Total synthesis of dictyodendrin B

Article abstract of DOI:10.1021/ja0541175

A concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl₃ and KC₈) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH₂Cl₂ solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl₃, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral -OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C. Copyright

Full text of DOI:10.1021/ja0541175

Published on Web 07/29/2005
Total Synthesis of Dictyodendrin B
Alois Fu¨rstner,* Mathias M. Domostoj, and Bodo Scheiper
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received June 22, 2005; E-mail: fuerstner@mpi-muelheim.mpg.de
Scheme 1 a
The finite lifespan of somatic cells results from the shortening
of single-stranded “telomeric” DNA protecting the ends of the
chromosomes. These telomeres are progressively shortened with
successive rounds of replication until they reach a critical length
at which apoptosis is triggered to prevent further aging. Tumor cells,
however, are able to maintain their telomeric ends by the action of
telomerase. This enzyme has reverse-transcriptase properties and
is overexpressed in >85% of all malignant cells but is virtually
absent in normal tissue1 and, therefore, constitutes a particularly
promising molecular target in the quest for more selective chemo-
therapeutic agents for the fight against cancer.2
Since the number of telomerase inhibitors from natural sources
is fairly limited,2,3 a recent publication disclosing the structure and
activity of the dictyodendrins is particularly noteworthy.4 These
very scarce alkaloids isolated from the marine sponge Dictyoden-
drilla Verongiformis effect 100% telomerase inhibition at a
concentration of 50 µg/mL, although no further biochemical
profiling was reported. Dictyodendrins, such as 1-3, are close
relatives of the spirocyclic aldose reductase inhibitor 45 and
constitute the first naturally occurring pyrrolo[2,3-c]carbazole
derivatives known in the literature. With the hope to contribute to
the biological assessment of these structurally unique compounds,6
we launched a program aiming at the development of a concise,
flexible, and potentially scalable entry into this class of marine
alkaloids. The total synthesis of dictyodendrin B (1) outlined below
represents the first step along these lines.
Acetophenone 5 served as appropriate starting material,7 which
was protected as isopropyl ether 6 prior to condensation with
p-MeOC6H4CHO (Scheme 1). The resulting chalcone 7 was
exposed to toluenesulfonylmethyl isocyanide (TosMIC) and NaH
at low temperature8 to afford pyrrole 8 after in situ N-alkylation
with p-MeOC6H4(CH2)2Br. Subsequent reduction of the nitro group
a Conditions: (a) 2-bromopropane, K2CO3, DMF, 100 °C, 99%; (b)
p-MeOC6H4CHO, NaOMe, MeOH, 70 °C, 74%; (c) (i) TosMIC, NaH, THF,
-30 °C; (ii) p-MeOC6H4(CH2)2Br, reflux, 83%; (d) Fe powder, aq. HCl,
EtOH, 96%; (e) 10, CH2Cl2, Et3N, DMAP cat., 89%; (f) TiCl3/2 KC8, DME,
pyridine, reflux, 71-93%; (g) hν, MeCN, Pd/C cat., C6H5NO2, 81%; (h)
NBS, THF, 0 °C, 69%; (i) (i) MeLi, THF, -78 °C; (ii) n-BuLi, -78 °C;
(iii) p-MeOC6H4CHO, -78 °C f rt, 97%; (j) TPAP (10%), NMO, MS 4
Å, CH2Cl2 (0.01 M), 66% (17), 16% (16); (k) BCl3, CH2Cl2, -20 °C, 85%;
(l) Cl3CCH2OSO2Cl, DABCO, CH2Cl2, 92%; (m) (i) BCl3, TBAI, CH2Cl2,
0 °C f rt; (ii) Zn, HCOONH4, MeOH, 58%.
with Fe/HCl provided aniline 9 in excellent yield on a multigram
scale, which was condensed with acid chloride 109 under standard
9
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10.1021/ja0541175 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
conditions to give amide 11 as the key compound of the envisaged
synthesis route.
Previous investigations from this laboratory had shown that
ketoamides, on treatment with low-valent titanium, convert to indole
derivatives even in the presence of other reducible sites.10-12
Application of this protocol to substrate 11 afforded the desired
product 12 in up to 93% isolated yield on exposure to titanium-
graphite (prepared from TiCl3 and 2 KC8)13 in refluxing DME.
Thereby, it turned out beneficial to buffer the slightly Lewis acidic
reaction medium with pyridine to prevent partial cleavage of the
labile enol ether moiety in the substrate. Indole 12 thus formed is
set up for subsequent closure of the dictyodendrin core by a 6π-
electrocyclization.14 This transformation proceeded smoothly upon
irradiation of 12 with UV light (Hanovia Hg lamp, 250 W) in
MeCN; addition of Pd/C and nitrobenzene15 to the reaction medium
causes concomitant aromatization of the product initially formed,
thus giving rise to the desired pyrrolocarbazole 13 in 81% yield in
a single operation.
a Conditions: (a) BBr3, cyclohexene, CH2Cl2, -78 °C f rt, 49%, cf.
text
Acknowledgment. We thank Prof. N. Fusetani, Tokyo, for
providing samples of the dictyodendrins and copies of the original
NMR spectra. B.S. and M.M.D. thank the Fonds der Chemischen
Industrie and the Alexander-von-Humboldt foundation for fellow-
ships, respectively. Generous financial support by the MPG
(Chemical Genomics Center) and the Merck Research Council is
gratefully acknowledged.
Initially, a Friedel-Crafts acylation of the activated 2-position
of 13 was envisaged to complete the carbon skeleton of 1.16 In the
presence of Lewis acids, however, this compound is subject to a
complex skeletal rearrangement rather than acylation, thus forcing
us to pursue a different route. Gratifyingly, treatment of 13 with
NBS resulted in a selective bromination to give the somewhat
unstable product 14, which was subjected to metal-halogen
exchange with n-BuLi (after deprotonation of the -NH group with
MeLi). The resulting aryllithium species could be quenched with
p-MeOC6H4CHO to afford product 15 in excellent yield.17
The subsequent oxidation of the benzylic alcohol moiety in 15
under various conditions turned out rather capricious and afforded
variable amounts of a byproduct 16 in addition to the expected
ketone 17. Extensive NMR investigations were necessary to unravel
the constitution of 16 as an unsymmetrical dimer, in which the
two subunits are connected via C8 and the carbazole N-atom,
respectively.18 The dimeric nature of 16, however, suggested that
the oxidation might respond to the dilution of the reaction mixture.
In fact, the yield of the desired ketone 17 could be increased to
66% when the oxidation was performed in dilute (0.01 M) CH2Cl2
solution with tetra-n-propylammonium perruthenate (TPAP, 10 mol
%) and NMO.19 Selective cleavage of the isopropyl ether in 17
with BCl3 followed by reaction of the resulting phenol 18 with
Supporting Information Available: Full experimental details and
copies of spectra of relevant intermediates. This material is available
free of charge via the Internet at http.//pubs.acs.org.
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20
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