Synthesis and structures of new C2-symmetrical chiral macrocycles containing the ephedrine moiety

Article abstract of DOI:10.3987/COM-08-11583

Three kinds of novel C₂-symmetrical chiral macrocyclic compounds containing an ephedrine moiety have been designed and synthesized; two of their crystal structures have been determined.

Full text of DOI:10.3987/COM-08-11583

HETEROCYCLES, Vol. 78, No. 4, 2009
891
HETEROCYCLES, Vol. 78, No. 4, 2009, pp. 891 - 897. © The Japan Institute of Heterocyclic Chemistry
Received, 17th October, 2008, Accepted, 15th December, 2008, Published online, 17th December, 2008
DOI: 10.3987/COM-08-11583
SYNTHESIS AND STRUCTURES OF NEW C2-SYMMETRICAL CHIRAL
MACROCYCLES CONTAINING THE EPHEDRINE MOIETY
Yiwen Chen,1, 2 Mingzhang Gao,1 Songde Tan,1 Joseph H. Reibenspies,1 and
Ralph A. Zingaro1*
1. Department of Chemistry, Texas A&M University, College Station, TX
77843-3255, USA; 2. College of Bio-information, Chongqing University of Posts
and
Tele-communications,
Chongqing,
40064,
China;
Zingaro@mail.chem.tamu.edu
Abstract – Three kinds of novel C2-symmetrical chiral macrocyclic compounds
containing an ephedrine moiety have been designed and synthesized; two of their
crystal structures have been determined.
INTRODUCTION
Macrocyclic lactones or macrolides such as the erythromycins and cytochalasins have been shown to
display antibiotic and anticancer activities.1-3 The incorporation of geometrical rigidity by insertion of an
amide group in the ring of macrocyclic crown ether affects the binding properties and selectivity of
4-7
macrocyclic compounds with metal cations
and organic molecules.5,8,9 Kumar and co-workers have
reported that diamide-ester macrocyclic compounds showed extraordinary Ag+ binding strength with a
remarkable selectivity for Ag+ over other metal ions.10-12 Some diamide-containing macrocyclic
molecules have been utilized as new catalysts.13 Our group has recently reported on a series of new chiral
macrolides and their antifungal activity.14 Many chiral macrocyclic compounds have been applied in
chiral recognition and resolution of enantiomer and asymmetric catalytic reactions.15-17 Development of an
efficient method for their syntheses and their application has been a subject of considerable interest. In
order to develop new method for the synthesis of new chiral macrocycles and investigate their application
in metal complex abilities, biochemistry and asymmetric catalysis, we report the design and syntheses of
three kinds of new C2-symmetric chiral macrocycles containing the ephedrine moiety which is a good
natural chiral source synthon, but has only been rarely used in chiral macrocycles. 18 The X-ray crystal
structures of two of these compounds are also reported.

