A short synthesis of aspergillamide B. The marine natural product from Aspergillus sp.

Article abstract of DOI:10.1016/S0040-4039(02)01602-7

A short route to the marine natural product aspergillamide B has been developed. The key step is the stereoselective formation of the trans indole-enamide pharmacophore by indole-assisted dehydration from the functionalized aminoalcohol intermediate. HPLC and ¹H NMR analyses show that aspergillamide B is more stable in the cis rotamer form.

Full text of DOI:10.1016/S0040-4039(02)01602-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7639–7641
A short synthesis of aspergillamide B. The marine natural
product from Aspergillus sp.
Lucrecia Rivas,a,b Leticia Quintero,a,* Jean-Louis Fourreyb and Rachid Benhidab,c,
*
aCentro de Investigacio´n de la Facultad de Ciencias Qu´ımicas de la Universidad Auto´noma de Puebla, Puebla, Mexico
bInstitut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette, France
cLaboratoire de Chimie Bioorganique UMR-CNRS 6001, Universite´ de Nice-Sophia Antipolis, Parc Valrose, 06108 Nice cedex 2,
France
Received 5 July 2002; accepted 26 July 2002
Abstract—A short route to the marine natural product aspergillamide B has been developed. The key step is the stereoselective
formation of the trans indole–enamide pharmacophore by indole-assisted dehydration from the functionalized aminoalcohol
1
intermediate. HPLC and H NMR analyses show that aspergillamide B is more stable in the cis rotamer form. © 2002 Elsevier
Science Ltd. All rights reserved.
During the past few years, a number of bioactive
natural products featuring an indole-3-ethenamide sub-
structure have been isolated from various sources.
Among them, terpeptine,1 chondriamides2 and coscin-
amides,3 as well as aspergillamides A (1a) and B (1b),
are the most representative examples of this new class
of compounds. The latters, cytotoxic peptides, have
been structurally elucidated following their isolation in
low yields from an Aspergillus sp. (Fig. 1).4
provide the enamide moiety, in its thermodynamically
stable trans configuration (Scheme 1). Following these
observations, we have examined the dehydration pro-
cess starting from the aminoalcohols 3a and 3b (Scheme
2). These derivatives were obtained in moderate yield
To date, a number of procedures allowing the forma-
tion of enamides have been developed.5 Interestingly, a
library of aspergillamide analogues were recently pre-
pared by Do¨mling and co-workers6 using the Ugi multi-
component reaction.7 Several of these analogues were
found to be more active than the natural asper-
gillamides. However, as a major drawback, the Ugi
multicomponent reaction7 gave in general a mixture of
regio- and diastereoisomers,6 and, stereocontrolled pro-
cesses are usually required to overcome this difficulty.8
Herein, we describe the first stereoselective synthesis of
aspergillamide B taking advantage of a simple dehydra-
tion of a suitably functionalized aminoalcohol interme-
diate as outlined in Scheme 1.
To design this sequence, we thought that the electron
rich indole unit might assist water elimination to
* Corresponding author. Tel.: +00 33 (04) 92 07 61 53; fax: +00 33
(04) 92 07 61 51; e-mail: benhida@unice.fr
Figure 1. Structure of aspergillamides.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01602-7

7640
L. Ri6as et al. / Tetrahedron Letters 43 (2002) 7639–7641
Scheme 1. The proposed synthetic pathway allowing to the
trans-enamide products.
Scheme 3. Synthesis of aspergillamide B. Reagents and condi-
tions: (i) HOBT, EDC, DMF, N-Boc,N-Me-phenylalanine;
(ii) dioxane–HCl; (iii) APTS, toluene, 60°C; (iv) N-Ac-leucine,
HOBT, EDC, DMF, DIEA; (v) 6% Na–Hg, Na2HPO4, diox-
ane–methanol.
Interestingly, as expected, upon acidic treatment
(APTS-toluene) 5b underwent a clean conversion into
the single trans-enamide product 6b, as confirmed by
1H NMR [l (H-enamide)=6.24 ppm and J=14.6
Hz].13 Alternatively, 6a and 6b were obtained from 4a
and 4b, respectively, using the same dehydration pro-
cess which led to the Boc-protected enamides 7a and
7b, followed by Boc-deprotection (7b“6b, 51%). The
coupling of 6b and the commercially available N-acetyl-
leucine under standard conditions yielded the protected
aspergillamide 8b in 78% yield. The benzenesulfonyl
protecting group of compound 8b was cleanly removed
by treatment with Na–Hg14 to give aspergillamide 1b in
72% yield.15 In the present case, this protecting group
was found to be more resistant to the cleavage when
using more conventional procedures.16 Finally, HPLC
analysis17 of aspergillamide 1b showed a mixture of cis-
and trans-amide rotational isomers (see Fig. 1) which
equilibrated in favour of the stable cis rotamer. The cis
conformation was evidenced by the high field signal (lH
at −0.16 ppm) of one of the two hydrogens of the
leucine methylene group facing the phenyl ring (Ph-
Scheme 2. Synthesis of aminoalcohols 3a and 3b.
(34%) from aldehydes 2a and 2b, respectively, follow-
ing: (i) Henry reaction9 using nitromethane aldol con-
densation and (ii) subsequent hydrogenolysis of the
nitroalcohol intermediates. Interestingly, cyanosilyla-
tion of the same starting material (2b) using ZnI2 as
catalyst10 afforded quantitatively the cyanohydrine
intermediate which was then reduced with LAH in
THF into compound 3b in 72% overall yield.11
The coupling of aminoalcohol 3a or 3b with N-Boc,N-
Me-phenylalanine12 (HOBT/EDC) was achieved in
quantitative yield affording compounds 4a and 4b (95–
98%), respectively, as equimolar mixture of two
diastereoisomers (Scheme 3). Removal of the Boc-pro-
tecting group of compound 4b provided the aminoalco-
hol 5b.
1
shielding effect, see H NMR),15 in line with literature.4

