Despite its industrial importance metal-catalyzed hydroformylation has not found much application in organic synthesis. This may be primarily due to the difficulty in controlling selectivity issues in the course of this interesting carbon-carbon bond forming reaction. In the last decade a number of excellent solutions to these problems have been devised. Thus, frontiers of chemo-, regio-, diastereo-and enantioselectivity control in the course of the hydroformylation and their application in organic synthesis are the major focus of this review. Mechanistic and conceptual background have been included where appropriate. Additionally, recent progress in the field of domino reactions employing the hydroformylation as a key step is covered.
A new concept for the construction of bidentate ligands for homogeneous metal complex catalysis is described. The concept relies on the self-assembly of monodentate ligands through hydrogen bonding. As a prototype of such systems, 6-diphenylphosphanyl-2-pyridone (6-DPPon) was shown to form a chelate in the coordination sphere of a transition metal center through unusual pyridone/hydroxypyridine hydrogen bonding (X-ray). This hydrogen bonding stays intact in a catalytic reaction as proven upon highly regioselective hydroformylation of terminal alkenes. Regioselectivities and reactivities observed rank the 6-DPPon/rhodium system among the most active and regioselective catalysts for n-selective hydroformylation of terminal alkenes.
The odd couple: Inspired by the principle of DNA base pairing a conceptually new approach for the generation of a heterobidentate‐ligand library based on self‐assembly through hydrogen‐bonding is realized. From a 4×4 library a catalyst that shows outstanding activity and excellent regioselectivity could be identified (see scheme; FGR=functional group, Do=donor group).
The first chiral ligand library based on self-assembly through complementary hydrogen-bonding was realized. From a 10 x 4 ligand library, catalysts that show excellent activity and enantioselectivity for the asymmetric rhodium-catalyzed hydrogenation have been identified.
Motivated by previous findings which had shown that transition metal catalysts based on the 6-diphenylphosphanylpyridone ligand (6-DPPon, 2) display properties as a self-assembling bidentate ligand-metal complex, we have performed a thorough study on the bonding situation of this ligand, alone and in the coordination sphere of a late transition metal. Thus, combining a number of spectroscopic methods (UV-vis, IR, NMR, X-ray), we gained insights into the unique structural characteristics of 2. These experimental studies were corroborated by DFT calculations, which were in all cases in good agreement with the experimental results. The free ligand 2 prefers to exist as the pyridone tautomer 2A and dimerizes to the pyridone-pyridone dimer 4A in solution as well as in the crystal state. The corresponding hydroxypyridine tautomer 2B is energetically slightly disfavored (ca. 0.9 kcal/mol within the up-conformer relevant for metal coordination); hence, hydrogen bond formation within the complex may easily compensate this small energy penalty. Coordination properties of 2 were studied in the coordination sphere of a platinum(II) center. As a model complex, [Cl(2)Pt(6-DPPon)(2)] (11) was prepared and investigated. All experimental and theoretical methods used prove the existence of a hydrogen-bonding interligand network in solution as well as in the crystal state of 11 between one 6-DPPon ligand existing as the pyridone tautomer 2A and the other ligand occupying the complementary hydroxypyridine form 2B. Dynamic proton NMR allowed to determine the barrier for interligand hydrogen bond breaking and, in combination with theory, enabled us to determine the enthalpic stabilization through hydrogen-bonding to contribute 14-15 kcal/mol.
The structural integrity and flexibility provided by intermolecular hydrogen bonds leads to the outstanding properties of the 6-diphenylphosphinopyridin-(2H)-1-one ligand (see scheme) in the rhodium-catalyzed hydroformylation of terminal alkenes, as demonstrated by the combination of spectroscopic methods and DFT computations. Hydrogen bonds were also detected in a competent intermediate of the catalytic cycle.
Hydroformylation of alkynes is an underdeveloped atom-economic and redox-neutral method to prepare enals. Applying a new electron poor self-assembling ligand system provides the first general rhodiumcatalyst for the chemo-and stereoselective hydroformylation of dialkyl-as well as diaryl-substituted alkynes to furnish enals in excellent chemo-and stereoselectivity.Scheme 1 Self-assembling catalyst systems for the hydroformylation of alkenes and alkynes.
The structures of the O-glycosyltransferase LanGT2 and the engineered,
C—C bond-forming variant LanGT2S8Ac show how the replacement of a single
loop can change the functionality of the enzyme. Crystal structures of the
enzymes in complex with a nonhydrolyzable nucleotide-sugar analogue revealed
that there is a conformational transition to create the binding sites for the
aglycon substrate. This induced-fit transition was explored by molecular docking
experiments with various aglycon substrates.
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