Catalyst Discovery and Optimization Using Catalyst Arrays

Intramolecular carbon-hydrogen insertion of metal carbenes generated by catalytic decomposition of diazocarbonyl compounds is a facile methodology for carbon-carbon bond formation. The reaction involves presumably the insertion of in situ-generated metallocarbenes, often catalyzed by rhodium complexes, into C-H bonds [105]. In 1995, Lim and Sulikowski disclosed active copper catalysts for this type of reaction and used them in the synthesis of chiral indolyl derivatives from diazoesters [106]. Subsequently, Burgess and colleagues used a highly parallel screening approach for the optimization of ligand/metal/solvent combinations for the same reaction (Scheme 32.18) [107].

Major Diastereomer 75 % yield, dr = 3.5:1

Scheme 32.18. Discovery and optimization of high-throughput catalyst screening. l-Menth, a new catalyst for the intramolecular C-H l-menthyl; dr, diastereomeric ratio; DDQ, insertion reaction of Rh carbenes from a-diazo 2,3-dichloro-5,6-dicyano-l,4-benzoquinone. esters for the synthesis of indolyl derivatives by

A library of 96 catalytic systems was created in a standard microtiter/filtration plate in order to accommodate incremental variation of the reaction parameters. Combinations of five different natural or synthetic chiral ligands, seven metal precursors, and four solvents were evaluated in a high-throughput fashion using an HPLC device equipped with an autosampler. Subsequent data analysis not only identified two superior catalyst systems based on a bis-(oxazoline) ligand but also led to the identification of a novel and unexpected Ag(I)-based catalytic system with an overall increased diastereoselectivity compared with the original system. Using the optimized set of reaction conditions (AgSbF6, THF, 25 °C, 24 h), the desired product was obtained in 75% yield and in a diastereomeric ratio of 3.5:1.

Burgess and coworkers demonstrated in several examples the value of a multidimensional screening for catalyst optimization. Using a small library of a novel phosphine oxazoline ligand class obtained by a divergent ligand synthesis approach [82, 85], parallel assaying was employed to evaluate and optimize application of these ligands. The novel ligands were screened simultaneously in a customized parallel reaction block bearing a 27- or 34-well format. The asymmetric alkylation of 1,3-diphenylpropenyl acetate with malonate was chosen as a classical test reaction (Scheme 32.19) [84]. Product evaluation and analysis were performed in an automated serial fashion by means of a conventional HPLC equipped with a chiral stationary phase. The parallel screening format allowed for a rapid assessment of various influential reaction parameters, including solvent effects, ligand substitution pattern, presence or absence of ions, ligand-to-metal ratios, and solvent effects on the enantiomeric excess and absolute configuration.

R = Ph, Me, R' = CO Me, COfBu Scheme 32.19. High-throughput screening of phosphine oxazoline ligands in Pd-catalyzed asymmetric allylic alkylation reactions.

Allylic alkylation products with an enantiomeric excess as high as 94% were observed. In a closely related experiment, using the same instrumental set-up, ligands, metal sources, and additives, but a more difficult to control methyl-substituted allylic substrate, the best enantiomeric excess was determined to be 74% [83]. The related divergent ligand synthesis strategy and an identical instrumental set-up for the high-throughput catalyst screening as described above revealed novel so-called "propeller-shaped," C3-symmetric triarylphosphines as chiral ligands [108, 109]. The ligands were screened in an allylic amination reaction with phthalimide as the nucleophilic component, resulting in N-Substituted phthalimide derivatives were obtained with up to 82% enantiomeric excess.

Taylor and Morken uncovered an effective catalyst for the diastereoselective reductive aldol reaction with the aid of an arrayed catalyst evaluation protocol [110]. An array of 192 experiments in glass 96-well microtiter plates was used to evaluate the interdependence of a variety of reaction variables such as the metal precursor, the ligand, and the hydride source in a parallel fashion. The parent test reaction was the reductive coupling of methyl acrylate and benzaldehyde (Scheme 32.20).

Scheme 32.20. Catalytic stereoselective reductive aldol reaction by parallel catalyst array evaluation.

Each reaction was analyzed for relative conversion and stereoisomer ratios by conventional gas chromatography employing chiral stationary phases (GCCSp). Several relationships between reaction condition and yield could be rapidly concluded, including that catechol borane was a superior reducing agent with the largest number of catalysts under the reaction conditions. The novel catalyst derived from [(COD)RhCl]2, Me-DuPhos, and Cl2PhSiH provided generally moderate yields (1569%) for a variety of other substrates but with a high syn stereoselection of up to 23:1 syn/anti. The study demonstrated a rapid assessment of the interdependence of reaction parameters showing that traditional empirical catalyst development approaches, where reaction variables are independently optimized, may not have revealed all active catalyst formulations found within the array.

