New Perspectives in the Chemistry of Marine Pyridoacridine Alkaloids

Abstract

Secondary metabolites from marine organisms are a rich source of novel leads for drug development. Among these natural products, polycyclic aromatic alkaloids of the pyridoacridine type have attracted the highest attention as lead compounds for the development of novel anti-cancer and anti-infective drugs. Numerous sophisticated total syntheses of pyridoacridine alkaloids have been worked out, and many of them have also been extended to the synthesis of libraries of analogues of the alkaloids. This review summarizes the progress in the chemistry of pyridoacridine alkaloids that was made in the last one-and-a-half decades.

Keywords: marine alkaloids; pyridoacridines; total synthesis.

Figure 1

Structure of amphimedine (1) and the 11H-pyrido[4,3,2-mn]acridine scaffold (2).

Figure 2

Structures of the ascididemin-type pyridoacridine alkaloids: ascididemin (3), bromoleptoclinidinone (4), neocalliactine acetate (5), 10-hydroxyascididemin (6).

Scheme 1

First total synthesis of ascididemin (3): (a) CeCl₃·7H₂O, EtOH, air; then conc. H₂SO₄/AcOH (73% over two steps); (b) N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl, AcOH (59% over two steps).

Scheme 2

Synthesis of ascididemin isomer 11. Reagents and conditions: (a) CeCl₃·7H₂O, EtOH, air; then conc. H₂SO₄/AcOH (27% over two steps); (b) N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl, AcOH (23% over two steps).

Scheme 3

Synthesis of pyridoacridine natural products 3–6 and synthetic ascididemin analogues 5-methoxyascididemin (17) and deazaascididemin (18): (a) CeCl₃·7H₂O, MeOH, O₂ (50%–80%); (b) Fe₂(SO₄)₃, conc. H₂SO₄/AcOH, O₂ (44%–86%).

Scheme 4

Synthesis of ascididemin-type pyridoacridines 21 and 22 by Copp: (a) CeCl₃·7H₂O, MeOH, air (22%–92%); then conc. H₂SO₄/AcOH (81%–94%); (b) NH₄Cl, (CH₂O)_n, AcOH (76%–83%).

Scheme 5

Synthesis of ascididemin (3) through anionic ring closure: (a) Malononitrile, NH₄OAc, toluene/AcOH; (b) dimethylformamide dimethyl acetal, CH₂Cl₂; (c) HCl gas, AcOH (81% over three steps); (d) 3-methylpyridin-2-ylzinc bromide, PEPPSI-iPr, THF (80%); (e) NaH, DMF; (f) O₂ (69% over two steps) [20]; Synthesis of the ring A analogues 18, 30–34; (g) Negishi or Suzuki cross-coupling reactions (44%–88%); (h) NaH, DMPU (19%–29%).

Scheme 6

Synthetic approach towards deazaascididemin (18): (a) Benzaldehyde, AcOH, Et₃N, H₂O, FeSO₄, tert-BuOOH (51%); (b) dimethylformamide diethyl acetal, DMF; then H₂SO₄, AcOH (39%); (c) POBr₃, anisole (27%); (d) Bu₃SnH, AIBN, toluene (5%).

Scheme 7

Unsuccessful approach to the ascididemin precursor 40 giving benzo[f]pyrido[2′,3′:3,4]pyrrolo[2,1-a][2,7]naphthyridine (41): (a) H₂SO₄, H₂O (43%).

Scheme 8

Synthesis of ring A analogues of ascididemin 18, 31, 45–48 through an intramolecular trifluoromethanesulfonic acid-aided Friedel-Crafts-type cyclization step: (a) Methyl pyruvate, H₂O₂, FeSO₄, H₂SO₄, AcOH; then MnO₂, CH₂Cl₂ (93% over two steps); (b) (hetero)areneboronic acid, Pd(Ph₃P)₄ (cat.), K₂CO₃, THF, H₂O (41%–75%); (c) CF₃-SO₃H, microwave irradiation (63%–92%).

Scheme 9

TMPMgCl·LiCl-mediated synthesis of ring A analogues 18, 31, 45–48 and isomers 11 and 30 of ascididemin (3): (a) For Suzuki cross-coupling reactions: areneboronic acid, Pd₂(dba)₃, P(tBu)₃, KF, THF (73%–80%); for Negishi cross-coupling reactions: pyridylzinc compounds, Pd(dba)₂, P(2-furyl)₃, THF (71%–76%); (b) TMPMgCl·LiCl, THF (27%–39%).

Figure 3

Structures of the amphimedine-type pyridoacridine alkaloids: amphimedine (1), neoamphimedine (54), deoxyamphimedine (55) and demethyldeoxyamphimedine (56).

Scheme 10

Synthesis of demethyldeoxyamphimedine (56): (a) Toluene, N₂ atmosphere (0.8%); (b) NaOH, CHCl₃ (96%).

