Putting “umpolung” to work in synthesis of nitrogen-bearing stereocenters

Professor Li Deng‘s lab in the Brandeis Chemistry Department has recently published a high-profile paper in Nature, disclosing an important advance in the chemical synthesis of organic molecules containing nitrogen. Li Deng writeup 1

A great number of important drugs contain at least one nitrogen atom connected to a “stereogenic” carbon atom. Stereogenic carbons are connected to four different groups, making possible two different configurations called “R-” or “S-”. In synthesizing a drug, it can be disastrous if the product does not have the correct R/S configuration.  For instance, the morning-sickness drug Thalidomide caused birth defects in ~10,000 children because it was a mixture of R and S molecules.Li Deng writeup 2

Selective preparation of only R or only S molecules containing nitrogen is a major challenge in organic chemistry. Many recent approaches have formed such stereocenters by use of an electron rich “nucleophile” to attack an electron poor “imine”. Deng is now the first to report an unconventional strategy in which the polarity of the reaction partners is reversed. In the presence of base and a creatively designed catalyst, the imine is converted into an electron rich nucleophile, and can attack a variety of electrophiles. Deng’s catalysts are effective in minute quantities (as low as 0.01 % of the reaction mixture), and yield products with R- or S- purities of 95-98 %.

In addition to Professor Deng, authors on the paper included former graduate student Yongwei Wu PhD ’14, current Chemistry PhD student Zhe Li, and Chemistry postdoctoral associate Lin Hu.

Wu Y, Hu L, Li Z, Deng L. Catalytic asymmetric umpolung reactions of imines. Nature. 2015;523(7561):445-50. (commentary)

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