Novel C2-symmetric macrocycles bearing diamide-diester groups: Synthesis and enantiomeric recognition for primary alkyl ammonium salts

Article abstract of DOI:10.1021/jo702210c

(Chemical Equation Presented) We synthesized a series of novel macrocycles with diamide-diester groups (S,S)-1, (S,S)-2, (S,S)-3, and (R,R)-1, derived from dimethyloxalate and amino alcohols by high dilution technique, and evaluated enantiomeric recognition properties of these macrocycles toward primary alkyl ammonium salts by ¹H NMR titration. Taking into account the host employed, important differences were observed in the K_a values of (R)-Am and (S)-Am for (S,S)-1 and (R,R)-1 hosts, K_S/K_R = 5.55 and K_R/K_S = 3.65, ΔΔG_o = 0.43 and -0.32 kJ mol^-1, respectively. There seems a general tendency for the host to include the guests with the same absolute configuration.

Full text of DOI:10.1021/jo702210c

Novel C2-Symmetric Macrocycles Bearing Diamide-Diester
Groups: Synthesis and Enantiomeric Recognition for Primary Alkyl
Ammonium Salts
Murat Sunkur, Deniz Baris, Halil Hosgoren, and Mahmut Togrul*
Chemistry Department, UniVersity of Dicle, Faculty of Art and Science, 21280-Diyarbakır, Turkey
mtogrul@dicle.edu.tr
ReceiVed NoVember 12, 2007
We synthesized a series of novel macrocycles with diamide-diester groups (S,S)-1, (S,S)-2, (S,S)-3, and
(R,R)-1, derived from dimethyloxalate and amino alcohols by high dilution technique, and evaluated
1
enantiomeric recognition properties of these macrocycles toward primary alkyl ammonium salts by H
NMR titration. Taking into account the host employed, important differences were observed in the Ka
values of (R)-Am and (S)-Am for (S,S)-1 and (R,R)-1 hosts, KS/KR ) 5.55 and KR/KS ) 3.65, ∆∆Go )
0.43 and -0.32 kJ mol-1, respectively. There seems a general tendency for the host to include the guests
with the same absolute configuration.
Introduction
important biological activities of many chiral substances depend
a great deal on the stereochemistry. That is why design,
synthesis, and structural activity relationships of enantioselective
receptors are still vital areas of research.11 Recently, much
attention has been paid to the development of molecular
receptors that recognize chiral molecules.
Enantiomeric recognition is an essential process in living
organisms involving the differentiation of one enantiomer of
the guest from the other by a chiral host. Examples of
enantiomeric discrimination can be found in many natural
processes such as enzyme-substrate interactions, immunological
responses, the mechanism of drug action, and the storage and
retrieval of genetic information.1 The development of chiral
artificial receptors with the properties chiral recognition has
attracted increasing attention because of their high sensitivity
and potential applications in pharmaceuticals,2,3 analysis,4,5
biology,6 catalysis,7-9 and sensing.10 The chemical and more
The study of enantiomeric recognition of amine and protoned
amine compounds is of significance because these compounds
are basic building blocks of biological molecules. Amino acids
are major components of proteins in natural living systems, and
their versatile abilities to form complexes with a variety of
molecules present various types of interaction modes.12 Since
Cram et al. reported their pioneering research on the use of chiral
macrocyclic ligands in enantiomeric recognition,13 a great
number of chiral artificial receptors have been synthesized and
studied. Among these, chiral macrocyclic compounds involving
* Corresponding author. Tel.: +90 412 2488550/3183. Fax: +90 412
2488300.
(1) Horvath, G.; Hutszthy, P.; Szarvas, S.; Szokan, G.; Redd, J. T.;
Bradshaw, J. S.; Izatt, R. M. Ind. Eng. Chem. Res. 2000, 39, 3576.
(2) Choi, S. H.; Huh, K. M.; Ooaya, T.; Yui, N. J. Am. Chem. Soc. 2003,
125, 6350.
