Synthesis and catalytic properties of diverse chiral polyamines

Article abstract of DOI:10.1016/j.tetlet.2008.07.108

Chiral polyamines can be utilized for a variety of potential applications, ranging from asymmetric catalysis to nonviral gene delivery systems for DNA and RNA. They can also be utilized to solubilize carbon nanotubes. Thus, methods for the straightforward synthesis of chiral polyamines are needed. We present herein two synthetic strategies for accessing chiral polyamines. The potential of these chiral amines to catalyze two organic reactions with a high degree of chiral induction was also explored.

Full text of DOI:10.1016/j.tetlet.2008.07.108

Tetrahedron Letters 49 (2008) 5746–5750
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and catalytic properties of diverse chiral polyamines
*
Mindy Levine, Craig S. Kenesky, Shengping Zheng, Jordan Quinn, Ronald Breslow
Columbia University, Department of Chemistry, 3000 Broadway, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral polyamines can be utilized for a variety of potential applications, ranging from asymmetric cata-
lysis to nonviral gene delivery systems for DNA and RNA. They can also be utilized to solubilize carbon
nanotubes. Thus, methods for the straightforward synthesis of chiral polyamines are needed. We present
herein two synthetic strategies for accessing chiral polyamines. The potential of these chiral amines to
catalyze two organic reactions with a high degree of chiral induction was also explored.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 12 June 2008
Revised 17 July 2008
Accepted 18 July 2008
Available online 24 July 2008
1. Introduction
We synthesized two chiral amines from the coupling of cyclen
with Boc-protected amino acids, followed by deprotection, and
Chiral polyamines have been utilized for a variety of applica-
tions. First, polyamines are polycationic at neutral pH; as such,
they interact strongly with both DNA and RNA.1 They can therefore
be utilized as effective nonviral gene delivery agents.2 Second, chi-
ral polyamines are efficient catalysts for various organic transfor-
mations.3 Polyamines have also been used to solubilize carbon
nanotubes.4 Finally, chiral polyamines are excellent ligands for
many transition metals.5 Due to their numerous applications,
high-yielding synthetic strategies for their preparation are in great
demand. We present herein two synthetic strategies for accessing
chiral polyamines, and the potential of these chiral amines to
catalyze two organic reactions.
reduction with dimethylsulfide-borane (Fig. 2). These compounds
could potentially serve as chiral ligands for lanthanide metals.
The synthesis of compound 6a proceeded to yield a potential 8-
coordinate ligand. In our synthesis of compound 6b, only three of
the four acylations took place to yield a potential 7-coordinate
chiral ligand.
Additionally, we synthesized C2-symmetric chiral amines via
borane-mediated amide reduction. We synthesized compound 7a
from the coupling of 1,2-diaminobenzene with Boc-protected
phenylalanine, followed by deprotection, and reduction with
dimethylsulfide-borane (Fig. 3). We synthesized compound 7b
via an analogous sequence.
Finally, we synthesized two other chiral amine catalysts (Fig. 4).
We synthesized L-a
-methylvaline 8 using methodology9 developed
2. Synthetic strategy I—synthesis of chiral amines from the
reduction of chiral amides
by Seebach.10 We synthesized chiral pyridine 9 from commercially
available precursors in good yield.11
Chiral polyamines can be obtained via the reduction of polypep-
tides and proteins, which present a myriad of chiral centers with
diverse substituents. Previous work in our group demonstrated
that small peptides with up to three residues could be reduced
to the corresponding chiral amines using borane complexed to
THF.6 Other researchers have also demonstrated that the synthesis
of polyamines via the reduction of polypeptides is possible;7 how-
ever, many of these methods require harsh conditions to break up
the amine-borane complex.8
3. Synthetic strategy II—Synthesis of chiral polyamines via
polymerization
Previously, Saegusa synthesized polymer 12 from the cationic
polymerization of oxazoline 10, followed by hydrolysis of the for-
myl groups (Eq. 1).12 These polymers were effective catalysts in
the asymmetric transamination of ketoacids to amino acids, yield-
ing L
-valine in up to 66% ee.13 In an effort to fully explore the chem-
We synthesized five oligopeptides with up to eight amino acid
residues via standard solution-phase peptide coupling. We reduced
these oligopeptides to the corresponding polyamines in excellent
yield by refluxing them with excess dimethylsulfide-borane in
THF (>20 equiv of borane per carbonyl) (Fig. 1).
istry of these polymers, we synthesized a variety of polymeric
analogues.
Synthesis of S-benzyl chiral polyamines:
We synthesized polymer 15 via the cationic polymerization of
THF, which was terminated with a sub-stoichiometric amount of
benzyloxazoline 10. Further cationic polymerization of benzyl-
oxazoline followed by hydrolysis yielded the poly-THF polyamine
block co-polymer 15 (Eq. 2).14
* Corresponding author. Tel.: +1 212 854 2170; fax: +1 212 854 2755.
E-mail address: rb33@columbia.edu (R. Breslow).
Synthesis of poly-THF polyamine block co-polymers:
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.108

