Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology

Article abstract of DOI:10.1021/ol502201d

An expedient synthesis of the indole alkaloid nazlinine is reported. Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process.

Full text of DOI:10.1021/ol502201d

Letter
pubs.acs.org/OrgLett
Expedient Preparation of Nazlinine and a Small Library of Indole
Alkaloids Using Flow Electrochemistry as an Enabling Technology
Mikhail A. Kabeshov,† Biagia Musio,† Philip R. D. Murray, Duncan L. Browne, and Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
S
* Supporting Information
ABSTRACT: An expedient synthesis of the indole alkaloid
nazlinine is reported. Judicious choice of flow electrochemistry
as an enabling technology has permitted the rapid generation
of a small library of unnatural relatives of this biologically
active molecule. Furthermore, by conducting the key electro-
chemical Shono oxidation in a flow cell, the loading of
electrolyte can be significantly reduced to 20 mol % while
maintaining a stable, broadly applicable process.
n the context of organic synthesis an enabling technology can
Ibe defined as a technique that permits strategic disconnec-
tions that would otherwise be difficult to achieve by alternative
means. In addition to this, enabling technology may also permit
other benefits such as increased process safety, increased
reproducibility, improved reactivity, and scalability of the
designed method. In recent years there has been a resurgence
of some of the more traditional enabling technologies, such as
photo-1 and electrochemistry,2 as well as the incorporation and
understanding of new techniques such as mesoscale flow
chemical methods in the context of natural product synthesis.3
It is important to continue to explore, develop, and understand
what these alternative methods are capable of providing for the
modern synthesis chemist, who, as well as being under increased
time pressures, must also consider environmental, economical,
and safety factors when planning research. Herein we describe
how the judicious choice of continuous flow electrochemistry as
Figure 1. Naturally occurring biologically active tetrahydro-β-carbo-
lines.
an enabling tool permits the straightforward preparation of a
library of unnatural congeners of the indole alkaloid nazlinine
(1b).
Flow electrochemistry is an attractive prospect for synthesis,
particulalrly when measured against the green agenda.9,10
Specifically the narrow distance between electrodes offers
excellent potential to minimize or perhaps even eliminate the
use of wasteful electrolytes altogether. However, this must be
offset against the stability of the working cell, as a narrow distance
between electrodes can also lead to increased chances for salt
bridging across the divide. We therefore set out to assess the
Shono oxidation of N-Boc pyrrolidine within the flux electro-
synthesis module.11−13 Initially we found that the use of steel or
platinum coated electrodes in conjunction with an equi-
stoichiometric amount of tetraethylammonium tetrafluoroborate
electrolyte resulted in no conversion to the desired product
(entries 1 and 2, Table 1). Changing this to a carbon anode was
suitable to bring about the α-methoxylation reaction (entry 3,
Nazlinine, first isolated in 1991 from the plant Nitraria
schoberi, displays serotonergic properties.4 Nazlinine itself also
serves as a platform molecular architecture, from which
numerous other indole alkaloids are reported to derive
biosynthetically (Figure 1).5 A structurally related family, the
tryptargines, also exhibit neurotoxic capabilities thus making this
class of natural products interesting probes for medicinal
chemistry programs.6
Given the relatively simple structure of nazlinine, we were
surprised to find that only two syntheses are reported in the
literature, neither of which lends itself to the modular preparation
of structural analogues.7 Here we report a versatile two-step
route to the nazlinine scaffold which hinges around the
electrochemical oxidation of readily available cyclic amines (or
their protected carbamate forms), to provide α-methoxyamine
building blocks which feed into the key Pictet−Spengler reaction
to furnish a compound library.8
Received: July 25, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. α-Methoxylation of N-Boc Pyrrolidine Using an
Microfluidic Electrolytic Cell
Scheme 1. α-Methoxylation of N-Protected Cyclic Amines in
the Microfluidic Electrolytic Cell
a
a
b
entry
anode
steel
R+X− (mol %)
conversion (purity), %
1
2
3
4
Et4N+ BF4− (100)
Et4N+ BF4− (100)
Et4N+ BF4− (100)
Et4N+ BF4− (20)
Et4N+ BF4− (10)
Li+ BF4− (20)
0
Pt-coated
carbon
carbon
carbon
carbon
carbon
0
99(90)
98(95)
90(95)
97(85)
5
c
5
6
7
Na+ Cl− (20)
a
Steel electrode used as a counter electrode; I maintained constant at
43 mA; flow rate 120 μL min−1; 0.1 M solution of 10a in MeOH used.
