Synthesis and computational analysis of conformationally restricted [3.2.2]- and [3.2.1]-3-azabicyclic diamines

Article abstract of DOI:10.1016/j.tetlet.2017.09.033

Conformational restriction is a useful approach for ligand design in organic and medicinal chemistry. This manuscript reports the facile synthesis and in silico conformational analysis of two new diastereomeric [3.2.2]-3-azabicyclic, two new [3.2.1]-3-aza-8-oxy-bicyclic and one new [3.2.1]-3-azabicyclic diamine scaffolds. A conformational analysis of these structures along with calculation of carbon–carbon/carbon–nitrogen bond angles was carried out and compared to those in the flexible 1,3-diaminopropane template upon which they were based. It is of particular importance that these scaffolds have bond lengths and angles that can overlap with low energy conformers of the flexible diamine. Such information is useful for ligand design in organic chemistry and for development of structure activity relationships and in silico screening in medicinal chemistry.

Full text of DOI:10.1016/j.tetlet.2017.09.033

Accepted Manuscript
Synthesis and Computational Analysis of Conformationally Restricted [3.2.2]-
and [3.2.1]-3-Azabicyclic Diamines
Sreedhar Reddy Tummalapalli, Rohit Bhat, Craig Waitt, Henk Eshuis, David P.
Rotella
PII:
S0040-4039(17)31161-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.033
TETL 49303
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2017
11 September 2017
13 September 2017
Please cite this article as: Tummalapalli, S.R., Bhat, R., Waitt, C., Eshuis, H., Rotella, D.P., Synthesis and
Computational Analysis of Conformationally Restricted [3.2.2]- and [3.2.1]-3-Azabicyclic Diamines, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.033
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Synthesis and Computational Analysis of Conformationally Restricted [3.2.2]- and
[3.2.1]-3-Azabicyclic Diamines
Sreedhar Reddy Tummalapalli, Rohit Bhat, Craig Waitt, Henk Eshuis*,
David P. Rotella*
Department of Chemistry and Biochemistry
Montclair State University
1 Normal Avenue
Montclair NJ 07043
eshuish@montclair.edu
rotellad@montclair.edu

Abstract:
Conformational restriction is a useful approach for ligand design in organic and
medicinal chemistry. This manuscript reports the facile synthesis and in silico
conformational analysis of two new diastereomeric [3.2.2]-3-azabicyclic, two new
[3.2.1]-3-aza-8-oxy-bicyclic and one new [3.2.1]-3-azabicyclic diamine scaffolds. A
conformational analysis of these structures along with calculation of carbon-
carbon/carbon-nitrogen bond angles was carried out and compared to those in the
flexible 1,3-diaminopropane template upon which they were based. It is of particular
importance that these scaffolds have bond lengths and angles that can overlap with low
energy conformers of the flexible diamine. Such information is useful for ligand design
in organic chemistry and for development of structure activity relationships and in silico
screening in medicinal chemistry.

Introduction
Diamines are widely used in medicinal chemistry for the preparation of G-protein
coupled receptor (GPCR) ligands and enzyme inhibitors and in organic chemistry as
ligands in a range of chemical reactions.1 In medicinal chemistry conformational
restriction in a scaffold is valuable to probe specific regions of space in a protein in an
attempt to optimize affinity.2 Recent examples include the discovery of a potent,
selective M1/M4 [3.2.1] bicyclic agonist 1a which was superior to an analogous
piperidine derivative 1b3 and Gosling et al. reported the synthesis and use of ( )-endo-
3-azabicyclo[3.2.1]octane-6-amine 24 to study adenosine receptor interactions. (figure
1).
Figure 1: Representative recent examples of conformationally restricted diamines.
To extend the diversity of bicyclic diamines available in organic and medicinal
chemistry, we now report the racemic synthesis and characterization of the unknown
exo isomer (3) of 2, the previously unknown 8-oxa-3-azabicyclo[3.2.1]octane amines 4
and 5 as well as the ring expanded [3.2.2]nonane amines 6 and 7 (figure 2). The
oxygen-containing analogs represent conformationally restricted morpholine rings.
Morpholine has been explored as a catalyst for a number of organic transformations.5

Figure 2: Bicyclic diamine target molecules
Furthermore, we carried out an in silico investigation of the conformational
stability and rigidity of the scaffolds and their structural resemblance to low energy
conformations of 1,3-diaminopropane. Here, we use Density Functional Theory (DFT) to
investigate the relative stability of the boat-like conformation vs. the chair-like
conformation of 2 and 3-7. Overlaying the optimized structures for these compounds on
low-energy conformations of 1,3-diaminopropane unit provides insight in the degree of
distortion of the diamine unit in the scaffolds.
Results and discussion
Our approach to the synthesis of these molecules is similar to that employed by
Gosling (scheme 1).
Diels-Alder cycloaddition between ethyl acrylate and
cyclopentadiene, furan and 1,3-cyclohexadiene provided known [3.2.1] and [3.2.2]-
bicyclic esters as a separable mixture of exo and endo isomers, followed by
saponfication and stereospecific Curtius rearrangement.4,6 Endo/exo stereochemistry in
each ester intermediate was established by comparison to the NMR spectra of each
compound in the literature and confirmed following base-mediated hydrolysis to known
acids 9-12.6a,b Acid 8 is commercially available. The Diels-Alder reaction between 1,3-
cyclohexadiene and ethyl acrylate leading to bicyclo[2.2.2]-octene esters 13 and 14