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Ed. 2003, 42, 4640.
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(10) Kubo, Y.; Maeda, S.; Tokita, S.; Kuba, M. Nature 1996, 382, 522.
(11) Koskinen, A. Pure Appl. Chem. 1993, 65, 1465.
(12) Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. ReV. 1997, 95,
3313.
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(6) For a review on supramolecular technology, see: Reinhoudt, D. N.
Ed. ComprehensiVe Supramolecular Chemistry; Pergamon: New York,
1996; Vol. 10. Peczuh, M. W.; Hamilton, A. D. Chem. ReV. 2000, 100,
2479.
(13) Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D. J. J.
Am. Chem. Soc. 1973, 95, 2692.
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10.1021/jo702210c CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/12/2008
2570
J. Org. Chem. 2008, 73, 2570-2575

C2-Symmetric Macrocycles Bearing Diamide-Diester Groups
SCHEME 1. The Synthesis of Bis(amino alcohol)oxalamides
cyclophanes,14 crown ethers,15 and cyclodextrins16 are the
dominant structures. On the other hand, it is well known that
the rigid and C2-symmetric macrocycles are more selective for
protoned amines than the non-rigid and C2-symmetric mol-
ecules.12
It is also well known that the amide group has high affinity
for cations with high charge density. Many ionophores with
amide ligands are currently employed as chemical sensors that
can quantitatively and reversibly measure cationic analytes.17-19
Macrocyclic diesters and diamides are widely found in nature
and constitute an extensive range of natural products with
diverse biological activity.20-22 These natural compounds are
complex structures due to the presence of multi-functional
groups and their chirality. A number of macrocyclic compounds
containing diamide-diester groups have been synthesized.23
However, few examples have been reported, dealing with the
synthesis and chiral recognition studies of chiral macrocyclic
containing diamide-diester groups. Herein, we report the
synthesis of a series of novel, rigid, and C2-symmetric macro-
cycles having two amide and two ester groups in macrocyclic
ring by high dilution technique and evaluate enantiomeric
recognition properties of these macrocycles toward primary alkyl
1
ammonium salts by H NMR titration methods.
Results and Discussion
Synthesis. In the present study, chiral, rigid, and C2-
symmetric macrocycles (S,S)-1, (S,S)-2, (S,S)-3, and (R,R)-1
were synthesized from bis(amino alcohol)oxalamides (S,S)-4,
(S,S)-5, (S,S)-6, and (R,R)-2 as shown in Schemes 1 and 2. Chiral
bis(amino alcohol)oxalamides were synthesized from (R)-2-
amino-1-buthanol, (L)-leucinol, (L)-phenylalanilol, and (L)-
isoleucinol reacted with dimethyloxalate in methanol at room
temperature, respectively. Chiral bis(amino alcohol)oxalamides
were obtained with very high yield (g97%). Macrocyles were
synthesized from corresponding chiral bis(amino alcohol)-
oxalamides by high dilution technique. These macrocycles are
readily prepared in good yields in short synthetic sequences and
allow high modularity by simply changing the amino alcohol
moiety. The functionality of amides and esters is not only
suitable for binding but also ensures high rigidity. The structures
proposed for these new chiral bis(amino alcohol)oxalamides and
(14) For cyclophanes, see: Kearney, P. C.; Mizoue, L. S.; Kumpf, R.
A.; Forman, J. E.; McCurdy, A.; Dougherty, D. A. J. Am. Chem. Soc. 1993,
115, 9907. Pernia, J.; Kilburn, J. D.; Rowley, M. J. Chem. Soc., Chem.
Commun. 1995, 305. Ngola, S. M.; Kearney, P. C.; Mecozzi, S.; Russell,
K.; Dougherty, D. A. J. Am. Chem. Soc. 1999, 121, 1192.
