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within the macrocycle (Figure 7).
(Release 8.0) software using PM3, AMBER and MM+ methods and no influence of
solvents was taken into account in the calculations. 33,34 Circular Dichroism (CD)
measurements were carried out using Jasco-J-810 Spectropolarimeter in H 2O and
DMSO.
(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarbohydrazide 2: To a stirred solution of
(4R,5R)-dimethyl-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate 1 (4.76 g, 21.83 mmol)
in absolute ethanol (20 mL) was added hydrazine monohydrate (2.3 mL, 72.76 mmol)
and the mixture was refluxed for 12 h. The solvent was evaporated under vacuum and
the resulting oil was patitionated between ethyl acetate and water (10 mL). To the water
phase was added ethanol (200 mL) and anhydrous Na 2SO 4. The solvent was filtered off
and evaporated under vacuum to afford the title product as a white gummy material
(4.21 g, 88%). 1 H NMR (400 MHz, [D6]DMSO, 25 °C, TMS): δ = 9.3 (brs, 2H; NH),
4.4 (brs, 2H; CH), 4.2 (brs, 4H; NH 2), 1.3 ppm (s, 6H; CH 3); 13 C NMR (100 MHz,
[D6]DMSO, 25 °C, TMS): δ =167.8, 112.2, 77.2, 26.6 ppm; FT-IR: ṽ = 3316 (NH and
NH 2), 1660 cm –1 (C[dbond]O); HRMS (ESI-): m/z calcd. for [C 7H 14N 4O 4+ Na + ]:
241.0907 [M+ Na + ]; found: 241.0900.
Figure 7. Circular Dichroism spectra for the novel macrocycles and their precursors.
Conclusion
In summary, we have developed a versatile methodology for the
synthesis of a novel class of chiral non-racemic tetra-carbohydrazide
cyclophane macrocycles. Both (R) and (S) enantiomers can be
readily synthesised in short reaction steps, high purity and quantitative
yields. The novel macrocycles can be functionalized by
simple choice of the target ketone or diketal to be protected. This
can lead to the synthesis of supramolecular architectures with
fascinating structures and improved solubility. In addition, the
dicarbohydrazide precursors showed interesting molecular selfassembly
in the gas phase to form hydrogen bonded macrocycles,
which has been confirmed by ESI-TOF MS. Further studies aimed
at assessing the molecular recognition properties of the novel
macrocycles are under investigation.
Experimental Section
All the reagents used for the reactions were purchased from Sigma-Aldrich, Applichem
or Flucka (Germany) and were used as obtained. Whenever possible the reactions were
monitored by thin layer chromatography (TLC). TLC was performed on Macherey-
Nagel aluminium-backed plates pre-coated with silica gel 60 (UV 254). Melting points
were determined in open capillaries using a Buechl B-545 melting point apparatus and
are not corrected. Infrared spectra were determined using a Vector-33 Bruker FT-IR
spectrometer. The samples were measured directly as solids or oils; ṽ max values were
expressed in cm –1 and were given for the main absorption bands. 1 H-NMR and 13 C-
NMR spectra were acquired on a JEOL ECX-400 spectrometer operating at 400 MHz
for 1 H-NMR and 100 MHz for 13 C-NMR in [D6]DMSO or [D7]DMF using a 5 mm
probe. The chemical shifts (δ) are reported in parts per million and were referenced to
the residual solvent peak. The following abbreviations are used: s, singlet; m, multiplet;
br, broad signal. Mass spectra were recorded using Bruker HCTultra and high resolution
Bruker Daltonics micrOTOF instruments from DMSO, DMF and acetonitrile or water
using the positive electrospray ionisation ESI- and APCI-MS modes. Calibration was
