Manganese dioxide mediated one-pot synthesis of methyl 9H-pyrido[3,4-b] indole-1-carboxylate: Concise synthesis of alangiobussinine

Article abstract of DOI:10.3762/bjoc.7.164

The carboline ring system is an important pharmacophore found in a number of biologically important targets. Development of synthetic routes for the preparation of these compounds is important in order to prepare a range of analogues containing the carboline heterocyclic moiety. A manganese dioxide mediated one-pot method starting with an activated alcohol and consisting of alcohol oxidation, Pictet-Spengler cyclisation, and oxidative aromatisation, offers a convenient process that allows access to β-carbolines. This one-pot process for the preparation of methyl 9H-pyrido[3,4-b]indole-1- carboxylate has subsequently been used as the key step in the synthesis of alangiobussinine and a closely related analogue.

Full text of DOI:10.3762/bjoc.7.164

Manganese dioxide mediated one-pot synthesis of
methyl 9H-pyrido[3,4-b]indole-1-carboxylate:
Concise synthesis of alangiobussinine
Jessica Baiget1, Sabin Llona-Minguez1, Stuart Lang*2, Simon P. MacKay1,
Colin J. Suckling2 and Oliver B. Sutcliffe1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1407–1411.
1Strathclyde Institute of Pharmacy and Biomedical Sciences,
University of Strathclyde, 165 Cathedral Street, Glasgow, G4 0RE, UK
and 2WestChem, Department of Pure and Applied Chemistry,
University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
doi:10.3762/bjoc.7.164
Received: 12 August 2011
Accepted: 19 September 2011
Published: 12 October 2011
Email:
Stuart Lang* - stuart.lang@strath.ac.uk
Associate Editor: M. S. Sherburn
* Corresponding author
© 2011 Baiget et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkaloid synthesis; carboline; heterocycle; oxidation; tandem reaction
Abstract
The carboline ring system is an important pharmacophore found in a number of biologically important targets. Development of syn-
thetic routes for the preparation of these compounds is important in order to prepare a range of analogues containing the carboline
heterocyclic moiety. A manganese dioxide mediated one-pot method starting with an activated alcohol and consisting of alcohol
oxidation, Pictet–Spengler cyclisation, and oxidative aromatisation, offers a convenient process that allows access to β-carbolines.
This one-pot process for the preparation of methyl 9H-pyrido[3,4-b]indole-1-carboxylate has subsequently been used as the key
step in the synthesis of alangiobussinine and a closely related analogue.
Introduction
Carbolines are an important class of naturally occurring com- applications of these molecules highlights the importance of
pounds containing the β-carboline motif found in a number of carbolines as a synthetic target in medicinal chemistry. The for-
biologically active molecules, and which have recently been mation of the β-carboline ring system in nature is well under-
shown to be active against Alzheimer’s disease [1,2], bacterial stood and biosynthetically has been shown to proceed by means
infection [3], inflammation [4,5], HIV and AIDS [6] and of either a Pictet–Spengler or a Bischler–Napieralski cycliza-
various forms of cancers [7-12]. The wide range of therapeutic tion followed by an oxidative dehydrogenation process [13-15].
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Inspired by nature’s example, we wished to design a synthetic alcohol 1 and secondly it is used in order to promote the aroma-
route to the β-carboline scaffold, which was biomimetic and tisation [20] of tetrahydrocarboline 5, allowing effectively at
could be carried out in a single operation. One-pot cascade reac- least three operational steps to be carried out as part of a single
tions have many advantages over multistep sequences. These cascade process.
include a reduction of the time required to set up the reactions, a
removal of the need to isolate unstable intermediates, and a Results and Discussion
reduction of the time required for purifications. This leads to a Encouragingly our initial conditions, involving stirring the reac-
lowering of the overall reaction costs and in addition has the tion mixture in toluene at room temperature for 3 h followed by
advantage that there is less waste associated with reactions of heating under reflux overnight (Table 1, entry a), gave the
this nature and therefore less environmental impact.
desired β-carboline 6 in 44% yield as the only product isolated
from the reaction mixture. We decided to screen a range of
Taylor et al. [16-19] have shown manganese dioxide to be a different solvents to assess the optimum conditions in which to
robust reagent for carrying out oxidations on a wide range of carry out this transformation.
activated alcohols. They have shown that the aldehyde gener-
ated does not need to be isolated, but instead can be used in situ When the reaction was carried out in dichloromethane none of
allowing further manipulation with a range of suitable reagents, the desired product was formed, and only starting material was
leading to the formation of a variety of different types of mole- detected by both TLC and NMR (Table 1, entry b). Changing
cules as part of a one-pot procedure.
the solvent to chloroform showed that chlorinated solvents are
compatible in the reaction (Table 1, entry c), and that the low
We proposed that exposing methyl glycolate (1) to manganese temperature was more detrimental to the process than the nature
