Producing the single enantiomer of a bioactive chiral compound is an ongoing challenge. Chemocatalysis and biocatalysis often
are the key in asymmetric synthesis for producing a compound with desired yield and enantiopurity.
(IMAGE: DON BISHOP, BRAND X PICTURES, GETTY IMAGES)
Nonnatural amino acids
Nonnatural amino acids are important building blocks as chiral intermediates in small-molecule drug synthesis, and they also
play a crucial role in peptide synthesis. Researchers at Vanderbilt University's Vanderbilt Institute of Chemical Biology
in Nashville, Tennessee recently reported on their work that addresses one of the limitations in peptide synthesis, the difficulty
of incorporating nonnatural amino acids in peptides and controlling stereoselectivity. The team developed a novel way of making
amide linkages (1).
Amides typically are made by combining the acyl group from a carboxylic acid derivative with an amine with the elimination
of water. Although dehydrative approaches generally are used in amide formation, oxidative and radical-based methods also
can be used. In amide-bond formation, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during
the carbon–nitrogen bond-forming step (2).
The researchers' different approach instead used a-halonitroalkanes as the acyl source. The amines and nitroalkanes were activated
by an electrophilic iodine source that led directly to amide products. Preliminary observations supported a mechanism in which
the polarities of the two reactants were reversed during carbon–nitrogen bond formation relative to traditional peptide synthesis.
The nitroalkanes as acyl-anion equivalents provided a conceptually new route to amide and peptide synthesis and one that might
allow for efficient peptide synthesis that relies on enantioselective methods (1, 2).
A team led by Eric Jacobsen, professor of chemistry in the Department of Chemistry and Chemical Biology at Harvard University,
used organocatalysts, achiral thiourea-containing catalysts, for the asymmetric version of the Strecker synthesis. The Strecker
synthesis is a series of chemical reactions that synthesize an amino acid from an aldehyde or ketone. Although chemocatalysis
and enzymatic methods can be used to synthesize enantioenriched a-amino acids, synthesizing nonnatural amino acids is challenging.
Alkene hydrogenation may be used in the enantioselective catalytic synthesis of many classes of amino acids, but it is not
possible to obtain a-amino acids bearing aryl or quaternary alkyl a-substituents using this method (3, 4).
Patricia Van Arnum
The researchers addressed this problem through the Strecker synthesis, but used an organocatalyst that avoids the problem
of using a precious metal catalyst to control a key step in the synthesis. The Strecker synthesis, which involves the reaction
of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis, is used for the synthesis of racemic
a-amino acids. In an asymmetric Strecker synthesis, stoichiometric amounts of a chiral reagent can yield enantiomerically
enriched a-amino acids on gram and kilogram scales. The researchers reported that Strecker syntheses using substoichiometric
quantities of a chiral reagent could be an alternative, but catalytic methods in this approach have been limited to preparative
scales because of the complexity of the catalysts and the need to use hazardous cyanide sources (3, 4).
Instead, the researchers used a relatively simple chiral amido-thiourea catalyst to control the key hydrocyanation step for
the syntheses of highly enantiomerically enriched nonnatural amino acids. The catalyst is compatible with aqueous cyanide
salts, which are safer and easier to handle than other cyanide sources, thereby potentially making the method adaptable to
large-scale synthesis. The researchers used this method to obtain enantiopure amino acids that are not readily prepared by
enzymatic methods or by chemical hydrogenation (3, 4).