Scheme 11

Synthesis of demethyldeoxyamphimedine (56) by Melzer et al: (a) TMPMgCl·BF₃·LiCl, THF; then ZnCl₂; (b) 2-iodoaniline, Pd(dba)₂, P(2-furyl)₃, THF (50% over two steps); (c) POBr₃ (59%); (d) pyridylzinc compound 62, Pd(dba)₂, P(2-furyl)₃, THF (78%); (e) TMPMgCl·LiCl, THF (28%).

Scheme 12

Ireland’s synthesis of neoamphimedine (54): (a) CH₂N₂; then 10% Pd/C in cyclohexene/EtOH; then AcOH/Ac₂O (77% over two steps); (b) 10% Pd/C in cyclohexene/EtOH; then ethyl (2-nitrobenzoyl)acetate, m-xylenes (96%); (c) PPA (52%); (d) Tf₂O, CH₂Cl₂, Et₃N; then formic acid, Et₃N, DMF, Pd(OAc)₂, dppf (61% over two steps); (e) AcOH, H₂O, H₂SO₄; then NaNO₂; then CuCN (50%); (f) H₂SO₄ (80%); (g) N-methylamino acetaldehyde dimethyl acetal, EDC, CH₂Cl₂ (87%); (h) H₂SO₄ (43%); (i) 10% Pd/C, cyclohexene/EtOH; then CAN (30%).

Scheme 13

Improved synthesis of neoamphimedine (54): (a) Pd/C, H₂, MeOH; (b) Meldrum’s acid, trimethyl orthoformate (90% over two steps); (c) Ph₂O, reflux (87%); (d) Tf₂O, DMAP, 2,6-lutidine, CH₂Cl₂ (92%); (e) trimethyl-(2-nitrophenyl)stannane (80), CuI, Pd(OAc)₂, dppe, DMF (83%); (f) LiOH; following steps, see Scheme 12.

Scheme 14

Synthesis of neoamphimedine (54): (a) ClCO₂Et, Et₃N, THF; then MeI, NaH, THF; then DMAP, (CF₃SO₂)O, CH₂Cl₂ (74% over three steps); (b) Cu(NO₂)₂∙3H₂O, Ac₂O (96%); (c) Pd/C, H₂, MeOH; then Meldrum’s acid, trimethyl orthoformate (81% over two steps); (d) Ph₂O, reflux (83%); (e) POBr₃, THF (70%); (f) 2-(pivaloylamino)phenylboronic acid, Pd(PPh₃)₄, K₂CO₃, H₂O, EtOH, toluene (90%); (g) H₂SO₄/H₂O (64%); (h) BBr₃, CH₂Cl₂; then CAN/H₂O, MeCN (31%).

Figure 4

Structure of eilatin (90).

Scheme 15

Synthesis of eilatin (90): (a) Tf₂O, CH₂Cl₂, Et₃N (93%); (b) formic acid, Et₃N, Pd(OAc)₂, dppf, DMF (87%); (c) CAN, acetonitrile/H₂O (60%); (d) CeCl₃·7H₂O, 2-aminoacetophenone, EtOH (54%); (e) conc. H₂SO₄/AcOH (83%); (f) N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl, AcOH (75% over two steps); (g) 10% Pd/C, EtOH (85%).

Scheme 16

Synthesis of eilatin (90): (a) CeCl₃·7H₂O, 2-aminoacetophenone, EtOH (52%); (b) conc. H₂SO₄/AcOH (75%); (c) N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl, AcOH (41% over two steps).

Scheme 17

Biomimetic synthesis of eilatin (90): (a) NaIO₃, EtOH (15%); (b) BF₃·OEt₂, CH₂Cl₂ (no yield given); (c) NH₃, MeOH (no yield given) [34].

Scheme 18

Synthesis of postulated eilatin precursor 106: (a) NaIO₃, EtOH (60%); (b) BF₃·OEt₂, CH₂Cl₂ (70%).

Scheme 19

Synthesis of Ru^II-eilatin complex 109: (a) Pd(OAc)₂, Bu₄NBr, K₂CO₃, iPrOH, DMF (b) Ru(bpy)₂Cl₂·5H₂O, ethylene glycol, water (62%); (c) Pd/C, ethylene glycol-acetone (97%).

Scheme 20

Synthesis of eilatin (90): (a) Reflux (54%); (b) N,N-dimethylformamide diethyl acetal, DMF; then NH₂OH·HCl (41% over two steps); (c) acetic anhydride (66%); (d) 10% NaOH in H₂O/MeOH (84%); (e) MnO₂ (66%); (f) 2-aminoacetophenone, CeCl₃·7H₂O (74%); (g) 10% H₂SO₄ in AcOH (96%); (h) N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl (65% over two steps).

