Synthesis and evaluation of bicyclic 1,3-diols (BODOLs) as ligands for asymmetric catalysis

Abstract: Several ligands based upon 2-substituted bicyclic[2.2.2]octane-2,6-diols (BODOLs) were synthesized and evaluated in two catalytic reactions: I) the Ti(IV)-mediated catecholborane asymmetric reduction of prochiral ketones and II) as catalysts in the asymmetric addition of diethylzinc to aromatic aldehydes. The ligands were prepared by baker's yeast mono-reduction of bicyclo[2.2.2]octane-2,6-dione, followed by protection of the alcohol and then a sidearm was introduced in the 2-position by nucleophilic addition to the carbonyl group. Subsequent deprotection then gave the optically active 1,3-diols. In general, ligands with modifications of the bicyclic framework, and monocyclic analogues, did not produce as good enantioselectivities as ligands with the unmodified bicyclic[2.2.2]octane framework. The influence of steric and electronic properties of ortho-substituted aromatic groups positioned at the 2-position of the bicyclic framework were also examined and the steric effect was found to be important in the Ti(IV) catalyzed reductions, whereas heteroatoms (oxygen and sulfur) attached to the aromatic sidearm was of little (or no) importance. On the contrary, electronegative atoms (nitrogen or oxygen) incorporated in the sidearm were of importance in the additions of diethylzinc to benzaldehyde. The complexes formed in situ between Ti(OiPr)4 and BODOL ligands were studied by NMR spectroscopy and DFT computations. The complexes were found to be C2-symmetric µ-oxo bridged dimers in all of the studied cases; in particular the mixed complex between anisyl-BODOL and phenyl-BODOL indicated a dimeric composition. This, combined with a positive non-linear effect, suggested that the observed complexes may be the actual catalysts since the monomeric species were disfavored, according to both NMR- and computational- studies. When screening a library of yeast strains (for the asymmetric mono-reduction of bicyclo[2.2.2]octane-2,6-dione) it was observed that several strains gave different stereoselectivities, compared to that of the previously known baker's yeast, allowing the isolation of the diastereomeric keto-alcohol (+)-exo-6-hydroxy-2-oxo-bicyclo[2.2.2]octane. This compound formed an infinite helical supramolecular structure in the solid state, implying that structures based upon bicyclo[2.2.2]octane framework may be used as supramolecular building blocks for crystal engineering.