SCIENCE & TECHNOLOGY

NEW ROUTE TO CHIRAL a-AMINO COMPOUNDS Proline-catalyzed asymmetric reaction α-aminates unmodified aldehydes and ketones

IN A STUDY THAT COULD HELP CHANGE the way chiral amino acids are synthe­sized in the pharmaceutical and fine chemicals industries, two groups have developed proline-catalyzed reactions

for derivatizing aldehydes and ketones. Working independently, chemistry

professor Karl Anker Jorgensen and co-

CHIRAL L-Proline catalyzes asymmetric cc-amination reaction

0

Λ . R1

Aldehyde R 2 0 2 C

,C02R2

Azodicarboxylate

L-Proline

HN 0 |

C07R2 / υ υ 2

XOoR2

R1 • alkyl group R2 = alkyl or benzyl

group

workers at Aarhus University, Denmark, and assistant professor of molecular biol­ogy Benjamin List of Scripps Research In­stitute discovered the same proline-cat­alyzed direct asymmetric a-amination of unmodified aldehydes, using azodicar­boxylate reagents [Angew. Chem. Int. Ed., 41, 1790 (2002) and J. Am. Chem. Soc, 124, 5656 (2002), respec­tively}. Jorgensen's group has also developed a ketone ver­sion of the reaction \J. Am. Chem. Soc., 124,6254 (2002)}. The reactions use the amino acid proline as a benign organocatalyst.

The aldehyde a-amination "uses readily available and in­expensive achiral starting ma- List terials and can be carried out ~~~ under environmentally friendly and oper­ationally simple reaction conditions," Jor­gensen and coworkers note.

The aldehyde reaction allows for the practical and rapid synthesis of 2-oxazo-lidinones and other natural and nonnatur-

DANISH a-AM I NATO RS Jorgensen stands behind coworkers on his group's two chiral α-amination studies: (from left) Nagaswamy Kumaragurubaran, Anders Bogevig, Karsten Juhl, and Wei Zhuang.

al α-amino and α-hydrazino acid deriva­tives. And the ketone α-amination gives equally easy access to optically active a-hydrazino and α-amino ketones, as well as a range of α-amino alcohols.

Both reactions are efficient and highly selective, with yields and enantioselectiv-ities often around 90% and sometimes ex­ceeding 95%. "Major fine chemicals com­panies should be interested in the reactions because of their potential to make enan-tiomerically pure amino acids in a one-pot process," List says.

Such catalytic asymmetric a-amination reactions have generally required the use of preformed enolates of aldehydes and ke­tones as substrates. The ability to use un­modified aldehydes and ketones instead of preformed enolates simplifies the process considerably

List notes that in previous studies his group also developed the first proline-cat­alyzed asymmetric intermolecular aldol, Mannich, and Michael reactions. Howev­er, he believes the new aldehyde a-amina­tion reaction is probably the most useful of all. "I'm convinced the technology will

ο be applied in many academic | and industrial labs," he says. £ "I like the Jorgensen and £ List studies immensely" com-- ments chemistry professor £ David A. Evans of Harvard £ University, a pioneer in the S development of asymmetric s α-amination reactions. 'The " reactions provide access to

chiral α-amino carbonyl sub­strates with excellent enan-tioselectivities," he says. iThe Value added' is great. The reactions will be widely used

in the pharmaceutical industry." The advance "is most impressive," Evans

adds. List, Jorgensen, and others "are tak­ing my own 20-year research effort in this area and over-trumping me soundly!"— STU B0RMAN

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