Formation of 6-Azaindoles by Intramolecular Diels–Alder Reaction of Oxazoles and Total Synthesis of Marinoquinoline A

Abstract

A new variant of the intramolecular Diels−Alder oxazole (IMDAO) cycloaddition that provides direct access to 6azaindoles was developed. The IMDAO reaction was applied in a total synthesis of the aminophenylpyrrole-derived alkaloid marinoquinoline A, also featuring the use of a Curtius reaction for preparation of a 5-aminooxazole, a propargylic C,H-bond insertion, an in situ alkyne−allene isomerization, and a rutheniumcatalyzed cycloisomerization for benzene ring annulation to the 6-azaindole.T he intramolecular hetero-Diels−Alder reaction is a versatile method for generating monocyclic and polycyclic heteroarenes, 1 including pyridines, 2−4 pyrimidines, 5,6 quinolines, 7,8 and isoquinolines, 9,10 and has frequently been applied to complex target molecule synthesis. 11 As an extension of our intramolecular Diels−Alder furan (IMDAF) reaction for indole synthesis, 12,13 we now report a new variant of the intramolecular Diels−Alder oxazole (IMDAO) cycloaddition, 14,15 leading to 6-azaindoles. Furthermore, we apply this new reaction to the preparation of the pyrroloquinoline marinoquinoline A (Scheme 1).IMDAO reactions are well-established in the heterocyclic literature 16 and have previously been used in natural product synthesis. 17−19 However, to the best of our knowledge, this is the first application of this Diels−Alder variant for 6-azaindole synthesis, with the exception of some precedent for the generation of partially saturated heterocycles containing this core structure (Scheme 2). 20−23 We had previously identified conditions for a Diels−Alder cycloaddition route to indoles 4 from allenyl furans 3, but when we applied analogous conditions to oxazoles 5, we encountered experimental challenges with the preparation and

Intramolecular Diels–Alder Reactions of Oxazoles, Imidazoles, and Thiazoles

“…hypothesis is supported by the isolation of the bridged tricyclic cycloadduct 157, which was obtained in 73% yield after heating allenyl oxazole 156 in toluene at 140 °C (sealed tube) for 6.5 hours (Scheme 25). 68 This conversion is also in agreement with the proposed mechanism for the IMDAO cycloaddition.…”

“…67 In 2020, another total synthesis of marinoquinoline A was reported by Wipf and co-workers who employed an allene-IMDAO reaction to generate the azaindole moiety and a dienyne cycloisomerization to obtain the quinoline substructure (Scheme 23). 68…”

“…In agreement with this proposal, mild heating of 5-(allenylamino)oxazole 152 resulted in the formation of 6-azaindole 155 in 89% yield. 68…”

The Chemistry and Biological Applications of 3H‐Pyrrolo[2,3‐c]quinolines and Marinoquinolines

“…Finally, Boc group removal gave MQ A in 53% overall yield from intermediate 181 . The overall yield for MQ A was 12% over 11 steps [55] …”

Recent Applications of the Diels–Alder Reaction in the Synthesis of Natural Products (2017–2020)

“…In addition, this Diels-Alder protocol also illustrates the versatility of the oxazole ring in the preparation of other ring systems, such as azaindoles. Marinoquinoline A (isolated from a seaweed bacterium Rapidithrix thailandica by a HZI team), as well as other 6-azaindoles, possess several pharmaceutical properties such as antifungal, antibacterial, cytotoxic and antimalarial 88. Solvent-free, silica-catalyzed synthesis of divergent chromenones Suri et al envisioned for the synthesis of divergent chromenones 279 a three component, solvent-free, one-pot approach consisting of a Knoevenagel/ hetero-Diels-Alder reaction-cascade.…”