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.

Keywords: 22-hydroxyacuminatine; acuminatine; benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one; thermal cyclization; total synthesis.

Figure 1

Structures of natural products containing the indolizinone or quinolizinone scaffold [1,2,3,4,5,6,7,9,10].

Scheme 1

Key synthetic transformations for the synthesis of alangiumkaloids A and B.

Scheme 2

Retrosynthetic analysis of rosettacin (5).

Scheme 3

Synthesis of 3-substituted 2-iodoquinolines 20a, 21, and 23.

Scheme 4

Synthesis of key isoquinolone precursor 2-alkynylbenzaldehyde oxime 25.

Scheme 5

Synthesis of deacetyl compound 29 from predicted acetoxy compound 28c.

Figure 2

The NOESY and HMBC correlations of acetoxyisoquinoline 28c, and structure of 28b.

Scheme 6

Synthesis of rosettacin (5) by construction of C-ring.

Scheme 7

Synthesis of acuminatine (7).