Catalytic Z-Selective Cross-Metathesis in Complex Molecule Synthesis: A Convergent Stereoselective Route to Disorazole C₁

Abstract

A convergent diastereo- and enantioselective total synthesis of anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route is the application of catalytic Z-selective cross-metathesis (CM). Specifically, we illustrate that catalyst-controlled stereoselective CM can be performed to afford structurally complex Z-alkenyl–B(pin) as well as Z-alkenyl iodide compounds reliably, efficiently, and with high selectivity (pin = pinacolato). The resulting intermediates are then joined in a single-step operation through catalytic inter- and intramolecular cross-coupling to furnish the desired 30-membered ring macrocycle containing the critical (Z,Z,E)-triene moieties.

Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis

“…(3) Product purification would be more practical: organic halide reagents are more easily removable (sufficiently volatile) and do not afford pinacol byproduct that can be difficult to separate from the desired product. (4) Access to multifunctional molecules with an alkenyl–B(pin) as well as an alkenyl halide would be more feasible 27 .…”

Application of catalytic Z-selective olefin metathesis in natural product synthesis

“…27 In their recently reported total synthesis of 44, Hoveyda and coworkers utilized the dimeric structure of 44 to construct the macrocycle from two identical olefin rich oxazole fragments 45 by double cross-coupling. 28 Fragment 45 was prepared using two Z-selective CM reactions featuring a Mo MAP catalyst (Scheme 14). 29 Instead, a CM with vinylboronic acid pinacol ester and subsequent FGI was employed once more to avoid a substrate that has yet to be used successfully in CM reactions.…”

Stereoretentive Olefin Metathesis: An Avenue to Kinetic Selectivity

“…The first examples of kinetically Z-selective processes were reported by Schrock, Hoveyda, and coworkers, identifying both molybdenum-and tungsten-based systems to perform this transformation, which generated the desired Zolefins in high selectivity. [16][17][18][19][20][21][22][23][24][25][26] A large aryloxy-moiety shields one side of the catalyst, forcing the substituents on the generated metallacyclobutane to be all syn (Figure 1 (a)). Later, Grubbs and coworkers introduced a highly efficient, Z-selective olefin metathesis catalyst that utilized a cyclometalated rutheniumcarbene species.…”