(15) For crown ethers, see: Bradshaw, J. S.; Huszthy, P.; MacDaniel,
C. W.; Zhu, C. Y.; Dalley, N. K.; Izatt, R. M.; Lifson, S. J. Org. Chem.
1990, 55, 3129. Echegoyan, L.; Li, Y. J. Org. Chem. 1991, 56, 4193. Samu,
E.; Huszthy, P.; Somogyi, L.; Hollosi, M. Tetrahedron: Asymmetry 1999,
10, 2775. Togrul, M.; Askin, M.; Hosgoren, H. Tetrahedron: Asymmetry
2005, 16, 2771.
(16) For cyclodextrins, see: Maletic, M.; Wennemers, H.; McDonald,
D. Q. Angew. Chem., Int. Ed. Engl. 1996, 35, 1490. Liu, Y.; Zhang, Y. M.;
Qi, A. D.; Chen, R. T.; Yamamoto, K.; Wada, T.; Inoue, Y. J. Org. Chem.
1997, 62, 1826.
(17) Du, C. P.; You, J. S.; Yu, X. Q.; Liu, C. L.; Lan, J. B.; Xie, R. G.
Tetrahedron: Asymmetry 2003, 14, 3651.
1
macrocycles are consistent with data obtained from H, 13C
NMR, IR, and elemental analyses. All 1H and 13C NMR signals
1
were assigned on the basis of DEPT and H-13C correlation
(18) Kimura, E. J. Coord. Chem. 1986, 15, 1.
(19) Arnoud, N.; Picard, C.; Cazaux, L.; Tisnes, P. Tetrahedron 1997,
53, 13757.
experiment.
Enantiomeric Recognition Studies Using NMR Titration
Method. The main purpose of synthesizing these macrocycles
is to study their enantiomeric recognition for guest molecules.
The enantiomeric recognition can be characterized by various
spectroscopic methods, such as NMR, ultraviolet visible (UV-
(20) Roxburgh, C. J. Tetrahedron 1995, 51, 9767.
(21) Frensch, V. K.; Vogtle, F. Tetrahedron Lett. 1997, 2573.
(22) Kuroda, T.; Imashiro, R.; Seki, M. J. Org. Chem. 2000, 65, 4213.
(23) Gao, M. Z.; Gao, J.; Xu, Z. L.; Zingaro, R. A. Tetrahedron Lett.
2002, 43, 5001.
J. Org. Chem, Vol. 73, No. 7, 2008 2571

Sunkur et al.
SCHEME 2. The Synthesis of Macrocycle
SCHEME 3. Ammonium Perchlorate Salts Used as the
Guest
vis), fluorescence, and infrared (IR), which are powerful tools
used for the examination of the recognition ability of new chiral
macrocycles.24-30 NMR has become a routine tool for the study
of host-guest supramolecular chemistry, and there are now
hundreds of reports of studies where NMR titration was used
to measure intermolecular association.25,31,32
When the macrocycles absorb light at different frequency in
free and complexed states, the differences of chemical shifts in
the NMR spectra may suffice for the estimation of enantiomeric
recognition of thermodynamics. In NMR titration experiments,
the addition of varying concentration of guest molecules results
gradually in shifting of some chemical signals upfield or
downfield. The complexation of ammonium cations [G] with
chiral macrocycle [H] is expressed by eq 1:
method is that by working with a large excess of component
H, the concentration of uncomplexed H can be set equal to the
initial concentration, [H] ) [H]0. Relationships between known
quantities (initial concentrations) and experimental observations
can now be derived, Mathur et al.34 and Hannah and Ashbaugh35
have independently derived the NMR version of the Benesi-
Hildebrand equation. For all of the guests examined, plots of
calculated 1/∆δ values as a function of 1/[G]o values give a
linear relationship with a slope 1/Ka‚∆δmax and intercept
1/∆δmax, supporting the 1:1 complex formation.
