A practical synthesis of N-alkyl- and N,N′-dialkyl-polyamines This work is dedicated to the memory of our dear colleague and friend Mr. Charles Edward Price

Article abstract of DOI:10.1016/j.tetlet.2016.05.034

A variety of polyamines have been synthesized from their corresponding amino alcohols through a 3-step process. The synthesis predicates that the most likely impurities are of higher molecular weight and that distillation is effective at producing highly pure materials. This sequence is scalable, requires no protecting groups or chromatography, and provides the requisite polyamines in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2016.05.034

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical synthesis of N-alkyl- and N,N0-dialkyl-polyamines
Travis J. Haussener a, Paul R. Sebahar a,b, Hariprasada R. Kanna Reddy a, Dustin L. Williams c,
Ryan E. Looper a,
⇑
a Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA
b University of Utah Synthetic and Medicinal Chemistry Core Facility, 315 South 1400 East, Salt Lake City, UT 84112, USA
c Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of polyamines have been synthesized from their corresponding amino alcohols through a 3-step
process. The synthesis predicates that the most likely impurities are of higher molecular weight and that
distillation is effective at producing highly pure materials. This sequence is scalable, requires no protect-
ing groups or chromatography, and provides the requisite polyamines in moderate to good yields.
Ó 2016 Published by Elsevier Ltd.
Received 28 April 2016
Accepted 10 May 2016
Available online xxxx
This work is dedicated to the memory of our
dear colleague and friend Mr. Charles
Edward Price
Keywords:
Polyamine
Spermine
Spermidine
Norspermidine
Polyamines constitute a wide array of biologically active com-
pounds1 and are an essential component to the life cycle of both
prokaryotic and eukaryotic cells.2 Over the years numerous
academic3 and industrial4 groups have focused on the synthesis
and usage of natural and unnatural polyamines. These small mole-
cules have garnered a significant amount of interest recently due to
their potential for multiple applications in chemotherapeutics,5
antimalarials,6 antimicrobials,7 anti-HIV retrovirals,8 and as
pesticides.9
In addition, the natural polyamines putrescine, spermidine, and
spermine (Fig. 1) serve as endogenous regulators of cell division.1
Selective inhibitors of polyamine metabolism have led to a devel-
opment of a number of analogs with therapeutic use as antitumor
agents.5a,10,11 For example, N1,N11-diethylnorspermine was
advanced to phase II clinical trials for metastatic breast cancer.12
Modified norspermine derivatives, e.g., PG-11047 are also being
evaluated in the clinic for their use in relapsed and refractory
cancers.13
natural polyamino metabolite toxin that comes from the North
American funnel web spider Agelenopsis aperta has been shown
to be an antagonist of the N-methyl-
-aspartate receptor.15
D
While relatively structurally simple, the synthetic manipulation
of polyamines remains challenging. The presence of multiple
primary and secondary amines present regiochemical control chal-
lenges for most synthetic approaches. Additionally, the highly
polar nature of these compounds makes purification and analysis
difficult, especially when compounds with similar physiochemical
profiles (e.g., regioisomers, polyalkylations) represent the predom-
inant impurities. Not surprisingly most of the synthetically viable
methods for constructing these compounds either involve complex
protection and deprotection sequences3,6,9,16,17 or derivatization of
the natural compounds themselves.3,6,16 As a result, lengthy syn-
theses are often required to discriminate regiochemically pure
products which result in poor overall yields.
Given the fact that most mono and di-substituted polyamines
are not commercially available we sought an efficient and scalable
process to prepare N,N0di-substituted polyamines. Subsequent
incorporation of these individual polyamines into more complex
materials requires they be of high purity to mitigate the formation
of undesired products given the difficulties in purification of phys-
iochemically similar compounds.
