Synthesis of novel chiral macrocyclic polyamides derived from L-/D-tartaric acid

Article abstract of DOI:10.1080/00397910500214235

A convenient and efficient synthesis of chiral macrocyclic polyamides derived from L-/D-tartaric acid is reported. These chiral compounds could not only be used for chiral recognition, but also provide a feasible way to synthesize chiral macrocycles. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500214235

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Synthesis of Novel Chiral
Macrocyclic Polyamides
Derived from L‐/D‐Tartaric Acid
a
a
a
a
Baohua Li , Xuemei Yang , Kai Yang & Enqin Fu
a
Department of Chemistry, Wuhan University,
Wuhan, China
Published online: 18 Aug 2006.
To cite this article: Baohua Li , Xuemei Yang , Kai Yang & Enqin Fu (2005): Synthesis
of Novel Chiral Macrocyclic Polyamides Derived from L‐/D‐Tartaric Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:19, 2603-2608
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Synthetic Communications , 35: 2603–2608, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500214235
Synthesis of Novel Chiral
Macrocyclic Polyamides Derived
from L-/D-Tartaric Acid
Baohua Li, Xuemei Yang, Kai Yang, and Enqin Fu
Department of Chemistry, Wuhan University, Wuhan, China
Abstract: A convenient and efficient synthesis of chiral macrocyclic polyamides
derived from L-/D-tartaric acid is reported. These chiral compounds could not only
be used for chiral recognition, but also provide a feasible way to synthesize chiral
macrocycles.
2
Keywords: C -symmetry, chiral macrocyclic polyamides, synthesis, tartaric acid
Chiral recognition is a common phenomenon in nature, such as the interaction
between antibody and antigen, the catalytic synthesis in biological processes.
The study on chiral recognition has been one of the most interesting topics in
the field of supramolecular chemistry. Various kinds of artificial chiral host
[
1–3]
molecules have been synthesized for this reason.
macrocyclic polyamides that bear the dual features of macrocyclic polyamines
Among them, chiral
[4]
and glycopeptides can act as both hydrogen bond acceptors and donors. This
kind of chiral macrocycles has potential applications for enantiomeric
recognition, especially with neutral molecules and anions, such as drugs and
biomolecules. However, because of the difficulty of the preparation, only a
few reports about the synthesis and application of chiral macrocyclic
[
5]
polyamides have appeared.
Received in Japan April 10, 2005
Address correspondence to Enqin Fu, Department of Chemistry, Wuhan University,
Wuhan, China. E-mail: Fueq@chem.whu.edu.cn.
2
603

2604
B. Li et al.
In our previous articles, we reported the synthesis of several chiral
macrocyclic polyamides derived from L-amino acids and the results of these
1
chiral macrocycles as chiral solvating agents for H NMR spectroscopy.
[6]
The results revealed that this kind of compound exhibited good enantiomeric
discriminating ability for chiral carboxylic acids. It was found that the rigidity
and steric hindrance at the chiral macrocycle is helpful for the chiral recog-
nition and that the chiral macrocycle with C symmetry has better enantio-
2
meric discrimination than that with C symmetry. For the sake of obtaining
1
more chiral host molecules with enhanced ability for chiral recognition, we
have made use of L-/D-tartaric acid to synthesize another series of chiral
macrocyclic polyamides. The use of L-/D-tartaric acid as building blocks
allows for the convenient introduction of two chiral units into the macrocyclic
polyamides, which is expected to gain C symmetry. The synthetic route for
2
compounds 1–4 is shown in Scheme 1.
The synthetic route of compounds 1–3 involved two steps. L-/D-tartaric
acid was first converted into dimethyl 2,3-O-isopropylidene L-/D-tartarate by
reaction with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid
and then treated with the appropriate polyamines to afford the desired chiral
macrocyclic polyamides 1–3. An important intermediate with a pentacycle
was formed in the first step, which effectively facilitated the cyclization in
the second step. Forming the pentacycle also enhanced the rigidity and
steric hindrance of the macrocycles 1–3. The imines of the chiral macrocycle
3
were then modified using benzyl chloride to afford its derivative 4.
The introduction of the benzyl groups might provide compound 4 the p–p
interaction with guest molecules that could be helpful in chiral recognition.
Compared to the many reported methods for preparing chiral macrocyclic
polyamides, our synthetic approach has some advantages such as mild
conditions (rt), fewer reaction steps (two steps), and no need of N-protection
or highly dilute conditions.
Scheme 1.

