 has the highest calculated dipole of any organic molecule (6.2 D). 51 These materials, together with selectively uorinated tetralins (30), 52 hold great potential as drug discovery modules owing to their well-dened conformations and physicochemical proles. 53 3. Catalysis-based strategies to access short (#C 6 ), chiral fragments The structural and physicochemical diversity intrinsic to multivicinal uoroalkanes is expansive and renders this class of materials valuable in expanding (chiral) organouorine chemical space. This is evident from a comparative analysis of the van der Waals radii [Å 3 ] of common short alkyl groups with their selectively uorinated counterparts (Fig. 7). 54,55 Not only are the two partially uorinated groups (I and II) chiral, they have volumes and 3D topologies that are complementary to structurally related aliphatic groups. Furthermore, the inclusion of short, chiral uorinated moieties in the drug discovery portfolio redresses the current bias that favours isotropic groups over anisotropic fragments. The simplest member of the multivicinal uoroalkane family is structure I, which is based on 1,2-diuoroethane (13). These structures are intriguing on account of the stabilising hyperconjugative interactions that give rise to the iconic gauche conformation. 1,8b,10b,c This phenomenon can be rationalised by invoking stabilising s C-H / s* C-F interactions and gives rise to a temperature-dependent dipole moment (dm/dT <0) (Fig. 6, le). The gauche effect is a unique feature of uorinated materials and is not observed in the corresponding   chloro-or bromo-systems due to overriding repulsion. 56 Collectively, these structural features are compelling arguments for the development of efficient strategies to allow small chiral groups to be assessed in the context of contemporary drug discovery.

Catalysis-based vicinal diuorination of alkenes
Despite the popularity of uorine bioisosterism in medicinal chemistry, and the notable advances in uorination technologies that this has inspired, 57 the catalytic, stereoselective vicinal uorination of alkenes is comparatively under-developed. 58 Direct uorination using gaseous F 2 in a carrier gas been reported by Rozen and Brand, 59,60 but this approach presents safety and operational challenges for non-specialists that must be addressed (Fig. 8). As is evident from the conversion of coumarin 31 to product 32, the vicinal diuorination proceeds in a syn-selective fashion as was determined by coupling constant analysis ( 3 J HF ¼ 30 and 6 Hz). As a consequence, HF elimination occurs to generate the uorinated coumarin 33. Tius has demonstrated that XeF 2 enables the 1,2-diuorination of alkenes, thereby mitigating the safety concerns associated with handling strongly oxidising uorine gas. Despite the operational simplicity of this approach, XeF 2 is prohibitively expensive and translation to an enantioselective, catalysisbased platform would be challenging. 61 In 1998, Hara, Yoneda and co-workers reported the direct diuorination of alkenes using stoichiometric p-TolIF 2 (35) and Et 3 N$HF complex. 62 This I(III)-reagent-based approach proceeds via a type II invertive mechanism (Type II inv ), resulting in a net syn-addition (34 / 36). 58 Inspired by this seminal study, groups led by Jacobsen 63 and Gilmour 64 independently developed catalytic versions of this venerable transformation. Both strategies are predicated on the oxidation of simple aryl iodide organocatalysts, in the presence of an amine$HF complex, to generate the incipient ArIF 2 species in situ. 65,66 Whilst the Gilmour protocol employed Selectuor® and various amine : HF ratios to generate 35 in situ, the Jacobsen method employed m-CPBA as the terminal oxidant in conjunction with Olah's reagent to form the resorcinol derivative 37. Both groups disclosed preliminary validation of enantioselectivity, and this has since been expanded further to enable the generation of chiral motifs with broad functional group tolerance (vide infra). A scalable, electrochemical variant of the vicinal diuorination of alkenes mediated by p-TolIF 2 has also been reported by Lennox and co-workers. 67 In 2018, Gilmour and co-workers reported an enantioselective, catalytic vicinal diuorination of electron decient styrenes (e.g. 38) using a chiral resorcinol-derived aryl iodide (39, Fig. 9). 68 This study revealed the importance of Brønsted acidity in biasing regioselectivity (vicinal versus geminal, 40 and    9 The enantioselective, catalytic vicinal difluorination of electron deficient styrenes. * 98 : 2 e.r. after recrystallisation from CH 2 Cl 2 /npentane. 41, respectively) as a function of the amine : HF ratio. Varying amine : HF ratios are achieved by mixing commercially available amine$HF complexes, such as NEt 3 $3HF and Olah's reagent (Pyr$9HF). It is pertinent to note that the importance of Brønsted acid activators was reported by Cotter et al. 69 in the activation of iodobenzene dichloride 23c,70 by triuoroacetic acid.
