Application of Chiral Mixed Phosphorus/Sulfur Ligands to Palladium-Catalyzed Allylic Substitutions

Abstract

A modular approach to the synthesis of a class of mixed phosphorus/sulfur ligands was designed to identify important ligand structural features for enantioselective palladium-catalyzed allylic subsitutions of acyclic and cyclic ayllic esters. After a systematic variation of the ligand substituents at sulfur, phosphorus, and the ligand backbone, ligand 11k was found to be optimal in the palladium-catalyzed allylic substitution of 1,3-diphenylpropenyl acetate with dimethyl malonate or benzylamine in high yield and excellent enantioselectivity (95−98% ee). A similar optimization of the mixed phosphorus/sulfur ligand for the palladium-catalyzed allylic substitution of cycloalkenyl acetates showed that 49g afforded the highest enantioselectivities (91−97% ee). Application of this methodology to heterocyclic substrates was developed as an efficient approach to the enantioselective synthesis of 3-substituted piperidines and dihydrothiopyrans. Models for asymmetric induction are discussed based on the absolute stereochemistry of the products, X-ray crystallographic data, and NMR spectroscopic data for relevant π-allyl complexes.

Rhodium-catalyzed asymmetric ring opening reactions of oxabicyclic alkenes: Catalyst and substrate studies leading to a mechanistic working model

“…The proposal that nucleophilic attack occurs in an S N 2Ј fashion with inversion is consistent with the well documented mechanism of palladium -allyl chemistry (73)(74)(75)(76) and the proposed mechanism of rhodium-catalyzed reactions of allylic carbonates put forward by Evans (12). The proposal that the alkoxide moiety directs the nucleophilic attack by shifting the position of the metal on the allyl fragment has precedent in the chemistry of palladium where neighboring groups have been found to exert this type of directing influence (77,78).…”

Synthesis of chiral ferrocenylazines. Negishi cross-coupling or S N H reactions?

“…Planar chiral ferrocene derivatives are extensively used as ligands in versatile reactions of asymmetric synthesis [1][2][3][4][5][6][7][8][9][10]. An important place among the ligands of the ferroce series belongs to heterocyclic derivatives capable of forming complexes with metals and also with charged and neutral molecules [1,11].…”

Phosphinite Thioglycosides Derived from Natural D‐Sugars as Useful P/S Ligands for the Synthesis of Both Enantiomers in Palladium‐Catalyzed Asymmetric Substitution.

“…The close proximity of the chiral sulfur atom to the coordination sphere of the transition metal anticipates a good enantioselective discrimination in the catalytic process, provided that the low inversion barrier of the sulfur metal bond can be surmounted. 5,7 We have recently reported the preparation of C 2 -symmetric bis-thioglycosides as new homodonor S/S ligands in Pd(0)-catalyzed allylic alkylation of 1,3-diphenylpropenylacetate with dimethyl malonate.8 A subsequent study of the corresponding Pd(II) complexes has indicated that the good enantioselectivity achieved was a consequence of an efficient stereocontrol of the sulfur atom exerted by the exo-anomeric effect. 9 In the case of phosphinite thioglycosides I metal complexes, where the exo-anomeric effect is not operative, good stereocontrol of the sulfur atom is also predicted taking into account the strong steric and stereoelectronic interactions of the substituent at sulfur and the endocyclic oxygen of the pyranose ring.…”

“…The close proximity of the chiral sulfur atom to the coordination sphere of the transition metal anticipates a good enantioselective discrimination in the catalytic process, provided that the low inversion barrier of the sulfur metal bond can be surmounted. 5,7 We have recently reported the preparation of C 2 -symmetric bis-thioglycosides as new homodonor S/S ligands in Pd(0)-catalyzed allylic alkylation of 1,3-diphenylpropenylacetate with dimethyl malonate.…”

“…Following the seminal work of Evans,5 in this communication we report the first synthesis of mixed P/S ligands I derived from carbohydrates (Scheme 1), and their preliminary applications in a highly enantioselective palladium(0)-catalyzed allylic substitution. In our approximation both enantiomers of the allylated products have been obtained using pseudo-enantiomeric natural sugars as catalyst precursors.…”