(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• addition and cyclisation. Styrenyl (to 79a,c–e), acrylonitrile (to 79b) as well as acrylate-based alkenes could be inserted under the reaction conditions. The authors were then able to apply their method to the synthesis of isosteres of both boscalid (isostere = 80) and norharmane (isostere = 81) (Scheme

• ]propellane (129). Gassman reported the initial synthesis of [3.1.1]propellane (129) in 1980 [61], and this was recently optimised by Uchiyama (Scheme 13A) [47]. Cyclisation to the bridged structure 126 was achieved by enolate formation and intramolecular nucleophilic substitution of iodide diester 125. A

• substrate. Employing Lewis acid catalysis Deng and co-workers reported an alternative pathway to indole-derived BCHs. Polysubstituted BCHs were accessed by nucleophilic addition of the indole to the activated bicyclobutane followed by a Mannich cyclisation [81]. The synthesis of wide variety of tri- and

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• -step ynamide annulation and imidazolium ring-formation sequence. Metalation with Au(I), Cu(I) and Ir(I) at the C2 position provides an L-shaped NHC ligand scaffold that has been validated in gold-catalysed alkyne hydration and arylative cyclisation reactions. Keywords: annulation; carbene; gold

• [20][21] that should facilitate access to different groups at the oxazole C-2 position allowing a range of imidazolium-forming cyclisation strategies to be explored. Glorius and co-workers reported the formation of symmetrical NHCs by imidazolium ring formation from bisoxazoline motifs [22] but

• introduce a formamide motif in place of the amine or imine to allow the use of more forcing cyclisation conditions (Scheme 1a, path c). Oxazole 8a was obtained in good yield from 1a using only a slight excess of nitrenoid 7 and 2 mol % catalyst loading. Heating 8a in the presence of POCl3 afforded the 3

Tying a knot between crown ethers and porphyrins

• Maksym Matviyishyn and
• Bartosz Szyszko

Beilstein J. Org. Chem. 2023, 19, 1630–1650, doi:10.3762/bjoc.19.120

• synthesising these systems, including cyclisation reactions, self-assembly, and their remarkable reactivity. The potential applications of porphyrin-crown ether hybrids are also highlighted. Moreover, the discussion identifies the challenges associated with synthesising and characterising hybrids, outlining

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• of the 2-methylisoborneol synthase was investigated through enzyme incubations with several substrate analogs, giving access to two C12 monoterpenoids. Implications on the stereochemical course of the terpene cyclisation by 2-methylisoborneol synthase are discussed. Keywords: biosynthesis; enzymes

• model was proposed that proceeds through the S-adenosylmethionine (SAM) dependent methylation of geranyl diphosphate (GPP) to 2-methyl-GPP (2-Me-GPP), followed by a terpene cyclisation to 1 (Scheme 1A) [10]. The cyclisation cascade requires isomerisation to (R)-2-methyllinalyl diphosphate [22], followed

• by two sequential cyclisation reactions to A and B, and terminal quenching with water. This hypothesis was confirmed by the discovery of the biosynthetic genes coding for a GPP methyltransferase (GPPMT) and a type I terpene synthase termed 2-methylisoborneol synthase (2MIBS) [23][24]. Interestingly

Functional characterisation of twelve terpene synthases from actinobacteria

• Anuj K. Chhalodia,
• Houchao Xu,
• Georges B. Tabekoueng,
• Binbin Gu,
• Kizerbo A. Taizoumbe,
• Lukas Lauterbach and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1386–1398, doi:10.3762/bjoc.19.100

• 26 can be well understood from the cyclisation mechanism towards 23 (Scheme 1B). After substrate ionisation to A a 1,10-cyclisation leads to the (E,E)-germacradienyl cation (B) that can either be deprotonated to 24 or captured with water to yield 26. Both compounds are important neutral intermediates

• in sesquiterpene biosynthesis that can be reactivated by reprotonation for a second cyclisation to eudesmane (6,6-bicyclic) or guaiane (7,5-bicyclic) sesquiterpene hydrocarbons or alcohols, respectively [46][47]. Starting from 26, such a protonation induced cyclisation can lead to C that is the

• as plasticisers. A) Cope rearrangement of 24 and 26. B) Cyclisation mechanism from FPP to 23, identifying compound 26 as a biosynthetic intermediate and 24 as a side product. Terpene synthase homologs characterised in this study. Supporting Information Supporting Information File 162: Additional

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• was converted to the epoxide 7.5 by cyclisation in the presence of potassium carbonate in methanol, thus producing the interesting building block 7.5. A second option, optimized to avoid the formation of epoxide, used a hindered base and the reactive benzyltriflate as electrophile to achieve under

