Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate.

Esters of crotonic acid were brominated on a multigramme scale using a free radical procedure. A phase transfer catalysed fluorination transformed these species to the 4-fluorobut-2E-enoates reproducibly and at scale (48-53%, ca. 300 mmol). Asymmetric dihydroxylation reactions were then used to transform the butenoate, ultimately into all four diastereoisomers of a versatile fluorinated C4 building block at high enantiomeric-enrichment. The (DHQ)2AQN and (DHQD)2AQN ligands described by Sharpless were the most effective. The development and optimisation of a new and facile method for the determination of ee is also described; (19)F{(1)H} spectra recorded in d-chloroform/diisopropyl tartrate showed distinct baseline separated signals for different enantiomers.

Developing an asymmetric, stereodivergent route to selected 6-deoxy-6-fluoro-hexoses.

Free radical bromination and nucleophilic fluorination allows the conversion of methyl sorbate into the 6-fluoro analogue which undergoes sequential asymmetric dihydroxylation reactions. A range of 6-deoxy-6-fluorosugars were prepared by using different combinations of ligands. While the enantiomeric excesses obtained were comparable to those from other 6-substituted sorbates, the regioselectivity of dihydroxylation was moderate, with both 2,3- and 4,5-diols being obtained. A successful temporary persilylation strategy was evolved to convert the products of dihydroxylation rapidly to the fluorosugars 6-deoxy-6-fluoro-L-idose, 6-fluoro-L-fucose and 6-deoxy-6-fluoro-D-galactose, which were obtained in overall yields of 4%, 6% and 8% from methyl 6-fluoro-hexa-2E,4E-dienoate .

Interplay of structure and reactivity in a most unusual furan Diels-Alder reaction.

Difluorinated alkenoate ethyl 3,3-difluoro-2-(N,N-diethylcarbamoyloxy)-2-propenoate reacts rapidly and in high yield with furan and a range of substituted furans in the presence of a tin(IV) catalyst. Non-fluorinated congener 2-(N,N-diethylcarbamoyloxy)-2-propenoate fails to react at all under the same conditions. These reactions have been explored using density functional theory (DFT) calculations. They reveal a highly polar transition state, which is stabilized by the Lewis acid catalyst SnCl(4) and by polar solvents. In the presence of both catalyst and solvent, a two-step reaction is predicted, corresponding to the stepwise formation of the two new carbon-carbon bonds via transition states which have similar energies in all cases. Our experimental observations of the lack of reaction of the non-fluorinated dienophile, the stereochemical outcomes, and the rate acceleration accompanying furan methylation are all well predicted by our calculations. The calculated free energy barriers generally correlate well with measured reaction rates, supporting a reaction mechanism in which zwitterionic character is developed strongly. An in situ ring opening reaction of exo-cycloadduct ethyl exo-2-(N,N-diethylcarbamoyloxy)-3,3-difluoro-7-oxabicyclo[2.2.1]hept-5-enyl-2-endo-carboxylate, which results in the formation of cyclic carbonate ethyl 4,4-difluoro-5-hydroxy-2-oxo-5,7a-dihydro-4H-benzo[1,3]dioxole-3a-carboxylate by a Curtin-Hammett mechanism, has also been examined. Substantial steric opposition to Lewis acid binding prevents carbonate formation from 2-substituted furans.

Quantifying the reactivity of a remarkably long-lived difluorinated enol in acidic methanol via solution kinetics and electronic structure calculations.

A simple enol acetal underwent rapid cleavage in acidic solution to generate a difluorinated enol, which was sufficiently long-lived to be characterized by 2D NMR in a protic solvent at ambient temperature. Density functional theory calculations on a model reaction suggest that there are significant differences in protonation transition state timing between the fluorinated and nonfluorinated enols.