The development of a general strategy for the synthesis of tyramine-based natural products by using continuous flow techniques

Article abstract of DOI:10.1002/chem.201002102

A flowing future! A multistep, general flow chemistry protocol has been developed for the preparation of tyramine-based natural products. The process integrates room-temperature reactions with high-temperature Heck coupling reactions, where the heat has been supplied by microwave irradiation. As a proof of concept for 'scaling out' to attain larger quantities of the desired products, the four primary tyramine-based natural products were prepared on a gram scale using this synthetic protocol.

Full text of DOI:10.1002/chem.201002102

COMMUNICATION
DOI: 10.1002/chem.201002102
The Development of a General Strategy for the Synthesis of Tyramine-Based
Natural Products by Using Continuous Flow Techniques
Srinivas Achanta, Virginie Liautard, Robert Paugh, and Michael G. Organ*[a]
The movement of synthetic chemistry from a traditional
batch format (e.g., round-bottom flask or kettle reactor) to
a flowed platform offers many advantages.[1] In smaller reac-
tion channels, the chemical transformation itself can benefit
from improved mass and thermal transfer leading to en-
hanced kinetics and cleaner product mixtures with fewer by-
products. The latter benefits are significantly affected by the
introduction of both a space and time element to the reac-
tion process. For example, starting materials and/or catalysts
can be kept separate and only brought together at the point
of reaction and every resultant minute plug of reaction mix-
ture thus formed is continuously moved away from infusing
reactants eliminating many side reactions. Operationally, the
movement of synthesis to a flowed platform allows for real-
time reaction monitoring coupled with instantaneous
changes of reaction parameters that vastly truncates reaction
process optimization. Finally, once optimal conditions are
achieved, larger quantities of product can be obtained by
simply flowing using those parameters for the necessary
time (or in parallel reaction tubes) to accrue the desired
amount of product, a concept termed ’scale-out’.
We have been developing microwave-assisted, continu-
ous-flow organic synthesis (MACOS) and applying it in
single-step reactions including those promoted by thin-metal
films that line the reaction tube.[2] Most recently we have in-
vestigated by using the scale-out strategy with MACOS to
produce multigram quantities of benzo-fused sultams.[3]
Here we are furthering the development of this platform to
multi-step transformations for the production of tyramine-
based natural products entirely by flow[4] (see Scheme 1 for
target structures).[5–8] We are attracted to the members of
this family of natural products for their inherent biological
Scheme 1. Synthetic approach to the tyramine-based family of natural
products and analogues.
activity,[9–13] but additionally they can themselves serve as
templates for the diversity-oriented synthesis of analogues.
Indeed, family members contain alkylating sites, a Michael
acceptor for addition reactions, and in some cases halides
for substitution reactions (e.g., cross-coupling). As such, it
would be beneficial to demonstrate the capability to prepare
them potentially on at least a gram scale using a scale-out
synthetic approach. The retrosynthetic route that we devel-
oped to approach all of the members of this natural product
family by flow revolves around a Heck/alkylation sequence
(Scheme 1). Unsaturated amides 11 were prepared readily
by simple acylation of either tyramine itself (12, R4 =R5 =
H) or the appropriate derivative with acryloyl chloride.[14]
[a] Dr. S. Achanta, Dr. V. Liautard, R. Paugh, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J 1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200102102.
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12797

