Enantioselective Hydrogenation of Functionalized Ketones. Synthesis and Application of New Chiral Aminophosphine-Phosphinite Ligands

Abstract

The chiral new aminophosphine-phosphinites (AMPP's 1-7) have been synthesised and applied successfully in the enantioselective hydrogenation of dihydro-4,4-dimethyl-2,3-furandione 8, Nbenzylbenzoylformamide 9, and ethylpyruvate 10 providing the hydroxy products in up to 97, 95, and 80% ee, respectively.Transition metal catalysed enantioselective hydrogenation of ketones provides efficient ways to enantiopure hydroxy substituted building blocks for organic synthesis. For that purpose, the use of rhodium and ruthenium catalysts modified by chiral diphosphines has been the most successful. Up to date, an abundance of chiral bisphosphines have been developed for their application in the asymmetric hydrogenation of enamides, ketones and imines. 1 Interestingly, even though particularly efficient ligands have been reported, the design of new ligands has been continuously attracting research interest for more than two decades. 2 In fact, from a practical viewpoint, it is still of strong current interest to develop highly effective diphosphines ligands. 3Our interest in the synthesis of chiral diphosphines employing naturalproduct based precursors, i.e. aminoalcohols and their derivatives both easily accessible from the chiral pool, has allowed a convenient access to a large number of aminophosphine-phosphinite type ligands. The latter have been used with success in various asymmetric reactions. 4 A very successful application of such ligands is the asymmetric hydrogenation of functionalized ketones. 5 As a result of our observations, we concluded that two important points have to be fulfilled in order to obtain highly efficient AMPP ligands for the hydrogenation of carbonyl functions. Firstly, the presence of cycloalkyl substituents on the phosphorus atoms of the diphosphine increases both the rates and selectivities of the reaction. Secondly, the structure of the chiral backbone has to provide limited flexibility and beneficial steric factors allowing consequently increased enantioselectivities. This fact has already been proven by previous experimental results. 5,6 On the other hand, some of us have an ongoing interest in the synthesis of chiral aminoalcohol ligands derived from α-aminoacids and their application in asymmetric reactions such as the enantioselective addition of diethyl zinc to aldehydes 7 and the enantioselective reduction of prochiral ketones with BH 3 ·THF. 8 As a consequence, several "natural" and "artificial" auxiliaries presenting various steric and substitution patterns have been prepared and were tested for their catalytic and inductive abilities in the above reactions. As some of them seem to be particularly well suited for a transformation into diphosphines, we thought to use them in order to probe the above hypothesis. In this paper, we report the synthesis of the resulting new aminophosphine-phosphinites and their application in asymmetric hydrogenation of ketones.The three β-aminoalcohol precursors used in this study i.e. (S)-1-pyrrolidin-2-ylcyclopentanol, 9 (S)-2-hydroxymethyl azetidine, ...

Free and Cr(CO)3-Complexed Aminophosphine Phosphinite Ligands for Highly Enantioselective Hydrogenation of α-Functionalized Ketones

“…In our preliminary communication (see ref a), we reported only on the use of QuinoNOP ligands based on the less easily accessible ( R ) precursor (see ref b). However, all the catalytic reactions were carried out with both optical antipodes providing equivalent results.…”

“…It is anticipated that these modified AMPP ligands might supply enhanced enantioselectivities. In this paper, we report the development of a series of conformationally rigid chiral AMPP bisphosphanes and we establish their utility in enantioselective hydrogenation of α-functionalized ketones …”