Described herein are the total syntheses of salinosporamides via a strategy involving rapid construction of the pyrrolidinone core of the natural products from the simple amino acid serine. The key to the success of this synthesis was the stereoselective installation of three contiguous stereocenters on the pyrrolidinone core via a single aldol cyclization step, which employed the principles of ′memory of chirality” and dynamic kinetic resolution.

Abstract

The first total synthesis of (−)-salinosporamide D was achieved using d-serine as the sole chiral source. This approach stands out for its application of the principles of memory of chirality and dynamic kinetic resolution in the intramolecular aldol reaction of serine-derived oxazolidines. These strategies enabled the rapid construction of a pyrrolidinone core and installation of contiguous stereocenters. The key intermediate was readily obtained, culminating the asymmetric total synthesis of salinosporamide D. The total synthesis of salinosporamides A and I was also achieved using the same chemistry.