Pablo Etayo

Primary and Secondary Aminophosphines as Novel P-Stereogenic Building Blocks for Ligand Synthesis†

Chiral phosphine ligands are central to asymmetric metal catalysis. The effect of the majority of these ligands arises from the chirality of their backbones; however, P-stereogenic (P*) ligands have garnered renewed interest. After the decisive work of Knowles and co-workers with PAMP and DIPAMP ligands, several efficient syntheses of all-carbon P* compounds have been reported. In contrast, P* compounds that contain heteroatoms directly linked to the phosphorus center are scarce, and have found little application in catalysis. This class of substances includes secondary phosphine oxides, which exist in equilibrium with their trivalent phosphinite form. P* aminophosphines, which are the corresponding nitrogen analogues, are even more rare, as free primary aminophosphines tend to dimerize with the evolution of ammonia. However, Kolodiazhnyi et al. have reported that borane aminophosphines of type I are stable and that they can be obtained in diastereomerically pure form using 2-phenylethylamine as a chiral amine (Scheme 1). Nonetheless, type I compounds do not have any reported applications in asymmetric catalysis, nor has their hydrogenolysis been described. We envisioned that reductive cleavage of the arylethyl fragment should provide boraneprotected primary aminophosphines of type II, which would be amenable to further transformations and become useful P* building blocks in catalysis. Herein, we report the synthesis of enantiopure P-chiral primary and secondary aminophosphines (II) and diphosphinoamines (III). We began by investigating the hydrogenolysis of the known compound 1a, which contains a tert-butyl(phenyl)phosphinamine moiety (Scheme 2), under various

Asymmetric Homologation of Ketones. A New Entry to Orthogonally Protected (2R,4R)-Piperidine-2,4-dicarboxylic Acid

A new conformationally constrained analogue of glutamic acid has been synthesized efficiently in seven steps from a chiral 2-alkyl-4-piperidone. The synthesis is based on (a) the unprecedented asymmetric one-carbon homologation of the ketone controlled by the size of the N-substituent and (b) the appropriate manipulation of substituents at positions 2 and 4 of the piperidine ring, a step that involves two independent oxidation processes.

Unexpected epimerization at C2 in the Horner-Wadsworth-Emmons reaction of chiral 2-substituted-4-oxopiperidines.

The observed epimerization at C2 in the Horner-Wadsworth-Emmons (HWE) reaction of chiral 2-substituted-4-oxopiperidines has been investigated and, on the basis of the experimental results, a mechanism for this unexpected process has been proposed.

Ring-opening of enantiomerically pure oxa-containing heterocycles with phosphorus nucleophiles

Various oxa-containing heterocycles (i.e. enantiopure epoxide- and oxetane-based substrates) were subjected to ring-opening with phosphorus nucleophiles. The ring-opening reactions proceeded smoothly and the resulting 1,2-, and 1,3-phosphino alcohols were efficiently isolated as stable borane complexes. These derivatives arise from regio- and stereocontrolled syntheses based on ring-opening processes of oxa-containing heterocycles. The regio- and stereochemistry of the resulting chiral products were unequivocally confirmed in many cases via single-crystal X-ray diffraction analysis.

5,5′-Bistriazoles as axially chiral, multidentate ligands: synthesis, configurational stability and catalytic application of their scandium(III) complexes

The design and development of 5,5′-bistriazoles featuring aminomethyl substituents is discussed. An efficient synthetic procedure for the selective preparation of 4,4′-bis(aminomethyl)-5,5′-bistriazoles from commercially available propargylamine derivatives and benzyl azide has been optimized. The first experimental determination of the configurational stability of 5,5′-bistriazoles is disclosed on the basis of rotational energy barriers and half-life times. Fast racemization was observed for a bistriazole possessing solely axial chirality whereas a more heavily substituted bistriazole involving axial and central chirality proved to be configurationally stable. A successful catalytic application has been implemented by using a N,N-dimethylpropargylamine-derived 5,5′-bistriazole as a multidentate ligand controlling the product selectivity (single vs. double addition) in scandium(III)-catalyzed nucleophilic additions of indoles to isatin electrophiles.