Jacobsen and co-workers have reported an enantio-and diastereo-selective vicinal diuorination of cinnamamides (42 / 44) using a chiral resorcinol-based aryl iodide (43). 71 Regioselectivity is regulated through the anchimeric assistance of a Ntert-butyl amide substituent thereby suppressing phenonium ion rearrangement to deliver the geminal product (vide infra). This elegant solution enables the target diuorides to be generated in up to 98% ee (Fig. 10).
To date, this methodology 64 has been leveraged to validate the 1,2-diuoromethylene motif as a chiral hybrid bioisostere of triuoromethyl and ethyl (BITE group) 8b in several small molecule drug candidates (Fig. 11). Examples from this laboratory include the synthesis of a series of Vorinostat (Zolinza®) derivatives (45) containing a pendant chain capped with a vicinal diuoro motif. 72 The HDAC inhibitory behaviour of this compound set was evaluated relative to the non-uorinated systems. 73 In all cases, the FDA approved Vorinostat (Zolinza®) was used as a control. 74 Several of the compounds containing the 1,2-diuoroethylene unit showed greater in vitro potency than the clinically approved drug itself against HDAC1. This trend was found to be general with the BITE-modied HDAC inhibitors performing signicantly better than the ethyl derivatives.
BITE-modied analogues of the multiple sclerosis drug Fingolimod (Gilenya®) (46) have also been reported. 75 Through detailed physicochemical analyses, it was possible to demonstrate that introduction of the BITE group is accompanied by a signicant reduction in lipophilicity compared to the ethyl and triuoromethyl systems. Most recently, the BITE group has been validated as a hybrid bioisostere of the triuoromethyl and ethyl groups using matrix metalloproteases as structural probes. 76 To that end, a series of modied barbiturate inhibitors (47) were evaluated as inhibitors of MMPs 2, 8, 9 and 13. 77 The IC 50 values of the BITE-modied inhibitors were found to intersect those of the corresponding Et and CF 3 derivatives. 55 The vicinal diuorination of alkenes has recently been extended to a-triuoromethyl styrenes to generate uorinated analogues of the isopropyl group (Fig. 12). Although the hep-tauoroisopropyl group has become a privileged motif in agrochemical research 3,7 and currently features in drug candidates 78 and organocatalysts, 79 routes to generate a chiral analogue remained conspicuously absent. Exposing simple a-triuoromethyl styrenes (48) to uorination conditions (various amine$HF complexes, Selectuor®) in the presence of a chiral resorcinol catalyst ((R,R)-49), 80 it was possible to generate chiral products efficiently (50) and with good levels of enantioselectivity. 81 An interesting conformational feature of this motif is that the C(sp 3 )-CF 3 bond is orthogonal to the plane of the aryl ring, thereby enabling stabilising hyperconjugative interactions, 82 whilst mitigating 1,3-allylic strain. 83 Moreover, the stereoelectronic gauche effect manifests itself as was determined by single crystal X-ray analysis of several derivatives. In an extension of this methodology, the vicinal diuorination of a-triuoromethyl-b-diuoro-styrenes (51 / 52) was achieved through in situ generation of p-TolIF 2 (35) by treatment of p-TolI with Selectuor® in the presence of pyr$9HF complex. 84 In line with the previous analysis, the structure displayed a degree of Fig. 10 The enantio-and diastereoselective vicinal difluorination of cinnamamides. Fig. 11 Small molecule drugs modified with the BITE group. pre-organisation with one of the C(sp 3 )-CF 3 bonds aligned with the p-system of the adjacent aryl ring. Curiously, a phthalimide derivative was found to display orthogonal C-F.C]O interactions with a neighbouring molecule in the solid state. This may prove to be useful given the increasing prominence of these interactions in medicinal chemistry. 11,85 3.2 Catalysis-based geminal diuorination of alkenes Hypervalent iodine platforms have a venerable history in halogenation chemistry, 86 and have also been successfully harnessed to generate geminal diuorination patterns (Fig. 13). Seminal examples include Hara and Yoneda's use of stoichiometric quantities of p-TolIF 2 (35) to enable a diuorinative ring contraction of alkenes. 