Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes.

A catalytic methodology for the enantioselective addition of alkylzirconium reagents to aliphatic aldehydes is reported here. The versatile and readily accessible chiral Ph-BINMOL ligand, in the presence of Ti(OiPr)4 and a zinc salt, facilitates the reaction, which proceeds under mild conditions and is compatible with functionalized nucleophiles. The alkylzirconium reagents are conveniently generated in situ by hydrozirconation of alkenes with the Schwartz reagent. This work is a continuation of our previous work on aromatic aldehydes.

Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines vial-phenylalanine-derived dihydroisoquinoline N-oxides.

The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans-1,3-disubstituted N-hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this nitrone provided access to 3-(2-hydroxyalkyl)isoquinolines 12 as single diastereomers.

Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes.

A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(OiPr)4, proceeds under mild and convenient conditions, and no premade organometallic reagents are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles and a broad range of aromatic aldehydes.

Synthesis of Aminoindolizidines through the Chemoselective and Diastereoselective Catalytic Hydrogenation of Indolizines.

Indolizidines are bioactive heterocyclic compounds of great potential normally prepared following multistep routes. However, to the best of our knowledge, the synthesis of 1-aminoindolizidines has never been reported. Herein, 1-(dialkylamino)-3-substituted indolizidines have been straightforwardly synthesized using an atom-economic protocol that involves a copper-catalyzed three-component synthesis of indolizines followed by heterogeneous catalytic hydrogenation. The latter was found to be chemoselective using platinum(IV) oxide as the catalyst at 3.7 atm, providing the aminoindolizidines in modest-to-high yields (35-95%) and high diastereoselectivity (92:8 to >99:1). It has been experimentally demonstrated that the hydrogenation occurs through the intermediate 5,6,7,8-tetrahydroindolizine, which contains a pyrrole moiety. Moreover, the diastereomerically pure 1-(dibenzylamino)-3-substituted indolizidines could be further transformed into the corresponding monobenzylated or fully debenzylated aminoindolizidines by selective hydrogenolysis catalyzed by Pt/C or Pd/C, respectively, under ambient conditions.