H + G {K
\
} H‚G
(1)
Under the condition employed herein, chiral R-(1-napthyl)
ethylamine perchlorate salts ((R)-Am and (S)-Am) were selected
as the guest molecules (Scheme 3). The association constant of
the supramolecular systems formed was calculated according
to the modified Benesi-Hildebrand equation (eq 2), where [H]o
and [G]o refer to total concentration of macrocycles and organic
ammonium salts, respectively. The original Benesi-Hildebrand
experiment was an optical spectroscopy study of the association
of iodine with aromatic hydrocarbons.33 The key feature of this
1/∆δ ) 1/(Ka‚∆δmax‚[G]o) + 1/∆δmax
(2)
where ∆δ ) (δG - δobs), and ∆δmax ) (δG - δH‚G).
It is a well-known fact that crown ethers form very stable
complexes with ammonium salts by means of a hydrogen-bond-
ing network, thus making them useful in many applications;36-38
(24) de Boer, J. A. A.; Reinhoud, D. N. J. Am. Chem. Soc. 1985, 107,
5347.
(25) Samu, E.; Huszthy, P.; Horvath, G.; Szollosy, A.; Neszmelyi, A.
Tetrahedron: Asymmetry 1999, 10, 3615.
(26) Fielding, L. Tetrahedron 2000, 56, 6151.
(27) Wang, W.; Ma, F.; Shen, X.; Zhang, C. Tetrahedron: Asymmetry
2007, 18, 832.
(28) Hirose, K. J. Inclusion Phenom. Macrocycl. Chem. 2001, 39, 193.
(29) Togrul, M.; Turgut, Y.; Hosgoren, H. Chirality 2004, 16, 351.
(30) Turgut, Y.; Sahin, E.; Togrul, M.; Hosgoren, H. Tetrahedron:
Asymmetry 2004, 15, 1583.
(34) Mathur, R.; Becker, E. D.; Bradley, R. B.; Li, N. C. J. Phys. Chem.
1963, 67, 2190.
(35) Hannah, M. W.; Ashbaugh, A. L. J. Phys. Chem. 1964, 68, 811.
(36) Izatt, R. M.; Zhu, C. Y.; Huszthy, P.; Bradshaw, J. S. In Crown
Compounds: Toward Future Applications; Cooper, S. R., Ed.; VCH
Publishers: New York, 1992; Chapter 12.
(37) Izatt, R. M.; Zhang, X. X.; Huszthy, P.; Zhu, C. Y.; Hathaway, J.
K.; Wang, T. M.; Bradshaw, J. S. J. Inclusion Phenom. Mol. Recognit.
Chem. 1994, 18, 353.
(31) Foster, R.; Fyfe, C. A. Prog. Nucl. Magn. Reson. Spectrosc. 1969,
4, 1.
(32) Connors, K. A. Binding Constant; Wiley: New York, 1987.
(33) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703.
(38) Chu, C. I.; Dearden, D. V.; Bradshaw, J. S.; Huszthy, P.; Izatt, R.
M. J. Am. Chem. Soc. 1993, 115, 4318.
(39) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568.
2572 J. Org. Chem., Vol. 73, No. 7, 2008

C2-Symmetric Macrocycles Bearing Diamide-Diester Groups
FIGURE 2. Job plot for macrocycle (S,S)-3 with (R)-Am.
FIGURE 3. Typical plot of 1/∆δ versus 1/[G]o for host-guest
complexation of (S,S)-3 and (R)-(-)R-(1-napthyl)ethylamine perchlorate
salt ((R)-Am).
