Academic Staff - Professor Charles Marson

• New synthetic methodology
• Anti-cancer compounds
• Enzyme inhibitors
• Catalytic asymmetric synthesis
• Enantiopure C 2 -symmetric compounds

tel: +44 (0)20 7679 4712
fax: +44 (0)20 7679 7463
internal phone: 24712
email: c.m.marson@ucl.ac.uk

Stereoselective Synthesis of Chiral Organofluorine Compounds and their Applications in Catalysis and Materials

Aims:-The stereocontrolled and chiefly enantioselective synthesis of new chiral fluorine compounds, especially compounds containing one or more -CHF- units, and an investigation into their catalytic and materials properties.

Summary:- Recently, our group achieved the enantioselective syntheses of vicinal difluoropyrrolidines 5 (Scheme 1), perhaps the first enantioselective synthesis of any vicinally substituted difluoro compound of C₂ symmetry.¹ Remarkably, the difluoropyrrolidines were found to be catalysts for asymmetric synthesis (Scheme 3). This is the first time that asymmetric induction mediated by a -CHF-CHF- unit been demonstrated, and hence the first example of catalysis by a compound whose chirality depends upon organofluorine asymmetry. The 3,4-difluoropyrrolidine system also appears to be the first catalyst lacking hydroxy groups that mediates enantioselective epoxidation under Sharpless conditions.

Background:- (a) Uses and synthesis of chiral organofluorine compounds. The stereoselective synthesis of organofluorine compounds^2,3,4 is of major importance in many fields, for example pharmaceuticals,^2,3,5 nucleoside and carbohydrate chemistry,^2b biochemistry,^5,6 and liquid crystals⁷ and polymers.⁸ Many fluorinated alpha-amino acids are potent antitumour and antiviral agents.^2a,5 Additionally, organofluoro ligands can be as powerful, or more so, than oxgyen ligands in coordinating metals.⁹ Whereas enantiocontrolled syntheses of monofluoro-organic compounds is well established, synthesis of an enantiopure vicinal difluoro compound, especially of C₂ symmetry, has not to our knowledge been reported,¹⁰ prior to our communication.¹ Generally, molecular fluorine adds to alkenes with syn-stereoselection, thereby precluding the formation of C₂ symmetric difluorides;¹¹ where trans-addition is observed, yields are usually low.¹² For example diethylaminosulfur trifluoride (DAST),¹³ one of the most commonly used reagents for the conversion of alcohols into fluorides, gives merely a trace of 1,2-difluorocyclohexanes, and with loss of stereointegrity compared with the initial cyclohexane-1,2-diol.¹⁴ Those failures emphasise the significance of the enantiocontrolled introduction of fluorine at two adjacent carbon stereocentres in a single operation which proved possible for the enantiopure vicinal difluorides 5.

Scheme 1. Synthesis of enantiopure trans-3,4-difluoropyrrolidines.

(b) Some physical properties of organofluorine compounds. Ferroelectric liquid crystals enable flat panel technology for large screens to be developed. The introduction of fluorine of defined absolute configuration radically alters the polarizability (crucial to high-speed switching devices) of ferroelectric liquid crystals (Scheme 2),^15,16 and such organofluorine compounds have been used to validate a 'bent cylinder' model for the molecular origins of ferroelectric polarization P in liquid crystals arising from ordered packing in a chiral smectic (C*) phase.¹⁵ Thus, for 6a (Scheme 2) a small value of P is predicted (and found), but for epimer 6b, a large value is predicted (and observed). Both the absolute and relative configuration of organic molecules can be predicted by measurement of the sign and magnitude of P (when the molecule is added as a dopant to an aryl ester host of low polarization).¹⁵ However, these fundamental studies involving polarizability as a result of molecular recognition are hampered by a general inability to create the sp³C-F bond with enantiocontrol. Thus, single enantiomer alcohols or epoxy alcohols have been found to give scalemic and epimeric mixtures, respectively (Scheme 2), and with no predictable rationale. Even in such simple systems, controlling the stereochemistry at the benzylic position (crucial to materials properties) is problematic. We seek new methodology that will deliver enantiocontrolled introduction of F at sp³C, whether in an alkyl chain, or at allylic or benzylic positions.

Scheme 2. Importance of F in ferroelectric liquid crystals, and the difficulties in obtaining enantiopure fluorides.

The synthesis of 5a and 5c are particularly suitable as subunits for liquid crystalline properties, and the scope of applications of difluoropyrrolidines 5 and their derivatives are currently being evaluated for use as liquid crystals and other new materials.

Catalytic features of difluoropyrrolidines:- Catalysis of the epoxidation of allylic alcohols by difluorides 5 was investigated; reactions were conducted in dichloromethane using 15 mol% of Ti(OⁱPr)₄ and 10 mol% of catalyst (Table 1, entries 2-7). In the absence of a catalyst, racemic 7 was obtained (81% yield). The diol 3a, derived (from (2R,3R)-(+)-tartaric acid, the natural isomer) afforded 2,3-epoxygeraniol (7) (97%), in 25% e.e. in favour of the (2S, 3S)-enantiomer (entry 2); however, the difluorinated catalyst 5b afforded a 90% yield of 2,3-epoxygeraniol (7) in 66% e.e., in favour of the opposite i.e. (2R, 3R)-enantiomer (Table 1, entry 5). Entries 3-5 suggest that fluoro groups can provide as good as or greater enantioselection than hydroxyl groups (entry 2), at least in cases where the catalyst incorporates a C₂ -CHF-CHF- unit that is part of a heterocyclic ring.

Scheme 3. Catalytic asymmetric epoxidation with 3,4-difluoropyrrolidines, and comparison with 3a.¹

The reversal of the major enantiomer of 2,3-epoxygeraniol when using catalyst 3 compared with catalyst 5 would be expected if the modes of binding of the hydroxyl and fluoro catalysts had important features in common. However, it is clear that the key catalytic species must be very different from the accepted model for Sharpless asymmetric epoxidation using tartrates (Scheme 4). In the catalytic asymmetric Sharpless epoxidation,¹⁷ free hydroxyl groups on the catalyst (dialkyl tartrate) are a prerequisite for enantioselectivity. In marked contrast to such Sharpless catalysts, the difluorides 5 lack hydroxyl groups and are incapable of deprotonation that could lead to ligand exchange, in yet 5 are viable catalysts for asymmetric epoxidation. Catalysis involving the difluorides 5 would appear to involve (a) co-ordination of titanium to the ring nitrogen atom (b) probably a monomeric catalytic assembly and (c) asymmetric induction that requires the fluorine atoms to have a significant spatial volume, a feature that is surprising in view of the generally accepted effective size of fluorine (attached to carbon) being smaller than a methyl group.

Scheme 4. Sharpless asymmetric epoxidation [using (2R,3R)-(+)-tartaric acid esters].

The presence of fluorine ligands in organic reactions mediated by catalysis is an emerging area of importance.¹⁸ In only one other study has chiral catalysis been a consequence of the spatial arrangement of the fluorine atoms.¹⁹ Consequently, the present examples are, to our knowledge, the first examples of asymmetric synthesis catalyzed by a C₂ symmetric vicinal difluoro compound. Extensions in this area will contribute to our research programme concerning the syntheses and uses of enantiopure organofluorine compounds.^1,20

Support from the EPSRC for a studentship (to R.C.M.) under the ROPA initiative is gratefully acknowledged.

References

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20. R. A. Decréau, C. M. Marson and K. E. Smith, Synth. Commun., 2002, accepted.

This page last modified 20 October, 2009