Total Synthesis of Ecteinascidin 743

Abstract

A straightforward synthesis of ecteinascidin 743 was accomplished from readily available l-glutamic acid as a single chiral source. Our novel synthesis features a concise and convergent approach for construction of the B-ring, consisting of a sequence involving a stereoselective Heck reaction between a diazonium salt and an enamide, oxidative cleavage of the resulting alkene, and intramolecular ortho substitution of the phenol by an aldehyde.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…In summary, there are three important pathways (Scheme 13): (A) combination of two fragments (I and II) via an oxazolidine intermediate, (B) acid-promoted macrocyclization via creation of carbon-sulfur bond with concomitant formation of a 10-membered ring, and (C) the intramolecular Pictet-Spengler reaction to obtain 71 [154][155][156][157]. The straightforward synthesis of 71, using 28 steps with 1.1% yield, started from L-glutamic acid as the single chiral source [158] while a 31 steps synthesis, with 1.7% yield, began from 3-methylcatechol [159]. The first conditions lead to the B-ring formation by stereoselective Heck reaction between diazonium salt and enamide, oxidative cleavage of the resulting alkane and intramolecular ortho substitution of phenol by aldehyde.…”

“…The first conditions lead to the B-ring formation by stereoselective Heck reaction between diazonium salt and enamide, oxidative cleavage of the resulting alkane and intramolecular ortho substitution of phenol by aldehyde. This pathway can form a diketopiperazine by Perkin condensation and the bicyclo [3.3.3]system by an N-acyliminium ion-mediated cyclization, and a regioselective Suzuki-Miyaura coupling (Scheme 13) [158]. In 2000, Cuevas et al [149] established the synthesis of 71 and 72 from cyanosafracin B, which is an antibiotic obtained from fermentation of the bacterium Pseudomonas fluorescens.…”

Cancer wars: natural products strike back

“…However, isolation of ecteinascidin 743 required complex and costly steps of purification with final yields less than 1 g/ton (Cuevas and Francesch, 2009). Several total syntheses have been reported, but they cannot be translated into industrial production (Corey et al, 1996; Endo et al, 2002; Chen et al, 2006; Zheng et al, 2006; Fishlock and Williams, 2008; Imai et al, 2012; Kawagishi et al, 2013). Eventually, this supply problem was solved by use of a complex semi-synthesis from cyanosafracin B, which is available in kilogram quantities by fermentation (Cuevas et al, 2000; Menchaca et al, 2003).…”

A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin

“…[1,[6][7][8][9] In 1996, the Corey group reported the first total synthesis of Et-743, [6] in which an intermolecular Strecker reaction and an internal Mannich bisannulation were used for elaboration of the tetrahydroisoquinoline core structure in combination with aC ÀSb ondforming cyclization and aP ictet-Spengler reaction to create the bridged 10-membered lactone and spiro ring system. Later, the Fukuyama, [7,9] Zhu, [8] Danishefsky [10] and Williams [11] groups reported three additional elegant total syntheses along with several formal synthetic routes.H owever,t hese routes remain far from practical for the preparation of Et-743, largely because of the requirement for de novo synthesis of unnatural amino acid residues (for installing right and left parts of Et-743). Thec urrent synthetic approach, either asymmetric hydrogenation of the corresponding dehydrophenalanine derivatives or asymmetric induction using chiral auxiliaries,n ot only requires the employment of expensive reagents that are difficult to access,b ut also increases the numbers of total synthetic steps (about 40-60 steps).…”

“…As depicted in Figure 2, we believed that Et-743 and lubinectedin could be assembled from hexacyclic amino nitrile 1 by using amacrocyclization method that was initially developed by Corey and co-workers, [6] and has also been applied in other semi-and total syntheses of Et-743. [7][8][9]12] The amino nitrile 1 could be prepared from amino alcohol 2 through an intramolecular Strecker reaction, while 2 could be obtained through aP ictet-Spengler reaction between alde- hyde 3 and (S)-5-(2-amino-3-hydroxypropyl)-2-methoxy-3methylphenol 4. [13] Thealdehyde 3 could be synthesized from phenol 5 through protection and subsequent oxidation, and the phenol 5 could be prepared from tetrahydroisoquinoline 6 using an unusual remote CÀHfunctionalization method.…”