The Enantioselective Formal Synthesis of Rhynchophylline and Isorhynchophylline

摘要

The spiral tetracyclic oxindole skeleton is a basic building block in various natural products and biologically active compounds, such as strychnofoline, strychnophylline, voachalotine oxindole, rhynchophylline, isorhynchophylline, and formosanine (Scheme 1). These natural products show interesting bioactivity profiles. For example, rhynchophylline and isorhynchophylline are isolated from Uncaria rhynchophylla (Rubiaceae), possessing antihypertensive and hypotensive properties. They may be of clinical potential in the therapeutic treatment of hypertension and stroke. Recent studies have revealed that these alkaloids also protect against glutamate-induced cytotoxicity in cultured rat cerebellar granule cells. Because of their interesting biological activity and sophisticated architecture, these alkaloids have garnered considerable interest in the synthetic community. Ban et al. have reported the first total synthesis of rhynchophylline and isorhynchophylline, through the condensation of a 2-oxytryptamine with an aldehyde by a Mannich reaction. Their results afford the configurationally labile oxindole skeleton and the nonselective introduction of the stereogenic center C-15. Thus, four separations of diastereomers were required. Then Martin and co-workers employed a sequence of two ring-closing metathesis reactions, one zirconocene-catalyzed carbomagnesation, and a subsequent nonselective oxidative rearrangement as key steps for the formal synthesis of rhynchophylline and isorhynchophylline. However, these methods proceed with modest stereochemical controls, and the products were prepared in racemic forms. To the best of our knowledge, in spite of these great efforts, no suitable system has been developed for the enantioselective synthesis of these alkaloids. Herein, we report the first enantioselective formal total synthesis of rhynchophylline and isorhynchophylline.