dioxide would result in the formation of aldehyde 2. This can of the solvent.
then undergo a condensation process with tryptamine (3)
allowing the generation of imine 4. This intermediate is set up The process was found to work best when 1,4-dioxane was used
appropriately to undergo a Pictet–Spengler cyclization reaction as the solvent, with a yield of 54% being achieved for this one-
resulting in the formation of tetrahydrocarboline 5. In the pres- pot tandem process under these conditions (Table 1, entry g).
ence of manganese dioxide intermediate 5 is not isolated, but Disappointingly, although it lowered the time required to carry
instead, undergoes a series of dehydrogenation reactions in out the reaction, the use of microwave irradiation led to a lower
order to furnish our desired, fully aromatic β-carboline 6 isolated yield of β-carboline 6 (Table 1, entries f and g),
(Scheme 1).
showing that conventional heating is preferred for this process.
This approach to the synthesis of β-carbolines is particularly We also observed that the use of solvents with lower boiling
elegant as the manganese dioxide has a dual purpose in the points, such as dichloromethane, chloroform and THF, did not
reaction. Firstly, it is used for the oxidation of the starting lead to complete conversion to the desired β-carboline 6, with
Scheme 1: Proposed mechanism for the formation of 6.
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Table 1: Optimisation of β-carboline 6 synthesis.a
Entry
Solvent
Additive (equiv)
Yield
a
b
c
d
e
f
toluene
none
44%
CH2Cl2
none
0%
CHCl3
none
39%
THF
none
45%
DMFb
none
26%
MeCN
none
51% (35%)c
54% (33%)c
0%
g
h
i
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
none
ZnCl2 (1)
ZnCl2 (0.1)
Ti(OiPr)4 (0.2)
52%
j
43%
aMnO2 (10 equiv), 4 Å molecular sieves, solvent, 3 h at room temperature followed by reflux overnight; bReaction carried out at 100 °C; cMethyl glyco-
late (1.5 equiv), MnO2 (10 equiv), 4 Å molecular sieves, solvent, 3 h at room temperature followed by heating in the microwave at 170 °C for
2–10 min.
both TLC and NMR analysis showing the presence of trypta- low yield as a byproduct by Laronze and coworkers. Alan-
mine (3) in the reaction mixture. We were also unable to detect giobussinine (7, Figure 1) is an alkaloid that is isolated from the
any of the nonaromatic intermediate 5, leading us to speculate leaves of Alangium bussyanum, a tropical shrub.
that the Pictet–Spengler cyclization step, involving conversion
of imine 4 to tetrahydrocarboline 5, is the step with the greatest
activation energy in the process.
In an attempt to lower this energy barrier we looked at adding
Lewis acids as additives [21] in the process. However, the use
of catalytic amounts of Lewis acids did not lead to an increase
in the yield of β-carboline 6 (Table 1, entries i and j) and the use
of one equivalent of zinc(II) chloride (Table 1, entry h) in-
Figure 1: Structure of alangiobussinine (7).
hibited all reaction.
This shows that while the use of Lewis acid additives is likely Our strategy for the completion of the synthesis of alangiobussi-
to help with the Pictet–Spengler cyclization step, it may inhibit nine (7) involved initial hydrolysis of carboline ester 6 with
other steps in the process, e.g., by forming a strong complex lithium hydroxide in a mixture of methanol and water. The
with methyl glycolate (1) and therefore stopping the manganese reaction mixture was then partitioned between dichloromethane
dioxide mediated oxidation step. This shows that although and water with the lithium carboxylate 8 being insoluble in both
Lewis acids can be used to activate Pictet–Spengler reactions, layers, but precipitating exclusively in the dichloromethane
the absence of a Lewis acid is optimum for this one-pot cascade layer. Lithium carboxylate 8 was therefore isolated in 78% yield
process.
by separation of the two layers followed by filtration, and could
be used directly in the next step without need for an additional
β-Carboline 6 is a useful intermediate, used by Panosyan and protonation step. Lithium carboxylate 8 was then converted to
Still [22] in their synthesis of xestomanzamine A. We wished to acid chloride 9, which was isolated and treated directly with
apply the preparation of β-carboline 6 as the key synthetic step tryptamine (3) to give access to alangiobussinine (7) in 67%
in the first reported synthesis of alangiobussinine, although the yield over the two steps (Scheme 2), with our spectroscopic
synthesis of dihydroalangiobussinine [23] has been reported in data being consistent with that of the natural product [24].
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Scheme 2: Preparation of compounds 7 and 10. Reagents and conditions: i) LiOH (10 equiv), MeOH–H2O, rt, overnight; ii) oxalyl chloride (5 equiv),
DMF (0.01 equiv), CH2Cl2, rt, 6 h; iii) tryptamine (3) (2 equiv), Et3N (3 equiv), MeCN, 0 °C to rt, overnight; iv) serotonine·HCl (2 equiv), Et3N (3 equiv),
MeCN, 0 °C to rt, overnight.
In addition to preparing alangiobussinine (7), we also used the Acknowledgements
same strategy to prepare its structural analogue 10, which was We thank CRUK for providing financial support and also the
achieved in a combined yield of 60% for both the acid-chloride University of Strathclyde for Ph.D studentships (Jessica Baiget
formation and amide-bond-formation steps. It was also possible and Sabin Llona-Minguez).
to use T3P®, along with Et3N, in order to couple lithium
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