Room-temperature aromatization of tetrahydro-β-carbolines by 2-iodoxybenzoic acid: Utility in a total synthesis of eudistomin U

Article abstract of DOI:10.1021/ol101688x

2-Iodoxybenzoic acid is a convenient reagent for the dehydrogenation of tetrahydro-β-carbolines to their aromatic forms under mild conditions. The utility of the method was demonstrated in a total synthesis of the marine indole alkaloid eudistomin U.

Full text of DOI:10.1021/ol101688x

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4086-4089
Room-Temperature Aromatization of
Tetrahydro-ꢀ-carbolines by
2-Iodoxybenzoic Acid: Utility in a Total
Synthesis of Eudistomin U
Joseph D. Panarese and Stephen P. Waters*
Department of Chemistry, The UniVersity of Vermont, 82 UniVersity Place,
Burlington, Vermont 05405
stephen.waters@uVm.edu
Received July 20, 2010
ABSTRACT
2-Iodoxybenzoic acid is a convenient reagent for the dehydrogenation of tetrahydro-ꢀ-carbolines to their aromatic forms under mild conditions.
The utility of the method was demonstrated in a total synthesis of the marine indole alkaloid eudistomin U.
The aromatic ꢀ-carboline moiety is found in numerous
natural products and synthetic congeners.1 Compounds
bearing this ring system display a diverse range of biological
properties including antimalarial,2 antitumor,3 and anti-HIV
activities.4 Others show potent binding affinities toward
benzodiazepine receptors in the central nervous system,
thereby acting as diazepam antagonists.5 In light of these
pharmacological properties, mild synthetic methods for the
construction of the ꢀ-carboline unit are desirable. One
strategy for its preparation centers on the formal dehydro-
genation of a suitable tetrahydro-ꢀ-carboline precursor.
Transformations of this type have been previously conducted
by heating the substrate with palladium on carbon6 or sulfur7
in refluxing cumene or xylenes over extended periods of time.
8
9
Other oxidizing agents such SeO2 and MnO2 also require
(5) (a) Hagen, T. J.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1987, 30,
750–753. (b) Hagen, T. J.; Guzman, F.; Schultz, C.; Cook, J. M.; Skolnick,
P.; Shannon, H. E. Heterocycles 1986, 10, 2845–2855. (c) Mu¨ller, W. E.;
Fehske, K. J.; Borbe, H. O.; Wollert, U.; Nanz, C.; Rommelspacher, H.
Pharmacol., Biochem. BehaV. 1981, 14, 693–699.
(1) For reviews on the chemistry and biology of ꢀ-carbolines, see: (a)
Love, B. E. Org. Prep. Proced. Int. 1996, 28, 3–64. (b) Cao, R.; Peng, W.;
Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479–500.
(6) (a) Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.;
Yamanaka, E.; Hutchins, L.; DiPierro, M.; Cook, J. M. J. Org. Chem. 1979,
44, 535–545. (b) Hibino, S.; Miko, O.; Masataka, I.; Kohichi, S.; Takashi,
I. Heterocycles 1985, 23, 261–264. (c) Coutts, R. T.; Micetich, R. G.; Baker,
G. B.; Benderly, A.; Dewhurst, T.; Hall, T. W.; Locock, A. R.; Pyrozko, J.
Heterocycles 1984, 22, 131–142.
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Hamann, M. T. Org. Lett. 2006, 8, 2591–2594. (c) Boursereau, Y.; Coldham,
I. Bioorg. Med. Chem. Lett. 2004, 14, 5841–5844.
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K. R.; Boyd, M. R. J. Nat. Prod. 2001, 64, 1454–1456. (c) Prinsep, M. R.;
Blunt, J. W.; Munro, M. H. G. J. Nat. Prod. 1991, 54, 1068–1076.
