Synthesis of the Azaoxoaporphine Alkaloid Sampangine and Ascididemin‐Type Pyridoacridines through TMPMgCl·LiCl‐Mediated Ring Closure

Abstract

We report the synthesis of the azaoxoaporphine alkaloid sampangine (4) and a series of ring A analogues and isomers of the marine pyridoacridine alkaloid ascididemin (2). This approach starts from readily available 1‐bromo[2,7]naphthyridine (12) or 4‐bromobenzo[c][2,7]naphthyridine (5), and the ring A scaffold bearing an ester moiety is introduced by a Suzuki or Negishi cross‐coupling reaction. The final cyclization step was achieved through a directed remote ring metallation with the Knochel–Hauser base (TMPMgCl·LiCl; TMP = 2,2,6,6‐tetramethylpiperidinyl), followed by intramolecular trapping of the ester group.

Pyridoacridines in the 21st Century

“…Synthesis of 4-deaza-ascididemine 89 and structures of ascididemine isomers 126 and 109. [73] The base-promoted closure of two rings using sodium hydride in N,N′-dimethylpropyleneurea (DMPU) from the fluoronitrile 127 neatly leads directly to 4-deaza-ascididemine 89, with formation of two rings, though the yields in this example and substituted variants, were only moderate (Scheme 40). [74] The mechanism of the anionic ring closure is detailed in Scheme 12.…”

Current Applications of Suzuki–Miyaura Coupling Reaction in The Total Synthesis of Natural Products: An update

“…Compound 317 was upon cyclization involving a directed remote ring metalation via treatment with the Knochel-Hauser base (TMPMgCl·LiCl; TMP = 2,2,6,6tetramethylpiperidinyl), and subsequent intramolecular trapping of the ester moiety gave the desired natural product Deazaascididemin 314 in acceptable overall yield (Schemes 52 and 53). [171] Discoipyrroles A-D were, isolated from the marinederived Bacillus hunanensis strain SNA-048 by MacMillan et al and reported in 2013. Their structures were elucidated by employing conventional spectroscopic methods and spectral analysis.…”

New Perspectives in the Chemistry of Marine Pyridoacridine Alkaloids

“…Due to the fact that the above-mentioned protocol [ 24 ] only allows for the introduction of electron-rich carbocyclic and heterocyclic ring A substitutes, Plodek et al developed a new approach to the pyridoacridine ring system in which electron-deficient (hetero)arenes also serve as sources for ring A [ 25 ]. The introduction of the ring A scaffolds was achieved through Suzuki cross-coupling of 4-brombenzo[ c ][2,7]naphthyridine ( 42 ) with (hetero)areneboronic acids bearing an ester moiety in the ortho position or through Negishi cross-coupling with pyridylzinc compounds which were obtained by regioselective ring metalation of ethyl nicotinate or ethyl isonicotinate.…”

“…The introduction of the ring A scaffolds was achieved through Suzuki cross-coupling of 4-brombenzo[ c ][2,7]naphthyridine ( 42 ) with (hetero)areneboronic acids bearing an ester moiety in the ortho position or through Negishi cross-coupling with pyridylzinc compounds which were obtained by regioselective ring metalation of ethyl nicotinate or ethyl isonicotinate. The resulting 5-substituted benzo[ c ][2,7]naphthyridines 49 were metalated regioselectively at the peri position (C-5) with Knochel’s TMPMgCl·LiCl (2.2 equivalents), and intramolecular nucleophilic attack of the resulting arylmagnesium species 50 at the ester group furnished ring A analogues 18 , 31 , 45 – 48 and isomers 11 and 30 of ascididemin in poor-to-modest yields ( Scheme 9 ) [ 25 ]. This key step was inspired by the synthesis of demethyldeoxyamphimedine published by the Bracher group in 2014 [ 26 ] (see below).…”