An Improved Class of Phosphite-Oxazoline Ligands for Pd-Catalyzed Allylic Substitution Reactions

Abstract

A method for generation of Pd/phosphite-oxazoline catalysts containing an alkyl backbone chain has been successfully applied to Pd-catalyzed allylic substitution reactions. By carefully selecting the substituents at both the alkyl backbone chain and the oxazoline of the ligand, as well as the configuration of the biaryl phosphite group, high activities (TOF > 8000 mol substrate × (mol Pd × h)−1) and excellent enantioselectivities (ee’s up to 99%) have been achieved for many hindered and unhindered substrates with a wide range of C-, O-, and N-nucleophiles (73 substitution products in total). Moreover, DFT and NMR studies of the key Pd-allyl complexes allowed us to better understand the origin of the excellent enantioselectivities observed experimentally. The useful application of the Pd/phosphite-oxazoline catalysts was demonstrated by the syntheses of many chiral carbobicycles, with multiples stereocenters, by simple sequential reactions involving Pd-allylic substitution and either 1,6-enyne cyclization or Pauson–Khand enyne cyclization.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…Compared to Pd/ L63 , the Pd/ L64 catalyst provided higher activities (TOF up to 8000 h –1 ) and excellent oenantiocontrol in a wider range of mono- and symmetrically disubstituted substrates ( ee values up to >99%, 74 examples in total; Schemes 71 and 72 ). 230 High enantioselectivities were achieved in a wide range of symmetrically disubstituted linear allylic acetates, containing alkyl or aryl substituents, with many C-nucleophiles including α-substituted malonates, malononitrile, diketones, 2-cyanoacetates and pyrroles ( Scheme 71 ). The Pd/ L64 catalyst also showed excellent enantioselectivities with various primary and secondary amines, containing either alkyl or aryl groups, using benzylic, allylic and alkylic alcohols as well as silanols ( Scheme 71 ).…”

“…However, the regioselectivities in favor of the branched product diminished when using α-substituted malonates (e.g., regioselectivities dropped from 83% using dimethyl malonate to 60% using dimethyl 2-methylmalonate). 230 …”

“…The second family is formed by the phosphite-oxazoline ligands L64 and L65 ( Figure 5 ), which displayed even broader substrate scope (70 compounds in total). 230 Mechanistic studies by NMR spectroscopy and DFT calculations showed that the ratio of the Pd allyl intermediates that provide the two enantiomeric substitution products is influenced by the ligand design. The enantioselectivity is mostly governed by the relative ratio of the endo and exo isomers.…”

Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

“…There has been interest in using P,N ligands because they can discriminate between the two terminal allylic carbons based on their electronic differentiation, directing the nucleophile towards the allylic carbons trans to the phosphorus atom. Some common ligands used for this reaction include the PHOX ligands, phosphite-oxazoline ligands, and aminoalkyl-phosphine ligands 7,[18][19][20][21][22] . These ligands can control exo-endo preference through the chiral oxazoline/amine moiety which, thanks to the trans phosphorus, is in close proximity to the reacting allyl terminus (Fig.…”

Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

“…Some common ligands used for this reaction include the PHOX ligands, phosphite-oxazoline ligands, and aminoalkyl-phosphine ligands. 6,[17][18][19][20][21] These ligands can control exo-endo preference through the chiral oxazoline/amine moiety which, thanks to the trans phosphorus, is in close proximity to the reacting allyl terminus (Figure 1C). 16 There have been a few methods developed to predict stereoselectivity in asymmetric catalysis.…”