Amines Bearing Tertiary Substituents by Tandem Enantioselective Carbolithiation-Rearrangement of Vinylureas

Michael Tait, Morgan Donnard, Alberto Minassi, Julien Lefranc, Beatrice Bechi, Giorgio Carbone, Peter O’Brien, and Jonathan Clayden
Org. Lett.
DOI: 10.1021/ol3029324

clayden1

Asymmetric construction of tertiary stereocentres next to nitrogen is a significant challenge in organic synthesis with only a few robust approaches available. Clayden and co-workers report a method of preparing α-tertiary amines asymmetrically that allows the introduction of a high degree of molecular complexity.

Their approach involves, initially, an asymmetric carbolithiation of a vinylurea under the influence of a chiral ligand for lithium. This step introduces an alkyl substituent and sets the configuration of the stereocentre next to nitrogen. The addition of DMPU to the reaction accelerates a subsequent aryl migration from the ‘other side’ of the urea to the lithiated carbon centre. Aryl migration occurs with retention of stereochemistry.

The real utility of this reaction is shown in the ability to select which enantiomer of the product is formed by using either naturally occuring (-)-sparteine (A) or a (+)-sparteine surrogate (B) as the chiral ligand.

clayden2

The reaction has been applied to various substrates. Showing, in particular, variation in the introduced alkyl substituent and, remarkably, extension to the migration of a styrenyl group (the product of which is unstable and rearranges under mildly acidic conditions).

clayden3

The desired complex amine adducts can be prepared by the deprotection of the urea products under basic conditions.

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One thought on “Amines Bearing Tertiary Substituents by Tandem Enantioselective Carbolithiation-Rearrangement of Vinylureas

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