Bidirectional synthesis of montamine analogs

Article abstract of DOI:10.1016/j.tetlet.2013.07.134

Reported herein is a bidirectional synthesis of symmetric N,N′-diacyl hydrazide compounds closely resembling the alkaloid natural product montamine. In the process, di-tert-butyl hydrazine-1,2-dicarboxylate was smoothly dialkylated with alkyl halides, then Boc deprotected and acylated with an acetate-protected acid chloride derived from ferulic acid. After acetate removal, simple montamine analogs were obtained in excellent overall yields. Fischer indole synthesis with 4-methoxyphenylhydrazine hydrochloride and dihydrofuran provided 5-methoxytryptophol, which was then elaborated to the 1,2-bis(5-methoxyindol-3-yl)hydrazide structure bearing the substitution pattern found in montamine.

Full text of DOI:10.1016/j.tetlet.2013.07.134

Tetrahedron Letters 54 (2013) 5489–5491
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bidirectional synthesis of montamine analogs
Melanie B. Freitas, Kelly A. Simollardes, Caroline M. Rufo, Chantel N. McLellan, Gabrielle J. Dugas,
⇑
Leslie E. Lupien, Elizabeth A. Colby Davie
Assumption College, 500 Salisbury Street, Worcester, MA 01609, USA
a r t i c l e i n f o
a b s t r a c t
Reported herein is a bidirectional synthesis of symmetric N,N0-diacyl hydrazide compounds closely
resembling the alkaloid natural product montamine. In the process, di-tert-butyl hydrazine-1,2-dicarbox-
ylate was smoothly dialkylated with alkyl halides, then Boc deprotected and acylated with an acetate-
protected acid chloride derived from ferulic acid. After acetate removal, simple montamine analogs were
obtained in excellent overall yields. Fischer indole synthesis with 4-methoxyphenylhydrazine hydrochlo-
ride and dihydrofuran provided 5-methoxytryptophol, which was then elaborated to the 1,2-bis(5-meth-
oxyindol-3-yl)hydrazide structure bearing the substitution pattern found in montamine.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 11 July 2013
Accepted 26 July 2013
Available online 2 August 2013
Keywords:
Montamine
Bidirectional synthesis
Alkylation
Fischer indole synthesis
Aryl ether demethylation
Many plant species within the genus Centaurea have been used
in traditional medicine for the treatment of various ailments.1
Centaurea montana, also known as the mountain cornflower, is a
plant native to Europe and Australia.2 The seeds of C. montana con-
tain a number of natural products3–5 including montamine (1).6
This natural product has a unique dimeric N,N0-diacyl hydrazide
structure and displays cytotoxicity against CaCo-2 colon cancer
against CaCo-2 cells (IC50 = 81.0 lM). Moschamine appears to be
derived from another common natural product, ferulic acid (3).7
The production of 1 and 2 hints at a possible biosynthesis of 1 by an
oxidative dimerization of 2, though no such pathway has yet been
reported. The near half potency of moschamine compared to mon-
tamine raises questions about the mode of cytotoxicity of both
compounds. To address these questions, we have been pursuing
a flexible synthesis of montamine and analogs to conduct a struc-
ture–activity relationship study.8 We focused on a bidirectional
synthesis starting from a hydrazine core.9 While hydrazine appears
to be an attractive starting compound for the elaboration of mon-
tamine analogs through symmetric dialkylation followed by diacy-
lation, this is not a viable strategy because hydrazine is prone to
nonselective alkylation.10 Instead, we selected di-tert-butyl hydra-
zine-1,2-dicarboxylate (4) to force symmetric dialkylation.11–15 We
envisioned that subsequent removal of the BOC groups followed by
diacylation would furnish montamine analogs (see Scheme 1).
We tested the feasibility of our route through the synthesis of a
simple montamine analog in which butyl groups were added in the
dialkylation process (Scheme 2). This process proceeded smoothly
as previously reported,15 furnishing 5 in 90% yield when NaH and 4
equiv of butyl bromide were used. (Yields were lower and the reac-
tion was significantly slower when Cs2CO3 was used.) Next, we
investigated conditions for the BOC deprotection and found the
in situ generation of HCl through treatment with methanol and
acetyl chloride16 to be efficacious and convenient. The crude
deprotected residue was immediately subjected to different acyla-
tion conditions. Disappointingly, coupling attempts with ferulic
acid under several standard conditions did not cleanly afford the
desired N,N0-diacyl hydrazide structure. We next turned to the
use of the acetate-protected acid chloride (6)17 derived from ferulic
cells (IC50 = 43.9 lM). Notably, the amide monomer, moschamine
(2), is also produced by the plant with a reported cytotoxicity
⇑
Corresponding author. Tel.: +1 508 767 7264; fax: +1 508 767 7241.
E-mail address: ecolbydavie@assumption.edu (E.A.C. Davie).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.134

