Reaktionen an Indolderivaten, XVII. Die biogenetisch orientierte Totalsynthese von DL‐Camptothecin und 7‐Chlor‐camptothecin

Abstract

Es wird die biogenetisch orientierte Uberfiihrung der Indolvorstufe 3 iiber die Verbindungen 4, 6, 10, 12, 15, 17, 20 und 24 in das anti-Tumor-wirksame Alkaloid Camptothecin (1) sowie in das 7-Chlor-camptothecin (2) beschrieben. Reactions with Indole Derivatives, XVII l) The Biogenetically Orientated Total-Synthesis of DL-Camptothecin and 7-ChlorocamptothecinThe biogenetically patterned transformation of the easily available indole derivative 3 via the compounds 4, 6, 10, 12, 15, 17, 20, and 24 into the anti-tumor alkaloid camptothecin (1) as well as 7-chlorocamptothecin (2) is described.In der vorstehenden Arbeit sind bereits die biogenetischen Zusanimenhange zwischen den Indolalkaloiden und dem wegen seiner interessanten anti-Tumor-und anti-Leukamie-Aktivitat bekannt gewordenen Chinolin-Alkaloid Camptothecin (1) dargelegt worden. Es sei hier jedoch auch auf die starke Toxizitat des Naturstoffes, die nur recht geringe Dosen zulaRt, und auf die recht hohe Stabilitat des Molekuls hingewiesen, die zu einer Anreicherung im Korper fuhrt. X Wir waren der Meinung, da13 der von uns beschriebenel) und uber die Stufen Indol -Chinolon -Chlorchinolin -Chinolin verlaufende Weg besonders gut zur Syn-these2) dieses Naturstoffes geeignet sein sollte, da man auf diese Weise in die Lage ver-1) XVI. Mitteil.: J. Warneke und E. Winterfeldt, Chem. Ber. 105, 2120 (1972), vorstehend. 2) Nachdem unsere Experimente abgeschlossen waren, wurden in rascher Folge zwei Totalsynthesen dcs Carnptothecins veroffentlicht: 2a) G. Stork und A . Schultz, J. Amer. chem. SOC. 93, 403 (1971); 2b) R. Volkmann, S. Dunishefsky, J . Eggler und D . M . Solomon, J. Amer. chem. SOC. 93, 5577 (1971).

The Witkop-Winterfeldt-Oxidation of Indoles

“…2 Wenkert had postulated that the pyrroloquinoline moiety of the natural product and clinically relevant anti-leucemia drug camptothecin (99) is biosynthetically formed by oxidation of a corresponding carboline derivative and subsequent Camps reaction [42]. Winterfeldt strategy in his total synthesis of (±)-camptothecin (99) (Scheme 21) [43]. Importantly, with the selection of inorganic bases he identified reaction conditions which allow the direct conversion of indoles into quinolones without isolation of the dicarbonyl intermediates.…”

“…In model studies preceeding the total synthesis of camptothecin Winterfeldt investigated the direct conversion of indoles to quinolones for a variety of substrates. (Scheme 22 and 23) [7,43,50]. In particular, the oxidation of the natural product ajmalicine (104) occurred in an excellent yield of 92%.…”

Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals

“…[40] For instance, compound 69 a was reported as ak ey intermediate in the synthesis of 70,a potent phosphodiesterase type 5(PDE5) inhibitors. [41] Its preparation through as inglee nantioselective and catalytic step in 80 %y ield and 85 % ee would shorten the synthesis of 70 by three steps. Hiemstra and co-workersfurther demonstrated the usefulness of this method by synthesizing the tetracyclic indole alkaloid (À)-arboricine.…”

Biomimetic Synthesis of Alkaloids with a Modified Indole Nucleus

“…Soon after Hutchinson's biosynthesis was published, Winterfeldt and coworkers completed the first biomimetic total synthesis of this molecule [8], following Hutchinson's findings (Scheme 5.3). Their synthesis started from known compound 31, which was converted into 32 via diisopropyl-carbodiimide (DIC) mediated amide bond formation.…”