Simple polyamines are also incorporated into more complex
natural products and pharmaceuticals (Fig. 1). Squalamine and
Trodusquemine, are amino-sterols isolated from the dogfish shark
that are being pursued for multiple indications including wet
age-related macular degeneration and breast cancer.14 AG-416, a
We envisioned a straightforward process relying on amino-
alcohols as useful starting materials, whereby the amine and
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2016.05.034
0040-4039/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Haussener, T. J.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.05.034

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T. J. Haussener et al. / Tetrahedron Letters xxx (2016) xxx–xxx
(92%)
(35%)
(78%)
(50%)
(42%)
(36%)
(45%)
(41%)
Figure 1. Important natural and non-natural polyamines.
alcohol could serve as an orthogonal nucleophile/electrophile pair
(Scheme 1).
This strategy ensures that isolated intermediates can be purified
by crystallization (steps 1–2) and upon distillation of the final com-
pound (step 3), impurities are of significantly higher molecular
weight such that the product is obtained in high purity. Herein
we detail this process that permits the preparation of a variety of
N,N0-dialkylpolyamines with high regiochemical integrity, that
minimizes side reactions and has been demonstrated on a large
scale (>100 g).
(33%)
(12%)
Our approach began with reductive amination of readily avail-
able 3-amino-1-propanol (Fig. 2). Addition of one equivalent of
an aldehyde and subsequent reduction with sodium borohydride
cleanly afforded the desired amine. We found this reaction to be
robust requiring no solvent or drying agent and worked for a vari-
ety of aldehydes. The initial addition of the aldehyde to the amine
is highly exothermic and necessitates careful addition at a lower
temperature depending on the scale (>25 g requires slow addition
and cooling).18 Conversion of the alcohol to a suitable leaving
group was achieved through bromination, which was accom-
plished by the treatment of the alkyl amino alcohol with aq HBr
at reflux.19 Excess HBr was distilled off to afford the crude HBr salts
1a–j which were recrystallized from MeOH/ether to provide
Figure 2. Alkylated hydrobromide salts via reductive amination of amino-alkyl-
alcohol.
research grade material with adequate purity (>90%) judged by
1H NMR (Fig. 2).
This sequence when conducted with 3-amino-1-propanol and
isobutyraldehyde gave 3-bromo-N-isobutylpropylamine (1a) in
92% isolated yield.20 These reaction and recrystallization condi-
tions were optimized to this substrate. However the sequence is
amenable to a variety of alkyl, branched-alkyl, and benzylic side
chains to provide the N-alkylated-bromopropranes (e.g., 1b–j) in
good to moderate yields.
Displacement of the bromide with a diamine was then opti-
mized. We anticipated that any reaction with an equimolar ratio
of diamine to the HBr salt would provide a complex mixture of
products. This was indeed observed by thin layer chromatography
in several of our initial studies. However, these undesired alkyla-
tions would be of significantly higher molecular weight. Thus to
minimize these undesired alkylation reactions, an excess (10–
20 equiv) of diamine was used and the temperature of the reaction
was carefully controlled.
These conditions ensured that three general species are in solu-
tion (1) the excess diamine; (2) the N-alkyl-triamine, and (3)
higher molecular weight oligomers. Fractional distillation is effi-
cient at separating these three fractions and enables recovery of
a significant amount of unreacted diamine. Reaction of 3-bromo-
N-isobutylpropylamine with 10 equiv of diamino propane gave
N-isobutylnorspermidine. Fractional distillation of the reaction
mixture gave 20–30% recovery of diaminopropane and a 71%
Scheme 1. Formation of the requisite polyamine through a reductive amination,
activation, and substitution sequence.
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T. J. Haussener et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
isolated yield of the product 2a when conducted on a >100 g
scale.21 This lot of 2a appeared to be a single compound by 1H
NMR and was judged to be >91% pure by LCMS, with all individual
impurities <2%.
As shown in Figure 3 this method is general for the synthesis of
alkyl spermidine and norspermidine derivatives 2b–n (Fig. 3). A
wider scope of substrate could be envisioned, the only constraint
being the ability of the final products to be purified by fractional
vacuum distillation. We qualitatively note that compounds in this
series with a total carbon number <16 are usually amenable to dis-
tillation under common laboratory conditions. Another important
aspect of this sequence is that, prior to distillation a basic aqueous
workup is required. This can diminish yields as in some cases the
smaller amphipathic polyamines can be distributed in the aqueous
layer.
