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

Trianglimine formation mechanism by ESI-TOF MS
yield. [9] Reviewing the literature evidence and our previous
experience it can be concluded that when the two
dialdehyde functionalities deviate from an ideal dihedral angle
O=C ... C=O,thereactioncangivetwoormoreproducts.Obtaining
the desired [3+3]-cyclocondensation macrocycle requires
careful optimization of the reaction conditions such as concentration
and time or alternatively the addition of a template as
illustrated by González-Álvarez et al. [31] andSaggiomoand
Lüning, [32] to achieve a maximum yield and high purity of the
desired product, which should be the [2+2]- or [3+3]-macrocycle.
Stoichiometry dependence and NMR investigations
In order to gain more insight into the mechanism of the reaction
we conducted the [3+3]-cyclocondensation reaction using
different stoichiometries of (1R,2R)-1,2-diaminocyclohexane
and terephthaldehyde 2 or isophthaldehyde 3. In the case of
terephthaldehyde 2 we found that the macrocycle 4 was cleanly
formed using a 1:1 stoichiometry and an excess of the dialdehyde
(1:2 and 1:5). If an excess of the diamine component was
used (2:1), the yield of the macrocycle was dramatically reduced
and no macrocycle at all was obtained using higher excess (5:1)
of the diamine 1. Using isophthaldehyde 3 theoppositeresults
were observed. The macrocycle 5 was obtained using an excess
of (1R,2R)-1,2-diaminocyclohexane 1 whereas reduced yields or
no macrocycle were obtained using an excess of the dialdehyde
component.
In order to gather more insight, to rationalize this unusual
behavior and to identify the reaction intermediates we followed
the reaction of 2 and 1 at 0.1 M in CDCl 3 with a 1:1 stoichiometry
of the components by 1 H-NMR, 1 H- 1 H-COSYand 1 H- 1 H-TOCSY
NMR. For both reactions we recorded the 1 H-NMR spectrum
every 5 min for 2 h and the 2D spectra every 30 min for 2 h.
In case of the terephthaldehyde 2 the signals of the two
starting materials disappeared and after 10 min the first
intermediate began to accumulate. After 20 min the signals
Figure 5. Computed structures for intermediates 10, 12, 16 and 18 at the PM3
level using a Polak-Ribiere conjugate gradient with rms