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Zheng, Y. T.; Liu, J. K. Chem. BiodiVersity 2008, 5, 447–460. (b) Wang,
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25, 1081–1091. (b) Still, I. J. W.; McNulty, J. Heterocycles 1989, 29, 2057–
2059. (c) Qifeng, W.; Rihui, C.; Manxiu, F.; Xiangdong, G.; Chunming,
M.; Jinbing, L.; Huacan, S.; Wenlie, P. Eur. J. Med. Chem. 2009, 44, 533–
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10.1021/ol101688x  2010 American Chemical Society
Published on Web 08/17/2010

1
high temperatures and must often be used in excess. Organic-
based reagents capable of effecting the dehydrogenation are
limited to quinone-derived reagents such as chloranil10 and
DDQ,11 and yields are often unsatisfactory. Trichloroiso-
cyanuric acid (TCCA) has recently been identified as an
additional oxidant.12
We were prompted to seek a mild set of conditions for
the aromatization of tetrahydro-ꢀ-carbolines during our
studies in alkaloid synthesis. Aiming to improve upon
existing methodologies, we desired a process that would
employ an inexpensive oxidant and proceed smoothly at
ambient temperature. In this Letter, we describe a new
method to achieve this transformation and demonstrate its
utility in a total synthesis of the marine indole alkaloid
eudistomin U.
Drawn to examples by Nicolaou and co-workers of
iodine(V)-mediated syntheses of pyridines from N-hetero-
cyclic precursors,13 our attention turned to hypervalent iodine
reagents such as the Dess-Martin periodinane and 2-io-
doxybenzoic acid (IBX).14 A survey of conditions revealed
that each could effect the dehydrogenation, though a large
excess of the former reagent was required to achieve
comparable yields (Table 1, entries 1 and 2). Placement of
were observed by H HMR analysis of the crude reaction
mixtures. Gratifyingly, addition of tetrabutylammonium
bromide (TBAB)15 with acetonitrile as the solvent led to
enhanced conversions (Table 1, entries 5 and 6). Under these
conditions, the desired products could be obtained in good
yields within 2 h. Overall, the presence of the ester function
at C(3) was important for good conversions; substrates
without this group either did not oxidize completely (entry
7) or were mostly inert (entry 8) toward the reaction
conditions.
Following the optimized procedure, the generality of the
method was explored. A number of tetrahydro-ꢀ-carbolines,
obtained by Pictet-Spengler condensation of tryptophan
methyl ester with the appropriate aldehyde, were examined
(Table 2). Yields were generally good and appeared to be
dependent on the electronic characteristics of the substituent
at C(1); substrates bearing electron-donating groups (Table
2, entries 2 and 3) afforded higher yields than those with
electron-withdrawing groups (Table 2, entries 4 and 5).
Overall, the conditions proved to be tolerant of aromatic
functional groups and did not require protection of the indole
nitrogen. We note that these mild conditions offer some
advantages over those previously described for the dehy-
drogenation of a few of these substrates, particularly in regard
to reaction time and temperatures. For example, aromatiza-
tion of 1b to ꢀ-carboline 2b (Table 2, entry 2) was previously
reported to occur in 73% yield after exposure to sulfur in
refluxing xylenes for 48 h,16 while a 77% yield was obtained
using selenium dioxide in refluxing dioxane.17 Similarly,
ꢀ-carboline 2a (Table 2, entry 1) has been previously
obtained from 1a in 75% yield upon treatment with sulfur
in xylenes for 6 h17 and in 80% yield employing Pd/C in
xylenes after 43 h.7a
Table 1. Optimization Studies on the IBX-Mediated
Aromatization of Tetrahydro-ꢀ-carbolines
We next turned our attention to substrates bearing aliphatic
or heteroaromatic substituents at C(1), as these systems
yield
(%)b
entry
R1/R2
reaction conditionsa
DMP (5.5 equiv),
CH2Cl2, rt, 13 h
IBX (2.5 equiv),
DMSO, rt, 24 h
IBX (2.5 equiv),
DMSO, 45 °C, 9 h
IBX (2.0 equiv),
DMSO, rt, 2.5 h
IBX (2.0 equiv), TBAB
(0.5 equiv), MeCN, rt, 2 h
IBX (2.0 equiv), TBAB
(0.5 equiv), MeCN, rt, 2 h
IBX (2.0 equiv), TBAB
(0.5 equiv), MeCN, rt, 2 h
IBX (2.0 equiv), TBAB
(0.5 equiv), MeCN, rt, 2 h
(9) (a) Yin, W.; Srirama Sarma, P. V. V.; Ma, J.; Han, D.; Chen, J. L.;
Cook, J. M. Tetrahedron Lett. 2005, 46, 6363–6368. (b) Dantale, S. B.;
So¨derberg, B. C. G. Tetrahedron 2003, 59, 5507–5514.
