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

H. F. Nour, A. M. Lopez-Periago and N. Kuhnert
4, 5 and 6. The closer the nucleophilic amino and the electrophilic
carbonyl groups are in space the more rapidly ring
closure will occur. The lowest energy conformations for intermediates
10, 12, 16 and 18 are shown in Fig. 5. It can be
concluded from the computational calculations that the
nucleophilic and electrophilic groups in intermediates 12
and 18 are located 4.62 and 4.25 Å apart in space. This
certainly allows facile ring closure due to conformational bias.
Furthermore, the formation of the [2+2]-cyclocondensation
macrocycle 6 is in complete agreement with the computed
structure 16 in which the reactive sites are 4.66 Å separated.
Unlike the case with intermediate 16, intermediate 10 cannot
cyclocondense to the corresponding [2+2]-macrocycle because,
in terephthaldehyde, the dihedral angle O=CC=O biases
intermediate 10 to a conformation in which the reactive
nucleophilic and electrophilic sites are separated by 9.74 Å. This
distance does not permit cyclocondensation to the [2+2]-
macrocycle but it rather permits further condensation with
one molecule of (1R,2R)-1,2-diaminocyclohexane 1 and another
molecule of terephthaldehyde 2 to form trianglimine 4.
Similar to the [3+3]-cyclocondensation reactions of (1R,2R)-
1,2-diaminocyclohexane 1 with tere- 2 and isophthaldehyde 3
which constitute symmetrical dialdehyde building blocks, the
cyclocondensation reaction of (1R,2R)-1,2-diaminocyclohexane
1 with non-symmetrical dialdehydes was investigated. The
reaction was monitored as described with tere- 2 and isophthaldehyde
3 using ESI-TOF MS. Interestingly, a total of ten different
intermediates were detected and their structures were
assigned based on their high-resolution m/z values. To the best
of our knowledge, the detection and structural assignment of
ten reaction intermediates in a one single reaction have not
previously been reported, illustrating the power of mass spectrometry
in mechanistic studies of multistep and cascade
reactions. Recently, we reported the synthesis of 3-phenoxybiphenyl-4,4′-dicarbaldehyde
19 from the corresponding
4-bromo-2-fluorobenzaldehyde via nucleophilic aromatic
substitution reaction with phenol followed by Suzuki coupling
with 4-formylphenylboronic acid. [18] It is worth noting that
3-phenoxybiphenyl-4,4′-dicarbaldehyde 19 constitutes a nonsymmetrical
dialdehyde building block and its reaction with
(1R,2R)-1,2-diaminocyclohexane 1 has resulted in the formation
of a mixture of regioisomeric C 3 -symmetrical 30 and nonsymmetrical
31 trianglimines as shown in Fig. 6. [18]
The mechanism of the [3+3]-cyclocondensation reaction
was studied and confirmed by ESI-TOF MS (Scheme 3).
A solution of 3-phenoxybiphenyl-4,4′-dicarbaldehyde 19
in DCM was stirred at room temperature with (1R,2R)-
1,2-diaminocyclohexane 1 at 0.1 M for 8 h. Aliquots were
taken every 2 h, diluted with DCM and a few drops of
MeOH were added before it was directly infused into the
ESI-TOF mass spectrometer. Intermediates 20–29 were
detected and assigned based on their high-resolution m/z
values (Table 3). Figure 7 shows the ESI-TOF mass spectra
for all the intermediates which were detected 2 h after the
startofthereaction.
Dynamic reversibility of trianglimine formation
Should the cyclocondensation reaction be fully reversible as
suggested by the reversible nature of the imine bond (C=N) formation,
the design of dynamic combinatorial libraries would be
feasible. [33] Ultimate proof of reversibility has been defined by
Sanders and co-workers. [34–43] Here reversibility is demonstrated
by reaching the same equilibrium composition of a mixture
from different starting points of the reaction system. For
this reason we undertook a series of crossover experiments. In
a first series we mixed two sets of the non-symmetrical trisubstituted
trianglimines 31 and 32 in DCM and the reaction was
monitored with ESI-TOF MS (Scheme 4).
Trianglimines 31 and 32 were synthesized following
our strategy from non-symmetrical dialdehyde building
blocks. [18] The two macrocycles were mixed together in DCM
Table 4. ESI-TOF MS data in the positive ion mode for the products of imine exchange reactions
Entry Calcd. m/z Measured m/z Molecular formula Error [ppm]
1078
20, 22 a 399.2067 399.2063 C 26 H 26 N 2 O 2 1
30, 31 a 1141.5666 1141.5629 C 78 H 72 N 6 O 3 3.2
32 a 1333.7576 1333.7542 C 81 H 96 N 12 O 6 2.5
42, 47 a 463.2704 463.2723 C 27 H 34 N 4 O 3 4.1
20, 22 b 399.2067 399.2046 C 26 H 26 N 2 O 2 5.2
42, 47 b 463.2704 463.2688 C 27 H 34 N 4 O 3 4.6
20, 22 c 399.2067 399.2060 C 26 H 26 N 2 O 2 1.6
30, 31 c 1141.5666 1141.5680 C 78 H 72 N 6 O 3 1.2
34-37 c 1205.6303 1205.6242 C 79 H 80 N 8 O 4 5
38-41 c 1269.6939 1269.6941 C 80 H 88 N 10 O 5 0.1
42, 47 c 463.2704 463.2693 C 27 H 34 N 4 O 3 2.6
43-46 c 747.3541 747.3510 C 47 H 46 N 4 O 5 4.1
20, 22 d 399.2067 399.2067 C 26 H 26 N 2 O 2 4.8
30, 31 d 1141.5666 1141.5658 C 78 H 72 N 6 O 3 0.7
34-37 d 1205.6303 1205.6249 C 79 H 80 N 8 O 4 4.4
38-41 d 1269.6939 1269.6923 C 80 H 88 N 10 O 5 1.2
42, 47 d 463.2704 463.2695 C 27 H 34 N 4 O 3 1.8
43-46 d 747.3541 747.3501 C 47 H 46 N 4 O 5 5
a Dynamic reversibility of trianglimines 31 and 32 (3 h); b dynamic reversibility of compounds 1, 19 and 33 (3 h); c dynamic
reversibility of trianglimines 31 and 32 (46 h); d dynamic reversibility of compounds 1, 19 and 33 (46 h).
wileyonlinelibrary.com/journal/rcm Copyright © 2012 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom. 2012, 26, 1070–1080