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• [36] via the polyphosphoric acid (PPA) catalysed cyclisation of 2,2'-diaminobibenzyl (20) at elevated temperatures (Scheme 3) [37][38]. 1.3 Catalytic dehydrogenation An early synthesis of 5H-dibenzo[b,f]azepine (1a) involved the gas phase dehydrogenation of 10,11-dihydro-5H-dibenzo[b,f]azepine (2a) to

• , several methods of carboxamidation were tested, thus allowing the authors to synthesize carbamazepine (CBZ) derivatives of 43. 3 Metal-catalysed cyclisation Diverse metal-catalysed coupling methods exist for the preparation of the dibenzo[b,f]heteropine ring system. The following approaches are broadly

• -pyridobenzazepines 60b via cyclisation of 2,2'-dihalostilbene analogue 58 through a Pd-catalysed double Buchwald–Hartwig amination. The stilbene analogues 58 were prepared by a Wittig reaction with reported yields of the desired Z-isomer around 55%. The amination step was performed on a series of primary alkylamines

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• initial formation from farnesyl diphosphate, these neutral intermediates can become reprotonated for a second cyclisation to reach the bicyclic eudesmane and guaiane skeletons. This review summarises the accumulated knowledge on eudesmane and guaiane sesquiterpene hydrocarbons and alcohols that

• is terminated by deprotonation to yield a terpene hydrocarbon or by nucleophilic attack of water to generate a terpene alcohol. For the precursor of sesquiterpenes FPP six initial cyclisation modes are possible (Scheme 1). After ionisation to A either a 1,10-cyclisation to the (E,E)-germacradienyl

• cation (B) or a 1,11-cyclisation to the (E,E)-humulyl cation (C) is possible. Reattack of diphosphate at C-3 results in nerolidyl diphosphate (NPP) that can undergo a conformational change by rotation around the C-2/C-3 single bond, which allows reionisation to D. This intermediate can react in a 1,10

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• polycyclic skeletons of triterpenoids and steroids are created by oxidosqualene cyclases (OSCs) from the universal substrate 2,3-oxidosqualene [5]. As different folding modes (chair–boat–chair vs chair–chair–chair) and different ring sizes can occur during this cyclisation cascade, resulting triterpene and

• catalyse the initial C22,16 dihydroxylation of cholesterol (3) [35]; in contrast, the related CYP DzCYP90B71 was found to catalyse only the first hydroxylation at C22 [66]. This step is followed by a rate-limiting cyclisation step through unstable furostanol intermediate 14 that involves CYP-catalysed

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• -butyloxycarbonyl (Boc)-protected threonine using bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) [14][15] and Hünig’s base to give 9. Cleavage of the Boc group with 5% TFA followed by basic treatment resulted in the cyclisation to the dioxopiperazine 10. Acetylation and subsequent treatment with LiClO4 and

• 13. Removal of the Cbz group by catalytic hydrogenation proceeded with spontaneous cyclisation to 14. With this material, the elimination of the MOM group smoothly proceeded by treatment with KH and 18-crown-6 in THF at 25 °C to 15, that upon removal of the Boc group with TFA and 1,3-dimethoxybenzene

Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

• Nisha Devi and
• Virender Singh

Beilstein J. Org. Chem. 2022, 18, 926–934, doi:10.3762/bjoc.18.92

• –Spengler (P-S) or Bischler–Napieralski (B-N) cyclisation, introduction of a formyl group at C-1 or C-3 position of the β-carboline frameworks may provide a new route for generating unlimited diversity at C-1 as well as at the C-3 position of β-carbolines. As depicted in Figure 2, 1-formyl-β-carbolines and

• 3-formyl-β-carbolines are decorated with different sites for diversification which make these synthons a promising template for the construction of β-carboline-fused frameworks via C-1 N-9, C-1 N-2 and C-3 N-2 cyclisation. Similarly, β-carboline-substituted molecular frameworks can be generated at C

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• Kian Donnelly Marcus Baumann School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland 10.3762/bjoc.18.27 Abstract An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation

• ]. Various other methods to access this heterocyclic moiety have been reported in the literature, with many focusing on either cyclodehydration or cyclodesulphurisation (Scheme 1) [27]. However, in recent years, there have been a number of oxidative cyclisation protocols reported to access the same 1,3,4

• -oxadiazole unit [28][29][30][31][32][33]. In 2012, Guin and co-workers described the iodine-mediated cyclodesulphurisation of thiosemicarbazides, yielding the corresponding 1,3,4-oxadiazoles [32]. Subsequently, Yu and co-workers reported the iodine-mediated oxidative cyclisation of acyl hydrazones to form

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• diastereoisomer increased. A similar trend was observed when starting from the enantiomerically enriched 3a (Table 2, entry 3). It has been shown that substituted oxindoles can be converted to indolopyrans via intramolecular cyclisation [33]. We also tried synthesizing 4H-pyrans in acidic conditions but no