Heck reactions are generally
run at relatively high tempera-
tures (> 1008C) for several
hours. However, for the flow
sequence to be effective, the re-
action has to reach a high level
of completion during the time
in which it is receiving micro-
wave irradiation while it is tra-
versing the reaction capillary;
this is in the order of minutes.
To explore how the Heck reac-
tion could be made to perform
under flow conditions,[15] we
first examined a simplified set
Scheme 2. Heck reaction between fragments 10 and 11.[16]
of starting materials (Table 1). As a control, we performed
the reaction first under batch conditions in an oil bath
(Table 1, entry 1) and found that 18 h were required to ach-
result of the target products undergoing a second Heck reac-
tion.[17] With some investigation, it was found that the excess
tryamine from the acylation reaction (used crude in the next
step) was present as the HCl salt and was being deprotonat-
ed by the triethylamine that was originally used for the sub-
sequent Heck reaction. The resultant tyramine free base (in
excess) then underwent a Michael reaction with compound
11, the initially formed desired product, thus removing it
from the reaction mixture; the aryl iodide, now in excess
due to the depletion of 11, underwent a second undesired
Heck coupling. This problem was overcome by the use of
equimolar quantities of tryamine and acryloyl chloride and
only a slight excess of Hunigꢁs base in the Heck reaction,
which now led to good yields of analogues 1 and 3 (see
bottom of Scheme 2). The addition of tetrabutylammonium
bromide and Hunigꢁs base, which has a soluble conjugate
acid, were key to this yield improvement and instrumental
to producing larger quantities (vide infra).
Table 1. Optimization of the Heck reaction.
Entry
14
[equiv]
Conc. of
Time or
Temp.
Conversion
[%][d]
G
13[a] [m]
flow rate[b]
[8C][c]
1
2
3
4
5
6
7
1.5
1.8
1.8
1.8
1.5
1.8
1.8
0.6
0.6
0.6
0.6
0.6
0.9
1.5
18 h
20
20
15
20
90
100
76
85
94
92
65
complex
mixture
100
135
125
140
110
140
20
20
With the first two steps worked out, we extended the flow
process to include a subsequent alkylation step to approach
7 and aplysamine 6 (8) (Scheme 3).[18] Acylation proceeded
cleanly and the crude material was used directly, as usual, in
the Heck reaction. Coupling of mono bromide 11a proceed-
ed uneventfully and in excellent recovery. However, unex-
pectedly, the dibromide (11b) underwent reduction of one
of the bromides. To probe the origin of this undesired reac-
tion, we first repeated it with identical reactions conditions
only in batch, and the same result was attained. Thus, the
side reaction is not a consequence of flow. Clearly, the pro-
pensity for reduction diminishes when one of the bromides
is removed as we never observed reduction in the case of
11a. Perhaps the hydroxyl group in 17 makes the ring elec-
tron-rich enough to avoid oxidative addition of a single bro-
mide under these reaction conditions, but the presence of
the second bromide tips the balance and activates the ring.
The next question is the hydride source for this reduction.
We suspected the phenol and to test this we protected it as
a methyl ether; this halted reduction confirming the phenol
as the source of the problem.
[a] Concentration is based on 14. [b] The experiment in entry 1 is a batch
reaction performed in an oil bath for 18 h, all other entries are flowed re-
actions and the rate listed is in mLminÀ1. [c] The temperature listed in
entry 1 is of the oil bath. All other temperatures are the temperature re-
corded off the surface of the reaction capillary by the internal IR sensor
of the Biotage Initiator Synthesizer. [d] Percent conversion is determined
by taking an aliquot from the eluent stream from the capillary (crude ma-
terial) and calculating the ratio of the peaks of the starting materials and
product in the proton NMR spectrum.
ieve full conversion. Knowing that the flowing reaction only
resides for a few minutes in the microwave irradiation zone,
we irradiated it with enough power to create temperatures
well in excess of 1008C (Table 1, entries 2–7). With optimi-
zation of concentration, flow rate, and temperature, excel-
lent levels of conversion were attained using MACOS.
Using the conditions outlined in Table 1, entry 5, compounds
1, 2, 5, and 6 were prepared from their corresponding Heck
precursors (10 and 11, where compound 11 was used directly
from the acylation procedure) in 32, 22, 48, and 46% yield,
respectively (Scheme 2).[16]
From the above applied results, some shortcomings of the
Heck conditions were realized. Most importantly, yield
dropped off sharply, which was found to be primarily the
Carrying on with the preparation of the final tyramine an-
alogues, we set out to alkylate the phenol position. The reac-
tion was thought to work best with a soluble base that had a
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Chem. Eur. J. 2010, 16, 12797 – 12800