structural features of the host-guest complexes is essential in
understanding the origin of the chiral recognition. The choice
of these macrocycles was based on the fact that rigid and C2-
symmetric generally form more stable complexes than the non-
rigid and C2-symmetric. The binding constant, Ka, of the
complexes of the macrocyles (S,S)-1, (S,S)-2, (S,S)-3, and
(R,R)-1 with R-(1-napthyl)ethylamine perchlorate salts [(R)-Am,
(S)-Am] were determined by the Benesi-Hildebrand equation
on the basis of the NMR spectrum of the complexes in CD3CN
collected at 25 ( 0.1 °C. Binding constant (Ka) and the Gibbs
free energy changes (-∆Go) of these hosts with guest molecules
obtained from usual curve-fitting analyses (R > 0.9897) of the
observed chemical shift changes are summarized in Table 1,
along with enantioselectivity KR/KS or ∆∆Go calculated from
-∆Go for the complexation of (R/S)-R-(1-napthyl)ethylamine
perchlorate salts by these hosts.
FIGURE 1. Typical NMR spectrum of guest’s CH (methine) proton,
and changes upon the addition of constant concentration of guest ((R)-
Am) molecule (1.33 × 10-3 M) to the (S,S)-3 host molecule at various
concentrations (0-6.55 × 10-3 M).
in particular, those bearing chiral centers on their rings core
are of great interest in their usage in stereoselective applica-
tions.12 The model compounds, easily synthesized as compared
to crown ethers, might be considered to be cyclic esters
possessing crown ether-like rings, and are predicted to behave
in a similar mode to accommodate ammonium salts. In addition,
because they hold carbonyl and amide functions on their rings,
they are expected to be superior to crown ethers. These functions
are thought to make the ring more rigid, which is a preferential
prerequisite for a host to include a guest more tightly.
Important differences were observed in the Ka values of (R)-
Am and (S)-Am for (S,S)-1 and (R,R)-1 hosts, KS/KR ) 5.55
and KR/KS ) 3.65, ∆∆Go ) 0.43 and -0.32 kJ mol-1
,
We first examined the binding properties of novel diamide-
diester macrocycles (R,R)-1, (S,S)-1, (S,S)-2, and (S,S)-3 toward
(R)-Am and (S)-Am by using 1H NMR titration. The concentra-
tion of guest was fixed at 1.33 × 10-3 M in CD3CN. The NMR
spectrum of CH (methine) at guest was monitorized, with
addition of various concentrations (0-6.55 × 10-3 M) of host.
respectively, as shown in Table 1. On the other hand, differences
in Ka values of (R)-Am and (S)-Am for (S,S)-2 and (S,S)-3 hosts
were moderate, KR/KS ) 0.94 and 1.23, ∆∆Go ) -0.02 and
-0.05 kJ mol-1, respectively. There seems a general tendency
for the host to include the guests with the same absolute
configuration. The host bearing benzyl group with (S)-config-
uration forms a more stable binding of complexes with the
enantiomer of guest with (S)-configuration. This observation
can be confirmed by an ERF (enantiomer recognition factor)
of 5.55 (KS/KR), which corresponds to approximately 70% ee.
This can be seen for the complex of the host with two
enantiomers as seen in Figure 4. It is clearly indicated that the
former 1 is more stable than the latter 2 because it is quite
apparent that the enantiomer with (S)-configuration fits better
than the one with (R)- as the bulky naphthyl group in the former
is placed opposite the benzyl side chain in the cavity of the
1
For the guest CH, H NMR signal (quartet) gradually shifted
downfield upon addition of the hosts (Figure 1). The Job’s plot
based on the chemical shift changes supported the 1:1 stoichi-
ometry of host-guest complexes (Figure 2). Typical plots for
the complexation of (S,S)-3 host with R-(1-napthyl)ethylamine
perchlorate salt (guest) are shown in Figure 3.
The determination of Ka values for chiral host-guest interac-
tion provides information about the capability of the chiral host
to recognize enantiomers of the chiral guest under given sets
of condition. The correlation of degree of recognition with the
J. Org. Chem, Vol. 73, No. 7, 2008 2573

Sunkur et al.