The enzyme mechanism of patchoulol synthase

• Houchao Xu,
• Bernd Goldfuss,
• Gregor Schnakenburg and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 13–24, doi:10.3762/bjoc.18.2

• Chemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.18.2 Abstract Different mechanisms for the cyclisation of farnesyl pyrophosphate to patchoulol by the patchoulol synthase are discussed in the literature. They are based on isotopic labelling experiments, but the

• reactivated by protonation for further cyclisation steps, while previously discussed intra- and intermolecular hydrogen transfers are not supported. Furthermore, the isolation of the new natural product (2S,3S,7S,10R)-guaia-1,11-dien-10-ol from patchouli oil is reported. Keywords: biosynthesis; DFT

• ), seychellene (11) and pogostol (12) as further side products [8]. The biosynthetic mechanism of the formation of compound 3 was investigated by several groups through isotopic labelling experiments. In 1987, Croteau et al. have suggested a pathway through 1,10-cyclisation of FPP to the (E,E)-germacradienyl

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• –Miyaura cross-coupling; Introduction Peptide cyclisation emerged as a popular approach to limit conformational mobility in order to enhance the binding affinity towards a biological target. Moreover, cyclic peptides are more stable against proteolytic digestion and can provide an improved membrane

• ]. Additionally, halotryptophans were incorporated in pentapeptides as building blocks for macrocyclisation by Suzuki–Miyaura cross-coupling (SMC) aiming at the preparation of bicyclic peptides [71]. Recently, intramolecular SMC has been successfully applied to side chain-to-tail cyclisation between

• oxidation could be minimised by improved cleavage conditions under argon. Replacing sSPhos by tri(o-tolyl)phosphine (P(o-Tol)3), that had successfully been applied for peptide cyclisation by on-resin SMC [78][80], led to incomplete conversion. The cyclisation of the same peptide with the regioisomer 6

Me₃Al-mediated domino nucleophilic addition/intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines; a convenient approach for the synthesis of substituted 1-aminoisoquinolines

• Krishna M. S. Adusumalli,
• Lakshmi N. S. Konidena,
• Hima B. Gandham,
• Krishnaiah Kumari,
• Krishna R. Valluru,
• Satya K. R. Nidasanametla,
• Venkateswara R. Battula and
• Hari K. Namballa

Beilstein J. Org. Chem. 2021, 17, 2765–2772, doi:10.3762/bjoc.17.186

• achieved by treating 2-(2-oxo-2-phenylethyl)benzonitriles with amines in the presence of Me3Al. The reaction proceeds via a domino nucleophilic addition with subsequent intramolecular cyclisation. This method provides a wide variety of substituted 1-aminoisoquinolines with good functional group tolerance

• . Furthermore, the synthetic utility of this protocol was demonstrated in the successful synthesis of the antitumor agent CWJ-a-5 in gram scale. Keywords: 1-aminoisoquinolines; CWJ-a-5; intramolecular cyclisation; 2-(2-oxo-2-phenylethyl)benzonitriles; nucleophilic addition; Introduction Heterocyclic compounds

• suitably tailored benzonitriles 3 were cyclized in an intramolecular fashion by installing nuclophilic nitrogen onto the nitrile functionality would generate 1-aminoisoquinolines. Herein we describe our efforts on a Me3Al-mediated nucleophilic addition followed by an intramolecular cyclisation of 2-(2-oxo

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• (GFPP, C25) for sesterterpene biosynthesis. Type I terpene synthases (TPSs) activate these acyclic molecules by the abstraction of diphosphate to produce a reactive allyl cation that can initiate a cascade reaction through typical carbocation chemistry, including cyclisation reactions by intramolecular

• possible explanation may be that for efficient catalysis to yield a cyclic product the substrate needs to be tightly bound in the active site. If the space is too large, this may allow for too much conformational flexibility of the substrate which may prevent an efficient terpene cyclisation reaction. The

• , CHCl3) [13]) revealed that this product was nearly a racemate. This unexpected finding is explainable by two different cyclisation modes of GGPP to the (R)- and the (S)-cembranyl cation (A, Scheme 1). The cationic centre of (R)-A may be in close proximity to an active site water, which may be able to

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• quenched aldol outlet stream was directed into a cooled receiver vessel, to which trifluoroacetic anhydride (TFAA) was simultaneously added, creating a net semi-continuous process. Subsequent ammonia-mediated cyclisation of the resultant diene followed by alkylation with the chlorotriazolinone 48 yielded

• mixture is biphasic, and a preliminary separation is carried out before entering the reactor coil. After discontinuous purification procedures, the product 82 was yielded in 98% purity (72% yield). The second step, instead, is an acid-catalysed cyclisation which employs the same tubular reactor at lower