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M. B. Freitas et al. / Tetrahedron Letters 54 (2013) 5489–5491
acid and found that diacylation was smooth as long as an excess of
6 was used (6 equiv were optimal). The acetate protecting groups
were removed from the crude residue through refluxing with
NaOMe in methanol,18 providing a rotameric mixture of diacyl
hydrazide 7 in 88% yield over the BOC removal, acylation, and ace-
tate removal steps. Since these 3 steps represent six chemical
transformations, the overall yield is particularly notable because
it indicates that each individual reaction averaged >97% yield with
only one purification needed.
Encouraged by the synthesis of 7, we turned our attention to
installation of the requisite (indolyl)ethyl group in place of a sim-
ple alkyl group. We were concerned about elimination complicat-
ing the dialkylation step because of the formation of a conjugated
alkene. To investigate this potential competing process, we chose a
simple model system using a phenyl group in place of the more
complex indole moiety (Scheme 3). Indeed, the formation of sty-
rene was observed in reaction mixtures by crude NMR analysis,
but good yields of 8 were still obtained. Reactions conducted with
Cs2CO3 in place of NaH were slower and lower in yield, although
less styrene was formed. Elaboration of compound 8 to the corre-
sponding montamine analog 9 was carried out in excellent yield
over 3 steps.
Scheme 2. Proof-of-concept case.
With the successful synthesis of diacyl hydrazide 9 containing
(aryl)ethyl groups, we aimed to introduce the needed 2-(5-
hydroxyindolyl)ethyl portion to complete the synthesis of monta-
mine. While 5-hydroxytryptophol is an attractive starting material,
its cost was prohibitive to our investigation. Instead, we synthe-
sized 3-(2-hydroxyethyl)-5-methoxyindole (commonly known as
5-methoxytryptophol, 11) via the Fischer indole synthesis with
4-methoxyphenylhydrazine hydrochloride (10) and 2,3-dihydrofu-
ran (Scheme 4).19,20 While the yield of this reaction was modest, it
nevertheless provided an affordable, one-step route to an indole
appropriately functionalized with an oxygen substituent at the 5-
position and ethyl alcohol moiety at the 3-position. Alcohol 11
was subjected to tosylation conditions, affording ditosylate 12 in
good yield.
With ditosylate 12 in hand, we tested its suitability as an elec-
trophile in the dialkylation of di-tert-butyl hydrazine-1,2-dicar-
boxylate (4). When NaH was used as the base, a complex
mixture of products was formed with strong indication of compet-
ing elimination. When the base was changed to Cs2CO3, the reac-
tion proceeded smoothly, albeit slowly. After stirring for 36 h at
room temperature, dialkylated product 13 was isolated in 81%
yield as a mixture of rotamers. When allowed to stir for 5 days, a
quantitative yield was obtained (Scheme 5).21 Additionally, excess
ditosylate was easily recovered in good yield and purity. Subjec-
tion of 13 to our standard sequence of conditions for BOC removal,
acylation, and acetate removal was successful in introducing the
feruloyl functionality while concomitantly removing the Ts pro-
tecting groups, furnishing advanced montamine analog 14 in 55%
yield.
Scheme 3. Introduction of an (aryl)ethyl group.
With the synthesis of montamine being our ultimate goal, we
attempted to demethylate the indole aryl ethers after dialkylation
to avoid selectivity issues with the feruloyl aryl methyl ethers. We
expected that 13 would undergo demethylation22,23 and BOC
deprotection24 upon exposure to BBr3. Indeed, this reaction
Scheme 4. Fischer indole synthesis with dihydrofuran.
produced one major product which lacked the signature methyl
ether and BOC singlets in the 1H NMR spectrum. However, upon
analysis by LRMS, the expected mass was 2 units lower than
expected, leading us to suspect that the N–N bond was also
Scheme 1. Proposed bidirectional synthetic route.

