A Highly Stereoselective Total Synthesis of Unnatural N-Methyl Tubulysin

This study involved the development of a new and scalable procedure for the stereoselective total synthesis of unnatural N -methyl tubulysin. The procedure encompasses linear sequence of 30 steps with an overall yield of 1.2%. The Tuv unit was prepared by diastereoselective synthesis from l -valine following MacMillan α-hydroxylation and an improved thiazole formation strategy. The stereocenters of the Tup unit were generated by using an Evans asymmetric aldol reaction initiated by l -phenylalanine. Notably, epimerization was completely avoided during all amide-forming reactions. The procedure that forms the basis of this sequence can be reliably performed on a gram scale and represents a significant improvement over previously reported syntheses of these and related tubulysin analogues. The scalability, associated yields, excellent stereoselectivity, and mild reaction conditions are the advantageous features of this approach.