Phosphinamines

The first successful axially chiral phosphinamine ligand in asymmetric catalysis was QUINAP 60 (Figure 8) reported by Brown in 1993 and the original synthesis has since been modified.94 The donor nitrogen atom is incorporated in an isoquinoline unit to form a six-membered chelate ring. 

Quinazolines take part in the same types of reactions as pyrimidines, but because of their additional benzene ring, the products of these reactions may have the added feature of hindered rotation. An example of this is the synthesis of 2-phenyl-Quinazolinap by Guiry and co-workers <99TA2797>. Suzuki coupling of 4-chloro-2-phenylquinazoline (115) with boronic acids 116 led to 117 (R = OMe). These intermediates were parlayed into phosphinamines 117 (R = PPh2) and then subjected to chiral resolution to produce new chiral phosphinamine ligands for asymmetric catalysis. 

Kiely, D. and Guiry, PJ. (2003) Palladium complexes of phosphinamine ligands in the intramolecular asymmetric Heck reaction. Journal of Organometallic Chemistry, 687, 546-561. Dounary, A.B., Hatanaka, K., Kodanko, J.J. et al. (2003) Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl... 

Kiely, D. and Guiry, P.J. (2003) Palladium complexes of phosphinamine ligands in the intramolecular asymmetric Heck reaction. J. Organomet. Chem., 687, 545-61. 

Introduced by Alexakis et al., copper-phosphinamine systems also stand out as effective catalysts for the addition of organoaluminium reagents to cychc enones [46, 47]. In many cases, and in particular with challenging substrates, phos-phinamine ligands (Fig. 4) outperform the phosphoramidite counterparts. 

For example, phosphinamine ligands are not only efficient in the addition of linear organoaluminium reagents to both bulky and non-bulky p-substituted cyclic enones (Scheme 13) but perform particularly well with p-aryl-substituted cyclic enones, giving higher yields and enantioselectivities than phosphoramidite hgands (Scheme 14 versus Scheme 5). 

Fig. 4 Effective phosphinamine ligands for the copper-catalysed ECA of organoaluminium reagents to p,p-disubstituted enones...

Regarding the challenging p-substituted cyclopenten-2-one substrates, phosphinamine ligands give moderate, comparable enantioselectivities to phosphor-amidites, as shown in Scheme 15. 

Scheme 13 Copper-phosphinamine-calalysed ECA of organoaluminium reagents to p-substituted cyclohexenones by Alexakis [46,47]...

Scheme 16 Copper-phosphinamine-catalysed ECA of alkenyl aluminium reagents (prepared by hydroalumination with DIBAL-H) to P-substituted cyclic enones by Alexakis [48,49]...

General observations and limitations on the copper-phosphinamine-catalysed CA of alkenyl aluminium reagents include ... 

The versatile phosphinamine ligands are also suitable for the copper-catalysed ECA of organoaluminium reagents to a,p-unsaturated lactams, including p-methyl-substituted 8-lactams, whose reaction allows the formation of all-carbon quaternary stereogenic centres in moderate yields and good enantioselectivities, as exemplified in Scheme 22 [57]. 

Scheme 24 Copper-phosphinamine-catalysed ECA of aryl aluminium reagents to p-substituted...

The copper-NHC-catalysed addition of organoaluminium reagents to cyclo-hexenones and cycloheptenones reported by Hoveyda [58] is, in some cases, slightly less selective than those performed in the presence of phosphoramidites or phosphinamine catalysts (<90% ee for the imidazolium ligands versus <99% ee that the phosphoramidites and phosphinamine can provide). However, NHC-Cu catalysis provides better results (up to 97% ee and 97% conv) when challenging cyclopentenones and bulky p-substituted cycUc enones (bearing n-butyl, alkynyl, aryl or an ester group as the p substituent) are used as substrates (Scheme 25). 

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