A Chiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis

Abstract An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the iPr group is reported. The difluorination of readily accessible α‐CF3‐styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X‐ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation.

Short, unfunctionalised aliphatic groups (C 1 -C 4 ) are ubiquitous structural features in the natural product repertoire, and are particularly conspicuous in polyketides and terpenes. [1] This is a logical consequence of iterative biosynthesis algorithms that process low molecular weight fragments into higher homologues. [2] Introduced under the auspices of acetylor propionyl-CoA, [3] complemented by electrophilic paradigms involving methyltransferases (SAM), [4] these motifs appear to be vestigial in nature. However, they often encode for a highly specific function and thus delineating their biosynthetic origins has been intensively pursued. Indeed the value of harnessing small aliphatic groups to enhance the physicochemical profiles of drug candidates is exemplified by the "magic methyl effect". [5] Interrogating the stereochemical course of enzymatic methylation has a venerable history, due to the achiral nature of this motif and the pre-conditions associated with designing a chiral bioisostere to track the possible translation of stereochemical information. [6,7] Arigonis celebrated synthesis of chiral acetic acid remains a tour de force in stereocontrolled synthesis, and a master class in orbital symmetry to craft an isotopically orthogonal motif ( 1 H, 2 H and 3 H, Figure 1, top). [8] Whilst this isotope strategy remains expansive in the field of mechanistic enzymology, small fragment-based bioisosterism in drug design relies on stable isotopes to enhance the pharmaco-kinetics and -dynamics of drug candidate performance. [9] Molecular editing with fluorine (H!F) has proven to be particularly effective, [10] and is reflected in the increasing number of fluorinated small molecules reaching the market. [11] This is a consequence of fluorines low steric demand, low polarisability and the stability of the C-F bond. Given the success of achiral perfluoroalkyl groups in drug discovery, catalysis and agrochemistry, [12] routes to small, chiral, 3D fluoroalkane motifs would be advantageous to expand the available chemical space. This includes the C 2 (BITE group) [13] which is a bioisosteric hybrid of the ethyl and trifluoromethyl groups. [14] Cognisant of the prevalence of (C 3 ) isopropyl units in bioactive natural product leads and small molecule Centre: Selected functional small molecules containing the achiral i Pr (pharmaceutical) and CF(CF 3 ) 2 (catalysis and agrochemical) units. [12] Bottom: Design of a main group catalysis approach to generate a chiral fluorinated analogue of i Pr. pharmaceuticals (Figure 1 centre), a catalysis-based strategy to access a differentially fluorinated analogue of the i Pr group was initiated. Harnessing I(I)/(III) catalysis, [15] it was envisaged that a formal 1,2-addition of fluorine across the alkene moiety [16] of simple a-trifluoromethyl styrenes would generate a stereogenic centre bearing F, CH 2 F and CF 3 groups (Figure 1, bottom).
The success of this catalysis-based approach would be contingent on the in situ oxidation of a chiral aryl iodide organocatalyst to generate an ArIF 2 species [17] that would be sufficiently active to engage a sterically-congested, electrondeficient alkene. If successful, the resulting pentafluoroisopropyl surrogate would constitute a chiral C 3 building block in which the lability of the methine proton is mitigated. [18] Moreover, the constituent hyperconjugative interactions intrinsic to the internal vicinal-difluoro motif [19] would manifest themselves in conformation. To identify conditions that would enable the target fluorinated isopropyl motif to be generated from simple a-trifluoromethyl styrenes, a process of reaction optimisation was conducted ( Figure 2, 1 a!2 a).
