Synthetic studies and biosynthetic speculation on marine alkaloid chartelline

Article abstract of DOI:10.1039/b803797c

Synthetic studies and biosynthetic speculation on chartelline inspired by an unexpected reaction are described. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803797c

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Synthetic studies and biosynthetic speculation on marine alkaloid
chartellinew
Shigeo Kajii, Toshio Nishikawa* and Minoru Isobe
Received (in Cambridge, UK) 5th March 2008, Accepted 14th April 2008
First published as an Advance Article on the web 9th May 2008
DOI: 10.1039/b803797c
Synthetic studies and biosynthetic speculation on chartelline
inspired by an unexpected reaction are described.
Chartellines A–C (Fig. 1), highly halogenated marine alkaloids
isolated in the 1980s, have been recently paid rapidly increas-
ing attention from the synthetic organic community, although
significant biological activities have not been reported.1 These
alkaloids posses an extraordinary unique molecular architec-
ture densely packed with three biologically important hetero-
cycles: indolenine (indole derivative), b-lactam and imidazole.
Fig. 1 The structure of chartellines A–C and the conformation of
The conformation is also quite unique in that the indolenine
chartelline A.
moiety is stacked with the imidazole through Z-alkene with
gem-dimethyl group and b-chloroenamide moiety as spacer.
Recently, Baran et al. reported the first total synthesis of
chartelline C based on their biosynthetic hypothesis,2 and
several other groups have reported their extensive synthetic
work towards chartelline and its related alkaloids.3–5 Herein,
we describe our endeavor towards the synthesis of chartelline
C (3) on the basis of our own synthetic methodology, and a
biosynthetic consideration of chartelline and its related natural
products, inspired from an unexpected reaction encountered
during this study.
the ester with LiAlH4, oxidation with IBX and alkynylation of
the resulting aldehyde with Ohira–Bestmann’s reagent.9 With
the two segments in hand, we examined the coupling reaction
between 6 and 7.
One issue to consider in this coupling was the regioselec-
tivity between the two bromo-substituents within indole seg-
ment 6. Taking into account several precedented examples of
regioselective palladium catalyzed cross-coupling of dihaloge-
nated heteroaromatics,10 we anticipated the bromide at the
2-position of the indole would be more reactive than at the C-6
position in the Sonogashira reaction.11 To our delight, the
coupling between acetylene 7 and dibromoindole 6 took place
in the presence of Pd2(dba)3–PPh3 and CuI as catalyst under
carefully degassed conditions to afford the desired coupling
product 11 as a single regioisomer (Scheme 3).12 It is worth-
while noting that neither the other regioisomer nor the doubly
alkynylated indole was detected under these conditions.
Reduction of the sterically hindered acetylene within 12 to
the corresponding (Z)-olefin in the presence of 6-bromoindole
proved to be very difficult. Numerous experiments led us to
find that acetylene 12 prepared from 1113 was successfully
reduced with Zn–Cu14 in the presence of hydrochloric acid to
give (Z)-alkene 13 in good overall yield.15 It is noteworthy that
We have studied the synthesis of chartelline C according to
a synthetic plan based on our own methodologies,6 (1)
b-lactam formation through nucleophilic substitution by the
3-position of indole at amide nitrogen,6b (2) synthesis of
N-hydroxyenamide by N-acylation of oxime (Scheme 1).6c
We envisaged that the indolenine-spiro-b-lactam could be
synthesized from macrolactam 4 by a transannular variant
of the b-lactam formation. The macrocyclic N-hydroxyena-
mide 4 would be constructed by the intramolecular N-acyla-
tion of oxime 5 as a precursor, which was retrosynthesized into
an indole segment 6 and alkynylimidazole segment 7.
2,6-Dibromoindole acetic acid methyl ester 6 as the indole
segment was easily prepared from indole-3-acetic acid methyl
ester by regioselective bromination7 followed by Boc-protec-
tion.8 On the other hand, the alkynylimidazole segment 7 was
synthesized from vinyl imidazole 8 reported by Wood.5 Dihy-
droxylation of the vinyl group was followed by protection of
the diol as an acetonide to give 9 in good overall yield
(Scheme 2). The benzyl group was deprotected under hydro-
genolysis, and the ester group within compound 10 was then
converted to acetylene 7 in three steps, including reduction of
Graduate School of Bioagricultural Sciences, Nagoya University,
Chikusa, Nagoya, 464-8601, Japan. E-mail: nisikawa@
agr.nagoya-u.ac.jp; Fax: +81 52 7894111; Tel: +81 52 7894115
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b803797c
Scheme 1 Synthetic plan for chartelline C.
Chem. Commun., 2008, 3121–3123 | 3121
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Scheme 2 Synthesis of imidazole segment 7.
