Synthesis of antifungal N-isoprenyl-indole alkaloids from the fungus Aporpium caryae

Article abstract of DOI:10.1016/S0040-4039(02)02193-7

The synthesis of two antifungal alkaloids 1 and 2 is described. It involves the N-isoprenyl-indole brominated key-intermediate 3 prepared by introduction of the isoprenyl group on the indole core itself.

Full text of DOI:10.1016/S0040-4039(02)02193-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8839–8841
Synthesis of antifungal N-isoprenyl-indole alkaloids from the
†
fungus Aporpium caryae
‡
Giorgio Della Sala, Daniela Capozzo, Irene Izzo, Assunta Giordano, Antonella Iommazzo and
Aldo Spinella*
Dipartimento di Chimica, Universit a` di Salerno, Via S. Allende, 84081 Baronissi, Salerno, Italy
Received 3 October 2002; accepted 4 October 2002
Abstract—The synthesis of two antifungal alkaloids 1 and 2 is described. It involves the N-isoprenyl-indole brominated
key-intermediate 3 prepared by introduction of the isoprenyl group on the indole core itself. © 2002 Elsevier Science Ltd. All
rights reserved.
Basidiomycetes are known to produce a series of bio-
logically active compounds. Recently from the wood-
Herein we wish to report a novel synthesis of metabo-
lites 1 and 2 through the intermediate 3, based on the
direct isoprenylation of the nitrogen atom of the indole
core. This strategy might be useful in general for syn-
thesis of N-isoprenyl-indole natural compounds where
it is advisable to start from an indole-type precursor.
1
inhabiting fungus Aporpium caryae, two indole
metabolites 1 and 2, possessing antifungal activity, have
2
been isolated. These compounds are characterized by a
N-isoprenyl-indole substructure which is common to
other natural aminoacids and alkaloids produced by
terrestrial or marine microorganisms and showing inter-
Primarily we effected the bromination of indole afford-
3
esting bioactivities. Cyclomarins aminoacids and the
ing 3-bromo-indole (6). Many methods to accomplish
4
antitumor dihydroxyquinone Asterriquinone are some
6
this transformation are available in literature. We
valuable examples.
6a
gained the best results (96%) with Br in DMF. In our
2
hands, bromination with 2 mol. equiv. of Me SiBr and
3
6
b
dimethyl sulfoxide, differently to what reported, gave
1
2
,3-dibromo-indole as shown by comparison of H and
C NMR data, instead of 6.
1
3
6c
Successively, as depicted in Scheme 2, the bromo-com-
pound 3 was obtained from 6 in four steps. Being
position 3 occupied, nitrogen became the better nucle-
ophilic site: 3-bromo-indole’s sodium salt could be eas-
ily alkylated with methyl 3-bromo-propionate to
Recently these compounds have been objects of syn-
thetic studies and just last year, Sugiyama et al.
reported the synthesis of 1 and 2 from the 3-bromo-
7
furnish a-methyl ester 7.
5
derivative 3, obtained from indoline (4) (Scheme 1). In
this strategy the isoprenyl unit was introduced on the
indoline and the indole core was then formed after
oxidation.
Keywords: natural products; antifungal indole alkaloids; N-isoprenyl
indole; Sharpless dihydroxylation.
*
Corresponding author.
†
Dedicated to the memory of Professor G. Sodano.
Current address: Istituto di Chimica Biomolecolare, CNR, Via
Campi Flegrei, 34-80078- Pozzuoli, Napoli, Italy.
‡
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02193-7

8
840
G. Della Sala et al. / Tetrahedron Letters 43 (2002) 8839–8841
Scheme 2. Reagents and conditions: (a) Br , DMF, rt, 96%; (b) NaH, DMF, rt; (c) CH CH(Br)COOMe, 50°C, 93%; (d) t-BuOK,
2
3
MeI, THF, rt, 72%; (e) DIBALH (1.3 equiv.), CH Cl , −78°C, 61% (9), 34% (10); (f) TPAP, NMO, CH Cl , mol. sieves, rt, 91%;
2
2
2
2
+
3
−
(
g) Ph PCH Br , NaH, THF, rt, then 9, rt, 70%; (h) t-BuLi, THF, −100°C; (i) ClCOOMe, −78°C, 89%; (j) OsO (1 mol%),
3
4
(
DHQ) PYR (1.1 mol%), K Fe(CN) , K CO , H O/t-BuOH 1:1, 0°C, quantitative yield, 69% ee.
2
3
6
2
3
2
The introduction of a second a-methyl group by treat-
pound. The unnatural enantiomer, (R)-6, was formed
1
3
ment of the ester enolate with CH I, proved to be
in 89% ee when (DHQD) PYR was used instead.
3
2
harder than expected. No reaction was observed
employing many bases, such as n-BuLi, LDA, NaH-
MDS, LiCl/LDA/DMPU and NaH at different temper-
atures. We were able to obtain good results only by
slow addition of t-BuOK, 1 M THF solution, to a
In conclusion, antifungal compounds 1 and 2 were
efficiently prepared, respectively, in six and seven steps
and 36% overall yield starting from indole (5). Further
applications of compound 3 as intermediate in the
synthesis of other N-isoprenyl-indole natural com-
pounds are currently subject of our studies.
mixture of 7 and CH I, at room temperature. Further-
3
more, reaction time proved to be decisive: optimal yield
(
72%) was found after 15 min. Lower yield (50%) was
observed after 4 h and a worsening (33%) after 72 h.
Acknowledgements
Selective reduction with DIBALH (1.3 mol. equiv.) of
the resulting a,a-dimethyl ester 8, gave a mixture of the
related aldehyde 9 and alcohol 10, respectively, in 61
We are grateful to Dr. Simona Francese for the realiza-
tion of the ESMS spectra. This work has been sup-
ported by the MURST (‘PRIN: Chimica dei Composti
Organici di Interesse Biologico’).
8
and 34% yields. TPAP-catalyzed oxidation allows to
recycle alcohol 10 and therefore to obtain 9 in 92%
overall yield from 8.
9
The target intermediate 3 was obtained by Wittig
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