Divergent Ligand Synthesis for Enantioselective Alkylations

In 1998, Burgess and coworkers highlighted in several examples the value of divergent ligand synthesis strategies for the preparation of focused ligand libraries

Best Catalyst:

2. Deprotection

2. Deprotection

Model Reaction:

Model Reaction:

68 % yield, 94 % ee Scheme 32.10. Solid-phase approach for the identification of a catalyst for the asymmetric aza-Diels-Alder reaction.

68 % yield, 94 % ee Scheme 32.10. Solid-phase approach for the identification of a catalyst for the asymmetric aza-Diels-Alder reaction.

and the use of automated ligand screening [82, 83]. By definition, divergent syntheses of chiral ligands are characterized by an optically pure material being produced and then subsequently being used to prepare many ligands of a structurally similar class of ligands.

Based on L-serine, a chiral building block (''chiral synthon = chiron'') was prepared as a key intermediate that was then converted into a family of 13 novel chiral phosphine oxazoline ligands using several different routes and employing conventional organic solution synthesis [82]. It was shown that the divergent ligand synthesis approach was very suitable for efficiently accessing this ligand class with good diversity in terms of steric bulk and/or electronic pertubation (Fig. 32.13).

The ability of these ligands to asymmetrically catalyze the addition of dimethyl malonate to 1,3-diphenylprop-2-enyl acetate was investigated [84]. The best of these ligands gave a palladium complex that catalyzes the allylic alkylation with up to 94% ee.

In a different modular approach to generate chiral catalysts for the same trans-

co2h

Ivie u

Ivie u

PPh2

L-Serine

Chiral Building Block "Chiron"

Phosphane Oxazoline

Fig. 32.13. Divergent approach to phosphine oxazoline ligands. Boc, tert-butyloxycarbonyl; R, alkyl and aryl.

formation, Gilbertson and coworkers synthesized a phosphine oxazoline ligand library from amino acids and phosphinocarboxylate building blocks (Scheme 32.11) [85]. Following amide formation between phosphinocarboxylates and amino acids, the carboxy group of the amino acid was reduced to an alcohol. These molecules could then be cyclized with the Burgess reagent and reduced in the presence of Raney Ni to give a 13-member library of phosphine oxazoline ligands. The best of these ligands gave a palladium complex that catalyzes the addition of dimethylmal-onate to 1,3-diphenylprop-2-enyl acetate in 99% yield and in 98% enantiomeric excess.

R1 = H, Me, Ph; R2 = Me, Bn, i-Pr, f-Bu Scheme 32.11. Divergent synthesis of new phosphino-oxazoline ligands.

Gilbertson and coworkers also used solid-phase chemistry to synthesize a library of 77 chiral phosphines that contain the b-turn structural motif [86]. Coordination of palladium gave metal complexes that catalyzed the addition of dimethylmalo-nate to cyclopentenyl acetate in up to 80% ee.

Kobayashi and coworkers developed a solid-phase strategy to synthesize novel pentamine ligands for the enantioselective a-alkylation of lithium amide enolates [87]. The synthesis started with polymer-supported piperazine which was coupled with three different amino acids using standard peptide synthesis protocols followed by the addition of N,N-dialkylglycine. At this stage, the resulting compounds were cleaved off the resin, the terminal secondary amine was methylated, and the

1. LIBH4

2. Burgess Reagent

1. LIBH4

2. Burgess Reagent

Raney-Ni

Raney-Ni amide moieties were reduced using BH3THF to give a library of 20 chiral penta-mines. From this set of ligands, only moderate selectivities were obtained. Through modification of the N-methylpiperazine moiety, one complex was identified that catalyzes the alkylation of piperidinepropionamide with good yields and up to 84% ee (Scheme 32.12).

Scheme 32.12. Chiral pentamine ligand for the enantioselective a-alkylation of lithium amide enolates.

Scheme 32.12. Chiral pentamine ligand for the enantioselective a-alkylation of lithium amide enolates.

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