L. Ri6as et al. / Tetrahedron Letters 43 (2002) 7639–7641
7641
1
In conclusion, we have realized the first stereoselective
synthesis of aspergillamide B, in short linear steps. In
vitro cytotoxicity assays of aspergillamide B and the
intermediates 6b and 8b were evaluated against the KB
cell line. These products were found to be active in a
micromolar range [IC50: 10 mM for 1b, 3 mM for 6b and
2.3 mM for 8b]. The application of this strategy to the
synthesis of other enamide-natural products and ana-
logues (in indole and non-indole series) together with
the photoisomerization aspergillamide A“asper-
gillamide B is in progress and will be given in due
course.
11. Compound 3a: H NMR (250 MHz, CDCl3): l 8.10 (d,
J=8.1 Hz, 1H), 7.50 (m, 2H), 7.20 (m, 2H), 4.90 (m, 1H),
3.00 (m, 2H), 2.60 (bs, 3H), 1.60 (s, 9H); 13C NMR (62.5
MHz, CDCl3): l 149.60, 135.70, 128.40, 124.40, 122.60,
122.50, 121.99, 119.50, 115.30, 83.60, 66.20, 47.33, 27.74.
HRMS calcd for C15H20N2O3: 276.147. Found: 276.148.
1
Compound 3b: H NMR (400 MHz, CDCl3): l 7.96 (d,
J=8.4 Hz, 1H), 7.86 (m, 2H), 7.71 (d, 1H, J=8.0 Hz),
7.68 (s, 1H), 7.47–7.33 (m, 3H), 7.26 (t, 1H, J=7.7 Hz),
7.14 (t, 1H, J=7.7 Hz), 6.7 (br s, 3H), 5.12 (dd, 1H,
J=3.3 and 4.0 Hz), 3.46–3.28 (m, 2H); 13C NMR (100
MHz, CDCl3): l 137.69, 135.43, 134.26, 129.46, 128.49,
126.95, 125.44, 124.98, 123.82, 120.69, 119.69, 113.81,
71.59, 64.79. MS (ESI+): m/z 633 (2M+1), 317 (MH+),
299 (MH+−H2O).
Acknowledgements
12. N-Boc,N-Me-phenylalanine was prepared in quantitative
yield from N-Boc-phenylalanine (NaH, CH3I, DMF):
[h]D=−28.2° (c 1, EtOH), lit. −28.1° (c 1, EtOH). See:
Omamoto, K.; Abe, H.; Kuromizu, K.; Izumiya, N.
Mem. Fac. Sci. Kyushu Univ. Ser. C 1974, 9, 131–138.
We are grateful to Christiane Tempete for the biologi-
cal evaluation, to Marie-The´re`se Adeline for HPLC
analysis and to CONACYT (Mexico) for a research
grant to L. Rivas (Grant 121999).
1
13. Compound 6b: H NMR (400 MHz, CDCl3): l 9.26 (d,
1H, J=11.0 Hz), 8.01 (d, 1H, J=8.1 Hz), 7.85 (m, 2H),
7.69 (d, 1H, J=7.7 Hz), 7.54–7.45 (m, 2H), 7.38–7.15 (m,
10H), 6.24 (d, 1H, J=14.6 Hz), 3.90 (bs, 1H), 3.39 (dd,
1H, J=4.4 and 7.0 Hz), 3.22 (dd, 1H, J=4.4 and 7.0 Hz),
2.82 (m, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3):
l 171.03, 138.06, 137.00, 135.60, 133.93, 129.36, 129.18,
128.08, 127.21, 126.81, 125.16, 123.69, 123.37, 122.26,
120.46, 119.49, 113.87, 104.09, 65.78, 38.90, 35.38. MS
(ESI+): m/z 482 (M+Na), 460 (M+1), 148.
References
1. Kagamizono, T.; Sakai, N.; Arai, K.; Kobinata, K.;
Osada, H. Tetrahedron Lett. 1997, 38, 1223–1226.
2. Davyt, D.; Entz, W.; Fernandez, R.; Mariezcurrena, R.;
Mombru, A. W.; Saldana, J.; Dominguez, L.; Coll, J.;