TABLE 1. Binding Constant (Ka), the Gibbs Free Energy Changes (-∆Go), and Enantioselectivities KR/KS or ∆∆Go for the Inclusion of R/S
Guest with the Chiral Host Macrocycles in CD3CN at 25 °C
-∆Go
∆∆Go
b
host
guesta
Ka (M-1
)
KR/KS
(kJ mol-1
)
(kJ mol-1
)
(R,R)-1
(R,R)-1
(S,S)-1
(S,S)-1
(S,S)-2
(S,S)-2
(S,S)-3
(S,S)-3
(R)-Am
(S)-Am
(R)-Am
(S)-Am
(R)-Am
(S)-Am
(R)-Am
(S)-Am
7752.9 ( 0.019
2122.9 ( 0.028
1230.7 ( 0.011
6835.7 ( 0.021
2507.4 ( 0.036
2669.4 ( 0.026
1211.2 ( 0.029
988.6 ( 0.041
3.65
2.22
1.90
1.76
2.19
1.94
1.96
1.76
1.71
-0.32
+0.43
0.02
0.18 (KS/KR ) 5.55)
0.94 (KS/KR ) 1.07)
1.23
-0.05
a NapEtHClO4: R-(1-napthyl)ethylamine perchlorate salts. b ∆∆Go ) -∆Go(R) - ∆Go(S)
.
Conclusion
We have synthesized a series of novel macrocycles having
diamide-diester groups (S,S)-1, (S,S)-2, (S,S)-3, and (R,R)-1,
derived from dimethyloxalate and amino alcohols by high
dilution technique, and evaluated enantiomeric recognition
properties of these macrocycles toward primary alkyl ammonium
salts by 1H NMR titration. These macrocycles are readily
prepared in short synthetic sequences and allow high modularity
by simply changing the amino alcohol moiety. The functionality
of amides and esters is not only suitable for binding but also
ensures high rigidity. The macrocycles have shown a consider-
able binding affinity and consequently enantiomeric discrimina-
tion against amine salts.
FIGURE 4. Schematic diagram of the enantiomeric recognition mode
of amine salts by hosts.
Experimental Section
Macrocyclic (S,S)-1. This experiment was conducted under high
dilution technique. A 2 L, four-necked, round-bottomed flask, fitted
with a mechanical stirrer and two-faced condenser, was charged
with 1 L of benzene and tritely amine equivalent to the produced
HCl. The solution was refluxed vigorously while (S,S)-4 (1.5 g,
4.2 mmol) in dry THF/DMF (w:w,70/30 ) 100 mL) and diacide
dichloride 2 (0.86 g, 5mmol) in dry benzene (100 mL) were added
dropwise at the same rate. After the addition was complete, the
reaction mixture was refluxed for further 5 days. The solution was
cooled to room temperature, filtered, and solvent was evaporated
under vacuum. The white solid resulting was crystallized from an
ethanol-acetonitrile mixture (2:1). Macrocyclic (S,S)-1: yield (1.26
g, 63%); mp 289-290 °C; IR (KBr) ν 3298 (N-H), 3086 (Ar-
H), 3059 (Ar-H), 3028 (Ar-H), 1759 (CdO, ester), 1731 (CdO,
ester), 1659 (CdO, first amide band), 1516 (CdO, second amide
FIGURE 5. Schematic diagram of binding interaction between amine
salts and host (S,S)-1.
host, whereas in the latter, these two groups are located in the
same face, causing unfavorable steric interactions. One may
argue that in the former model, location of two aromatic rings
facing opposite may give rise to favorable π-π interaction and
H-bonding (Figure 5), thus accounting for the relative stability
of the complex. As to the binding ability of the host possessing
ethyl side chains with (R)-configuration, it was observed that it
has the highest binding affinity among the host, preferably
accommodating the enantiomer with (R)-configuration with ERF
of 3.65 (KR/KS), hence resulting in approximately 57% ee.
