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The application of reaction calorimetry and process modelling to allow for the rapid and safe scale-up of a Vilsmeier formylation reaction to the pilot plant will be described. This transformation was a key step in the preparation of the backbone amide linker (the so-called “BAL” handle) for solid-phase chemistry. In particular, use was made of Auto-MATE equipment from Hazard Evaluation Laboratories (HEL) and “Reaction Simulator” software to derive a thermokinetic model which allowed us to simulate heat-flow data on-scale. The model was then refined using a HEL SIMULAR 1-L calorimeter, and a direct comparison of the data showed there to be a 20% error in the enthalpy data gathered from the smaller Auto-MATE. The use of a preformed Vilsmeier reagent and dichloromethane as a reaction solvent gave a “square-wave” profile typical of a feed-controlled reaction. These conditions were successfully scaled to a 50-L pilot-plant vessel.

The synthesis of ( S )-2-quinolylalanine through asymmetric hydrogenation with ( S,S )-Et-DuPHOS-Rh is described. The reaction has been extended to other 2-pyridylalanie derivatives.

An efficient “one-pot” synthesis of (R)- and (S)-2-bromo-5-phthalimidopentanoic acid from ornithine is described. Subsequent reaction with potassium thiobenzoate affords a concise, scaleable route to (R)- and (S)-enantiomers of 2-benzoylsulfanyl-5-phthalimidopentanoic acid, an intermediate in the synthesis of MMP inhibitors.

Wittig condensation of the stabilised phosphoranes 9, 10 and 26 with 1-formyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose 11 leads to the vinylogous carbonates 12, 13 and 22. The salts 27–30 and 44, prepared from the corresponding carbonyl compounds, ethyl formate and sodium methoxide, react with acetobromoglucose 21 to give compounds 22–25 and 43.The vinylogous esters/carbonates 12, 13, 22–25 and 43 undergo stereoselective catalytic hydrogenations under mild conditions to give mainly the dihydro derivatives 14, 15, 31–34 and 16. Although the selectivity for re-face addition is modest (ranging from 85:15 to 67:33), it is possible to isolate the dihydro derivatives 15 and 31–33 in acceptable yields (ranging from 71 to 49%) simply by fractional crystallisation. Acidic hydrolysis of compound 31 provides (αS)-α-hydroxymethyl-γ-butyrolactone 39 in high yield with an ee of ∼96%.A model to account for the role of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl unit in the stereoinduction process is presented.

New methodology for the stereoselective α-oxymethylation of esters/lactones is described.

A library of enantiomerically pure mandelic acid derivatives has been prepared using a palladium on carbon catalysed Suzuki reaction. The chirality was derived from enantiomerically pure 4-bromomandelic acid which was obtained by resolution with α-methylbenzylamine.

Dispiroketal formation as a new method for the selective protection of trans diequatorial vicinal diols in carbohydrate systems is reported.

New methodology for the stereoselective α-oxymethylation of esters/lactones is described.

An efficient synthesis of racemic tert-leucine from trimethylpyruvic acid using a Leuckart type reaction is described. A facile resolution of an intermediate with α-methylbenzylamine allows entry into either (R)-or (S)-tert-leucine.

Wittig condensation of the stabilised phosphoranes 9, 10 and 26 with 1-formyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose 11 leads to the vinylogous carbonates 12, 13 and 22. The salts 27–30 and 44, prepared from the corresponding carbonyl compounds, ethyl formate and sodium methoxide, react with acetobromoglucose 21 to give compounds 22–25 and 43.The vinylogous esters/carbonates 12, 13, 22–25 and 43 undergo stereoselective catalytic hydrogenations under mild conditions to give mainly the dihydro derivatives 14, 15, 31–34 and 16. Although the selectivity for re-face addition is modest (ranging from 85:15 to 67:33), it is possible to isolate the dihydro derivatives 15 and 31–33 in acceptable yields (ranging from 71 to 49%) simply by fractional crystallisation. Acidic hydrolysis of compound 31 provides (αS)-α-hydroxymethyl-γ-butyrolactone 39 in high yield with an ee of ∼96%.A model to account for the role of the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl unit in the stereoinduction process is presented.

A range of enantiomerically enriched aromatic β-amino acids with high e.e. have been prepared via enzymatic resolution of ethyl ester derivatives.

Dispiroketal formation as a new method for the selective protection of trans diequatorial vicinal diols in carbohydrate systems is reported.

N-methylmorpholine-N-oxide (NMO) in acetonitrile solution will oxidise activated primary halides to aldehydes and secondary halides to ketones in good yields at room temperature.

A range of enantiomerically enriched aromatic β-amino acids with high e.e. have been prepared via enzymatic resolution of ethyl ester derivatives.

A scaleable “one-pot” preparation of (R)-2-bromo-5-phthalimidopentanoic acid from (R)-ornithine is described. The use of this chirality pool method allowed for rapid development of the process. Ace...

A concise, scaleable synthesis of narwedine from 3,4-dimethoxybenzaldehyde is described. The procedure features a simple modification to the Barton phenolic coupling route.

An efficient synthesis of racemic tert-leucine from trimethylpyruvic acid using a Leuckart type reaction is described. A facile resolution of an intermediate with α-methylbenzylamine allows entry into either (R)-or (S)-tert-leucine.