Total Syntheses of the 3H-Pyrrolo[2,3-c]quinolone-Containing Alkaloids Marinoquinolines A–F, K, and Aplidiopsamine A Using a Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Pathway

Abstract

Compounds 1−6 and 11 representing key members of the marinoquinoline family of natural products, together with the related marine alkaloid aplidiopsamine A (12), have been synthesized using various combinations of palladiumcatalyzed Ullmann cross-coupling and reductive cyclization processes involving a C3-arylated pyrrole as the common intermediate. These natural products have been characterized by single-crystal X-ray analyses and evaluated as inhibitors of acetylcholinesterase (AChE) with congener 2 proving to be the most active.

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

“… Synthesis of the late stage precursor N ‐oxide 153 and total synthesis of MQ A‐C , MQ E and MQ K , as reported by Bolte and co‐workers [53] …”

“…A S N 2 reaction of the bromo ketone 163 with adenine afforded the alkylated adenine 164 . Finally, the reduction of the nitro group with Raney cobalt produced aplidiopsamine A in 92% yield, with an overall yield of 72% starting from the arylpyrrole 44 [53] …”

“…Docking with human acetylcholinesterase (4BDT) helped to understand how such substituent effects operate. The 3 H‐ pyrrolo[2,3‐ c ]quinoline framework of MQ B participates in π‐stacking interactions with the aromatic residues of tyrosine (Y337) and tryptophan (W86) with an orientation that allows the C4 isobutyl group to insert into a nearby pocket, thus enhancing binding, presumably through van der Waals interactions [53] …”

“…The reaction of each ketone with NaOMe in MeOH resulted in cleavage of the tosyl groups thus affording MQ 161 (85%) and the MQ F (85%). The overall yield for the natural MQ F was 16% after four steps [53] …”

Total synthesis of pyrrolo[2,3-c]quinoline alkaloid: trigonoine B

“…Thus, the development of a convenient and efficient synthetic route to the pyrrolo[2,3- c]quinoline skeleton has attracted considerable attention from organic and medicinal chemists. The total syntheses of aplidiopsamine A (2) [5][6][7][8][9] and marinoquinolines 3 [10][11][12][13] have been achieved by various synthetic strategies. Nevertheless, the total synthesis of trigonoine B (1) has not yet been reported.…”