Chiral Macrocyclic Polyamides
EXPERIMENTAL
2605
IR spectra were obtained on a Nicolet 170SX FT-IR spectrophotometer.
Proton magnetic resonance spectra were recorded in CDCl on a Varian
3
Mercury VX300 FT-NMR spectrometer (Varian, USA) with TMS as
internal reference operating at 298 K. All melting points are uncorrected.
Mass spectra (FAB) were recorded on a ZAB-3F-HF spectrometer. Optical
rotations were measured with a Perkin-Elmer model 341LC polarimeter
using the sodium D line at 589 nm. All elemental analyses were determined
on a Perkin–Elmer 204B elemental autoanalysis apparatus.
L-/D-tartaric acid was purchased and directly used. Polyamines and 2,2-
dimethoxypropane were commercially available and distilled before use.
Reactions were carried out under an atmosphere of dry nitrogen, and the
analytical solvents (methanol, cyclohexane) were dried prior to use. Dimethyl
[7]
2
,3-O-isopropylidene L-/D-tartrate was prepared according to the literature.
Dimethyl 2,3-O-isopropylidene L-/D-tartrate: A mixture of L-/D-tartaric
acid (30 g, 0.2 mol) and p-toluenesulfonic acid (0.2 g, 1.05 mmol) was added
to 2,2-dimethoxypropane (85 mL, 0.684 mol) with methanol (12 mL) and
heated to reflux under nitrogen until a dark red homogeneous solution was
obtained. Cyclohexane (130 mL) was added and the flask was fitted with a
3
0-cm Vigreux column and a reflux distilling head. The mixture was heated
to reflux with magnetic stirring and the azeotropes were slowly removed
until the temperature at the solvent head was approximately 77.58C. After
the mixture had cooled to room temperature, anhydrous potassium
carbonate (approximately 3 g, 0.21 mol) was added, and the mixture was
stirred until the reddish color had abated. The solvent was removed, and the
residue was distilled under vacuum to afford the product as a pale yellow oil.
Dimethyl 2,3-O-isopropylidene-L-tartrate:
1
A pale yellow oil, bp
2
0
20–1228C (8 mm Hg); 37 g (85% yield). [a] ¼ 2 49.18 (c ¼ 1.0,
D
1
MeOH). H NMR (300 MHz, CDCl ): d ¼ 4.73 (s, 2H, 2OCHCO), 3.74
3
(
s, 6H, 2OCH ), 1.41 (s, 6H, 2CH ).
3 3
Dimethyl 2,3-O-isopropylidene-D-tartrate:
1
A pale yellow oil, bp
0
2
20–1228C (8 mm Hg); 35 g (80% yield). [a] ¼ þ 48.88 (c ¼ 1.0,
D
1
MeOH). H NMR (300 MHz, CDCl ): d ¼ 4.80 (s, 2H, 2OCHCO), 3.82
3
(
s, 6H, 2OCH ), 1.49 (s, 6H, 2CH ).
3 3
General Procedure for the Preparation of Chiral
Macrocyclic Polyamides
Dimethyl 2,3-O-isopropylidene L-/D-tartrate (4.32 g, 0.02 mol) was dissolved
in absolute methanol (100 mL) and then added to a solution of polyamines

2606
B. Li et al.
(0.02 mol) in 100 mL of absolute methanol and stirred at 358C under nitrogen
for 8 days; then, the solvent was evaporated to dryness. The residue was
purified using chromatography with a alkaline alumina column (100–200
mesh or 200–300 mesh) as absorbent and with methanol–chloroform
(0–0.5 : 100–99.5) as eluant to give the crude product, and then the product
was crystallized by the suitable solvent (acetonitrile or chloroform/n-butyl
ether) to afford a white solid.
(1R,14R)-16,16-Dimethyl-15,17-dioxo-3,6,9,12-tetraazadicyclo[12.3.0]-
heptadecane-2,13-dione (1): The residue was chromatographed on alkaline
alumina column (100–200 mesh, CHCl as eluant). The crude product was
3
crystallized from acetonitrile to afford a white powder, yield 10%. Mp
2
0
1
2
41–2438C, [a]D ¼ þ112.18 (c ¼ 1.0, MeOH). H NMR (300 MHz,
CDCl ): d ¼ 6.76 (s, 2H, 2CONH), 4.42 (s, 2H, 2OCH), 3.67–3.62 (m, 2H,
3
2
CONHCHH), 3.28–3.22 (m, 2H, CONHCHH), 2.83–2.81 (m, 2H,
CONHCH CHHNHCH ), 2.73–2.65 (m, 6H, 2CONHCH CHHNHCH
2,
2
2
2
2
1
3
NHCH CH NH), 1.64 (s, 2H, 2 NH), 1.53 (s, 6H, 2CH ). C NMR
2
2
3
(
75 MHz, CDCl ): d ¼ 168.396, 112.916, 79.073, 48.611, 48.186, 39.404,
3
2
1
6.846. IR (KBr, cm ): 3318, 2938, 2880, 1651.6, 1547, 1456, 1385,
2
1
5
þ
216, 1129. MS(FAB): 301 [M þ 1] . Anal. calcd. for C H N O : C,
1
3 24 4 4
1.98; N, 18.65; H, 8.05. Found: C, 51.93; N, 18.96; H, 7.75.
(1R,17R)-19,19-dimethyl-18,20-dioxo-3,6,9,12,15-pentazadicyclo[15.3.0]-
petrosilane-2,16-dione (2): The residue was chromatographed on alkaline
alumina column (100–200 mesh, CHCl as eluant).The crude product was
3
crystallized from acetonitrile to afford a white powder, yield 12%. Mp
0
2
1
1
75–1768C, [a]D ¼ þ61.18 (c ¼ 1.0, MeOH). H NMR (300 MHz,
CDCl ): d ¼ 7.50 (s, 2H, 2CONH), 4.52 (s, 2H, 2OCH), 3.83–3.77 (m, 2H,
3
2
CONHCHH), 3.12–3.08 (m, 2H, 2CONHCHH), 2.87–2.68 (m, 12H,
1
CH NHCH ), 1.49 (s, 9H, 2CH , 3CH NHCH ); C NMR (75 MHz,
3
3
2
2
3
2
2
CDCl ): d ¼ 170.526, 112.345, 77.481, 50.143, 49.672, 48.640, 38.404,
3
21
2
1
5.994. IR (KBr, cm ): 3096, 3013, 2925, 1683, 1601, 1503, 1446, 1373,
248, 1226, 1188, 1026. MS(FAB): 344 [M þ 1] . Anal. calcd. for
þ
C H N O : C, 52.46; N, 20.39; H, 8.51. Found: C, 52.63; N, 19.96; H, 8.26.
15 29 5 4
(
1S,14S)-16,16-dimethyl-15,17-dioxo-3,6,9,12-tetraazadicyclo[12.3.0]-
heptadecane-2,13-dione (3): The residue was chromatographed on alkaline
alumina column (200–300 mesh, CH OH/CHCl ¼ 0.5/99.5 as eluant).
3
3
The crude product was crystallized from choroform/n-butyl ether to afford
20
a white powder, yield 19%. Mp 2428C, [a] ¼ 2113.58(c ¼ 1.0, MeOH).
D
1
H NMR (300 MHz, CDCl ): d ¼ 6.89 (s, 2H, 2CONH), 4.43 (s, 2H, 2OCH),
3
3
.70–3.65 (m, 2H, 2CONHCHH), 3.24–3.19 (m, 2H, 2CONHCHH), 2.87–
.81 (m, 2H, CONHCH CHHNHCH ), 2.69–2.65 (m, 6H, CONHCH
2
CHHNHCH , NHCH CH NH), 2.01 (m, 2H, 2 NH), 1.53 (s, 6H, 2CH ).
2
2
2-
1
3
C
2
2
2
3
NMR (75 MHz, CDCl ): d ¼ 168.501, 112.927, 79.020, 48.515, 48.073,
3

