A short synthesis of de-'prenyl'-ardeemin

Article abstract of DOI:10.1016/S0040-4039(03)00556-2

A four-step synthesis of the ardeemin framework by starting from N-2-aminobenzoyl-α-amino esters is described. In the last step, the acid promoted cyclization of the 1,4-anti-4-alkyl-1-(3-indolylmethyl)-2,4-dihydro-1H-pyrazino[2,1-b] quinazoline-3,6-diones occurs irreversible and stereocontrolled.

Full text of DOI:10.1016/S0040-4039(03)00556-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3367–3369
A short synthesis of de-‘prenyl’-ardeemin
Fernando Herna´ndez, Carmen Avendan˜o* and Mo´nica So¨llhuber*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
Received 24 February 2003; accepted 27 February 2003
Abstract—A four-step synthesis of the ardeemin framework by starting from N-2-aminobenzoyl-a-amino esters is described. In
the last step, the acid promoted cyclization of the 1,4-anti-4-alkyl-1-(3-indolylmethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-
3,6-diones occurs irreversible and stereocontrolled. © 2003 Elsevier Science Ltd. All rights reserved.
The ability of N-acetylardeemin (1), a metabolite of the
fungus Aspergillus fischerii (var. brasiliensis), to restore
vinblastine sensitivity to a previously resistant tumour
cell line1,2 led to its inclusion in the great variety of
synthetic and naturally occurring MDR reversal
agents.3 The up to now unique total synthesis of 1,
which was developed by Danishefsky (nine steps and
12.5% overall yield),4,5 involved as the key step the
preliminary construction of the pyrroloindole 2a
through a kinetically controlled process followed by
introduction of the reverse prenyl group (2b). We have
shown that precursors of de-‘prenyl’-5-acetylardeemin
(5a), may be obtained as diastereomeric mixtures by
acid-promoted cyclization and subsequent acylation of
Figure 1.
Keywords: ardeemins; quinazolinediones; pyrroloindole; acid-promoted cyclizations.
* Corresponding authors. Tel.: +34 91 394 1821/23; fax: +34 91 394 1822; e-mail: avendano@farm.ucm.es; msollhub@farm.ucm.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00556-2

3368
F. Herna´ndez et al. / Tetrahedron Letters 44 (2003) 3367–3369
tryptophan cyclo-dipeptides.6 Thus, cyclo-(
L-Trp-D-
The acid-promoted cyclizations of compounds 4b,c in
which the H(5a) and H(15b)-protons (ardeemin num-
bering) are in an anti relationship, were performed in
neat trifluoroacetic acid affording the stable com-
pounds (−)-5b (63%) and (−)-5c (46%) as the only
reaction products.15 The relative configuration of 5 was
established unequivocally by NOESY experiments,
where the syn relationship between the methyl or iso-
propyl substituent at C(8) and the H(15b)-proton was
observed.16
Ala) afforded compound 3, a in 72% d.e.7 In this paper
we report a short and much more efficient protocol to
de-‘prenyl’- ardeemin (5b) and its iso-propyl analogue
(5c) in which the construction of ring C was undertaken
in the last stage of the process (Fig. 1).
Scheme 1 outlines the general synthesis of compounds
4. Acylation of the
D
-a-amino esters with o-nitrobenz-
oyl chloride under Schotten–Baumann conditions, fol-
lowed by catalytic hydrogenation of the nitro group
(10% Pd/C, 1.5 atm), afforded the aryl amides 6 in 80%
When 4d was submitted to acid promoted cyclization
only starting material was recovered,17 in spite of the
different reaction conditions assayed. This failure may
be due to an inadequate conformation of the indole
ring, which is pseudoaxial in this compound instead of
pseudoequatorial as in 4b,c (Scheme 2). This pseudo-
axial disposition was confirmed by NOESY experiments
(NOE between H-4ax and H-2% of the indolyl moiety)
and by the chemical shift of the C-1 carbon atom.18
overall yield. Reaction of 6 with Fmoc-
L-Trp in DMF,
using 1-isobutoxycarbonyl-2-isobutoxy-1,2-dihydro-
quinoline (IIDQ) as coupling reagent,8 gave compounds
7 in nearly quantitative yields. Cyclization of 7 to
benzoxazines 8 was accomplished in 68–88% yield by
using triphenylphosphine–iodine and Huning’s base in
dry dichloromethane.9,10 Treatment of 8 with 20% pipe-
ridine in dichloromethane produced the corresponding
piperidine amidine,11 which was refluxed in acetonitrile
(2 h) rearranging12–14 to the expected 1-(3-indolyl-
methyl)pyrazino[2,1-b]quinazoline-3,6-diones 4 in good
overall yields.
In summary, the ardeemin framework can be
approached stereoselectively by acid promoted cycliza-
tion of 1,4-anti-4-alkyl-1-(3-indolylmethyl)pyrazino[2,1-
b]quinazoline-3,6-diones. De-‘prenyl’ ardeemin (−)-5b
Scheme 1.
Scheme 2.