87 The antipodal ring expansion has recently been reported by this laboratory to generate conformationally biased uorinated tetralins. 52 A silver-mediated geminal diuorination of styrenes has been developed by Szabó and co-workers using a uoroiodoxazole reagent. 88 Moreover, Murphy and co-workers have disclosed the geminal diuorination of phenylallenes using stoichiometric p-TolIF 2 via Lewis acid activation. 89 Catalysis-based platforms have been developed to complement these reagent-based approaches and include Kitamura and co-workers protocol to generate 2,2-diuoroethylarenes from simple styrenes using p-TolI as the catalyst with m-CPBA as the oxidant. 90 This laboratory has also reported the geminal diuorination of styrenes and extended it to include asubstituted styrenes bearing uorine-containing groups ( Fig. 13A; 53 / 55 and 54 / 56). 91 The diuorination of alkenyl N-methyliminodiacetyl boronates has been reported by Fan and co-workers to generate synthetically useful building blocks for subsequent diversication. 92 Particularly relevant to this Perspective dedicated to short, chiral uorine-containing groups is the development of an enantioselective, catalytic 1,1-diuorination of alkenes (57) to construct diuoromethylated stereocenters (58) by Jacobsen and co-workers (Fig. 13B). 93 Key to the success of this transformation is a stereospecic phenonium ion rearrangement 94 to deliver highly versatile building blocks with excellent levels of enantioselectivity. The same laboratory has also leveraged a conceptually related reaction design, proceeding via bromonium ion formation, to process simple vinyl bromides to optically active diuorinated alkyl bromides (Fig. 13C, 59 / 61). 95 Bromonium ion formation is a feature in the geminal diuorination of a-(bromomethyl)styrenes reported by this laboratory to generate electrophilic linchpins (Fig. 13D, 62 / 64). 96 Although the transformations discussed in Section 3.2 do not generate a stereogenic centre at the uorine bearing carbon atom, their inclusion in this Perspective is instructive. Collectively, I(III) species have been central to the development of catalysis-based methods to enable the 1,1-and 1,2-diuorination alkenes, whilst also facilitating access to 1,3-diuoro motifs. [97][98][99]

Conclusions
Short, alkyl groups are prominent in the natural product repertoire and are a logical consequence of the iterative biosynthesis algorithms that underpin their genesis. The importance of these seemingly inconspicuous motifs in biology is reected in the development of many synthetic bioactive small molecules in which the "magic methyl" effect manifests itself. Chiral antipodes of these structural units have a venerable history in mechanistic enzymology and would augment the existing drug module portfolio. However, with the exception of branched hydrocarbons, this requires the impractical introduction of deuterium and tritium. Hydrogen to uorine (bio) isosterism, to generate multivicinal uoroalkanes, proves an alternative to address this challenge and develop materials with unique properties. In what may be considered a conceptual merger of two units that are prevalent in nature; namely short alkyl groups and (vicinal) oxidation patterns, a plethora of selective processes have been reported that leverage I(I)/I(III) catalysis to expand organouorine chemical space into chiral regions. Integrating these uorine-containing fragments in focussed drug and agrochemical discovery libraries will fully reveal the physicochemical potential of these materials which will, in turn, provide an impetus for further innovation in the eld. In recent years, the seemingly innocent replacement of H/ OH by F in stereochemically complex biomolecules has led to striking changes in orientation when bound by the target enzyme: this has broad implications for molecular recognition and chemical biology in a more general sense. 100,101 Expanding organouorine chemical space has an important role to play in the design of molecular function and main group catalysis is currently centre stage.

Author contributions
The manuscript was conceived by all authors and written by RG with input from SM and JH.

Conflicts of interest
There are no conicts to declare.