Natural Product Synthesis in Flow
COMMUNICATION
natural products and analogues that is based on a combina-
tion of room-temperature alkylation and deprotection pro-
cesses with microwave-heated Heck coupling. The protocol
has been demonstrated to be suitable for scale-out, meaning
that we can prepare, in principle, any quantity of these com-
pounds we require without the need for process reoptimiza-
tion. Applications of multistep, flow synthesis of natural
products of progressing complexity are underway in our lab-
oratory.
Acknowledgements
This work was supported by NSERC (Canada), the ORDCF (Ontario)
and the NIH Center for Chemical Methodologies and Library Develop-
ment at the University of Kansas (P50 GM069663).
Keywords: flow chemistry · Heck reaction · microwave
chemistry · tyramine
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Scheme 3. Full protocol to prepare brominated tyramine derivatives 7
and 8.[16]
soluble conjugate acid that could facilitate kinetic deproto-
nation of the phenol. With only minor optimization, potassi-
um trimethylsilanoxide was loaded into one syringe along
with 16 or 17, while the alkyl bromide was loaded into a
second syringe. Substitution proceeded cleanly providing the
corresponding alkylated products 19 and 20. It was deter-
mined that deprotection with TFA could not be carried out
in DMF. Thus, the solvent had to be swapped out to CH2Cl2
meaning that the two steps could not be flowed directly
from one to the next. Nevertheless, deprotection also pro-
ceeded nicely at room temperature providing desired prod-
ucts 7 and 8 with excellent recovery (Scheme 3).
As mentioned, we were developing a process to make the
compounds in this natural product series with an eye on the
potential to produce larger quantities of final product. To
this end, compounds 1 and 2 were prepared on a 1.02- and
1.64-gram scale using the corresponding two-step sequence
described in Scheme 2. Compounds 7 and 8 (aplysamine 6)
were prepared by using the four-step protocol detailed in
Scheme 3 in final quantities of 1.5 and 0.63 grams, respec-
tively.
[5] For the isolation and biological activity of aplysamine 6, see: M. S.
Buchanan, A. R. Carroll, G. A. Fechner, A. Boyle, M. Simpson, R.
Addepalli, V. M. Avery, J. N. A. Hooper, T. Cheung, H. Chen, R.
Quinn, J. Nat. Prod. 2008, 71, 1066–1067.
[6] For the isolation of ailanthamide, see: J.-J. Chen, C.-Y. Chung, T.-L.
Hwang, J.-F. Chen, J. Nat. Prod. 2009, 72, 107–111.
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Tsai, I. S. Chen, J. Chin. Chem. Soc. 2004, 51, 1065–1072.
[8] For the isolation of N-trans-feruloyl tyramine and N-trans-coumaro-
yl tyramine, see: a) T. Okuyama, S. Shibata, M. Hoson, T. Kawada,
H. Osada, T. Noguchi, Plant Methods 1986, 171–174; b) T. Yoshi-
hara, K. Yamaguchi, S. Takamatsu, S. Sakamura, Agri. Biol. Chem.
1981, 45, 2593–2598.
[9] For cytotoxicity studies involving tyramines, see; G. Zhao, Y. Hui,
K. Rupprecht, J. L. McLaughlin, J. Nat. Prod. 1992, 55, 347–356.
[10] For use of tyramines as antioxidants and cytoprotectives, see: H. To-
mosaka, Y.-W. Chin, A. A. Salim, W. J. Keller, H. Chai, D. A. King-
horn, Phytother. Res. 2008, 22, 979–981.
In summary, we have developed a general synthetic
method for the preparation of a number of tyramine-derived
[11] For the use of tyramines to cleave DNA, see: J. Ma, S. H. Jones,
S. M. Hecht, Bioorg. Med. Chem. 2004, 12, 3885–3889.
Chem. Eur. J. 2010, 16, 12797 – 12800
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. G. Organ et al.
[12] For the use of tyramines to inhibit acetylcholinesterase, see: D. K.
Kim, K. Lee, Arch. Pharmacal Res. 2003, 26, 735–738.
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Org. Chem. 2009, 5, No. 21.
[16] For complete experimental details and full spectral characterization
of all new compounds, see the Supporting Information.
[17] For the structure of the double-Heck product and full spectral char-
acterization, see the Supporting Information.
[18] During the course of our studies, the first synthesis of aplysamine 6
was reported, see: N. Ullah, K. M. Arafeh, Tetrahedron Lett. 2009,
50, 158–160.
[13] For the use of tyramines to inhibit nitric oxide synthase, see: Y.
Kim, M. S. Han, S. Lee, J. Kim, Y. C. Kim, Phytother. Res. 2003, 17,
983–985.
[14] Tyramine, or one of its analogues (1.0 equiv) was reacted with
acryloyl chloride (1.0 equiv) and Hunigꢁs base (1.1 equiv) in DMF.
The crude amide was used directly in the subsequent Heck reaction.
[15] For other examples of the Heck reaction performed by using flow
techniques, see: a) N. Nikbin, M. Ladlow, S. V. Ley, Org. Proc. Res.
Received: July 22, 2010
Published online: October 7, 2010
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