Clive A. Smith

Synthesis of 4,4-difluoroglycosides using ring-closing metathesis

4-Deoxy-4,4-difluoro-glycosides have been synthesised for the first time via a direct sequence involving ring-closing metathesis and indium-mediated difluoroallylation with 1-bromo-1,1-difluoropropene in water. Two protecting group strategies were explored, one to allow protection of the primary C-6 hydroxyl group throughout the sequence, while the second was intended to allow deprotection after RCM and before dihydroxylation. The benzyl ether could be used in the first role, and pivaloyl is effective in the second. Dihydroxylations were highly stereoselective and controlled by the orientation of the glycosidic C-O bond.

Towards novel difluorinated sugar mimetics; syntheses and conformational analyses of highly-functionalised difluorinated cyclooctenones

Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT (19)F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers.

A stereodivergent asymmetric approach to difluorinated aldonic acidsElectronic supplementary information (ESI) available: preparation of 1 and 2a, NMR and electrospray for 14 (deuterium exchanged), chiral HPLC traces for 7a and 7b, optical rotations for 7a?8b. See http://www.rsc.org/suppdata/cc/b4/b405067c/

A (bromodifluoromethyl)alkyne has been deployed in a stereoselective route to difluorinated aldonic acid analogues, in which a Sharpless asymmetric dihydroxylation reaction and diastereoisomer separation set the stage for phenyl group oxidation.

(1R*,3S*,8S*)‐2,2‐Difluoro‐3,8‐dihydr­oxy‐5,5‐dimethyl­cyclo­oct‐4(Z)‐en‐1‐yl N,N‐diethyl­carbamate

The structure of the title compound, C15H25F2NO4, is reported and reveals a pseudorotational relationship between the ring conformation of this compound and that of an isomeric by-product reported in the following paper.

(1S*,2S*,4S*)-3,3-Difluoro-2,4-dihydroxy-5,5-dimethylcyclooct-5(Z)-en-1-ylN,N-diethylcarbamate

Conformational equilibria in eight-membered carbocycles occur via two main processes, pseudorotation and ring inversion. The latter exchanges substituent groups between equatorial and axial environments in a pseudo-enantiomeric relationship. Ring inversion is usually the more energetically demanding process; barriers to inversion exchange of 7.3–8.5 kcal mol 1 have been reported, with smaller barriers (ca 5 kcal mol ) (Servis & Noe, 1973) for the pseudorotation. [For early attempts to apply variable-temperature NMR to these phenomena, see Anderson et al. (1969) and St Jacques et al. (1966).] Recent work from our group has attempted to define these processes for a trio of difluorinated cyclooctenyl systems (Fawcett, Griffith et al., 2005). We were interested in observing a pseudorotational relationship between the ring conformations in the pair of reduction products (1) and (2), obtained upon treatment of a precursor ketone with sodium borohydride.