Manta, E. J. Nat. Prod. 1998, 61, 1560–1563.
3. Bokesch, H. R.; Pannell, L. K.; McKee, T. C.; Boyd, M.
R. Tetrahedron Lett. 2000, 41, 6305–6308.
4. Toske, S. G.; Jensen, P. R.; Kauffman, C. A.; Fenical, W.
Tetrahedron 1998, 54, 13459–13466.
14. (a) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven,
T. R. Tetrahedron Lett. 1976, 3477–3478. For recent
examples, see: (b) Sasaki, N. A.; Dockner, M.; Chiaroni,
A.; Riche, C.; Potier, P. J. Org. Chem. 1997, 62, 765–770;
(c) Iradier, F.; Gomez Arrayas, R.; Carretero, J. C. Org.
Lett. 2001, 3, 2957–2960.
5. (a) Brettle, R.; Mosedale, A. J. J. Chem. Soc., Perkin
Trans. 1 1988, 2185–2195; (b) Xiao, D.; East, S. P.;
Joullie´, M. M. Tetrahedron Lett. 1998, 39, 9631–9632; (c)
Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem.,
Int. Ed. 2000, 39, 4308–4310 and references cited therein;
(d) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333–
1336; (e) Wang, X.; Porco, J. A., Jr. J. Org. Chem. 2001,
66, 8215–8221; (f) Fu¨rstner, A.; Brehm, C.; Cancho-
Grande, Y. Org. Lett. 2001, 3, 3955–3957; (g) Ribe´reau,
P.; Delamare, M.; Ce´lanire, S.; Que´guiner, G. Tetra-
hedron Lett. 2001, 42, 3571–3573; (h) Lin, S.; Danishef-
sky, S. J. Angew. Chem., Int. Ed. 2002, 41, 512–515.
6. Beck, B.; Hess, S.; Do¨mling, A. Bioorg. Med. Chem. Lett.
2000, 10, 1701–1705.
7. (a) Ugi, I. Angew. Chem., Intl. Ed. Engl. 1982, 21, 810–
819; (b) Ugi, I. J. Prakt. Chem. 1997, 339, 499–516.
8. For an example of asymmetric Ugi reaction, see: Linder-
man, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999,
64, 336–337 and references cited therein.
9. For a recent review, see: Luzzio, F. A. Tetrahedron 2001,
57, 915–945.
10. Evans, D. A.; Caroll, G. L.; Truesdale, L. K. J. Org.
Chem. 1974, 39, 914–917.
15. Synthetic aspergillamide 1b: 1H NMR (400 MHz, ace-
tone-d6): l 10.25 (bs, 1H), 7.81–7.74 (m, 2H), 7.60–7.22
(m, 9H), 7.16–7.05 (m, 2H), 6.69 (d, 1H, J=14.6), 4.99
(dd, 1H, J=3.6 and 10.6 Hz), 4.60 (m, 1H), 3.31 (dd, 1H,
J=3.6 and 14.3 Hz), 3.14 (dd, 1H, J=11.0 and 14.3 Hz),
2.88 (s, 3H), 2.01 (s, 3H), 1.60 (m, 1H), 1.19 (m, 1H),
0.80–0.68 (2d, 6H, J=6.8 Hz), −0.16 (m, 1H); 13C NMR
(100 MHz, acetone-d6): l 172.86, 171.56, 166.18, 138.66,
137.38, 129.87, 129.28, 128.89, 128.32, 126.72, 125.61,
122.97, 121.78, 120.30, 119.48, 119.40, 112.79, 106.98,
62.54, 47.03, 38.01, 33.84, 28.62, 23.96, 22.67, 21.78,
19.75. MS (EI): m/z 474 (M+), 317.
16. (a) Greene, T. W. Protective Groups in Organic Synthesis,
3rd ed.; Wiley-Interscience: New York, 1999; (b) Mg/
MeOH: Muratake, H.; Natsume, M. Heterocycles 1989,
29, 783–794.
17. The reverse-phase HPLC analysis was carried out using a
Waters Symmetry (4.6×250 mm) column and heptane–
isopropanol (95/5, v/v) as eluant (1 mL/min).