To that end, simple aryl iodides were investigated as inexpensive catalysts in conjunction with Selectfluor as the terminal oxidant to generate the key ArI(III)F 2 species. [17] Initial studies were performed in chloroform at ambient temperature using an amine:HF ratio of 1:7.5 and the reactions were examined by 19 F NMR spectroscopy using an internal standard. Iodobenzene proved to be a perfectly effective catalyst for this transformation to generate (AE)-2 a and 3 a in a 2.5:1 ratio (86 % combined yield). The latter product arises from phenonium ion rearrangement and has been exploited in a range of catalysis-based geminal difluorination processes. [20] Repeating the reaction with p-iodotoluene (5) led to a notable improvement in yield (> 95 %) with comparable regioselectivity in favour of the desired vicinal product 2 a (2.2:1). Electronic modulation was not well tolerated with the ester derivative 6 proving to be a less active catalyst under comparable conditions (26 %). Control experiments in the absence of catalyst led to < 5 % yield and demonstrate the strongly deactivating nature of the trifluoromethyl group that inhibits background reactions such as those reported by Lal and co-workers using HF sources and Selectfluor . [21] To explore the scope and limitations of this catalysisbased difluorination of a-CF 3 -styrenes, the effect of Brønsted acidity [22] was probed as a function of the amine:HF ratio. [16b] Figure 2. Catalyst identification. Standard reaction conditions: a-CF 3 -pchlorostyrene 1 a (0.2 mmol), catalyst (20 mol %), Selectfluor (1.5 equiv), amine:HF 1:7.5 (0.5 mL), CHCl 3 (0.5 mL), ambient temperature, 24 h. The yield is the sum of vicinal and geminal difluorination products. The regioselectivity ratio (vic:gem) and yield were determined by 19 F NMR spectroscopy using a,a,a-trifluorotoluene as internal standard. Control experiment without catalyst: yield < 5 %. This led to the identification of methods A, B and C, reflecting amine:HF ratios of 1:4.5, 1:6 and 1:7.5 respectively (Figures 3 and 4). Method A proved to be highly effective in generating the electron rich products 2 b-2 d with high levels of regioselectivity favouring formation of the desired vicinal product (> 20:1, up to 86 %). The presence of the CF 3 group clearly distinguish this substrate class from the parent styrenes, which rearrange to generate the geminal product. [20] Control reactions again confirmed the necessity for the catalyst. The seemingly subtle change to Method B proved to be optimal for substrates 2 e-2 k, enabling the generation of alkyl derivatives (2 e-2 h, up to > 20:1, vic:gem) as well as the electron deficient aniline derivative 2 i (74 %, 15.5:1).
Comparable efficiency and selectivity were also noted for the biphenyl system 2 j and adduct 2 k. Augmenting the amine:HF ratio further to Method C provided optimised conditions to access products 2 a,l-2 q. Whereas employing higher HF ratios/ Brønsted acidities under the conditions developed by this laboratory tend to favour 1,1-difluorination, [20f] electron-deficient a-CF 3 -styrenes proved to be notably more recalcitrant to rearrangement and the vicinal products predominated throughout. Given the importance of aryl bromides in contemporary medicinal chemistry, where the C(sp 2 )-Br provides a handle for subsequent cross-coupling, the synthesis of 2 l was conducted on a 1 mmol scale. Despite the volatility of the product, the vicinal product could be isolated in 43 % yield. Products 2 m, 2 n and 2 o behaved similarly and were generated in a vicinal:geminal ratio of ca. 3:1. Given the prominence of aniline fragments bearing isopropyl units in drug and agrochemical discovery (See Figure 1), the phthalimide 2 p was generated cleanly in 61 % yield. Finally, access to the disubstituted aryl 2 q was realised, this time with an improvement in regioselectivity (5.0:1). Having established conditions to enable the vicinal difluorination of a-CF 3 -styrenes via I(I)/(III) catalysis, attention was focussed on a preliminary validation of an enantioselective variant. Whilst catalyst p-iodotoluene 5 is a highly competent catalyst, sites to append stereodirecting groups are conspicuously absent. The investigation was therefore repeated with resorcinol derivatives 7-9 in which proximal stereocentres might induce enantioinduction. Whereas catalysts 7 and 8 proved to be moderately effective, balancing the electronic effects of the