b
c
1
Detected by H NMR. 0.2 M solution of 10a in MeOH used; flow
rate 100 μL min−1.
Table 1), a result in agreement with previous studies, which show
that N-Boc protected amines and methanol have very close redox
potentials, such that changing the electrode can easily tip the
balance between substrate or solvent oxidation pathways in the
system.7
a
Electrolysis was performed in an undivided cell with a carbon anode
b
and steel cathode; yields shown are isolated yields after FCC.
Isolated yield, no purification by FCC needed.
It was also found that the electrolyte loading could be lowered
to 20 mol % while the conversion and product purity remained
high (entry 4, Table 1). The system was shown to be stable under
these conditions, and the electrolysis was run continuously to
process 10 mmol of material within ∼14 h with no variation in
either conversion or the product purity being observed
throughout the run. Notably, the electrolyte loading could be
lowered still further to 10 mol % (entry 5, Table 1); however, a
higher concentration of the starting material and lower flow rates
were necessary to offset the poorer conductivity of the reaction
media. It was also found that the cell was less stable under these
conditions. Regarding alternative electrolytes, it was observed
that LiBF4 was effective but provided a low quality product (entry
6, Table 1), whereas simple NaCl provided poor conversion
(entry 7, Table 1).
With the optimal procedure in hand (entry 4, Table 1), the
continuous flow conditions were applied to the α-methoxylation
of a series of cyclic amines varying in ring size and protecting
group. It was shown that N-protected pyrrolidine, piperidine,
azepane, and morpholine can all be successfully methoxylated
using the electrochemical apparatus affording the corresponding
products 11a−i with high yields and purity (Scheme 1).
Furthermore, several protecting groups, such as tert-butylcarba-
mate, benzylcarbamate, acetyl and trimethylsilylethylcarbamate,
can all be carried through the process successfully.
Next, we attempted the Pictet−Spengler reaction between the
electro-synthesized imine precursor (11a) and tryptamine (12a)
under the conditions previously reported successful for the
reaction of 2,3,4,5-tetrahydropyridine with tryptamine.7b Un-
fortunately these preliminary experiments were unsuccessful
(entry 1, Table 2). Working on the hypothesis that 0.2 equiv of
acid was not sufficient to deprotect the nitrogen, liberate the
imine from the aminal, and buffer the basic tryptamine nitrogen,
we increased the loading to 6 equiv of TFA, affording 10% of the
desired product (entry 2, Table 2). By contrast, changing the acid
to HCl and the solvent to methanol allowed the desired reaction
to proceed with 50% conversion at reduced temperatures (entry
3, Table 2). Nonvolatile camphor sulfonic acid (CSA) further
Table 2. Optimization of the Reaction of N-Boc α-
Methoxypyrrolidine with Tryptamine
a
b
entry
acid (n equiv)
time (h)
t (°C)
solvent
yield (%)
1
2
3
4
5
6
7
8
TFA (0.2)
TFA (6)
HCl (6)
CSA (6)
CSA (6)
CSA (6)
TFA (6)
H3PO4 (6)
15
90
90
50
50
H2O
0
15
H2O
10
15
MeOH
MeOH
MeOH
H2O
50
15
80
c
0.5
0.5
0.5
0.5
130
52
c
130
90(87)
71
c
130
H2O
c
130
H2O
67
a
Reaction conditions: Tryptamine (1 equiv, 0.1 M), α-methoxycarba-
b
mate (2 equiv), heated in a sealed tube. Detected by 1H NMR;
numbers in parentheses represent isolated yield. Heated in a
c
microwave.
improved this to 80% conversion (entry 4, Table 2). Turning to
microwave irradiation as an enabling technology, proven to
rapidly increase reaction rates by permitting work at hyper-
thermal conditions, we were able to reduce the reaction time
from 15 h to 30 min, initially with a reduced yield of 52% (entry 5,
Table 2). With a change of solvent to water this became a 90%
conversion, corresponding to an isolated yield of 87% (entry 6,
Table 2). Under these microwave heating conditions neither
TFA nor phosphoric acid provided a better reaction than CSA.