Scheme 21

Synthesis of isoeilatin (119): (a) mCPBA, CH₂Cl₂ (88%); (b) N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl (38% over two steps); (c) acetic anhydride (80%); then 10% NaOH in H₂O/MeOH; then MnO₂, toluene (50% over two steps); (d) 2-aminoacetophenone, CeCl₃·7H₂O; then 10% H₂SO₄ in AcOH; then N,N-dimethylformamide diethyl acetal, DMF; then NH₄Cl (38% over four steps).

Scheme 22

Synthesis of isoeilatin (119): (a) AcOH/Et₃N (7%); (b) NH₃ in methanol (43%). Synthesis of dibenzoeilatin (125); (c) CeCl₃·7H₂O, EtOH (36%); (d) AcOH/H₂SO₄/Et₃N (no yield given).

Figure 5

Structures of the styelsamines A–D (126–129) and cystodytins A–K (130–140).

Scheme 23

Synthesis of styelsamine (127, 148–152) and cystodytine analogues (139, 153–157): (a) CeCl₃·7H₂O, Ag₂O, MeOH/AcOH (2:1), then 6 M HCl (6%–20%); (b) Ag₂O (one equiv.), MeOH (13%–79%).

Scheme 24

Synthesis of analogues of styelsamine alkaloids: (a) 4 M HCl/MeOH (1:1) (158, 60% and 159, 45%); (b) for 160 and 161: corresponding carboxylic acid, DMF, CH₂Cl₂, Et₃N, PyBOP (160, 88% and 161, 48%); for 162: dihydrocinnamoyl chloride, THF, Et₃N (43%).

Scheme 25

Synthesis of styelsamine C (128): (a) 10% Pd/C, cyclohexene/EtOH (60%); (b) Meldrum’s acid, trimethyl orthoformate (94%); (c) diphenyl ether, reflux (83%); (d) POBr₃ (78%); (e) phenylboronic acid, EtOH/toluene, K₂CO₃, Pd(PPh₃)₄ (94%); (f) N,N-dimethylformamide dimethyl acetal, 170 °C (91%); (g) NaIO₄, THF/H₂O (90%); (h) P(OEt)₃ (65%); (i) BBr₃ in CH₂Cl₂ (86% over two steps).

Figure 6

Structures of sebastianines A (172) and B (173).

Scheme 26

Synthesis of sebastianine A (172) and its regioisomer 183: (a) Toluene, reflux, then MnO₂ (no reaction conditions given) (R = Ts, 8%; R = H, 6%); (b) NaOH, CH₂Cl₂ (85%–92%); (c) NaOH, CH₂Cl₂ (95%–98%).

Figure 7

Structures of arnoamines A (184), B (185), C (186), and D (187).

Scheme 27

Synthesis of arnoamine B (185): (a) from 167: 2-bromophenylboronic acid, H₂O/toluene, K₂CO₃, Pd(PPh₃)₄ (85%); (b) N,N-dimethylformamide dimethyl acetal, DMF (83%); (c) Zn, AcOH/H₂O (21%); (d) Pd(OAc)₂, P(CMe₃)₃, K₂CO₃, xylene (81%).

Scheme 28

Synthesis of arnoamine B analogue 200: (a) Me₂SO₄, 2 M NaOH, H₂O, dioxane (95%); (b) HNO₃, Ac₂O (194, 63% and 195, 30%); (c) from 194: H₂, Raney nickel, isopropanol (no yield given); (d) Meldrum’s acid, trimethyl orthoformate (95%); (e) diphenyl ether, reflux (80%); (f) POCl₃ (96%); (g) Bu₃SnH, AIBN, benzene (97%).

Scheme 29

Synthesis of arnoamine B (185) by Kubo: (a) iodobenzene, CuI, (CH₂NHMe)₂, K₃PO₄, toluene (80%); (b) 10% Pd-C, methanol; (c) Meldrum’s acid, trimethyl orthoformate (66% over two steps); (d) Ph₂O, reflux; then POCl₃ (70% over two steps); (e) Bu₃SnH (30 equiv.), AIBN (15 equiv.), toluene (90%).

Scheme 30

Synthesis of subarine (212) by Delfourne: (a) POBr₃, PBr₃ (79%); (b) KMnO₄, KOH, H₂O; (c) DCC, MeOH (88% over two steps); (d) 2-(NHBoc)C₆H₄SnMe₃, Pd(PPh₃)₄, 1,4-dioxane (210, 63% ; 211, 18%); (e) Et₃N, CH₂Cl₂ (98% for both reactions).

Scheme 31

Synthesis of subarine (212) by Lotter and Bracher: (a) KMnO₄, KOH, H₂O (b) H₂SO₄, MeOH (73% over two steps); (c) 2-iodoaniline/2-bromoaniline, CH₂Cl₂, Me₃Al, heptane (216, 40%; 217, 35%); (d) Bu₃SnH, AIBN, benzene (7% from 216).