M. B. Freitas et al. / Tetrahedron Letters 54 (2013) 5489–5491
5491
cal Society Petroleum Research Fund for partial support of this re-
search (48347-GB1). High resolution mass spectrometry analysis
was carried out at the University of Illinois on a Q-Tof Ultima
mass spectrometer which was purchased in part with a grant
from the National Science Foundation, Division of Biological
Infrastructure (DBI-0100085). Thanks are extended to Xiaopeng
Bai and Vera Bodmer (GlaxoSmithKline) for assistance with
obtaining NMR data.
Supplementary data
Supplementary data (experimental procedures, NMR spectra
(1H and 13C) and HRMS data for new compounds) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.07.134.
References and notes
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Scheme 5. Synthesis of an advanced montamine analog.
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Scheme 6. Demethylation attempt.
17. Prepared as reported by: Hosoda, A.; Nomura, E.; Mizuno, K.; Taniguchi, H. J.
Org. Chem. 2001, 66, 7199–7201.
18. O-Ac-feruloyl amides were reported to hydrolyze under these conditions:
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oxidized25,26 producing the corresponding diazo compound 15
(Scheme 6). Further evidence supporting this structure assignment
is the observation that the compound could not be acylated under
our standard conditions. To circumvent this issue, we attempted to
demethylate the indole before it was added to the hydrazine
framework. Unfortunately, all efforts to demethylate 5-methoxy-
tryptophol (11) have led to significant decomposition.
20.
A related Fischer indole synthesis of 5-substituted tryptophols using 2-
While the total synthesis of montamine remains elusive, we
ethoxytetrahydrofuran has been reported. The tryptophol products are
converted to the corresponding O,N-ditosylates. Adachi, H.; Palaniappan, K.
K.; Ivanov, A. A.; Bergman, N.; Gao, Z.-G.; Jacobson, K. A. J. Med. Chem. 2007, 50,
1810–1827.
have developed
a flexible, bidirectional route to symmetric
N,N0-diacyl hydrazide compounds containing two feruloyl units,
including a compound possessing two 2-(5-methoxyindol-3-yl)-
ethyl portions that parallels the structure of montamine (1). Our
process is efficient, providing significant quantities of these
analogs for biological assays. Further investigations are focused
on synthesizing 2-(5-oxyindol-3-yl)ethyl alcohols with protecting
groups that are orthogonal to other conditions in our synthetic
sequence and more labile than aryl methyl ethers.
21. The authors of Ref. 9 report that attempts to dialkylate 4 with an indolyl
mesylate similar to 12 were unsuccessful.
22. Palmer, B. D.; Thompson, A. M.; Booth, R. J.; Dobrusin, E. M.; Kraker, A. J.; Lee, H.
H.; Lunney, E. A.; Mitchell, L. H.; Ortwine, D. F.; Smaill, J. B.; Swan, L. M.; Denny,
W. A. J. Med. Chem. 2006, 49, 4896–4911.
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24. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups for Organic Synthesis;
John Wiley & Sons: Hoboken, New Jersey, 2007. 4th ed.; pp 725–735.
25. Oxidation of the N–N bond in hydrazine carboxylates to the corresponding
diazenes is known to occur in the presence of Br2: (a) Zeigler, F. E.; Wender, P.
A. J. Am. Chem. Soc. 1971, 93, 4318–4319; (b) Zeigler, F. E.; Wender, P. A. J. Org.
Chem. 1977, 42, 2001–2003.
Acknowledgments
26. For other known hydrazine oxidation methods, see this report and the
references cited within: Drug, E.; Gozin, M. J. Am. Chem. Soc. 2007, 129,
13784–13785.
Assumption College is acknowledged for support of this work.
Acknowledgment is made to the donors of the American Chemi-