The metal-catalyzed addition of amines to carbon double bonds, especially of acrylic acid derivatives yielding b-amino acid derivatives, which are useful in peptide analogs or as precursors of optically active amino alcohols, diamines, and lactams, is of utmost importance. Kawatsura and Hartwig uncovered several late transition metal complexes that catalyze the addition of amines to acrylic acid derivatives using a novel parallel colorimetric assay to analyze the addition of primary and secondary alkyl amines to substrates with C=C bonds [111]. All possible combinations of seven metal precursors and 11 phosphine ligands were evaluated in a glass 96-well microtiter plate format for catalytic activity in the addition of piperidine or octyl-amine to methacrylonitrile as representative experiments (Scheme 32.21).

Scheme 32.21. Transition metal-catalyzed addition of amines to acrylic acid derivatives.

The colorimetric ''spot'' test allowed for qualitative evaluation of secondary amines present in the reaction mixture either by consumption of secondary amine or

Scheme 32.20. Catalytic stereoselective reductive aldol reaction by parallel catalyst array evaluation.

Scheme 32.21. Transition metal-catalyzed addition of amines to acrylic acid derivatives.

by formation of secondary amine products. Catalysts derived from [Rh(COD)2]BF4, [Ir(COD)2]BF4, and [Ru(p-cymeneCl2)]2 and several phosphine ligands were cata-lytically active in the addition of piperidine to methacrylonitrile, while Pd(OAc)2 showed activity in the addition of octylamine to the substrate. The results were confirmed in scale-up experiments and the scope and limitations of the reaction of alkylamines with acrylic acid derivatives were assessed in more detail.

In 1998, Whiting and colleagues reported a parallel array screening approach to chiral catalyst discovery in the Lewis acid-catalyzed aza-Diels-Alder reaction of an N-aryl imine with Danishefsky's diene [112], a reaction known not to proceed under normal thermal cycloaddition conditions (Scheme 32.22) [113].



1) Ligand, Lewis acid Solvent, Additive

2) Hydrolysis

High-Throughput Screening

1) Ligand, Lewis acid Solvent, Additive

2) Hydrolysis

Best Conditions:

Best Conditions:

Mgl2, MeCN 2,6-lutidine

Scheme 32.22. Parallel screen for asymmetric induction in Lewis-acid catalyzed aza-Diels-Alder reaction of a N-aryliminodienophile with Danishefsky's diene.

Using multiple-well plates, discrete homochiral Lewis acid complexes were individually generated in solution from four different metal salts, three different common enantiopure ligands, three different solvents, and two different additives. Screening was performed sequentially in about 1 week by measuring the enantiomeric excesses and conversions by means of an automated HPLC equipped with a chiral stationary phase to result in 144 sets of approximate yields and enantiomeric excesses. Reproducibility was confirmed and the most efficient chiral Lewis acid was a combination of MgI2 and (R,R)-1,2-diphenylethylenediamine in acetonitrile in the presence of 2,6-lutidine to afford the N-arylpiperidinone in 97% enantiomeric excess.

Hydrosilylation of substrates such as acetophenones with ruthenium catalysts requires mixed P/N ligands for activity and selectivity; neither pure P/P-chelating nor pure N/N-chelating ligands show activity and selectivity alone [114]. Based on that knowledge and adapting Noyori and coworkers' concept of mixed ligand-ruthenium complexes as precatalysts [115], Frost and coworkers developed an efficient ruthenium-catalyzed asymmetric hydrosilylation of ketones using high-throughput parallel screening to optimize ligand combinations for the target reaction [116]. A small 50-member mixed ligand library of ruthenium diamine/ diphosphine complexes (precatalysts) was prepared in situ by addition of enantio-merically pure tol-BINAP ligands to a ruthenium precursor [RuCl2(C6H6)2], followed by addition of various monoimine or diamine ligands. Diphenylsilane and the precatalysts were added to a solution of acetophenone as the substrate to synthesize the corresponding 1-phenyl ethanols (Scheme 32.23).

Scheme 32.23. High-throughput screening of ruthenium hydrosilylation catalysts to determine the optimal P/P and N/N ligand combination.

Yield and enantiomeric excesses were assayed by serial high-performance liquid chromatography (HPLC) and gas chromatography (GC). For various ruthenium diamine/diphosphine complexes, catalytic performance trends (yield, enantiose-lectivity, and absolute configuration) could be observed. The results obtained from parallel screening were confirmed by traditional serial experiments. The most effective catalyst formulation could be further improved by the addition of catalytic amounts of AgOTf to yield a catalyst that is active and selective in the hydrosilylation of a variety of aromatic ketones. For example, 1-phenyl ethanol was obtained from acetophenone in 53% yield and in 82% enantiomeric excess.

Huffman and Reider from Merck Research Laboratories reported the discovery of improved conditions for the diastereoselective reductive amination in the large-scale synthesis of the angiotensin converting enzyme (ACE) inhibitor elanapril [117]. Using a multidimensional screening approach, the effects of various heterogeneous catalyst formulations and a variety of additives were assayed (Scheme 32.24).




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