The Development of Novel Antibiotics Using ... - Jacobs University

that two distinct conformational isomers could result from intramolecular
hydrogen bonding (C=O…HN) and π-π stacking interactions.
calculations. Structures of the novel macrocycles (i.e., macrocycle
10) were energy minimised using HyperChem software (Release
8.0) as shown in Figure 6. 33
Table 1. ESI- and APCI-TOF MS data for the novel macrocycles
Cpd
Molecular
Formula
Calcd. m/z Meas. m/z Error
(ppm)
Yield
(%)
2 C 7H 14N 4O 4 241.0907 241.0900 3.0 88
4 C 7H 14N 4O 4 241.0907 241.0900 3.1 77
7 C 20H 36N 8O 8 539.2548 539.2572 - 4.4 55
9 [a] C 20H 36N 8O 8 539.2545 539.2550 - 0.3 56
10 C 42H 40N 8O 10 839.2760 839.2795 - 4.3 97
11 C 54H 50N 10O 8 989.3705 989.3668 3.8 99
12 C 42H 40N 8O 10 839.2760 839.2744 1.9 94
13 C 54H 50N 10O 8 989.3933 989.3752 - 4.8 99
14 C 48H 48N 8O 10 897.3566 897.3526 4.5 98
15 C 60H 58N 10O 8 1047.4512 1047.4521 - 0.9 99
16 C 48H 48N 8O 10 897.3566 897.3539 3.0 88
17 C 60H 58N 10O 8 1047.4512 1047.4509 0.3 89
9 [b] C 20H 36N 8O 8 517.2729 517.2706 4.3 -
9 [c] C 30H 54N 12O 12 775.4057 775.4022 4.5 -
9 [d] C 40H 72N 16O 16 1033.5385 1033.5420 - 3.4 -
Figure 5. Graphical representation showing changes of chemical shift in response to
increased temperature, (A) 1 H-NMR spectrum was recorded at ambient temperature
after cooling the sample.
[a], [b], [c] and [d] are self-assembled macrocycles (a-d).
Figure 4. Stacked 1 H-NMR spectra for macrocycle 10 showing changes in δ in response
to increased temperature, 400 MHz in DMF-d 7.
The change in chemical shifts in response to increased temperature
can be graphically visualised by plotting the values of chemical shift
(δ in ppm) versus temperature (K) as shown in figure 5. It can be
inferred that intramolecular hydrogen bonds break upon heating,
resulting in upfield shift of the associated (NH) protons.
Our hypothesis of conformational isomers is further supported by
2D-NMR experiments. 2D-ROESY spectrum for macrocycle 10
showed through space interactions of two (NH) protons with two
azomethine protons (HC=N) and two methine protons (See supporting
information). The other (NH) protons showed through space
interactions only with two azomethine protons (HC=N), while no
interactions were observed with methine protons. In order to further
understand the nature of the intramolecular hydrogen bonding, we
performed several molecular modeling studies. Data from 2D-
ROESY experiments were used for subsequent structure modeling
Figure 6. Computed structures for macrocycle 10 at the AMBER and PM3 levels using
a Polak-Ribiere conjugate gradient with rms ˂ 0.01 Kcal.mol –1 .
The molecular structures were optimised at the AMBER and PM3
levels using the Polak-Ribiere algorithm until the root-mean square
(RMS) gradient was 0.01 Kcal.mol –1 or less. The results of
molecular modeling are in good agreement with the data from 2D-
ROESY experiments. In solution, macrocycle 10 assumes conformation
10b which is highly stabilised by intramolecular hydrogen
bonding and π-π stacking interactions. The chirality of the novel
macrocycles and their precursors was confirmed by CD-spectroscopy
as shown in figure 6. All-R macrocycle 11 shows for example
a positive Cotton effect with a zero intercept at around 370 nm,
whereas its enantiomeric counterpart all-S 13 shows a negative
Cotton effect. Similar to trianglimines the observed Cotton effect is
a consequence of the interaction of the two aromatic chromophores
4