Phosphinoyl-aziridines as a new class of chiral catalysts for enantioselective Michael addition

Enantioselective Mannich Reaction Promoted by Chiral Phosphinoyl-Aziridines

“…In the first set of experiments, the chiral catalysts 1-4 containing a methylene linker between the aromatic ring and an aziridinyl nitrogen atom were applied in the title reaction ( In all cases, the corresponding Mannich products were formed in moderate chemical yields (27-43%) and moderate stereoselectivities (32-40% of ee, 8:1-10:1 of dr). It should also be noted that the use of catalysts with an opposite absolute configuration at the carbon atom of the aziridine subunit (Table 1, entries 1-2) led to the formation of both enantiomers of product 15, which is consistent with our earlier studies [3,24], showing that configuration at the carbon next to the amine moiety is crucial for the stereochemistry of the reaction.…”

“…Basing on the aforementioned results, a tentative transition-state model explaining the absolute configuration of Mannich products was proposed ( Figure 2). It should be mentioned that a similar model was described by us recently [24]. After deprotonation of an acidic proton of the ketone, complex A is generated.…”

“…Phosphine 12 was then oxidized with hydrogen peroxide to phosphine oxide 13 in a 79% yield. Finally, compound 13 was treated with Compounds 1-8 were synthesized according to procedures recently reported by our group [24] starting from either 2-(diphenylphosphino)benzoic acid (catalysts 1-4) or from o-bromoanisole (systems 5-8). Chiral catalyst 9, containing the free NH group, was obtained in a one-step process comprising a treatment of (S)-2-phenylaziridine with two equivalents of sec-BuLi and one equivalent of diphenylphosphinic chloride at −78 • C in anhydrous tetrahydrofurane (Scheme 1).…”

“…Based on our findings on the asymmetric Michael reaction [24], analogous systems 5-8 without the methylene group were tested in terms of catalytic activity in the asymmetric Mannich reaction ( Table 1, entries 5-8). As anticipated, chiral product 15 was created in higher yields (60-69%) and with higher stereoselectivity.…”

“…The chiral phosphorus-functionalized aziridines have been marginally mentioned in the chemical literature [19][20][21][22][23]. Very recently, an enantioselective Michael addition promoted by chiral phosphinoyl-aziridines was published by our group [24]. Taking into account our knowledge in the area of asymmetric organocatalysis [25][26][27] as well as with the Mannich reaction [3] and with regard to all of the above facts, we decided to prepare a series of chiral phosphorus-functionalized aziridines in order to test their catalytic activity in the direct asymmetric organocatalytic Mannich reaction of amine (p-anisidine), hydroxyacetone, and aromatic aldehydes.…”