Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin, a Water‐Soluble Analogue of Camptothecin

Abstract

A robust, practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin (T-2513, 5), which is a water-soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N-arylsulfonyl-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1,2,3,5-tetrahydroindolizin-7-yl)butanoate (8k) in 93% yield and 87% de. Optically pure compound 8k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5. This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi-gram scale in 6.3% overall yield (16 steps).

Asymmetric α‐Hydroxylation of a Lactone with Vinylogous Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst: Catalytic Enantioselective Synthesis of a Key Intermediate for (20S)‐Camptothecin Analogues

“… [a] Reactions were performed with 8 a (0.1 mmol), CHP (0.15 mmol), K 2 CO 3 (0.1 mmol), and catalyst (0.01 mmol) in toluene at 0 °C for 24 h. [b] Racemic 5 a and ( S )‐ 5 a were prepared according to ref. 8b and 8c, respectively. The enantiomeric excess and the absolute stereochemistry were determined by chiral HPLC analysis.…”

Development of Guanidine-Bisurea Bifunctional Organocatalyst Bearing Chirality at the Inner and Outer Sides of the Urea Groups, and Application to Enantioselective α-Hydroxylation of Pyranoindolizine Intermediate for Camptothecin Synthesis

“…Based upon the proposed transition state model, we further applied this reaction to the α-hydroxylation of pyranoindolidine derivatives 7 to obtain the corresponding hydroxylated compounds 8 via the extended enolate 7' with high enantioselectivity (Scheme 1b). The products 8 are key synthetic intermediates in the Friedländer condensation approach to CPT derivatives [14][15][16][17][18][19][20][21][22]. Subsequently, we developed the novel guanidine-bisurea bifunctional organocatalyst 10 (Scheme 1c) bearing a chiral center at the outer side of the urea groups [23].…”