resorcinol with a p-CO 2 Me in catalyst 9 led to notably superior catalysis (87 % yield, vicinal:geminal 3:1). As the logical next step, C 2symmetric resorcinol derivatives were investigated as summarised in Figure 5. [23,24] Reactions were performed under standard conditions with an amine:HF ratio of 1:7.5 in CHCl 3 at ambient temperature. Initially, the effect of modifying the substituent X was assessed using the methyl esters 10-13. Counterintuitively, augmenting the steric footprint at site X had a detrimental effect on selectivity. Catalyst 10 (X = Me) proved to be most effective, generating compound 2 a with 86:14 e.r. (> 95 % conversion, 88 % combined yield). Structural editing at site Y was not tolerated as exemplified by catalysts 14-16. As a control series, the C 1 -symmetric catalysts 17-19 were examined (Figure 5, lower). Direct comparison of 17 with the most promising scaffold 10 confirmed the importance of C 2 symmetry (72:28 versus 86:14 e.r.). Interestingly, substituting the methyl ester for benzyl (catalyst 18) did not erode selectivity, although efficiency was decreased. Moreover, the a-Bn catalyst (19) proved to be less efficient than the C 2 -symmetric derivative 12. Having identified catalyst 10 as the most promising scaffold to validate an  . Catalyst optimisation to enable preliminary validation of enantioselection. The conversion and combined yield (in parentheses) was determined by 19 F NMR spectroscopy of the crude reaction mixture using a,a,a-trifluorotoluene as internal standard. Enantioselectivity determined by chiral HPLC. Standard reaction conditions: a-CF 3 -p-chlorostyrene 1 a (0.2 mmol), catalyst (20 mol %), Selectfluor (1.5 equiv), amine:HF 1:7.5 (0.5 mL), CHCl 3 (0.5 mL), ambient temperature, 24 h.

Angewandte Chemie
Communications enantioselective process (please see the ESI for additional details) a representative selection of a-CF 3 -styrenes were subjected to the general catalysis conditions using 10 ( Figure 6).
To complement the plenum of methods available to construct short, unfunctionalised aliphatic groups for drug discovery, a catalysis-based strategy to access chiral, fluorinated surrogates of the isopropyl group has been developed. This serves to expands the current portfolio of fluorine drug modules for drug discovery (Figure 7, centre). [26] Despite the intrinsic steric and electronic challenges associated with generating highly fluorinated stereocentres, this I(I)/I(III) catalysis platform enables a-CF 3 -styrenes to undergo smooth vicinal difluorination (up to > 20:1 vicinal:geminal). Importantly, the CF 3 group effectively inhibits the dominant phenonium ion rearrangement associated with electron rich styrenes, allowing products such as 2 b to be generated with excellent levels of regiocontrol (> 20:1). Finally, preliminary validation of an enantioselective variant is disclosed. Whilst the sterically demanding phenyl and trifluoromethyl substituents (V vdW (CF 3 ) = 39.8 3 ) [10e, 27] render this intermolecular process challenging, it is gratifying to observe encouraging levels of enantioselectivity. A tentative induction model is proposed in which facial discrimination in the enantiodetermining fluorination is a precondition of selectivity. Since Xray analyses of 2 j and 2 p confirm that the major enantiomer is (S)-configured (Figure 7), it is conceivable that stabilising electrostatic interactions (RCF 2 dÀ F··· d+ H-CH 2 R), [28] may bias catalyst-substrate preorganisation. [29] Simple steric discrimination (CF 3 vs. Ph) is not consistent with the selectivities observed the C 1 -symmetric catalysts. The solid-state analysis also reveals a stereoelectronic gauche effect (s!s*; f FCCF = 69.98 and 518 for 2 j and 2 p, respectively) and that the CF 3 group is orthogonal to the plane of the p system (p!s*). [30] Exploring the physicochemical profile of this new motif in the context of drug discovery and contemporary agrochemistry is the focus of ongoing studies and will be reported in due course. Figure 6. The yield is the sum of vicinal and geminal difluorination products. The regioselectivity ratio (vic:gem) and yield were determined by 19 F NMR spectroscopy using a,a,a-trifluorotoluene as internal standard. Isolated yield of the vicinal product is given in parentheses. Enantioselectivity determined by chiral HPLC. a After recrystallisation. N.B.: The products are often highly volatile and care must be taken in the isolation.