1
2
3
4
5
6
7
8
Ph/H
70
60
50
55
77
89
53c
<5d
(10) (a) Lippke, K. P.; Schunack, W. G.; Wenning, W.; Mu¨ller, W. E.
J. Med. Chem. 1983, 26, 499–503. (b) Snyder, H. R.; Hansch, C. H.; Katz,
L.; Parmerter, S. M.; Spaeth, E. C. J. Am. Chem. Soc. 1948, 70, 219–221.
(11) (a) Yeun-Mun, C.; Hamann, M. C. Heterocycles 2007, 71, 245–
252. (b) Kobayashi, J.; Cheng, J.; Ohta, T.; Nozoe, S.; Ohizumi, Y.; Sasaki,
T. J. Org. Chem. 1990, 55, 3666–3670.
Ph/H
Ph/H
Ph/CO2Me
Ph/CO2Me
H/CO2Me
Ph/H
(12) (a) Haffer, G.; Nickisch, K.; Tilstam, U. Heterocycles 1998, 48,
993–998. (b) Tilstam, U.; Weinmann, H. Org. Process Res. DeV. 2002, 6,
384–393.
(13) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077–4082. (b) Nicolaou, K. C.; Mathison,
C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192–5201.
(14) For reviews, see: (a) Varvoglis, A. HyperValent Iodine in Organic
Synthesis; Academic Press: London, 1997. (b) Zhdankin, V. V.; Stang, P. J.
Chem. ReV. 2002, 102, 2523–2584. (c) Zhdankin, V. V. Curr. Org. Synth.
2005, 2, 121–145. (d) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656–
3665.
H/H
a DMP ) Dess-Martin periodinane, IBX ) 2-iodoxybenzoic acid,
(15) For discussions on the beneficial role of quaternary ammonium salts
in other IBX-mediated transformations, see: (a) Fontaine, P.; Chiaroni, A.;
Masson, G.; Zhu, J. Org. Lett. 2008, 10, 1509–1512. (b) Drouet, F.; Fontaine,
P.; Masson, G.; Zhu, J. Synthesis 2009, 1370–1374. (c) Shukla, V. G.;
Salgaonkar, P. D.; Akamanchi, K. G. J. Org. Chem. 2003, 68, 5422–5425.
(d) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G.
J. Org. Chem. 2007, 72, 662–665.
b
1
TBAB ) tetrabutylammonium bromide. Yield determined by H NMR
analysis of crude reaction mixture. c Product accompanied by 47% of 3,4-
dihydro-ꢀ-carboline intermediate. d Product accompanied by 30% of
3,4-dihydro-ꢀ-carboline.
(16) Nazari Formagio, A. S.; Santos, P. R.; Zanoli, K.; Ueda-Nakamura,
K. T.; Du¨sman Tonin, L. T.; Nakamura, C. V.; Sarragiotto, M. H. Eur.
J. Med. Chem. 2009, 44, 4695–4701.
an ester group at C(3) led to shorter reaction times (cf. Table
1, entries 3 and 4). In each case, however, amounts (∼30%)
of partially oxidized 3,4-dihydro-ꢀ-carboline intermediates
(17) Cao, R.; Peng, W.; Chen, H.; Hou, X.; Guan, H.; Chen, Q.; Ma,
Y.; Xu, A. Eur. J. Med. Chem. 2005, 40, 249–258.
Org. Lett., Vol. 12, No. 18, 2010
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Table 2. IBX-Mediated Oxidation of Tetrahydro-ꢀ-carbolinesa
Table 3. Mild Aromatization of Tetrahydro-ꢀ-carboline
Systemsa
a Reaction conditions: substrate (0.5 mmol), IBX (1.0 mmol), TBAB
(0.25 mmol), MeCN (5 mL), rt, 2 h. b Isolated, purified yields after flash
column chromatography.
a Reaction conditions: substrate (0.5 mmol), IBX (1.0 mmol), TBAB
(0.25 mmol), MeCN (5 mL), rt, 2 h. b Isolated, purified yields after flash
column chromatography.
bis-indole 1j was subjected to the reaction conditions,
ꢀ-carboline 2j was obtained in 71% yield (Table 3, entry
5).
would serve to further extend the scope of the methodology
and allow access to a variety of interesting ꢀ-carboline
scaffolds. Oxidation of 1f proceeded in good yield, as did
1g having two ester moieties (Table 3, entries 1 and 2).