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RESULTS AND DISCUSSION
As is shown in Scheme 1, benzene-1,3- or pyridine-2,6- dicarbonyl dichlorides undergoing the reaction
with (1R,2S)-(-)-ephedrine to give compounds 3: 3a, N1,N3-bis(1R,2S)-1-hydroxy-1-phenylpropan
-2-yl)-N1,N3-dimethylisophthalamide (or 3b, N2,N6-bis(1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-N2,N6-
dimethylpyridine-2,6-dicarboxamide) in 96% yields. In the subsequent step, benzene-1,3-dicarbonyl
dichloride, or pyridine-2,6- dicarbonyl dichloride, undergo condensation with compounds 3 in Et3N plus
DMAP dual-base catalyst system to form the macrolides 4a, 4b, 4c, 4d in about 20-40% yield.19
O
HO
O
H
X
Y
H
O
Ph
O
O
O
Me
N
O
X
Y
N
O
2
N
Cl
HN Me
O
N
Cl
O
X
Ph
Ph
Cl
CH2Cl2, Et3N
Cl
MeCN, Et3N
Ph
OH
HO
Ph
O
1
O
3
4a
, X=CH; Y=CH
4b, X=CH, Y=N
4c, X=N, Y=CH
4d, X=N, Y=N
Scheme 1
O
O
X
O
O
A
X
N
N
Cl
5
N
Cl
N
6a, X=CH; A=CH
6b, X=CH, A=N
6c, X=N, A=CH
6d, X=N, A=N
Ph
O
A
O
Ph
NaH, DMF
Ph
OH
HO
Ph
3
Scheme 2
In scheme 2, compounds 3 undergo condensation with 2,6-bis(chloromethyl)pyridine, or
2,6-bis(chloromethyl)benzene to give compounds 6a, 6b, 6c, 6d in about 20-30% yield using sodium
hydride as the base in a highly diluted DMF solution.19
As is shown in Scheme 3, 2,6-bis(chloromethyl)pyridine or 2,6-bis(chloromethyl) benzene undergo
reaction with ephedrine to form compounds 7 (1R,1’R,2S,2’S)-2,2’- (1,3-phenylenebis(methylene))bis
(methylazanediyl)bis(1-phenylpropan-1-ol) or (1R,1’R, 2S,2’S)-2,2’- (pyridine-2,6-diylbis(methylene))
bis(methylazanediyl) bis(1-phenylpropan-1-ol) in acetonitrile using K2CO3 (or Et3N) as the base at room
temperature in about 95% yield, and compounds 7 condense with 2,6-bis(chloromethyl)benzene or 2,6-
bis(chloromethyl)pyridine in DMF by using sodium hydride as base, stirring at room temperature for 24 h
to give compounds 8a, 8b, 8c, 8d in 15-30% yield.19
It is normally difficult to obtain the desired macrocycles in high yields during the last step of the

HETEROCYCLES, Vol. 78, No. 4, 2009
893
intermolecular condensing cyclization for the following reasons: 1) the intermolecular cyclization
procedure, 2) the inclusion of two geometrically rigid aromatic moieties and two amide bond units, 3) an
unfavorable decrease in the entropy of reaction and 4) the facile formation of chain and polymeric
by-products. For the purpose of minimizing these problems, the effect of solvent on ease of cyclization
was investigated. Acetonitrile was found to be the most satisfactory solvent for compounds 4 and DMF
was found to be better for compounds 6 and 8. Subsequently, various bases were studied in synthesis of
compounds 4. The inorganic bases, potassium carbonate and sodium hydroxide were found to have little
effect on cyclization. Triethylamine and pyridine can be used as bases, but the speed of cyclization and
the yield of product are relatively low. Alternatively, the combination of a base and a catalyst was
investigated for the purpose of promoting the cyclization. It was found that in the presence of pyridine or
triethylamine and 4-(dimethylamino)pyridine as catalysts, higher yields were achieved in the synthesis of
macrocycle 4. By employing the new dual-base catalyst combination, the reaction rate was also found to
increase significantly. All of the desired products have the crown ether-like structure. In the progress of
condensation, if some kind of transition intermediates could form by using K+, Ca2+ or other metal ions as
templates, it was possible to obtain the desired compound in higher yield. In the synthesis of
compounds 6 and 8, it was found that the rates and the yields of cyclization were increased remarkably by
the use of sodium hydride as a catalyst in anhydrous DMF. But to decrease the formation of polymers or
other side products, a highly diluted DMF solution was found to be necessary for the synthesis of
compounds 6 and 8.
A
HO
H
Ph
H
N
N
O
A
Me
B
N
2
N
Cl
HN Me
A
Cl
Ph
O
Ph
Cl
B
Cl
Ph
OH
MeCN, K2CO3
NaH, DMF
HO
Ph
5
7
8a, A=CH; B=CH
8b, A=CH, B=N
8c, A=N, B=CH
8d, A=N, B=N
Scheme 3
In order to obtain a deep and better understanding of the sterochemical properties of the new chiral
macocycles, crystallographic investigations were conducted. Colorless single crystals of 6c, 8d were
obtained by slowly evaporation from a mixture of methanol and chloroform (1:1 in volume), and their
X-ray crystal structures were successfully determined as illustrated in Figures 1 and 2.20 In 6c the two
amide oxygens lie on opposite sides of the pyridine plane. The two amide groups N2-C6-O3 and
N3-C19-O4 are twisted by 42.03(2)o and 63.22(2)o with respect to the pyridine ring. The two ester O,

