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.

A modular approach employing indene as common starting material, has enabled the straightforward preparation in three reaction steps of P-thioether ligands for the Pd-catalyzed asymmetric allylic substitution. The analysis of a starting library of Pthioether ligands based on rational design and theoretical calculations has led to the discovery of an optimized anthracenethiol derivative with excellent behavior in the reaction of choice. Improving most approaches reported to date, this ligand presents a broad substrate and nucleophile scope. Excellent enantioselectivities have been achieved for a range of linear and cyclic allylic substrates using a large number of C-, N-and O-nucleophiles (40 compounds in total). The species responsible for the catalytic activity have been further investigated by NMR in order to clearly establish the origin of the enantioselectivity. The resulting products have been derivatized by means of ring-closing metathesis or Pauson-Khand reactions to further prove the synthetic versatility of the methodology for preparing enantiopure complex structures. Scheme 1. Three-step synthesis of phosphite/phosphinite-thioether ligands L1-L7a-g from indene. (i) (R,R)-Mn-salen catalyst, 4-PPNO, aq. NaClO, CH2Cl2; 10 (ii) RSH, NaOH, dioxane/H2O (10:1); 11 (iii) ClP(OR 1 R 2 )2; (OR 1 R 2 )2= a-c, Py, toluene and (iv) ClPR 3 2; R 3 = d-g, NEt3, toluene.All ligands were characterized by 31 P{ 1 H}, 1 H and 13 C{ 1 H} NMR spectroscopy and HRMS. All data were in agreement with assigned structures. 13 See experimental section for purification and characterization details.

A set of complex tricyclic compounds containing several functional groups and multiple stereogenic centers has been prepared in only two steps with excellent diastereo-and enantioselectivities. The synthesis takes advantage of the highly versatile and enantioselective Pd-catalyzed allylic substitution of simple cyclic allylic acetates or carbonates to form chiral 1,6-, 1,7-and 1,8-enynes, which are then diastereoselectively transformed to the corresponding cyclopentenone-and cyclobutene-based tricyclic compounds.