Chiral Macrocyclic Polyamides
2607
2
9.280, 26.708. IR (KBr, cm ): 3354, 2935, 2885, 1632, 1572, 1441, 1379,
1
3
1
5
þ
252, 1118. MS(FAB): 299 [M 2 1] . Anal. calcd. for C H N O : C,
1
3 24 4 4
1.98; N, 18.65; H, 8.05. Found: C, 51.53; N, 18.26; H, 7.92.
(
[
1S,14S)-6,9-dibenzyl-16,16-dimethyl-15,17-dioxo-3,6,9,12-tetraazadicyclo
12.3.0]-heptadecane-2,13-dione (4): Benzyl chloride in 40 mL of absolute
acetonitrile was added dropwise to a suspension of macrocycle 3 (0.50 g)
and anhydrous potassium carbonate in 50 mL of absolute acetonitrile,
refluxed in nitrogen at 808C for 2 days, followed by filtration. The filtrate
was concentrated and standed to precipitate white solid. The solvent was
filtered and the precipitate was washed by acetonitrile. The crude product
was crystallized from acetonitrile to afford a white powder, yield 56%. Mp
2
D
0
1
1
80–1828C, [a] ¼ 263.38(c ¼ 1.0, MeOH). H NMR (300 MHz, CDCl ):
3
d ¼ 7.33–7.17 (m, 10H, 2Ph), 6.44 (s, 2H, 2CONH), 4.08 (s, 2H, 2OCH),
3
2
2
.66–3.61 (m, 2H, 2CONHCHH), 3.49 (s, 4H, 2CH Ph), 3.22–3.15 (m, 2H,
2
CONHCHH), 2.67–2.63 (m, 4H, 2CONHCH CHHN, NCHHCHHN), 2.52–
2
.48 (m, 2H, 2CONHCH CHHN), 2.42–2.35 (m, 2H, NCHHCHHN), 1.52
2
1
3
(
s, 6H, 2CH3). C NMR (75 MHz, CDCl ): d ¼ 167.786, 137.529, 129.453,
3
1
IR (KBr, cm ): 3304.17, 2933.10, 2805.95, 1654.59, 1549.42, 1514.58,
28.517, 127.623, 113.076, 78.788, 59.402, 52.051, 51.412, 36.780, 26.321.
2
1
1
4
455.97, 1378.49, 1258.99, 1211.16, 1110.64, 732.77, 700.62. MS(FAB):
þ
81[M þ 1] . Anal. calcd. for C H N O : C, 67.48; N, 11.66; H, 7.55.
2
7 36 4 4
Found: C, 67.77; N, 11.92; H, 7.30.
ACKNOWLEDGMENT
We grateful acknowledge the financial support from the Natural Science
Foundition of China (No. 20272045).
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