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HETEROCYCLES, Vol. 78, No. 4, 2009
py-N and two amide nitrogens are directed inwards toward the cavity. In 8d the molecule possess a
chair-like structure with two pyridine moieties occupying opposite positions. The dihedral angle between
two pyridine moieties is 5.11(2)o. The two phenyl groups are located on either sides of the molecule.
Figure 1. Molecular structure of 6c (50% probability ellipsoids, arbitary atom numbering).
Figure 2. Molecular structure of 8d (50% probability ellipsoids, arbitary atom numbering).
In summary, the syntheses of three kinds of new C2-symmetric chiral macrocyclic compounds containing
ephedrine moiety is described. The X-ray crystal structures of two of them have been obtained. The
application of these new compounds will be studied in the future.
ACKNOWLEDGEMENTS
The authors acknowledge the assistance of the Robert A. Welch Foundation (A-084).

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REFERENCES AND NOTES
1. C. J. Roxburgh, Tetrahedron, 1995, 51, 9767.
2. V. K. Frensch and F. Vögtle, Tetrahedron Lett., 1977, 18, 2573.
3. P. Wipf, S. Venkatraman, C. P. Miller, and S. J. Geib, Angew. Chem., Int. Ed. Engl., 1994, 33, 1516.
4. S. Irie, M. Yamamoto, K. Kishikawa, S. Kohmoto, and K. Yamada, Synthesis, 1995, 1179.
5. T. Fujita and J.-M. Lehn, Tetrahedron Lett., 1988, 29, 1709.
6. S. L. Wu, S. J. Frahklin, K. N. Raymond, and W. D. Horrocks, Inorg. Chem., 1996, 35, 162.
7. M. Z. Gao, J. H. Reibenspies, B. Wang, Z. L. Xu, and R. A. Zingaro, J. Heterocyclic Chem., 2004,
41, 899.
8. C. A. Hunter, Chem. Soc. Rev., 1994, 23, 101.
9. M. C. Mitchell, A. Cawley, and T. P. Kee, Tetrahedron Lett., 1995, 36, 287.
10. S. Kumar, R. Singh, and H. Singh, Bioorg. Med. Chem. Lett., 1993, 3, 363.
11. S. Kumar, N. Kaur, and H. Singh, Tetrahedron, 1996, 52, 13483.
12. S. Kumar, N. Kaur, and H. Singh, Tetrahedron Lett., 1996, 37, 2071.
13. H. Sharghi, A. R. Massah, H. Eshghi, and K. Niknam, J. Org. Chem., 1998, 63, 1455.
14. M. Z. Gao, J. Gao, Z. L. Xu, and R. A. Zingaro, Tetrahedron Lett., 2002, 43, 5001.
15. X. X. Zhang, J. S. Bradshaw, and R. M. Izatt, Chem. Rev., 1997, 97, 3313.
16. M. Z. Gao, Y. Q. Yang, and Z. L. Xu, Chin. J. Org. Chem., 2001, 21, 477.
17. Z. B. Li, J. Lin, M. Sabat, M. Hyacinth, and L. Pu, J. Org. Chem., 2007, 72, 4905.
18. F. Wudl and F. Gaeta, J. Chem. Soc., Chem. Commum., 1972, 107.
19. The general synthetic procedure for intermediates 3: To a cold (0 oC) solution of
(1R,2S)-(-)-ephedrine 2 (3.63 g, 22 mmol) and triethylamine (4.0 ml) in 80 mL of CH2Cl2 was added
a solution of benzene-1,3- or pyridine-2,6- dicarbonyl dichloride 1 (10 mmol) in 10 mL of CH2Cl2
over a period of 1 h. The reaction mixture was stirred at 0 oC for 3 h and then at rt for additional 5 h.
The precipitated from the solution was filtered, washed with 20 mL of CH2Cl2 and combined organic
layer was washed with 20 mL of H2O, dried over Na2SO4, concentrated. The crude product was
purified by column chromatography with silica gel as adsorbent and acetone-hexanes (2:1) as the
eluent to give pure compound 3 as a white solid. 3a, 96 % yield; mp 119-121 oC; [α]D25 -3.74° (C 0.3,
MeOH); 1H-NMR (300 MHz, acetone-d6) δ: 1.16 (6H, d, J = 2.0 Hz, CH3), 2.99 (2H, d, J = 9.0 Hz,
OH), 3.76 (6H, s, NCH3), 4.58-4.98 (4H, m, NCH and OCH), 6.68-7.48 (14H, m, Ar-H); MS(FAB):
461 (M++1, 60%), 443, 353, 296, 251, 154 (100%). 3b, 93 % yield; mp 157-159 oC; [α]D25 -12.2° (C
0.3, acetone); 1H-NMR (300 MHz, acetone-d6) δ: 1.32 (6H, d, J = 2.4 Hz, CH3), 2.88 (6H, s, NCH3),
3.20 (2H, d, J = 9.6 Hz, OH), 4.04-5.04 (4H, m, NCH and OCH), 6.98-7.88 (13H, m, Ar-H); MS
(FAB): 462 (M++1, 50 %), 445, 353 (100%). General procedure for the preparation of the
o
compounds 4. To a hot (50 – 70 C) solution of compound 3 (1.0 mmol) in 40 mL of MeCN was

