Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp³)H and C(sp²)H Functionalization Reactions

Abstract

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C-H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp(3))-H functionalization followed by a Catellani reaction, including C(sp(2))-H functionalization. A one-pot reaction involving both C(sp(3))-H and C(sp(2))-H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.

Palladium(0)-Catalyzed Benzylic C(<i>sp</i>³)–H Functionalization for the Concise Synthesis of Heterocycles and Its Applications

“…Synthesis of Pyrrolophenanthridine Alkaloids 37) Pyrrolophenanthridine alkaloids, which can be biogenetically produced by the dehydration and aromatization of lycorine, belong to the Amaryllidaceae alkaloids 104) (Fig. 3).…”

“…In this review, we provide a summary of our recent research on the Pd(0)-catalyzed benzylic C(sp 3 )-H functionalization reaction and its application. [33][34][35][36][37][38][39][40][41][42][43] 2. Pd-Catalyzed Benzylic C(sp 3 …”

Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Carbamoylation

“…Recently, we were able to access highly strained a-alkylidene-b-lactams from bromoalkenes, but this system, which was tailored for g-lactams, lacked generality and efficiency. [11] Inspired by the work of Takemoto and co-workers on the carbamoylation of 1 ary benzylic and cyclopropyl C-H bonds, [12] we envisioned that carbamoyl chlorides could constitute more appropriate substrates to construct the C(O)-Ca bond of b-lactams through Pd 0 -catalyzed C(sp 3 )-H activation (Scheme 1d). Carbamoyl chlorides are easily accessed from the corresponding 2 ary amines upon reaction with triphosgene, and can be engaged in the reaction without purification.…”

“…We report therein the development of a convenient method to synthesize b-lactams by C(sp 3 )-H carbamoylation, which is compatible with both 1 ary and 2 ary C-H At the outset of our work, we were aware that competitive decarbonylation, occurring prior to the C-H activation step and leading to secondary amine 3, would likely impact the reaction efficiency (Scheme 2). [12] To limit this side-reaction, we first conducted reactions under excess CO (balloon), as reported by Takemoto and co-workers (Table 1). Optimization studies were performed with TMB-protected [13] carbamoyl chloride 1a.…”

Palladium-Catalyzed Double C–H Functionalization of Arenes at the Positions <i>ortho</i> and <i>meta</i> to Their Directing Group: Concise Synthesis of Benzocyclobutenes

“…It is noteworthy that the alkynyloxy moiety works as a hydrogen acceptor in this case, thereby avoiding the need to add an oxidant and base to the reaction. 30) During the course of our recent studies, 31) we became interested in the way in which norbornene facilitates the ortho functionalization of aryl halides (Chart 1). According to the mechanism reported by Catellani, this reaction proceeds by the oxidative addition of an aryl halide to palladium(0) (Pd(0)) to give an arylpalladium intermediate (Chart 1a).…”