Synthesis and Scale Up of Chiral Alcohols and Epoxides

Björn Schlummer from Bayer discussed the various approaches that can be used to synthesize chiral building blocks, and described a number of these methods that are used at Bayer.  Chiral pool approaches can be used to produce chiral polyols amino-alcohols, starting with naturally occurring acids and reducing the carboxylic acid group.  Catalytic hydrogenation over ruthenium catalysts is possible at high temperatures and pressures but racemisation occurs under such forcing conditions.  Bayer have developed a promoted ruthenium catalyst containing rhenium that allows the catalytic reduction to be operated at lower temperatures where no racemisation is observed.  Substrates such as L-lactic acid, L-malic acid and L-tartaric acid give the corresponding diol, triol or tetraol.

Similarly amino acids can be reduced to amino-alcohols.  For “alkyl” amino acids, such as L-alanine or L-valine the product is the expected amino alcohol (L-alaninol or L-valinol), but for amino acids with aromatic side chains such as L-phenylalanine ring reduction also takes place giving L-cyclohexylalanine.

Bayer have also developed number of bisphosphine-derived complexes for asymmetric hydrogenation, such as BIBFUP and Cl-MeO-BIPHEP and the phosphite derived ligand.  The (R)-enantiomers of the ligands are shown below, but both enantiomers are available as the ligands are synthesized by a racemic route and then separated by resolution (EP 749,973, EP 1186609, AND DE 101 48 551).

The ruthenium complexes of these ligands are extremely effective for hydrogenation of α–ketoesters, b-ketoesters α,β-unsaturated acids to α–hydroxyesters, β-hydroxyesters and α-substituted carboxylic acids.  In comparative studies these catalysts give comparable results (chemical yield, ee) to the best alternative ligands, such as BINAP.

Finally he outlined developments in the application of the Julia-Colonna asymmetric epoxidation of electron poor olefins such as chalcones.  The standard method employs poly-leucine in triphasic conditions.  Chemists at Bayer realised that for the reaction to proceed the hydroperoxide anion has to be generated in the aqueous phase and then be transferred to the organic phase to effect the reaction.  So adding a phase transfer catalyst should and does improve the rate of reaction dramatically (Bayer patents pending: DE 10136131, DE 10136132, DE 10136485).  The method has the added advantage of making the work up of the reaction and recycle of the catalyst simpler.