Alcohol enantiomer conundrum cracked

UK chemists have discovered a straightforward new way to make chiral tertiary alcohols that gives selective access to either enantiomer.

Tertiary alcohols - hydroxyl groups attached to a central carbon bearing three alkyl chains - are found across a wide range of natural products, pharmaceuticals and agrochemicals. They can exist in one of two chiral, mirror image forms (enantiomers). However, controlling which enantiomer forms when making tertiary alcohols has traditionally been difficult.

Now, Varinder Aggarwal and colleagues at the University of Bristol has used boron-based chemistry to solve the problem. The team start from a secondary alcohol - in which the hydroxyl-bearing carbon is attached to only two alkly groups, with the fourth position being occupied by a hydrogen - which are relatively simple to synthesise in enantio-pure form. The Bristol chemists took a given enantiomer of a secondary alcohol, converted the hydroxyl group into a carbamate, and then lithiated the central carbon atom by displacing the hydrogen without disturbing the stereochemistry.

This lithiated compound is then reacted with one of two possible boron reagents - the reagent chosen deciding the ultimate stereochemistry of the final tertiary alcohol.   Boronate esters displace the lithium group with retention of stereochemistry, while boranes trigger an inversion. Heating this intermediate, and then oxidising with hydrogen peroxide, reveals the highly enantio-enriched tertiary hydroxide.

Aggarwal believes the stereochemical control stems from the oxygen atoms that are present in boronic esters but not in the borane. ’The lithiated carbamate that is generated can react with the boron reagent on the same side as lithium, or on the opposite side to lithium,’ he explains. ’We believed that one of the oxygens of the boronic ester co-ordinates with lithium, and so the boronic ester is delivered to the same side as lithium. In the absence of co-ordination, the lithiated carbamate reacts on the opposite side to lithium, which presumably reflects its inherent selectivity.’

Karl Hansen, of the drug company Amgen in Cambridge, Massachusetts, says the new method is ’impressive’. Hansen suggests that the work is ’likely to inspire others to explore the chemistry ofstable chiral anions in organic molecules, opening up new areas of research.’

Simon Hadlington

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