Editing the stereochemical elements in an iridium catalyst for enantioselective allylic amination

Abstract

Individual diastereomeric phosphoramidites and mixtures of diastereomeric phosphoramidites were evaluated in the iridiumcatalyzed amination of allylic carbonates. The original process was conducted with a phosphoramidite ligand containing a resolved 2,2-dihydroxy-1,1-binaphthyl (BINOL) group and a diastereomerically and enantiomerically pure bis(phenethyl)amino group. Evaluation of the structure of the active catalyst and relative rates for reactions in the presence of catalysts containing diastereomeric ligands led to the identification of a phosphoramidite that provided the amination product with enantiomeric excess similar to the original, more structurally and stereochemically complex ligand and that contains a racemic BINOLate and an N-benzylphenethylamino group on phosphorus.B iologically active molecules with stereocenters alpha to nitrogen range from single enantiomer pharmaceuticals to alkaloid natural products (1, 2). The classic routes to such chiral amines include resolution with chiral acids or initiation of the synthesis with a member of the existing optically active chiral pool that includes naturally occurring amino acids. However, the resolution typically requires disposal of at least half of the chiral amine, and many targets require a multistep synthesis from materials in the chiral pool. Thus, many synthetic approaches have been investigated for the preparation of ␣-chiral amines in an enantioselective manner.Two common approaches involve hydrogenation of an imine (3-5) and additions of nucleophiles to imines (6-12). The hydrogenation of imines is not yet a general process and can be used to form only primary or secondary amines. The addition of carbon nucleophiles to imines with high enantioselectivity has been limited also, and the highest selectivities typically require a chiral substituent at nitrogen that would ultimately be disposed or would require recycling (8). An alternative approach involves enantioselective formation of the carbon-nitrogen bond in the amine (6,7,13,14).Transition metal-catalyzed reactions of nitrogen nucleophiles with allylic electrophiles (15) provide the opportunity to form the carbon-nitrogen bond in an amine with stereoselectivity that is based on a catalytic amount of a chiral ligand bound to the transition metal. In most cases, a palladium catalyst has been used for this transformation (16,17). Although exceptions have been found (18), most palladium catalysts generate a terminal achiral allylic amine product from a linear allylic electrophile or a racemic branched allylic electrophile. Thus, a catalyst that would convert either a racemic branched allylic electrophile or an achiral terminal electrophile enantioselectively to a branched chiral amine product would provide a valuable synthetic tool (19-21). We recently reported an iridium complex containing a phosphoramidite ligand that catalyzes the reaction of amines with achiral linear allylic carbonates to form the branched allylic amine products with high enantioselectivity and regioselectivity (Eq. 1 and ...

Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

“…Based on the structure of the active catalyst, Andreas Leitner developed sterochemically edited complexes that are nearly equivalent in activity and selectivity as the original system 52,53. The phenethyl substituent attached the metallacyclic core of the structures in Scheme 2 and Figure 2 is distal from the metal center, and, we proposed that this substituent could be replaced by a group lacking any stereocenter (Figure 3).…”

Scalable Route to Chiral Phosphoramidites

“…Encouraged with this result, we extended this strategy to prepare bis-naphthyl phosphoramidite 5 (Scheme 2). This catalyst was found to be useful for iridium catalyzed amination of allylic carbonates (Leitner et al, 2004).…”

Regio‐ and Enantioselective Iridium‐Catalyzed N‐Allylation of Indoles and Related Azoles with Racemic Branched Alkyl‐Substituted Allylic Acetates

“…Iridium-catalyzed allylic amination has emerged as an important method for enantioselective C À N bond formation. [1][2][3][4][5][6][7][8][9] Pursuant to the pioneering work of Takeuchi, [1,2] studies from the laboratories of Helmchen, [3,4] Hartwig, [5,6] Carreira, [7] and You [8,9] have shown that chiral phosphoramidite-modified iridium complexes are especially effective in this regard (Figure 1). Like the parent palladium-catalyzed Tsuji-Trost reactions, [10] the iridium-phosphoramidite-catalyzed allylic alkylations occur via cationic p-allylmetal intermediates.Recently,wefound that p-allyliridium-C,O-benzoates,w hich are wellknown to promote nucleophilic allylation of carbonyl compounds, [11,12] are also effective catalysts for highly regio-and enantioselective electrophilic allylation of amines.…”