the bromo substituent in indole 12 was intact even when an
excess of Zn–Cu was used in this reaction. The acetonide
group was hydrolyzed and then cleaved with sodium periodate
to give the corresponding aldehyde, which was homologated
by the use of a Wittig reaction, thus providing vinyl ether 14.
The methyl ester of 14 was hydrolyzed with lithium hydroxide,
and the vinyl ether was hydrolyzed under acidic conditions in
the presence of O-allylhydroxylamine to furnish oxime 15,
which was set up for the macrolactamization. Compound 15
was transformed to acid chloride 1616 through silylation of the
carboxylic acid, benzoylation of the imidazole and chlorina-
tion with oxalyl chloride17 and then exposed to the cyclization
conditions. However, extensive examination of the reaction
proved the desired cyclization of 16 to be difficult.18
Scheme 4 Attempted cyclization.
acid was not necessary for the formation of 18. These results
strongly suggest a radical mechanism for the reaction, though
the detail is still not clear. Although the desired product 4 has
not been obtained, we envisioned that the unexpected product
18 might be a precursor for a macrolactam such as 4 (vide
infra). Further experiments led us to find that pentacyclic
product 18 was best obtained by refluxing 18 with AIBN in
DME (47% yield). Since a similar compound, namely indole
14 cyclized to give tetracyclic indolenine 1919 under the
optimized conditions, it indicates that 18 is formed through
ring closure of the eight-membered ring followed by formation
of the six-membered aminal. The facile formation of the eight-
membered ring is probably due to the Z-alkene linker with
geminal dimethyl group, which may fix the stacking between
the imidazole and indole rings to approximate the C-3 position
to the C-20 position (Scheme 5).
At this conjuncture, we turned to an alternative for the
construction of N-hydroxymacrolactam 4 by utilizing an
intramolecular condensation of O-allylhydroxamic acid with
aldehyde, which could be prepared from vinyl ether 14
(Scheme 4). Thus, the ester of 14 was transformed into
O-allylhydroxamate 17 in two steps including alkaline hydro-
lysis followed by condensation with O-allylhydroxylamine.
Upon refluxing 17 with p-toluenesulfonic acid and MS3A in
DME, the desired enamide product was not obtained, but
instead a pentacyclic indolenine 18 was obtained in 36% yield.
The structure was determined by NMR and MS experiments
as depicted in Scheme 4; connection between the C-3 and C-20
was elucidated by the HMBC spectrum, NOESY correlations
support the depicted stereochemistry, and a large coupling
constant (J2–3 = 9 Hz) indicates a trans-diaxial relationship
between these protons.
The finding of the unexpected reactions inspired us to
speculate an alternate biosynthetic pathway for the 12-mem-
bered macrolactam 24 from 20 as a precursor not through 21
(Scheme 5).20 Formation of an eight-membered intermediate
22 from 20 is followed by six-membered amide formation to
give rise to pentacyclic product 23, which undergoes decar-
boxylative fragmentation to macrolactam 24. The other bio-
genesis through the 12-membered lactam 21 is also possible;
intramolecular condensation of 20 would give compound 21,
which undergoes a transannular reaction resulting in the
formation of the pentacyclic compound 23. These proposed
biosynthetic pathways are also attractive as an alternative
Despite extensive examination, we could not find the con-
ditions to give the desired macrolactam 4 (X = H, R =
CH2–CHQCH2). However, during these experiments, we
noticed several crucial factors influencing the production of
18; the reaction did not proceed under argon atmosphere and
Scheme 3 Synthesis of oxime for the cyclization.
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Scheme 5 Proposed biosynthetic pathways.
synthetic route for 24. Further synthetic studies along this line
the same conditions: O. R. Sua
M. Melendez-Rodrıguez, E. Aquino-Torres, M. S. Morales-Rı
and P. Joseph-Nathan, Heterocycles, 2007, 71, 1539.
9. (a) S. Ohira, Synth. Commun., 1989, 19, 561; (b) G. J.
´
rez-Castillo, M. Sa
´
nchez-Zavala,
´
´
´
os
are being pursued in this laboratory.
Notes and references
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¨
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between the similar coupling partners reported by Magnus4.
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18. The conditions developed for N-acylation of oxime were employed
for attempted cyclization of 16. See ref. 6c.
19. The stereochemistry of 19 was determined by the NOESY correla-
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gem-methyl groups, as shown in Scheme 4.
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8. During preparation of this manuscript, synthesis of 2,6-dibro-
moindole-3-acetic acid methyl ester was reported under essentially
20. For biosynthetic considerations, see refs. 2 and 4.
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