M. Levine et al. / Tetrahedron Letters 49 (2008) 5746–5750
5747
Ph
Ph
Ph
R
N
R
N
H
OH
N
H
N
N
R
N
R
OH
Me
Ph
1: R=H, 99% yield
2: R=Me, 93% yield
3, 91% yield
Ph
Ph
Ph
Ph
Me
N
Me
Me
N
Me
N
Me
N
N
H
N
N
N
OH
Me
Me
Me
4, 63% yield
Ph
Ph
Ph
Ph
H
N
H
N
N
H
H
N
H
N
Me
N
H
N
N
H
OH
H
5, 95% yield
Figure 1. Chiral amines derived from reduced oligopeptides (% yield of the reduction).
NH2
Me
HN
Ph
N
N
Me
Me
NH
H2N
NH2
N
N
HN
N
N
N
H
N
Ph
Ph
6b
NH2
6a
Figure 2. Cyclen-derived chiral amines.
O
H2N
OH
N
N
N
N
H
H
H
H
Me
N
H2N
NH2
H2N
NH2
7a
7b
Ph
Ph
Ph
Ph
8
9
Figure 3. C2-symmetric chiral amines.
Figure 4. Other chiral amines.
Ph
Ph
Ph
OBu
1. MeOTs
N
*
KOH/BuOH
N
n
OBu
*
ð1Þ
N
n
2. BuOH
O
H
O
H
10
11
12