F. Herna´ndez et al. / Tetrahedron Letters 44 (2003) 3367–3369
3369
was obtained in four steps and 45% overall yield start-
ing from N-2-aminobenzoyl- -Ala methyl ester.
CH2Cl2 (20 mL) and 20% aqueous K2CO3 (20 mL). The
pH of the aqueous layer was adjusted to 7 and was
extracted with CHCl3. The organic layers were dried over
Na2SO4 and evaporated. The residue was purified by
chromatography (ethyl acetate/petroleum ether, (8:2 for
5b) and (6:4 for 5c)). 5b: mp 208–209°C; [h]2D5 −218.1 (c
D
Acknowledgements
1
0.16, CHCl3); IR (NaCl) 3336, 1676, 1605, 1469 cm−1; H
NMR (CDCl3) l 8.25 (dd, 1H, J=1.3 and 8.1 Hz, H-11),
7.75 (ddd, 1H, J=1.3, 7.1 and 8.3 Hz, H-13), 7.64 (dd,
1H, J=1.2 and 8.3 Hz, H-14), 7.48 (ddd, 1H, J=1.2, 7.1
and 8.1 Hz, H-12), 7.22 (d, 1H, J=7.7 Hz, H-1), 7.11 (dt,
1H, J=0.8 and 7.7 Hz, H-3), 6.80 (dt, 1H, J=0.8 and 7.7
Hz, H-2), 6.65 (d, 1H, J=7.7 Hz, H-4), 5.79 (d, 1H,
J=6.8 Hz, H-5a), 5.46 (q, 1H, J=7.2 Hz, H-8), 5.19 (br
s, 1H, N-Hi), 4.61 (dd, 1H, J=6.3 and 10.5 Hz, H-15b),
4.13 (t, 1H, J=7.0 Hz, H-16a), 3.08 (dd, 1H, J=6.3 and
13.2 Hz, H-16), 2.75 (ddd, 1H, J=7.2, 10.5 and 13.2 Hz,
H-16), 1.51 (d, 3H, J=7.2 Hz, CH3); 13C NMR (CDCl3)
l 166.7, 159.9, 150.7, 149.0, 147.0, 134.6, 128.7, 127.3,
127.2, 127.1, 126.8, 124.2, 120.4, 119.4, 109.3, 75.9, 57.2,
53.3, 44.5, 35.8, 16.7. Anal. calcd for C21H18N4O2: C,
70.38; H, 5.06; N, 15.63. Found: C, 69.97; H, 5.46; N,
15,47.
Financial support from CICYT (SAF 97-0143 and
SAF-2000-0130) and a research fellowship from CAM
for F.H. are gratefully acknowledged. The authors also
acknowledge
the
kind
collaboration
of
N.
Schendzielorz, J. Knoop and U. Neisen in the synthesis
of compounds 6 and 7.
References
1. Biological activity: Karwoski, J. P.; Jackson, M.; Ras-
mussen, R. R.; Humphrey, P. E.; Poddig, J. B.; Kohl, M.
H.; Scherr, W. L.; Kadam, S.; McAlpine, J. B. J.
Antibiot. 1993, 46, 374–379.
2. Isolation and structure: Hochlowski, J. E.; Mullally, M.
M.; Spantom, S. G.; Whittern, D. N.; Hill, P.; McAlpine,
J. B. J. Antibiot. 1993, 46, 380–386.
3. For reviews in this area, see: (a) Molecular and Cellular
Biology of Multidrug Resistance in Tumor Cells;
Robinson, I. B., Ed.; Plenum Press: New York, 1991; (b)
Avendan˜o, C.; Mene´ndez, J. C. Curr. Med. Chem 2002, 9,
1867–1901.
4. Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am.
Chem. Soc. 1994, 116, 11143–11144 (Preliminary work).
5. Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski,
A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem.
Soc. 1999, 121, 11953–11963 (Full paper).
16. The enantiomeric purity was measured by chiral HPLC
