A new method for the synthesis of β-amino acids


β-Amino acids and their derivatives hold significant importance in the fields of biological and synthetic chemistry. Although the Mannich reaction is among the most venerable and most taught named reactions in organic synthesis, its applicability is limited by several factors (including substitution pattern and chemoselectivity). The group of Nuno Maulide at the Institute of Organic Chemistry has now developed a transformation which formally yields the products of the Mannich reaction, while utilising entirely different starting materials and following a unique reaction mechanism. In this way, many problems associated with the classical Mannich process can be circumvented.

The new method, recently published in the Journal of the American Chemical Society, relies on the combination of two trademarks of the Maulide group: electrophilic amide activation and sulfonium rearrangements. While electrophilic amide activation enables a characteristic and unique chemoselectivity, the integration of enantiopure sulfinimines ensures that this reaction proceeds with high levels of enantioselectivity.

Computational studies, devoted to elucidating the reaction mechanism, uncovered a further remarkable feature of this transformation. While chemical intuition will often base its assessment of likely conformation and configuration on estimates of perceived steric hindrance, dissection of the contributing factors found attractive London dispersion forces to tip the scales in favour of the sterically more congested diastereomer.

Publication in JACS:

Deployment of Sulfinimines in Charge-Accelerated Sulfonium Rearrangement Enables a Surrogate Asymmetric Mannich Reaction; Minghao Feng, Ivan Mosiagin, Daniel Kaiser, Boris Maryasin and Nuno Maulide, J. Am. Chem. Soc. 2022, DOI: 10.1021/jacs.2c05368