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Final Activity Report Summary - MODULAR CHIRAPHOS (A Modular Approach to New Chiral Phosphorus Ligands for Enantioselective Catalytic Reactions)

Chiral is a word obtained from Greek meaning hand, and in chemistry the word is used to describe a molecule which cannot overlap with its mirror image, like ones left hand with ones right hand. These two images are called enantiomers. In the pharmaceutical industry, it is important to have methods available to synthesise drugs as only the left hand or the right hand molecules (enantioselective synthesis) and not both together as a mixture. Nature is able to do this quite easily, but chemists are still learning. Asymmetric catalysis is one of the methods which chemists can use to synthesise one enantiomer of a chiral compound. For a reaction that needs a catalyst and gives a chiral product, it is therefore possible to design and create specific chiral catalysts for that reaction. However, a chiral catalyst that gives a high enantioselectivity (favours the formation of one enantiomer of a product over the other) for one chemical reaction will be unlikely to be enantioselective for a different reaction.

Transition-metal-catalysed asymmetric transformations play an important role in the synthesis of complex organic molecules as well as in the industrial production of fine chemicals. In general, a chiral ligand is used to influence both the reactivity of the metal ion and direct the stereochemical course of the catalysed reaction. Chiral phosphorus ligands are among the most widely used for asymmetric transformations. The first scientific objective of this project was to synthesise, a new class of chiral bis(sulfonamido)-substituted phosphorus ligands, of general structure 1.

The class of ligands 1 was chosen as they display several potential sites of diversity(R1, R2, R3)modification of which allows for tuning of the steric, electronic and conformational properties of the ligand. A modular approach to the synthesis of ligands 1 was adopted using diamines 2, sulfonyl chlorides 3, amines 4 and phosphine 5 as the building blocks. A small library of ligands 1, consisting of 23 members, was prepared via two highly modular synthetic paths. The second objective of this project was to use the ligands 1 in a number of metal-catalysed asymmetric reactions of synthetic interest. We chose the conjugate addition of diethylzinc to cyclohexenone as a benchmark for our ligands, as this reaction is a useful reference for evaluating the activity and the enantioselectivity of our catalytic system.

Complete conversions to the product(>98%)were obtained for all the ligands studied, with enantiomeric excesses(ee)of up to 75%(75% ee means that there is 87.5% of the major enantiomer and 12.5% of the minor). These results were communicated in the European Journal of Organic Chemistry. Use of ligands 1 in 6 other metal-catalysed asymmetric reactions was subsequently investigated, but only poor results were obtained. Due to the difficulty in finding another successful application of our ligands 1, we began to explore another closely related subject: a modular approach to new chiral thioureas for enantioselective catalytic reactions.

The new objectives were to synthesise a new class of chiral thioureas and then to test them as organocatalysts(reactions using organocatalysts do not require the use of metals)in a range of asymmetric transformations. We formed a collaboration with the group of Prof. Roussel to develop the class of modular atropisomeric thiourea catalysts 11, for which they were able to separate the atropisomers of 9 via preparative HPLC. It was possible to create a library of chiral thioureas 11 by reaction of 10 with a variety of amines.

The chiral thioureas 11 were tested in various asymmetric transformations.Thioureas (aS/aR)-(R,R)-11h, (aR)-(R,R)-11h and (aR)-(S,S)-11i were found to be good organocatalysts for the cyanosilylation of a range of aldehydes.The best results were obtained with the branched aliphatic aldehydes cyclohexanecarboxaldehyde(quantitative yield and 68.1% ee)and isobutyraldehyde(82% yield and 69.0% ee)using (aS/aR)-(R,R)-11h, which is a mixture of two diastereomers.

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UNIVERSITA DEGLI STUDI DI MILANO
via G. Venezian 21
20133 MILANO
Italy