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HETEROCYCLES, Vol. 78, No. 4, 2009
added 4-(dimethylamino)pyridine (DMAP, 25 mg, 0.20 mmol), followed by a solution of compound
1 (2.0 mmol) in 20 mL of MeCN over a period of about 40 min. Then triethylamine (2.0 mL) was
added slowly to the reaction mixture over a period of 1 - 2 h and the reaction mixture was stirred for
another 10 h. A white precipitate, triethylamine hydrochloride formed, and was removed by filtration.
The filtrate was evaporated under reduced pressure to afford a residue, which was purified by
column chromatography (silica gel, acetone-hexanes) to provide white solid product 4. Selected
25
spectral data for compound 4a: mp: 242-244 oC. [α]D -335˚ (C 0.1, acetone). 1H-NMR (300 MHz,
CDCl3) δ: 1.06 (6H, d, J = 7.0 Hz, CH3), 3.05 (6H, s, NCH3), 4.52-4.63 (2H, m, NCH), 6.11 (2H, d,
13
J = 10.5 Hz, OCH), 7.26-8.90 (18H, m, Ar-H). C-NMR (75 MHz, CDCl3): 169.3, 167.5, 136.2,
135.0, 132.3, 129.7, 128.8, 128.5, 128.3, 128.1, 126.0, 124.2, 81.5, 61.8, 33.6, 9.9. MS (FAB): 591
(M++1, 16%), 310, 222 (100%). HRMS (ESI) calcd for C36H35N2O6, 591.2495 (M+H)+; found
591.2499. General synthetic procedure of compounds 6 or 8. The intermediate 3 or 7 (1.0 mmol)
was dissolved in 60 mL of anhydrous DMF; sodium hydride (72 mg, 3.0 mmol) was added into the
o
solution at 0 C with stirring over 30 min. Then the compound 5 (1.0 mol) in 20 mL of DMF was
then added slowly into the solution, the stirring was kept for 24 h at rt. The mixture solution was
poured into 200 mL of H2O, extracted with CHCl3 (3 × 40 mL). The combined organic layer was
washed with water, dried over the Na2SO4, filtered and concentrated. The residue was purified on the
silica gel column, eluented with the solution of CHCl3 and MeOH (100:2). The pure product 6 or 8
was obtained as a white solid. Selected spectral data for compound 6c: mp 207-208 oC. [α]D22 + 358˚
(C 0.1, MeOH). 1H-NMR (300 MHz, CDCl3) δ: 1.10 (6H, d, J = 6.6 Hz, CH3), 3.29 (6H, s, NCH3),
4.32-4.35 (2H, m, NCH), 4.62 (2H, d, J = 10.2 Hz, OCH), 4.80-5.10 (4H, m, OCH2), 7.10-7.60 (14H,
13
m, Ar-H), 7.70-8.20 (3H, m, Ar-H); C-NMR (75 MHz, CDCl3): 168.51, 153.78, 139.47, 138.97,
138.43, 129.99, 128.72, 128.43, 127.98, 127.69, 126.79, 125.06, 84.93, 73.39, 55.60, 33.95, 9.91;
MS (ESI): 570 (M++Li, 100%). HRMS (ESI) calcd for C35H38N3O4, 564.2862 (M+H)+; found
o
22
564.2867. Selected spectral data for compound 8d: mp 141-142 C. [α]D + 77˚ (C 0.1, MeOH).
1HNMR (300 MHz, CDCl3) δ: 1.14 (6H, d, J = 6.6 Hz, CH3), 2.32 (6H, s, NCH3), 2.86-2.90 (2H, m,
NCH), 3.50-4.00 (4H, m, NCH2), 4.36 (2H, d, J = 6.6 Hz, OCH), 4.68-4.72 (4H, m, OCH2),
13
7.00-7.42 (14H, m, Ar-H), 7.42-7.80 (2H, m, Ar-H); C-NMR (75 MHz, CDCl3): 160.58, 158.28,
141.78, 136.74, 136.52, 128.38, 127.19, 126.93, 121.24, 120.65, 82.13, 72.09, 65.28, 58.74, 42.10,
8.44. MS (ESI): 537 (M++1, 100%). HRMS (ESI) calcd for C34H41N4O2, 537.3229 (M+H)+; found
537.3219.
20. Crystallographic measurements were carried out on a Siemens P4 diffractometer with
graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) and 12 kW rotating generator. The data
were collected at 110 K. The structures were solved and refined using the programs SHELXS-97
(Sheldrick, 1997) and SHELXL (Sheldrick, 1997). The program X-Seed (Barbour, 1999) was used