carried out using a 0.1 M solution of sodium formate in the enhanced quadratic mode
prior to each experimental run. The results of measurements were processed using
Compass 1.3 data analysis software for a Bruker Daltonics time-of-flight mass
spectrometer (micrOTOF). Molecular modeling was carried out with HyperChem
(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dicarbohydrazide 4: To a stirred solution of
(4S,5S)-dimethyl-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate 3 (5.8 g, 26.60 mmol)
in absolute ethanol (20 mL) was added hydrazine monohydrate (2.8 mL, 88.68 mmol)
and the mixture was refluxed for 12 h. The solvent was evaporated under vacuum and
the resulting oil was partionated between ethyl acetate and water (10 mL). To the water
phase was added ethanol (200 mL) and anhydrous Na 2SO 4. The solvent was filtered off
and evaporated under vacuum to afford the title product as a white gummy material
(4.50 g, 77%). 1 H NMR (400 MHz, [D6]DMSO, 25 °C, TMS): δ = 9.3 (brs, 2H; NH),
4.4 (brs, 2H; CH), 4.3 (brs, 4H; NH 2), 1.3 ppm (s, 6H; CH 3); 13 C NMR (100 MHz,
[D6]DMSO, 25 °C, TMS): δ =167.8, 112.2, 77.2, 26.6 ppm; FT-IR: ṽ = 3316 (NH and
NH 2), 1660 cm –1 (C[dbond]O); HRMS (ESI-): m/z calcd. for [C 7H 14N 4O 4+Na + ]:
241.0907 [M+ Na + ]; found: 241.0900.
(2R,3R)-1,4-dioxaspiro-[4.5]-decane-2,3-dicarbohydrazide 7: To a stirred solution of
(+)-diethyl L-tartrate (7.5 mL, 44 mmol) in toluene (150 mL) were added 1,1-
dimethoxycyclohexane (10 mL, 65.8 mmol) and PTSA (103 mg, 0.54 mmol). The flask
was fitted with a Soxhlet extractor, reflux condenser and a thimble containing freshly
activated 4 Å molecular sieves (15 g). The mixture was refluxed for 7h, during which
the thimble was recharged with fresh molecular sieves twice. The reaction mixture was
neutralised with anhydrous sodium bicarbonate and the suspension was filtered off. The
solvent was evaporated under vacuum and the residue was partionated between ethyl
acetate and water, washed with saturated sodium bicarbonate (70 mL), brine (70 mL)
and dried with Na 2SO 4. The solvent was filtered off and evaporated under vacuum. The
crude oil (11.17 g) was dissolved without further purification in absolute ethanol (50
mL) and hydrazine monohydrate was added (4.4 mL, 140 mmol). The mixture was
refluxed for 7 h and the solvent was evaporated under vacuum. The residue was
dissolved in water (10 mL) and extracted with ethyl acetate (3×50 mL). The water
extract was dissolved in ethanol (200 mL), dried with Na 2SO 4 and evaporated under
vacuum to afford the title product as pale yellow gummy material (5.58 g, 55%). 1 H
NMR (400 MHz, [D6]DMSO, 25 °C, TMS): δ = 9.2 (brs, 2H; NH), 4.4 (brs, 2H; CH),
4.3 (brs, 4H; NH 2), 1.4-1.5 (m, 8H; CH 2), 1.2 ppm (m, 2H; CH 2); 13 C NMR (100 MHz,
[D6]DMSO, 25 °C, TMS): δ =167.9, 112.9, 76.9, 35.7, 24.9, 23.8 ppm; FT-IR: ṽ = 3313
(NH and NH 2), 1666 cm –1 (C[dbond]O); HRMS (ESI-): m/z calcd. for
[C 10H 18N 4O 4+Na + ]: 281.1220 [M+ Na + ]; found: 281.1231.
(2S,3S)-1,4-dioxaspiro-[4.5]-decane-2,3-dicarbohydrazide 9: To a stirred solution of
(-)-diethyl D-tartrate (7.5 mL, 44 mmol) in toluene (150 mL) were added 1,1-
dimethoxycyclohexane (10 mL, 65.8 mmol) and PTSA (103 mg, 0.54 mmol). The flask
was fitted with a Soxhlet extractor, reflux condenser and a thimble containing freshly
activated 4 Å molecular sieves (15 g). The mixture was refluxed for 7h, during which
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