• temperature (26 °C) and reaction time (2 minutes). The cooled solution of 82 in hexane is mixed in flow with sulfuric acid and then heated at 29 °C. After the cyclisation, the stream was quenched with water whilst the temperature was maintained around 45 °C. The hexane was then removed using a countercurrent

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• -1,3-diol [21][22]. For instance, deoxoprosophylline (5) as a cyclic 2-amino-1,3-diol target molecule was prepared by Kokatla et al. in an 8 step synthesis starting from Perlin aldehydes, via Pd(OH)2-catalyzed reductive azidoketon cyclisation [23]. Another synthetic pathway involves a stereoselective

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• , followed by a favoured 6-endo-trig cyclisation driven by the 4-methoxy group to form the 6,6-spirocycle 11. The addition of water and subsequent ring-opening would then form the acid 12, which upon elimination of water would then provide the observed acid chloride 13. We wished to also determine whether

• form the 6,6-spirocycle 19. A 1,2-rearrangement would then produce the observed product 17. Presumably the analogous dichloroalkenone 6d does not undergo this cyclisation due to the deactivation of the ring by the ketone towards nucleophilic attack. Conclusion In conclusion, we have shown that 1,1,1

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• cyclisation of 1-(1-azidovinyl)-4-methylbenzene (1a) in refluxing 2-MeTHF and cyclopentyl methyl ether (CPME) as green solvent candidates, and compared the results with the reaction conducted in toluene (Table 1). The reaction proceeded rapidly in CPME, while the use of 2-MeTHF resulted in longer reaction

Supramolecular polymers with reversed viscosity/temperature profile for application in motor oils

• Jan-Erik Ostwaldt,
• Christoph Hirschhäuser,
• Stefan K. Maier,
• Carsten Schmuck and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2021, 17, 105–114, doi:10.3762/bjoc.17.11

• cyclisation. Thus, all compounds feature a central BINAM unit, which is connected to the BUs (GCP or ACP) via a propionamide linker [29]. The synthesis of compound 1 was carried out starting from BINAM by coupling with GCP derivate 5 [12][13] after activation with thionyl chloride (see Figure 3). Deprotection

On the mass spectrometric fragmentations of the bacterial sesterterpenes sestermobaraenes A–C

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2020, 16, 2807–2819, doi:10.3762/bjoc.16.231

• initiate a cationic cyclisation cascade, leading to structurally highly complex and usually polycyclic terpenes in just one enzymatic transformation. The initially formed products are non-functionalised terpene hydrocarbons or, if the terminal cationic intermediate of the cyclisation cascade is trapped by

• rearrangement to a2•+ and a hydride shift to b2•+ (Scheme 3A). This hydride migration is in reverse order compared to a similar step along the cationic cyclisation cascade during the biosynthesis of 2 (Scheme S1 in Supporting Information File 1). The subsequent inductive ring opening to c2•+ and α-cleavage of

• carbons are marked by purple dots. Supporting Information Supporting Information File 428: Mass spectra of the unlabelled and 13C-labelled compounds 1–3, and the cyclisation mechanism from GFPP to 1–3 by SmTS1. Funding This work was funded by the DFG (DI1536/7-2).

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• Bach’s recent review on the subject [13]. Photocatalyst 174 was first used in a cyclisation reaction where the putative mechanism involves a hydrogen bonding complex 175 between the catalyst and quinolone substrate 176 (Scheme 26) [2]. Subsequent photoexcitation promotes a photoinduced electron transfer

• to generate diradical 177 that then adds to the alkene to form diradical 178. A SET between the ketyl radical and the α-carbonyl radical generates enolate intermediate 179, which after proton transfer regenerates the catalyst and releases the desired cyclisation product 180 in a moderate yield and

• :4. Recently, Knowles et al. used a similar tricatalytic system for the enantioselective cyclisation of sulfonamides 238 (Scheme 37) [98]. In this case, the proposed mechanism involves a PCET step to give an N-centred radical that then cyclises enantioselectively to give the alkyl radical

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• when the “cyclisation” operation is achieved from geminal motifs (Figure 7B). Significant logP reductions are observed, especially from the internal geminal fluorination motif as in G9 to E2 (0.72 logP units). Starting from a trifluoromethyl group (Figure 7C), similar logP reductions are achieved (e.g

• ., D5→E5 and G10→E5) which interestingly, are of the same magnitude as for the nonfluorinated derivatives (compare D1, G1 to E1, Figure 6). It is worth noting that “cyclisation” to give cyclopropanol derivatives substituted with a fluorinated methyl group (not shown) can also be considered. Marketed

• leads to a lipophilicity decrease, which remains the case when fluorination is present. For a C–F/C–H→C–C ‘cyclisation’, only minimal lipophilicity differences are observed (in either direction) when the C–F moiety was part on a monofluorinated motif. However, when the C–F moiety was part of a geminal