5748
M. Levine et al. / Tetrahedron Letters 49 (2008) 5746–5750
Ph
Ph
Ph
N
MeOH/NaOH
MeOTf
O
O
*
m
*
m
+
n
N
n
N
*
ð2Þ
*
O
H
O
O
H
13
10
14
15
We synthesized polymer 18 via the cationic mixed polymeriza-
tion of oxazolines 10 and 16, followed by hydrolysis of the formyl
groups to yield the mixed co-polymer (Eq. 3).
uvic acid to phenylalanine. Many other groups have studied the
synthesis of chiral amino acids from ketoacids via transaminase
mimics.15 Our research group has also had some success in achiev-
ing the asymmetric synthesis of amino acids from ketoacids using
Synthesis of mixed co-polymer:
Ph
Ph
H
O
Ph
N
MeOTf
N
H
MeOH/NaOH
N
N
+
*
*
ð3Þ
N
n
m
N
n
m
*
O
*
O
H
O
H
10
16
17
18
We synthesized polymers 20 via the cationic polymerization of
compound 10, which was terminated with commercially available
polyethyleneglycol (PEG) methyl ether (Eq. 4). Subsequent hydro-
lysis then yielded the chiral block co-polymers 20. We synthesized
two co-polymers via this method: polymer 20a contained 30
amine monomer units, terminated with PEG methyl ether with
approximate Mn = 2000. Polymer 20b contained 50 amine mono-
mer units, terminated with PEG methyl ether with Mn = 2000.
Synthesis of PEG-polyamine block copolymers:
chiral transaminase mimics.6,16 We used the newly synthesized
chiral amines in the transamination reaction of phenylpyruvic acid
to phenylalanine (Scheme 2). We found that in the presence of cop-
per(II) sulfate, moderate enantioselectivities were obtained in the
product phenylalanine. In the absence of copper(II) sulfate, only
very low enantioselectivies were observed.
In all of the transamination reactions, the chiral amines were
dissolved in methanol at the highest concentrations at which the
amines were soluble. The resulting stock solution was utilized in
Ph
Ph
Ph
N
MeOTf
MeOH/NaOH
O
O
*
*
m
*
*
m
ð4Þ
O
N
n
O
N
n
PEG-OMe terminator
H
O
O
H
20
10
19
Finally, we synthesized polymer 25 via the cationic polymeriza-
tion of oxazoline 23, followed by reduction of the amides using
dimethylsulfide-borane (Scheme 1).
the transamination reaction. The smaller amines 1–5 were soluble
in methanol at higher concentrations than the polyamines 15–25.
Polyamine 20b, with approximately 50 amine monomer units
and a long PEG chain, gave the highest ee in the phenylalanine
product (52.5 0.3% L ee). This chiral induction was substantially
higher than the induction achieved with the smaller chiral amines
(1–5), and occurred despite the lower concentration of the chiral
amine in the reaction mixture. Interestingly, the second-best
results were obtained with chiral amine 1 (24.9 5.8% L ee), which
4. Catalytic properties of chiral amines—reaction I: the
transamination of phenylpyruvic acid to phenylalanine
We explored the ability of the chiral amines to catalyze organic
reactions. First, we investigated the transamination of phenylpyr-
Ph
AcOH
Ph
MeOTs
N
OEt
OEt
OEt
Et
+
OH
Ph
Cl
H2N
69% yield
Cl
Et
O
94% yield
21
22
23
Ph
Me2S-BH3
N
100
N
100
THF
72% yield
Et
O
Et
24
25
Scheme 1. Synthesis of chiral polyamine 25.

M. Levine et al. / Tetrahedron Letters 49 (2008) 5746–5750
5749
The most effective catalyst is compound 3, which gave the desired
product in 83–94% yield and up to 45.9% ee. This compound was
more effective than monoamines like L-a-methylvaline 8 (92%
NH2
O
OH
C12H25
HO
S
yield, 2.9 0.5% ee in the presence of Zn(OAc)2), as well as large
polyamine 25 (59% yield, 4.6 1.7% ee in the presence of NiSO4)
and the polyamine-PEG block copolymers 20 (polymer 20a: 96%
yield, 3.1 0.4% ee in the presence of Zn(OAc)2). Compound 3 is
readily accessible from the reduction of the corresponding dipep-
tide. Furthermore, other dipeptide analogues are accessible via
peptide coupling of two amino acids, followed by reduction of
the carbonyls and N-methylation. Future work can be directed
toward the synthesis of other reduced dipeptides and their use
as chiral catalysts.
+
O
N
26
27
chiral amine
CuSO4
Ph
Ph
O
OH
OH
+
In summary, the synthesis of a diverse suite of chiral amines has
H2N
H2N
been described. These chiral amines range in size from an
a-
O
methyl amino acid to polymers with 100 chiral amine residues.
The use of these chiral amines in catalyzing two different organic
reactions has been explored, and the products were synthesized
in moderate to good enantioselectivities. Further applications of
these chiral amines are under investigation, including enamine
catalysis, and will be reported in due course.
28
major
minor
Scheme 2. Transamination of phenylpyruvic acid to phenylalanine.
is structurally similar to polyamine 20b (chiral benzyl groups, all
secondary nitrogens).
Supplementary data
5. Reaction II: the Michael addition
Synthesis and spectroscopic characterization of all new com-
pounds, HPLC parameters, reaction conditions, and full results for
the transamination reaction and the Michael reaction are available.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.108.
We explored the use of the chiral amines in the Michael addi-
tion of dimethylmalonate 30 to azachalcone 29 (Eq. 5). These
efforts complement the work of various other research groups in
the use of chiral organocatalysts in the Michael reaction.17 How-
ever, most of the effective organocatalysts are small molecules,
not organic polymers. The use of a chiral organic polymer could
create a macromolecular chiral and hydrophobic environment for
asymmetric organic reactions.
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