A divergent approach to the total synthesis of the marine pyridoacridine alkaloid eilatin and its synthetic isomer isoeilatin

Article abstract of DOI:10.1016/j.tetlet.2015.01.176

Herein we report the total synthesis of the heptacyclic pyridoacridine alkaloid eilatin (1) and its synthetic isomer isoeilatin (2). Starting from readily available 9-methyl-3,4-dihydroacridin-1(2H)-one (5) and 2-aminoacetophenone, a divergent synthesis gave alkaloid 1 in seven, and isomer 2 in eight steps.

Full text of DOI:10.1016/j.tetlet.2015.01.176

Accepted Manuscript
A divergent approach to the total synthesis of the marine pyridoacridine alkaloid
eilatin and its synthetic isomer isoeilatin
Alois Plodek, Franz Bracher
PII:
S0040-4039(15)00226-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.176
TETL 45846
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
12 January 2015
23 January 2015
27 January 2015
Please cite this article as: Plodek, A., Bracher, F., A divergent approach to the total synthesis of the marine
pyridoacridine alkaloid eilatin and its synthetic isomer isoeilatin, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.01.176
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Graphical abstract

A Divergent Approach to the Total Synthesis of the Marine
Pyridoacridine Alkaloid Eilatin and its Synthetic Isomer Isoeilatin
Alois Plodek and Franz Bracher*
Department für Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität
München, Butenandtstrasse 5-13, D-81377 München, Germany
*Corresponding author. Email: Franz.Bracher@cup.uni-muenchen.de, Phone: +49-89-2180-77301,
Fax: +49-89-2180-77802
Keywords: total synthesis; alkaloids; pyridoacridines; eilatin; isoeilatin
Abstract
Herein we report the total synthesis of the heptacyclic pyridoacridine alkaloid eilatin (1) and its
synthetic isomer isoeilatin (2). Starting from readily available 9-methyl-3,4-dihydroacridin-1(2H)-one
(5) and 2-aminoacetophenone, a divergent synthesis gave alkaloid 1 in seven, and isomer 2 in eight
steps.
The pyridoacridine alkaloids are a fascinating class of mostly tetra-, penta-, and hexacyclic aromatic
alkaloids with manifold biological activities, isolated from sessile marine invertebrates like sponges,
ascidians, corals and bryozoans.1 Until today, the symmetrical alkaloid eilatin (1) (Figure 1) is the only
known heptacyclic member of this alkaloid class, an octacyclic example is biemnadin. It was first
isolated in 1988 by Rudi et al.2 from a marine tunicate Eudistoma sp., collected in the Gulf of Eilat,
Israel.
Besides the high cyctotoxicity, which is caused by inhibition of topoisomerase II and the formation of
DNA-damaging radicals, 1 and its synthetic isomer isoeilatin (2) are able to build Ru(II)- and Os(II)-
complexes.3, 4, 5 Rudi et al.6 demonstrated that eilatin-containing octahedral ruthenium complexes

inhibit HIV-1 replication in CD4+ cells. Furthermore, 1 inhibts the in vitro proliferation of progenitor
cells in chronic myeloid leukemia.7
Figure 1
A few synthetic approaches towards 1 and 2 have been developed in the past. The first multistep total
synthesis of 1 was described by Nakahara et al. starting from a complex 4-arylquinolone.8 A very
simple, but low-yielding biomimetic approach towards 1 was reported by Kashman’s group.9 This
approach suggests that kynuramine and o-benzoquinone could be biosynthetic precursors of 1.9
Furthermore, Kashman also described an approach towards 2 starting from a kynuramine derivative
and 2,5-dihydroxy-1,4-cyclohexanedione.10
In continuation of our recent efforts on the synthesis of marine pyridoacridine alkaloids and analogues
thereof11 we worked out a new, divergent synthesis of 1 and 2, which substantially differs from the
above-mentioned approaches and opens a novel access to pyridoacridine alkaloids. As central
intermediates we selected the pyrido[2,3,4-kl]acridones 312 and 413, which represent common
substructures of many pyridoacridine alkaloids, and has been prepared earlier in multistep syntheses
for other purposes. Our strategy comprised preparation of both buildings blocks 3 and 4 starting from
a common, readily available acridone precursor 514 via the N-oxides 6 and 7 (Figure 1).
Synthesis of eilatin (1) started with a one-pot annulation of a pyridine-N-oxide ring to acridone 5 using
condensation with dimethylformamide diethyl acetal (DMF-DEA) followed by ring closure with
hydroxylamine hydrochloride15 to give N-oxide 6. As the methyl group attached to C-9 and the
methylene group at position 2 of 5 are both acidic positions16, reaction conditions for the first step had
to be optimized. Condensation of 5 with DMF-DEA (1.5 equiv, 30 min) carried out at temperatures
higher than 90 °C and following treatment with hydroxylamine hydrochloride (100 °C, 1 h) furnished
beside traces of the desired tetracycle 6 (4 %) mainly the isoxazole 8 in 14 % yield. Lower reaction
temperatures for the condensation step led to rising yields of N-oxide 6, whereas yields of side product
8 simultaneously decreased. The best yield (41 %) for 6 was obtained after condensation at 55 °C.
Negligible amounts of 8 were formed under these reaction conditions (Scheme 1). 23 % of the starting
material was recovered and no side products were isolated.
Scheme 1

