PHOX catalysts, enantioselective

The most extensively studied of these systems are the phosphino-oxazoline (PHOX) catalysts 14 (Fig. 29.2). Good enantioselectivity has been achieved with these catalysts over a broad range of substrates [7]. 

Another PHOX analogue has the aryl ring of the PHOX catalyst replaced by a thiophene unit 16 (Fig. 29.4) [15]. The synthesis is similar to that of the PHOX catalysts, starting with oriho-nu lallaliori of the thiophene. The catalysts showed similar selectivity to PHOX, and were used to hydrogenate substrates 1 and 2 with maximum enantioselectivities of 99% and 94%, respectively. 

The first of these was the phosphino-benzoxazine catalyst 27 (Fig. 29.14) [27]. This catalyst contains a six-membered benzoxazine ring in place of the five-membered oxazoline ring in the PHOX catalysts. It was hoped that this change would bring the chiral center on the ring into closer contact with the metal, resulting in higher enantioselectivities. However, enantiomeric excesses were only modest with the substrates chosen. 

Finally, the phosphinite-oxazole catalyst 29 (Fig. 29.16) was recently reported and used to hydrogenate a series of functionalized and unfunctionalized alkenes [31]. It was anticipated that the planar oxazole unit and the fused ring system would improve the enantioselectivity compared to the PHOX catalyst by increasing rigidity in the six-membered chelating ring [32]. Indeed, these catalysts... 

Moving away from ketones to other prochiral nucleophiles has also been an important goal in our group. We choose to explore lactam-derived substrates in part because we envisioned that the products formed would be useful intermediates in the synthesis of various alkaloids and because we would be able to modulate the electronics and sterics of the lactam enolate by attaching different groups at nitrogen with the aim of optimizing the enantioselectivity of the allylic alkylation. In the event, we chose to initially test tosyl-protected lactam allyl ester 29 and Boc-protected lactam aUyl ester 30 with two Pd PHOX catalysts in several solvents (Scheme 18). 

The development of Ir-chiral N,P ligand system opens another promising way for the hydrogenation of allylic alcohol and its derivatives. For example, a cationic Phox-Ir complex catalyzes the hydrogenation of ( )-2-methyl-3-phenyl-9-propen-l-ol in a highly enantioselective fashion.178 With 1 mol.% (5)-92-Ir catalyst, the hydrogenation proceeds completely to provide the chiral alcohol product in 96% ee. Under the same conditions, a para- Bu-substituted chiral alcohol derivative is obtained with 94% ee for the synthesis of lilial (Equation (59)). Heterocyclic N, P-ligand, HetPHOX 113, is also efficient for this reaction.191... 

Steric interaction was also clearly an issue for all of the systems investigated. Most notable is the large difference in the reactivity between ThrePHOX 6b- and PHOX 5c-based catalysts with respect to the substituents bound to the nitrogen atom. ThrePHOX consistently performed best with A-methyl-A-benzyl enamines while PHOX preferred a W-methyl-A-phenyl derivative. Lowering the temperature had a favorable outcome on enantioselectivity but slowed the reaction and caused drops in conversion for 5c and 6b. 

The first enantioselective, iridium-catalyzed allylic substitution was reported by Helmchen and coworkers soon after the initial report by Takeuchi. Helmchen studied catalysts generated from phosphinooxazoline (PHOX) ligands and [Ir(COD)Cl]2 for the reactions of sodium dimethylmalonate with cinnamyl acetates (Scheme 2) [50]. The alkylation products were isolated in nearly quantitative yield and were formed with ratios of branched-to-Unear products up to 99 1 and with enantioselectivities up to 95% ee. In this and subsequent studies with PHOX ligands [51,52], Helmchen et al. demonstrated that the highest yields and selectivities were obtained with a PHOX ligand containing electron-withdrawing substituents and... 

The counterion as well was found to strongly influence catalyst performance. Initial experiments with Ir-PHOX complexes gave high enantioselectivity and full conversion, but only at high catalyst loadings of 4 mol% (Scheme 2b) [9]. Lower catalyst loadings resulted in decreased conversion due to catalyst deactivation [14] with concomitant formation of an inactive trinuclear iridium hydride cluster 8 (Scheme 4) [15], analogous to the deactivation products observed with the Crabtree catalyst 6 [16]. 

Scheme 5 Enantioselective hydrogenation of trans-methyl stilbene 70 with PHOX-based Ir catalyst bearing different counterions...

The asymmetric arylation or alkylation of racemic secondary phosphines catalyzed by chiral Lewis acids in many cases led to the formation of enantiomerically enriched tertiary phosphines [120-129]. Chiral complexes of ruthenium, platinum, and palladium were used. For example, chiral complex Pt(Me-Duphos)(Ph)Br catalyzed asymmetric alkylation of secondary phosphines by various RCH2X (X=C1, Br, I) compounds with formation of tertiary phosphines (or their boranes) 200 in good yields and with 50-93% ee [121]. The enantioselective alkylation of secondary phosphines 201 with benzyl halogenides catalyzed by complexes [RuH (/-Pr-PHOX 203)2] led to the formation of tertiary phosphines 202 with 57-95% ee [123, 125]. Catalyst [(R)-Difluorophos 204)(dmpe]Ru(H)][BPh4] was effective at asymmetric alkylation of secmidaiy phosphines with benzyl bromides, whereas (R)-MeOBiPHEP 205/dmpe was more effective in the case of benzyl chlorides (Schemes 65, 66, and 67) [125—127]. 

The initially discovered ruthenium catalyst, [((i )-i-Pr-PHOX)2Ru(H)][BPh4], was found to be effective in the reaction of methylphenylphosphine with benzylic chlorides, providing the corresponding tertiary phosphine-borane products with high yields and moderate to high enantioselectivities, as shown in Scheme 2.44. 

Nishiyama and co-workers reported that iPr-PYBOX-Rh(III) catalyst promotes the highly enantioselective hydrosilylation of ketones (234). Asymmetric desymmetrization reactions of glutaric anhydride derivative were carried out by using Rh(I)-PHOX complexes (235). 

In situ catalysts formed from Pd(dba)2 precursor and PHOX-type ligands have shown high enantioselectivities in Heck reactions (280). It has to be noted that no C=C double bond migration, a common sidereaction in Pd-phosphine catalyzed reactions, has taken place. 

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