using a Chiracel OD column (26 cm×0.25 cm), UV-detec-
tion at 254 nm, employing hexane/2-propanol 9/1.
1
17. 4d: H NMR (500 MHz, CDCl3/CD3OD) l 8.02 (dd, 1H,
J=1.5 and 8.1 Hz, H-7), 7.76 (ddd, 1H, J=1.5, 7.0 and
8.3 Hz, H-9), 7.68 (dd, 1H, J=1.4 and 8.3 Hz, H-10),
7.42 (ddd, 1H, J=1.4, 7.0 and 8.1 Hz, H-8), 7.22 (d, 1H,
J=8.0 Hz, H-4%), 6.92 (dt, 1H, J=0.8 and 8.0 Hz, H-6%),
6.88 (s, 1H, H-2%), 6.78 (d, 1H, J=8.0 Hz, H-7%), 6.51 (dt,
1H, J=0.8 and 8.0 Hz, H-5%), 4.83 (t, 1H, J=4.3 Hz,
H-1), 4.24 (d, 1H, J=18.8 Hz, H-4), 3.49 (dd, 1H, J=4.6
and 14.6 Hz, CH2-Ar), 3.26 (dd, 1H, J=4.0 and 14.6 Hz,
CH2-Ar), 2.54 (d, 1H, J=18.8 Hz, H-4); 13C NMR (125
MHz, CDCl3/CD3OD) l 167.1 (C3), 160.8 (C6), 151.7
(C11a), 147.3 (C10a), 136.6 (C7%a), 135.4 (C9), 127.6
(C8), 127.0 (C3%a), 126.9 (C10), 126.8 (C7), 125.5 (C2%),
122.3 (C6%), 119.7 (C5%), 117.6 (C7%), 111.9 (C4%), 107.3
(C3%), 57.1 (C1), 44.5 (C4), 33.7 (CH2Ar).
6. Acylation is needed to avoid the reversal reaction.
7. Caballero, E.; Avendan˜o, C.; Mene´ndez, J. C. Tetra-
hedron: Asymmetry 1998, 9, 967–981.
8. Bodansky, M. Principles of Peptide Synthesis; 2nd ed.;
Springer Verlag: Berlin, 1993.
9. Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973–980.
10. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–
3606.
11. He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397–1399.
12. Hart, D. J.; Magomedov, N. Tetrahedron Lett. 1999, 40,
5429–5432.
13. Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432–
2433.
14. Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022–
1030.
15. General procedure for cyclization to de-‘prenyl’ ardeemin:
The corresponding 1-(3-indolylmethyl) derivative 4b,c
(0.207 mmol) was added in one portion to TFA (5 mL).
The solution was stirred for 20 min (compound 4b) or
2.30 h (compounds 4c) and was poured onto an exter-
nally ice-cooled, vigorously stirred, two-phase system of
18. In 1,4-dialkylated pyrazino[2,1-b]quinazoline-3,6-diones
the piperazine ring adopts for both diastereoisomers a flat
boat conformation, being the C(4)-substituent always
pseudoaxial despite of its relative size.19 In monoalkyl-
ated pyrazino[2,1-b]quinazoline-3,6-diones, both alterna-
tives, C(1) as well as C(4)-substitution, always adopt a
pseudoaxial disposition.20 The chemical shift values of
the C-1 carbon atom are higher in these compounds
compared to the 1,4-anti isomers, where the C-1 sub-
stituent is pseudoequatorial (lꢀ52).
19. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetra-
hedron: Asymmetry 2001, 12, 3019–3028.
20. Herna´ndez, F.; Lumetzberger, A.; Avendan˜o, C.; So¨llhu-
ber, M. Synlett 2001, 9, 1387–1390.