Boekelheide rearrangement (acetic anhydride, 50 °C, 2 h)17 of N-oxide 6 gave the acetoxy compound 9
in 66 % yield. Alkaline hydrolysis of 9 (10 % NaOH, 84 % yield) and subsequent oxidation of formed
alcohol 10 under mild conditions with MnO2 (5 equiv) in toluene concomitant with a ring dehydration
gave the pyridoacridone 3 in 66 % yield. Further conversion to eilatin (1) was accomplished following
a strategy previously reported by us for the total synthesis of the pyridoacridine alkaloid ascididemin.18
Thus, regioselective CeCl3-catalyzed oxidative amination19 of 3 with 2-aminoacetophenone afforded
compound 1120 in 74 % yield, a following acid-catalyzed cyclization step (10 % H2SO4 in AcOH) was
performed furnishing hexacycle 12 in 96 % yield. The final annulation was realized using 3 equiv
DMF-DEA and 5 equiv ammonium chloride yielding eilatin (1) in 65 % yield (Scheme 2).
Scheme 2
Isoeilatin (2) was obtained from intermediate 5 by N-oxidation to give compound 7, followed by
annulation of a pyridine ring (condensation with DMF-DEA, then ammonium chloride) to give
compound 13 in 38 % yield. In analogy to the conversion of isomeric N-oxide 6, this intermediate was
subjected to Boekelheide rearrangement, ester hydrolysis, and MnO2 oxidation to give building block
4. Oxidative amination with 2-aminoacetophenone, acid-catalyzed cyclization, and annulation of the
seventh ring were accomplished as described above for eilatin (1) in comparable yields, giving
isoeilatin (2) (Scheme 3).
Scheme 3
In conclusion, we have worked out a novel, divergent synthesis of the isomeric pyrido[2,3,4-
kl]acridone building blocks 3 and 4, and utilized these in the synthesis of the alkaloid eilatin (1) and its
synthetic isomer 2. These novel approaches also offer the opportunity for synthesizing substituted,
asymmetric analogues of the title compounds by simply utilizing ring-substituted 2-
aminoacetophenones for the synthesis of the pyrido[2,3,4-kl]acridone intermediates and/or the final
construction of the heptacyclic ring systems.

Supplementary data
Supplementary data (synthetic procedures and 1H / 13C NMR spectra) associated with this article can
be found in the online version, at….
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Figure 1 Retrosynthetic considerations towards the total synthesis of eilatin (1) and isoeilatin (2).
Scheme 1. One-pot annulation affording N-oxide 6 and side product 8. Reagents and conditions: (a)
DMF-DEA, DMF, 55 °C, 30 min; (b) DMF-DEA, DMF, 90 °C, 30 min; (c) NH2OH·HCl, AcOH,
100°C, 1h.

Scheme 2. Synthesis of eilatin (1). Reagents and conditions: (a) acetic anhydride, 50 °C, 2 h; (b) 10 %
NaOH in H2O/MeOH, 80 °C, 2 h; (c) MnO2, toluene, reflux, 4 h; (d) 2-aminocetophenone, CeCl3 × 7
H2O, rt, 3 h; (e) 10 % H2SO4 in AcOH, 90 °C, 20 min; (f) DMF-DEA, 120 °C, 30 min, then NH4Cl,
AcOH, 120 °C, 1h.
Scheme 3. Synthesis of isoeilatin (2). Reagents and conditions: (a) mCPBA, DCM, rt, 24 h; (b) DMF-
DEA, 55 °C, 30 min, then NH4Cl, AcOH, 120 °C, 1 h; (c) acetic anhydride, 50 °C, 2 h; (d) 10 %
NaOH in H2O/MeOH, 80 °C, 2 h; (e) MnO2, toluene, reflux, 4 h; (f) 2-aminocetophenone, CeCl3 × 7
H2O, rt, 3 h; (g) 10 % H2SO4 in AcOH, 90 °C, 20 min ; (h) DMF-DEA, 120 °C, 30 min, then NH4Cl,
AcOH, 120 °C, 1 h.