A Pot-Economical Approach to the Total Synthesis of Sch-725674

Abstract

A pot-economical total synthesis of antifungal Sch-725674, 1 is reported. The approach takes advantage of a number of one-pot, sequential transformations, including a phosphate tether-mediated one-pot, sequential RCM/CM/chemoselective hydrogenation protocol, a one-pot tosylation/acrylation sequence, and a one-pot, sequential Finkelstein reaction/Boord olefination/acetonide deprotection procedure to streamline the synthesis route by reducing isolation and purification procedures, thus saving time. Overall, an asymmetric route has been developed that is efficiently accomplished in seven pots from phosphate (S,S)-triene and with minimal purification.

Modular Synthesis of Novel Macrocycles Bearing α,β‐Unsaturated Chemotypes through a Series of One‐Pot, Sequential Protocols

“…Accordingly, natural product‐based macrocycles are attractive synthesis targets that have inspired efforts in methods and libraries development . Recently, we disclosed the application of one‐pot, sequential operations for the concise total synthesis of α,β‐unsaturated macrolactone Sch‐725674 (Figure ) . By combining an uninterrupted sequence of reactions in a single flask, one‐pot protocols enable the formation of multiple bonds and stereocenters in one synthetic step .…”

“…Inspired by these notable developments and motivated by the efficiency of our recent strategy applied to the synthesis of Sch‐725674, we planned to refine the method to access diverse natural product‐like α,β‐unsaturated macrolactones and surrogates. Herein, we describe the synthesis of novel macrocycles by efficient, one‐pot syntheses (Scheme ).…”

“…Efforts to macrolactone 1 a began by employing a phosphate tether‐mediated one‐pot, sequential RCM/CM/chemoselective hydrogenation[“H 2 ”] protocol to couple phosphate triene ( R,R )‐ 4 and cross‐metathesis (CM) partner 5 , providing bicyclic phosphate 6 (Scheme , path A; RCM=ring‐closing metathesis) . This first one‐pot event afforded phosphate triester 6 in 40 % overall yield over the course of three reactions, representing an average yield of 74 % for each reaction (74 % av/rxn, Scheme ).…”

“…[5a,13] Recently, we disclosed the application of one-pot, sequential operations for the concise total synthesis of α,β-unsaturated macrolactone Sch-725674 (Figure 1). [14] By combining an uninterrupted sequence of reactions in a single flask, one-pot protocols enable the formation of multiple bonds and stereocenters in one synthetic step. [15] This process circumvents the need for work-up and chromatography procedures between intermediary reactions with the ultimate goal of reducing time demands and waste generation.…”

“…[14,29] This first one-pot event derivatives. In particular, vinyl sulfonates and their analogs have a rich biological profile that has seen a resurgence in recent years due to their activities against enzymes involved in parasitic diseases [30] and cancer.…”