Higher binding tendency and lower ERF as compared to the
host with benzyl side chains could be ascribed to the fact that
methyl-ethyl interaction is expected to be less energetic than
that of methyl-benzyl interaction, thus making the complex of
the host bearing ethyl more stable than the benzyl bearing one.
As to the difference in ERF, this may be explained in a similar
manner. This may be attributed to favorable hydrophobic
interaction between naphthyl ring and ethyl. However, the NMR
shifts in ethyl group were not quite significant upon changes in
the concentration of guest (R)-Am to be accounted for in the
most stable complex. The relatively lower binding ability and
possible consequence of smaller ERF of hosts bearing iso- and
sec-buthyl groups toward guests remain to be answered. It is
possible that there should be an unfavorable steric interaction
between these groups and the naphthyl group of the guest.
band), 1130 (C-O-C), 1053 (C-O-C) cm-1; [R]34 ) -58 (c
D
1
0.04, CH3CN); H NMR (400 MHz, DMSO-d6) δ (ppm) 2.75-
2.87 (m, 4H, CH2Ar), 3.75-3.88 (m, 6H, CH2O and CH-N), 4.25-
4.57 (m, 4H, O-CH2-CdO), 7.17-7.26 (m, 10H, ArH), 8.60 (d,
J ) 10 Hz, 2H, NH); 13C NMR (100 MHz, DMSO-d6) δ (ppm)
35.04 (t, CH2Ar), 50.70 (d, CH-N), 65.77 (t, CH-CH2O), 65.82
(t, OCH2CdO), 126.71, 128.69, 129.33 (d, aromatic CH), 138.42
(s, quaternary aromatic), 160.12 (s, CdO amide), 169.56 (s, CdO
ester). Anal. Calcd (%) for C24H26N2O7: C, 63.42; H, 5.77; N, 6.16.
Found: C, 63.41; H, 5.78; N, 6.15.
Macrocyclic (S,S)-2. The reaction was carried out by the high
dilution technique as described above. Macrocyclic (S,S)-2: yield
(0.98 g, 49%); mp 278-279 °C; IR (KBr) ν 3297 (N-H), 1751
(CdO, ester), 1728 (CdO, ester), 1659 (CdO, first amide band),
1520 (CdO, second amide band), 1277 (OdC-O-C), 1130 (C-
O-C) cm-1; [R]33D ) -62.0 (c 0.1, CH3CN); 1H NMR (400 MHz,
DMSO-d6) δ (ppm) 0.84 (d, J ) 7.2 Hz, 6H, CH3 (a)), 0.86 (d, J
) 7.2 Hz, 6H, CH3 (b)), 1.12-1.20 (m, 2H, CH(CH3)2), 1.49-
1.60 (m, 4H,NCHCH2CH), 3.79-4.66 (m, 10H,CHN, CHN-CH2-
CdO and O-CH2-CdO), 8.50 (d, J ) 10 Hz, 2H, NH); 13C NMR
(100 MHz, DMSO-d6) δ (ppm) 21.91 (q, CH3 (a)), 23.54 (q, CH3
2574 J. Org. Chem., Vol. 73, No. 7, 2008

C2-Symmetric Macrocycles Bearing Diamide-Diester Groups
(b)), 24.76 (d, CH(CH3)2), 37.77 (t, CH2CH(CH3)2), 47.75 (d, CH-
N), 65.81 (t, CH-CH2-O), 66.31 (t, O-CH2-CdO), 160.43 (s
amide CdO), 169.52 (s, ester CdO). Anal. Calcd (%) for
C18H30N2O7: C, 55.95; H, 7.83; N, 7.25. Found: C, 55.93; H, 7.81;
N, 7.24.
