Addition of Non-stabilized Carbon-based Nucleophilic Reagents to Chiral N-Sulfinyl Imines

Herbage, M. A.; Savoie, J.; Sieber, J. D.; Desrosiers, J.-N.; Zhang, Y.; Marsini, M. A.; Fandrick, K. R.; Rivalti, D.; Senanayake, C. H.


Natural products and pharmaceuticals that contain chiral branched amines are compounds of considerable interest. One strategy for preparing chiral branched amines involves the addition of a nucleophile to an imine bearing a readily cleavable chiral auxiliary. Sulfinamide-based auxiliaries are well-suited to this approach because (i) many sulfonamides are commercially available or can be prepared by efficient synthetic methods, (ii) N-sulfinyl aldimines and ketimines can be prepared in a straightforward manner, (iii) the chiral amine products are obtained with high diastereomeric ratios across a wide range of carbon-based nucleophiles, and (iv) the N-sulfinyl group is cleaved under mild conditions.

This chapter focuses on the addition of non-stabilized, carbon-based nucleophiles to N-sulfinyl aldimines and ketimines. Specifically, additions of alkyl, alkenyl, aryl, allylic, propargylic, alkynyl, and cyano nucleophiles are presented. Factors that can influence the stereoselectivity of the addition reaction are presented, along with the most prevalent reaction conditions employed for each class of nucleophile. Nucleophilic additions to N-sulfinyl aldimines and ketimines are key steps in the syntheses of a number of drug discovery targets and natural products, examples of which are highlighted in this review.