Researchers Make Amines With Remote Chiral Centers In One Step | Chemical & Engineering News
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Web Date: January 7, 2016

Researchers Make Amines With Remote Chiral Centers In One Step

Organic Synthesis: Technique provides first direct single-step route to amines with chiral centers three or more carbon atoms from the amine nitrogen
Department: Science & Technology
News Channels: Organic SCENE
Keywords: synthesis, amines, γ-chiral amine, δ-chiral amine, reductive relay hydroamination
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ONE-STEP WONDER
A single-step reductive relay hydroamination converts allylic starting materials to γ-chiral amines, in which the chiral center is remote from the amine C–N bond.
Credit: C&EN
Reaction scheme shows copper hydride-catalyzed reductive relay hydroamination reaction in which benzoylated amines are added to allylic starting materials to produce γ-chiral (shown) or δ-chiral amines.
 
ONE-STEP WONDER
A single-step reductive relay hydroamination converts allylic starting materials to γ-chiral amines, in which the chiral center is remote from the amine C–N bond.
Credit: C&EN

Organic molecules that have a chiral center three or four carbon atoms from an amine nitrogen atom—called γ- and δ-chiral amines, respectively—are important structural elements in many pharmaceutical agents and natural products. So it would be nice if they were easy to make synthetically. But up to now, synthetic chemists have not been able to controllably add amines and other functional groups to positions more than one or two carbons from chiral centers without resorting to multistep procedures.

Stephen L. Buchwald of MIT and coworkers have overcome this long-standing challenge. They show how a previously developed synthetic approach, copper hydride-catalyzed hydroamination, can be extended to enantioselectively synthesize γ-chiral amines from allylic alcohols, allylic esters, and allylic ethers and δ-chiral amines from allylic epoxides (Nat. Chem. 2016, DOI: 10.1038/nchem.2418).

The extended procedure, copper hydride-catalyzed reductive relay hydroamination, works by installing an amine group three or four carbon atoms from one of the allylic starting material’s double-bonded carbons, which is converted to a chiral center in the reaction. The protocol is suitable for use with complex substrates containing a wide range of functional groups, making it potentially valuable for drug discovery. It can also be used to sequentially add amine groups to substrates with more than one allylic group.

During the reaction that forms a γ-chiral amine, ligand-bound copper from the catalyst adds to one of the double-bond carbons in the allylic alcohol, allylic ester, or allylic ether. The adduct eliminates a copper alkoxide—a ligated copper linked to the alcohol, ester, or ether—to form an alkene intermediate. The ligated copper catalyst then regenerates and adds to the intermediate in a way that moves copper one carbon atom from its point of attachment in the original adduct. The amine group from a separate hydroxylamine O-benzoate then substitutes for copper to yield the γ-chiral amine. A corresponding process with allylic epoxide starting materials produces δ-chiral amines.

Thomas C. Nugent of Jacobs University Bremen comments that until now the enantioselective synthesis of γ- or δ-chiral amines has been inefficient. The new single-step method, he says, represents “a sea change that will be particularly appreciated by pharmaceutical process chemists.”

 
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