Macrocyclic (S,S)-3. The reaction was carried out by the high
dilution technique as described above. Macrocyclic (S,S)-3: yield
(0.88 g, 44%); mp 280-282 °C; IR (KBr) ν 3282 (N-H), 1763
(CdO, ester), 1736 (CdO, ester), 1659 (CdO, first amide band),
DMSO-d6) δ (ppm) 0.84 (t, J ) 7.4 Hz, 6H, CH3), 1.46-1.52 (m,
4H, CHCH2CH3), 3.82-4.66 (m, 10H, CH-N, CH2O and
O-CH2-CdO), 8.45 (d, J ) 10 Hz, 2H, NH); 13C NMR (100 MHz,
DMSO-d6) δ (ppm) 10.99 (q, CH3), 22.39 (t, CH2CH3), 51.15 (d,
CH-N), 65.87 (t, CH-CH2-O), 65.97 (t, O-CH2-CdO), 160.73
(s, amide CdO), 169.56 (s, ester CdO). Anal. Calcd (%) for
C14H22N2O7: C, 50.91; H, 6.71; N, 8.48. Found: C, 50.88; H, 6.72;
N, 8.46.
1524 (CdO, second amide band), 1284 (OdC-O-C), 1149 (C-
Acknowledgment. Our work was supported by The Scien-
tific and Technical Research Council of Turkey (TUBITAK),
under project number 106T395, and Dicle University research
committee (DUBAP) under project numbers 06-FF-39 and 06-
FF-40. We thank the TUBITAK and DUBAP for supporting
this work. We are grateful to Professor Dr. Necmettin Pirinc-
cioglu and Dr. Murat Kizil (Dicle University) for their invaluable
contribution.
1
O-C) cm-1; [R]34 ) +153.0 (c 0.03, CH3CN); H NMR (400
D
MHz, DMSO-d6) δ (ppm) 0.85 (t, J ) 3.8 Hz, 6H, CH2CH3), 0.89
(d, J ) 4.0 Hz, 6H, CHCH3), 1.04-1.11 (m, 2H, CH2CH3 (a)),
1.38-1.40 (m, 2H, CH2CH3 (b)), 1.68-1.70 (m, 2H, CHCH3),
3.81-3.93 (m, 2H, CH-N), 3.97-4.65 (m, 8H, NCHCH2O and
OCH2CdO), 8.44 (d, J ) 12 Hz, 2H, NH); 13C NMR (100 MHz,
DMSO-d6) δ (ppm) 10.76 (q, CH2CH3), 15.84 (q, CHCH3), 25.78
(t, CHCH2CH3), 34.66 (d, CHCH3), 53.42 (d, N-CH-), 64.95 (t,
CH2O), 66.22 (t, OCH2CdO), 160.72 (s, amide CdO), 169.61 (s,
ester CdO). Anal. Calcd (%) for C18H30N2O7: C, 55.95; H, 7.83;
N, 7.25. Found: C, 55.94; H, 7.84; N, 7.23.
Macrocyclic (R,R)-1. The reaction was carried out by the high
dilution technique as described above. Macrocyclic (R,R)-1: yield
(1.14 g, 57%); mp 266.5-268 °C; IR (KBr) ν 3282 (N-H), 1767
(CdO, ester), 1735 (CdO, ester), 1659 (CdO, first amide band),
1520 (CdO, second amide band), 1296 (OdC-O-C), 1149 (C-
O-C) cm-1; [R]34D ) +96.0 (c 0.2, CH3CN); 1H NMR (400 MHz,
Supporting Information Available: Synthesis of aminoalcohols
and diamidediols (S,S)-4, (S,S)-5, (S,S)-6, (R,R)-2, and also 1H and
13C NMR spectra for compounds (R,R)-1, (S,S)-1, (S,S)-2, (S,S)-3,
(R,R)-2, (S,S)-4, (S,S)-5, (S,S)-6, and furthermore 1H-13C correlation
NMR spectra for compounds (R,R)-1, (S,S)-1, (S,S)-2, (S,S)-3.39
This material is available free of charge via the Internet at http://
pubs.acs.org.
JO702210C
J. Org. Chem, Vol. 73, No. 7, 2008 2575