Taking these reactions onto a two-step process in which a
small library of unnatural analogues could be prepared, the
output of the electrochemical cell underwent a simple solvent
exchange and filtration before passing into the second tricycle
forming step.14
It was found that this procedure was suitable for the
preparation of several structural relatives, which were furnished
B
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Letter
in moderate to excellent yields for the two-step process (Scheme
2). Tryptamines bearing bromo, fluoro, and methyl substituents
Scheme 3. Proposed Mechanism of the Pictet−Spengler
a
Reaction of Cyclic α-Methoxyamines with Tryptamines
Scheme 2. Synthesis of Nazlinine and Unnatural Congeners
via Two-Step Method
a
Computed (at ωB97XD/PVTZ//ωB97XD/PVDZ level using SMD
solvation (water as a solvent) model during geometry optimization)
reaction Gibbs free energies are listed; energy of 13 is set as a
reference for every entry.21
(compare Gibbs free energies of TS 15 for n = 1−3 with the
Gibbs free energies required to reach the iminium intermediate
14).20
In conclusion, we have identified flow electrochemistry as a
suitable enabling technology to permit the quick generation of a
compound library through the rapid preparation of protected
cyclic α-methoxyamines. These were then applied in a
subsequent Pictet−Spengler reaction, thus leading to an
expedient two-step method to access the biologically active
natural product nazlinine and related unnatural congeners. The
reported scaffolds could lead to the preparation of further
unnatural relatives of the indole alkaloids tryptargine, indolo-
quinolizidine, komaroidine, isokomarvine, and schobercine
(Figure 1). We have shown that by using a continuous flow
electrochemical cell substoichiometric loadings of electrolyte (20
mol %) are sufficient to effect the desired reaction over a range of
substrates and that the system is robust for overnight running.
participated in the reaction without incident. With regard to the
ring size of the methoxyamine component, however, there was a
notable difference in reactivity between the 5, 6, and 7 membered
systems. Indeed, further probing of the second step showed that
the optimal conditions for 5 and 7 membered imine precursors
(11a and 11c, 2 equiv, microwave, 130 °C, 30 min) were not
sufficient for the 6 membered analogue (11b), leading to a poor
25% conversion under the same conditions. It was found that this
could only be improved by increasing the number of equivalents
of the imine precursor to 5 and of CSA to 12, resulting in a 90%
conversion (Scheme 2). This interesting phenomenon can be
explained by computational studies at the Density Functional
Theory (DFT) level (Scheme 3).15,16 The linear iminium 14 is
the key intermediate in the Pictect−Spengler cyclization reaction
affording product 1 via a 6-endo-cyclization step which is
characterized by the single transition state 15 (Scheme 3).17 It
was found that the formation of iminium 14 in the presence of
tryptamine 12a from a 6 membered α-methoxyamine 1318
compared to its 5 or 7 membered analogues costs more energy
(compare Gibbs free energies of 14 for n = 1−3; Scheme 3).
Consequently, this holds up the rate determining cyclization
process and instead results in increased decomposition of the
intermediate materials.19 Notably, and perhaps as one might
expect, the calculations show that once the intermediate linear
iminum is reached the system needs to overcome the same rate
limiting barrier of 12.2 kcal mol−1 to get to the product,
irrespective of the size of the initial imine precursor ring size
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization, and
computational data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: svl1000@cam.ac.uk.
Author Contributions
†M.A.K. and B.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Philip Podmore of Syrris for
helpful discussions, and the EPSRC (Award No. EP/K009494/
1) and Pfizer for financial support.
C
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