Evolution of a Chemical Strategy Toward the Synthesis of Unsymmetrically Oxidized Nuphar Alkaloids

Here we describe the frustrations, joys, and unexpected turns experienced in our journey toward a successful strategy directed at the total synthesis of unsymmetrically oxidized Nuphar thioalkaloids. While many adjustments were made to our initial synthesis plan, our general approach to the construction of the central bis(spirothiolane) moiety remained unchanged. Specifically, each iteration of our synthesis design involved the formation of the thiaspirane motif through the stereodivergent coupling of a thietane with a metal carbenoid, followed by a Stevens-type rearrangement of the resulting sulfonium ylide. 1 Introduction 2 First-Generation Strategy 3 Second-Generation Strategy 4 Third-Generation Strategy 5 Conclusion