Novel Approach to the Construction of Fused Indolizine Scaffolds: Synthesis of Rosettacin and the Aromathecin Family of Compounds

Abstract

Camptothecin-like compounds are actively employed as anticancer drugs in clinical treatments. The aromathecin family of compounds, which contains the same indazolidine core structure as the camptothecin family of compounds, is also expected to display promising anticancer activity. Therefore, the development of a suitable and scalable synthetic method of aromathecin synthesis is of great research interest. In this study, we report the development of a new synthetic approach for constructing the pentacyclic scaffold of the aromathecin family by forming the indolizidine moiety after synthesizing the isoquinolone moiety. Thermal cyclization of 2-alkynylbenzaldehyde oxime to the isoquinoline N-oxide, followed by a Reissert–Henze-type reaction, forms the key strategy in this isoquinolone synthesis. Under the optimum reaction conditions for the Reissert–Henze-type reaction step, microwave irradiation-assisted heating of the purified N-oxide in acetic anhydride at 50 °C reduced the formation of the 4-acetoxyisoquinoline byproduct to deliver the desired isoquinolone at a 73% yield after just 3.5 h. The eight-step sequence employed afforded rosettacin (simplest member of the aromathecin family) at a 23.8% overall yield. The synthesis of rosettacin analogs was achieved by applying the developed strategy and may be generally applicable to the production of other fused indolizidine compounds.

Recent Advances in the Synthesis of Rosettacin

“…The mechanism of the generation of compound 12b from substrate 12a was proposed by the authors (Scheme 21). The addition of NHC to substrate 12a yields In 2023, Choshi et al reported a new method for the synthesis of rosettacin by using thermal cyclization and a Reissert-Henze-type reaction as the key step [41] (Scheme 22). Here, 2-Chloroquinoline-3-carbaldehyde 8a reacted with NaI and concentrated HCl to yield 2-iodoquinoline 13a.…”

Progress on the Synthesis of the Aromathecin Family of Compounds: An Overview

“…Initially, hydroxypyridone (38) was treated using Tf 2 O in pyridine to obtain a triflate (39) with an 89% yield, followed by the Heck reaction of 39 with methyl 2,4-pentadienoate (40) in the presence of PdCl 2 (PPh 3 ) 2 and Et 3 N to obtain an alkene (41) with a 64% yield (Scheme 5). Next, 41 was subjected to FVP cyclization to obtain pyrroloisoquinolin-5one (42) with a 77% yield; to introduce a carbonyl group to the 1-position, a ketone (43) with a 75% yield was obtained through SeO 2 and Dess-Martin periodinane (DMP) oxidations.…”

Ru(II) Catalyzed Oxidative Dehydrogenative Annulation and Spirocyclization of Isoquinolones with N‐Substituted Maleimides

“…(Figure 1). [2] In recent times, transition‐metal‐catalyzed functionalization of less reactive C−H bonds has become significant. Also C−C and C−X (X=heteroatom) bond formation through direct C−H bond transformation becomes significant.…”