(52%)
(60%)
(55%)
To further expand the scope of the synthesis, a series of disub-
stituted norspermidine analogs were generated (3a–d). Reductive
amination with the monoalkyated polyamines and various aldehy-
des provides several unsymmetrical di-substituted derivatives
(Fig. 4). N1,N11-Diethylnorspermine was selected as a rough tem-
plate for development of these di-substituted compounds. This
reductive amination is highly selective for the primary amine
(45%)
(45%)
Figure 4. Representative polyamines derivatives synthesized from the
3
step
method.
and is readily carried out without protecting groups. Once more
the effectiveness of this method was demonstrated using both
alkyl and aromatic aldehydes.
In summary, we have developed a new, efficient, and scalable
synthesis of a number of N-substituted polyamines. The synthesis
is amenable to the formation of a number of both N-substituted
and N,N0-disubstituted alkyl polyamines. This work has further
demonstrated a process that is straightforward and avoids a num-
ber of pitfalls outlined in previous Letters.
Acknowledgments
R.E.L. would like to thank the NIH, General Medical Sciences
(R01 GM090082), Amgen and Eli Lilly for financial support. P.R.S.
acknowledges Utah Science Technology and Research Initiative
(USTAR) for financial support. We thank Drs. David Hennings and
Phil Anderson (Array Biopharma) for analytical development.
Supplementary data
Supplementary data (characterization (1H, 13C NMR, HRMS) for
all compounds and experimental details for the preparation of
compound 3a–e) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2016.05.034.
References and notes
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Figure 3. Representative polyamines derivatives synthesized from the
method.
3 step
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T. J. Haussener et al. / Tetrahedron Letters xxx (2016) xxx–xxx
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18. General Procedure A for the preparation of the aminoalcohols: 3-Amino-1-
propanol (35.4 g, 0.58 mol, 1 equiv) was placed in a round bottomed flask and
cooled to 0 °C. Isobutyraldehyde (41.8 g, 0.58 mol, 1 equiv) was added over the
span of 20 min. The reaction was left to warm and stirred for 8 h. Sodium
borohydride (11.0 g, 0.29 mol, 0.5 equiv) in water (100 mL) was added slowly
to the reaction mixture. After bubbling had ceased the solution was extracted
with EtOAc (2 ꢀ 200 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to afford the amino-alcohol as a yellow oil (65.8 g, 97%) that
is used without further purification.
19. Prabhakaran, E. N. U.S. Patent 2010/0228004 A1, 2010.
20. General procedure B for the preparation of the bromoamine hydrobromides (1): 3-
(Isobutylamino)propan-1-ol (46.0 g, 0.39 mol, 1 equiv) was placed in a round
bottomed flask and cooled to 0 °C. HBr (294 mL in H2O) was carefully added.
The reaction mixture was heated to reflux for 16 h. The remaining HBr in H2O
was distilled off at 110 °C to provide the crude material as a brown solid which
was recrystallized from MeOH/Et2O to afford the HBr salt 1b as a white
crystalline solid (47.9 g, 92% from 3-Amino-1-propanol).
21. Representative procedure C for the preparation of the triamines (2): A round
bottomed flask was charged with 1,3 diaminopropane (500 mL, 5.40 mol,
10 equiv), cooled to 0 °C (ice/water) and to this solution was added 3-bromo-
N-isobutylpropan-1-amine hydrobromide salt (142.0 g, 0.540 mol, 1 equiv)
portion wise over the span of 1.5 h. The reaction mixture was warmed to rt and
stirred for 12 h. Excess 1,3 diaminopropane was removed under reduced
pressure, and the remaining semi-solid was taken up in 5% NaOH (400 mL) and
extracted with 85:15 CHCl3/i-PrOH (5 ꢀ 500 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification was accomplished by
fractional distillation (bp = 71–73 °C at 0.04 mm Hg) to afford pure N1-(3-
aminopropyl)-N3-isobutylpropane-1,3-diamine (2a) as a clear oil (71.7 g, 71%).
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Please cite this article in press as: Haussener, T. J.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.05.034