Solid-phase synthesis of chiral 3,4-diazaphospholanes and their application to catalytic asymmetric allylic alkylation

Abstract

Functionalized chiral diazaphospholanes ligate to a variety of transition metals, yielding chiral, catalytically active, metal complexes. Previous work has established that amino acid derivatization of the carboxyl groups of (R,R)-N,N-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-3,4-diazaphospholane (1) yields phosphines that are excellent ligands for palladium-catalyzed asymmetric allylic alkylation reactions. Alanine functionalization is particularly effective for allylic alkylation of 1,3-dimethylallyl acetate. Standard Merrifield resins and amino acid coupling methods are used to synthesize the bead-attached phosphine having the topology bead-linker-LAla-(R,R)-1-LAla-OMe, as a 1:1 mixture of linkage isomers. Use of this supported phosphine in Pd-catalyzed asymmetric allylic alkylation yields 92% enantiomeric excess, matching prior solution-phase results. A 20-member collection of amino acidfunctionalized phosphines on beads with the topology beadlinker-AA 2 -AA 1 -1-AA 1 -AA 2 was synthesized by using parallel solidstate methods and screened for efficacy in allylic alkylation. Resulting enantioselectivities indicate that the AA 1 position has the strongest effect on the reaction. Catalyst activities can vary widely with the nature of the phosphine ligand and the reaction conditions. Meaningful analysis of intrinsic catalytic activities awaits identification of the structure and abundance of the active catalyst.T he ubiquity of phosphine-ligated transition metals in homogeneous catalysis and the important role of chiral phosphines in the development of enantioselective catalysis advocates continued expansion of the diversity and applicability of novel chiral phosphines. We believe that key elements of such an expansion include (i) increasingly sophisticated catalyst-substrate interactions in the secondary coordination sphere of the metal, (ii) combinatorial elaboration of promising ''template'' structures, and (iii) application of solid-phase methods for both acceleration of synthesis and ''heterogenization'' of the chiral catalyst. This work demonstrates, on a small scale, a synthetic strategy for making resolved chiral phosphines that are rich in functional groups, their combinatorial elaboration by solid-phase synthesis, and their application to enantioselective asymmetric allylic alkylation (AAA) in both supported and solution phases.Ito and Sawamura (1) have coined the phrase ''secondary interactions'' to describe interactions between transition metal catalyst functional groups and complementary substrate functional groups that occur outside the primary coordination sphere. In principle, such interactions can include hydrogen bonding, Lewis acid-base, electrostatic, hydrophobichydrophilic, and reversible covalent attachment. Many of these motifs are thought to play important roles in nature's remarkably selective catalysts, enzymes (2). Several years ago we initiated a molecular modeling exercise to identify phosphine structures that promoted secondary interactions. Effectively, the model sought was one that e...

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