HETEROCYCLES, Vol. 78, No. 4, 2009
897
as an interface to the SHELX programs. X-ray analysis for 6c. C35H37N3O4, MW = 563.69,
Monoclinic, P2(1), Z = 2, a = 9.828(9) Å, b = 10.310(10) Å, c = 15.902(15) Å, α = 90°, β =
96.400(15)°, γ = 90°, V = 1601(3) Å3, Dcalcd = 1.171 g/cm-3, Mo Ka (λ = 0.71073 Å), F(000) = 602,
T = 293K, full-matrix least squares base on F2, R1 = 0.0764, wR2 = 0.1545, 379 parameters, GOF =
1.041. X-ray analysis for 8d. C34H40N4O2, MW = 536.70, Triclinic, P1, Z = 1, a = 6.2713 (4) Å, b =
8.1494(4) Å, c = 15.4947(8) Å, α = 80.944(4)°, β = 84.321(4)°, γ = 69.951(4)°, V = 733.77(7) Å3,
Dcalcd = 1.215 g/cm-3, Mo Ka (λ = 1.54178 Å), F(000) = 288, T = 110K, full-matrix least squares
base on F2, R1 = 0.0284, wR2 = 0.0727, 366 parameters, GOF = 1.079. Crystallographic data for the
structures 6c and 8d in this paper have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC 711112 and 711113. Copies of the data can be
obtained, free for charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44(0)-1223-336033 or email: deposit@ccdc.cam.ac.uk).