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Chiral Organometallics for Asymmetric Synthesis

Final Report Summary - COAST (Chiral Organometallics for Asymmetric Synthesis)

Project context and objectives

The objective of the COAST project (Chiral Organometallics for Asymmetric Synthesis) is to facilitate access to chiral organometallic reagents, which would be extremely useful as these allow the creation of new chiral C-C bonds. The creation of a method of broad scope for the generation of chiral organometallic reagents would have a major impact in academia and industry as it would provide ready access to essentially any chiral compound.

This project focuses on the generation of chiral nucleophiles with good leaving groups so that, on reaction with another organometallic, an ate complex will be formed and then, following 1,2-metallate rearrangement, a new chiral organometallic will be generated, which can be subsequently trapped by an electrophile. Having shown that chiral carbenoids can be generated from Hoppe’s lithiated carbamates and that they react with boron reagents, we now wish to explore the reactivity, limitations and scope of this reaction and the application of these new chiral boron species, boronic esters and potassium trifluoroborates salts, in new C-C bond-forming reactions.

Work completed
During this first year, we have been more focused on the enantiospecific lithiation-borylation of carbamates, synthesis of secondary and tertiary chiral boronic esters and potassium trifluoroborate salts and its application in the Rh-catalysed 1,2-addition to aldehydes. Chiral secondary and tertiary potassium trifluoroborate salts, which were prepared via homologation of boronic esters using Hoppe-type lithiated carbamates, show very broad substrate scope. A new and easy procedure for the purification and isolation of potassium trifluoroborate salts was found during the development of the project. Conditions for the azeotropic removal of pinacol from the reaction mixture were found to afford the desired potassium trifluoroborates of sufficient purity (> 95 %) in nearly quantitative yields irrespective of the nature of the product. Utility of this method is illustrated by the preparation of a broad range of enantioenriched secondary and tertiary potassium trifluoroborates.

Project results
The secondary and tertiary alkyl trifluoroborate salts synthesised were coupled with aldehydes in the presence of [RhCl(COD)]2 in good yield and with complete retention of stereochemistry of the initial chiral trifluoroborate salt. Although no diastereoselection was observed in the formation of the carbinol stereocentre, the oxidation to the corresponding ketone, particularly in the case of tertiary centres, creates novel ketones that would be hard to prepare by other methods. In fact, the complete retention of stereochemical information during the transformation of a chiral organometallic is rather rare in organic chemistry. The lack of ?-hydride elimination is also especially noteworthy and bodes well for future application to other classes of reactions. These results describe a very important advancement in the field of Rh-catalysed additions to aldehydes and in the field of coupling of chiral organometallic species. Studies in this area and the application of this methodology in the synthesis of biologically active molecules are currently in progress.
During the mechanism studies for this new reaction, we discovered that p-methoxybenzylic trifluoroborate salts react with aldehydes in the presence of Lewis or Brønsted acids to give homoallylic alcohols with concomitant dearomatisation of the aromatic ring. Using enantioenriched benzylic trifluoroborate salts leads to adducts with > 98 % retention of stereochemistry in most cases. The reactions are accompanied by dearomatisation of the aromatic ring which is especially synthetically useful since it leads to more functionalised products. The reactions show broad substrate scope in terms of both the benzylic trifluoroborate salts, which can be secondary or tertiary, and the aldehydes employed (aromatic/aliphatic). The use of enantioenriched benzylic trifluoroborate salts, which are easily accessible through the lithiation-borylation reaction, leads to adducts with almost complete retention of stereochemistry in most cases. This new reaction manifold extends the synthetic utility of benzylic boron reagents and the lithiation-borylation reactions that produce them.

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