Oxidation of 1h, a known ligand for the benzodiazepine
receptor bearing a 3-pyridinyl moiety,7a provided ꢀ-carboline
2h in 91% yield (Table 3, entry 3) and represents an
improvement over the 77% yield reportedly obtained using
selenium dioxide (9.4 equiv) in refluxing acetic acid.8b
Aromatization of 1i, a structural analogue of the anti-HIV
agent flazin,4a,18 was equally facile (Table 3, entry 4). When
The facility by which bis-indole 1j underwent dehy-
drogenation, together with the structural similarity of
ꢀ-carboline 2j to the naturally occurring indole alkaloid
eudistomin U, prompted us to undertake a total synthesis
of the natural product. Isolated from the marine ascidian
Lissoclinum fragile, eudistomin U was found to display
DNA-binding activity as well as strong antimicrobial
properties.19 Application of the IBX-mediated oxidation
would provide a direct entry to its unique framework.20
Pictet-Spengler condensation of N-acetyl indole-3-car-
boxaldehyde21 (3, Scheme 1) and tryptophan methyl ester
(18) Nakatsuka, S. I.; Feng, B. N.; Goto, T.; Kihara, K. Tetrahedron
(19) Badre, A.; Boulanger, A.; Abou-Mansour, E.; Banaigs, B.; Combaut,
G.; Francisco, C. J. Nat. Prod. 1994, 57, 528–533.
Lett. 1986, 27, 3399–3402
.
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Org. Lett., Vol. 12, No. 18, 2010

conditions proceeded smoothly, affording ꢀ-carboline 5
in 75% yield. Saponification of the ester moiety was
accompanied by loss of the N-acetyl group to provide
carboxylic acid 6. Cu/quinoline-mediated decarboxylation
of 6 furnished eudistomin U (7) whose spectroscopic data
was identical to that of natural material.19
Scheme 1
.
Application of the IBX-Mediated Aromatization in
the Total Synthesis of Eudistomin U
In summary, we have developed a convenient protocol for
the synthesis of aromatic ꢀ-carbolines via IBX-mediated
dehydrogenation of tetrahydro-ꢀ-carboline precursors. The
method provides a milder alternative to traditional metal-
based reagents and should prove useful in instances when
forcing conditions must be avoided. The procedure is
especially suited for projected SAR studies and should enable
ready access to a diverse array of ꢀ-carboline scaffolds for
biological evaluation. Finally, the utility of the process was
highlighted in a four-step total synthesis of the indole alkaloid
eudistomin U. Progress is underway in applying the meth-
odology toward the total synthesis of additional biologically
active alkaloid natural products.
Acknowledgment. We gratefully acknowledge the Uni-
versity of Vermont for financial support. This work was also
generously supported by the Vermont Genetics Network
through Grant No. P20 RR16462 from the INBRE Program
of the National Center for Research Resources (NCRR), a
component of the National Institutes of Health. We thank
Dr. John Greaves, Director of the Mass Spectrometry Facility
at the University of California, Irvine, for obtaining high-
resolution mass spectra.
provided tetrahydro-ꢀ-carboline 4 as diastereomers (76%
yield).22 Dehydrogenation of 4 under the optimized
(20) For previous syntheses, see: (a) Rocca, P.; Marsais, F.; Godard,
A.; Que´guiner, G.; Adams, L.; Alo, B. Tetrahedron Lett. 1995, 36, 7085–
7088. (b) Molina, P.; Fresneda, P. M.; Garc´ıa-Zafra, S. Tetrahedron Lett.
1995, 36, 3581–3582.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915–13928.
(22) The formyl group of indole-3-carboxaldehyde is known to be
weakly electrophilic as the compound tends to behave as a vinylogous amide.
Use of its N-acetyl congener suppressed this behavior and facilitated the
Pictet-Spengler reaction.
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