Formal Synthesis of Hapalindole O and Synthetic Efforts towards Hapalindole K and Ambiguine A

Abstract

The formal synthesis of D,L-hapalindole O has been accomplished intercepting Natsume's total synthesis route. The intercepted substrate was synthesized in an overall 36% yield over ten-synthetic steps compared to Natsume's overall 1% yield over eighteen-synthetic steps. In addition, advanced substrates for the continuing progress towards hapalindole K and ambiguine A has been synthesized. All routes described herein employ a novel silyl ether-based strategy accessing the 6:5:6:6 ring system, that has previously been used in our laboratory to access the total synthesis of D,L-hapalindoles J and U.

Total Synthesis of Pentacyclic (−)-Ambiguine P Using Sequential Indole Functionalizations

“…2 With the exception of four ambiguines, including A ( 1 ) and H ( 2 ), which are tetracyclic, the ambiguines possess a fused pentacyclic scaffold featuring a characteristic seven-membered ring moiety. Since the first reported isolation of ambiguine congeners in 1992 from Fischerella ambigua , 1a there have been continued efforts aimed at their total synthesis 3–5 given their intriguing structures. In addition, some members of the hapalindole family, such as the fischerindoles 6 and welwitindolinones, 6b,7 exert a broad spectrum of biological activities, including antimicrobial, antifungal, insecticidal, and anticancer activity as well as phytotoxicity.…”

“…No syntheses exist for the pentacyclic ambiguines ( 3 – 11 ) despite numerous reported attempts. 3 On the other hand, successful syntheses of tetracyclic ambiguine H ( 2 ) were disclosed by the Baran group in 2007 4 and the Maji group in 2018. 5 Presumably, the seven-membered E ring that is resident in the pentacyclic ambiguines poses an added synthetic challenge.…”