Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis

Abstract

Many biologically active macrocycles contain a C–C double bond through which various other derivatives are prepared; the stereochemical identity of the alkene or the resulting moieties can be critical to the beneficial properties of such molecules. Catalytic ring-closing metathesis (RCM) is a widely employed method for the synthesis of large unsaturated rings;1,2 however, cyclizations often proceed without control of alkene stereochemistry.2 Such shortcoming is particularly costly with complex molecules when cyclization is performed after a long sequence of transformations.2 Here, we outline a reliable, practical and general approach for efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% Z selectivity due to control induced by a tungsten-based alkylidene. Utility is demonstrated by stereoselective preparation of anti-cancer epothilone C [Ref. 3–5] and anti-microbial nakadomarin A [Ref. 6], previously reported syntheses of which have been marred by late-stage non-selective RCM.7–15 The tungsten alkylidene can be manipulated in air, promoting reactions carried out in a fume hood to deliver products in useful yields and high Z selectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways even under relatively high concentration (0.1 molar).

Effects of Alkali Metal Ion Cationization on Fragmentation Pathways of Triazole-Epothilone

“…For example, as one of the most attractive drugs for cancer therapy, epothilones and their relatives have evoked a vast research effort within academic and pharmaceutical research groups that include numerous total and partial syntheses and extensive structure-activity relationship studies [15][16][17][18][19][20][21]. Surely, it will be very important to know how the cationation by metal ions can affect structures and functions of these types of drugs.…”

“…Recently, chemical compounds with different macrocyclic rings inside themselves have attracted more interests in different research fields, including synthetic chemistry, natural products, and chemical biology [13][14][15][16][17][18][19][20][21]. For example, as one of the most attractive drugs for cancer therapy, epothilones and their relatives have evoked a vast research effort within academic and pharmaceutical research groups that include numerous total and partial syntheses and extensive structure-activity relationship studies [15][16][17][18][19][20][21].…”

Stereoretentive Olefin Metathesis: An Avenue to Kinetic Selectivity

“…[84,85] Since, many breakthroughs in olefin metathesis have been made using molybdenum catalysts. Recent advancements have built on the catalytic structure of Z-selective systems [16][17][18][19][20][21][22] and have provided access to valuable products through stereoretentive olefin metathesis.…”

“…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.…”

Black‐Swan‐Ereignisse in der organischen Synthese

“…Vor kurzem wurde ein Wolfram-Metathesekatalysator verwendet, um hohe Z-Selektivität bei der Synthese von Epothilon C und Nakadomarin A zu erzielen. [78] 5 [80] und Xanthin-Oxidase [81] ihre katalytische Aktivität in organischen Lçsungsmitteln beibehielten.…”