proceeded in our hands with 9:1 endo:exo selectivity. To obtain sufficient quantities of
the exo isomer 14, 13 was epimerized (LDA/THF, -78oC, acetic acid quench at 0o C)
leading to nearly a 1:1 mixture of that was efficiently separated by silica gel
chromatography. The resulting Boc-protected bicycloalkenes (15-19) were efficiently
converted to a diastereomeric mixture of diols (20a-e) using catalytic OsO4 and N-
methylmorpholine-N-oxide, followed by oxidative cleavage with sodium periodate to
furnish bisaldehydes that were not purified. The crude bisaldehydes underwent
reductive amination using benzylamine, catalytic acetic acid and sodium
triacetoxyborohydride in dilute 1,2-dichloroethane solution at room temperature
overnight leading to the desired Boc-protected bicyclic targets 21-25.
Scheme 1: Synthesis of [3.2.n]-bicyclodiamines
Computational Results

The relative energetics of templates 2-7 were studied to identify stable
conformations and the energy barriers associated with transitions between chair-like
and boat-like conformations – see Figure 3. The benzyl group was replaced by
hydrogen (R = H in Figure 3) and results are shown in Table 1. (Structural parameters
for all templates and data for oxabicycles 4 and 5 are included in the supplementary
information.) Templates with the more flexible two-carbon bridge (28 and 29) show no
significant difference in relative energy between the conformations shown in Figure 3.
(i.e. 13-14 and 15-16).
Figure 3: Conformational mobility of bicyclic diamines
The more restricted [3.2.1] structures 26 and 27 (with X = CH2) show a
preference for the chair-like conformation (e.g, 26 in Figure 3) of 5-8 kcal/mol. The
barrier heights for forward and reverse conversions range between 3.5 and 9.8
kcal/mol. For all templates, the reverse barrier is higher than the forward barrier, though
in case of the [3.2.2] scaffold the difference is insignificant. The position of the primary
amine group (exo or endo) does not significantly affect the relative energies of these
templates. Results from the random phase approximation (RPA) show no significant
difference with the DFT/B3-LYP results indicating that non-covalent interactions do not

play a significant role. The free energy barrier heights are very similar to the electronic
energies with a maximum difference of about 1 kcal/mol. Inclusion of solvation effects
changed the barrier heights by at most 1.3 kcal/mol (for the 9.0 kcal/mol reverse barrier
of 2) with no changes to the order of the relative energies (see Supporting Information
for Results). Thus, finite temperature effects and solvation do not change the qualitative
results.
Relative Energy
Structure
(kcal/mol)
[3.2.1]
DFT
0.2
5.5
RPA
0.3
5.7
2 chair-like
2 boat-like
3 chair-like
3 boat-like
0
7.9
0
8.5
[3.2.2]
6 chair-like
6 boat-like
7 chair-like
7 boat-like
1.3
1.5
0
1.3
1.5
0
0.7
0.9
Table 1: Relative energies (in kcal/mol) for the 8 studied template derivatives. DFT
calculations were at the B3-LYP/def2-TZVP level of theory. The RPA results were
obtained using PBE input orbitals with the def2-QZVPP basis set. On all templates, the
benzyl substituent was replaced by hydrogen.

Figure 4. Stick representations of 3 (blue, without benzyl substituent) and 1,3-
diaminopropane (red) overlapped to show extent of deviation.
The energetics of the templates are affected by addition of substituents. Adding
phenyl to the endocyclic nitrogen (R in Figure 3) effectively removes the barrier between
chair- and boat-like conformation due to the overlap of the π-system with the lone pair
electrons on the nitrogen which stabilizes the transition state. On the other hand, using
t-butyl as substituent has very little effect. The addition of t-butyl carbamate on the
primary nitrogen (R’ in Figure 3) results in only one type of minimum energy structure
per template: boat-like for 7, chair-like for 2, 3, 6. For the more restricted [3.2.1]
structures, this is in agreement with the findings in Table 1 where the chair-like structure
was preferred. The substituent alters the potential energy surface in such a way that a
local minimum for the boat-like conformation can no longer be found.
Finally, the optimized structure for 1,3-diaminopropane was mapped onto the
propane diamine unit contained in the templates to investigate to what extent its
structure is preserved the bicyclic units. The energetically most stable structures display
a gauche arrangement for the NCCC dihedral angles7 and resemble the minimum-
energy structure of 1,3-diaminopropane to a high degree. Addition of substituents on the
primary (t-butyl carbamate) and nitrogen (benzyl or t-butyl) does not significantly change
the structure of the propane diamine unit.
Conclusions
We synthesized and characterized five new racemic bicyclic diamines based on
[3.2.1] and [3.2.2] templates using chemistry that is scalable and efficient. These
structures are conformationally restricted 1,3-propanediamines that are of interest in

organic and medicinal chemistry as building blocks for development of structure-activity
relationships in enzyme inhibitors and receptor ligands. Calculations showed that there
are two distinct orientations (chair-like and boat-like) of the ring containing the
secondary nitrogen with a comparatively low energy barrier (< 9 kcal/mol) between
these conformations. Chair-like conformations are more stable for the [3.2.1] templates,
whereas interestingly in the [3.2.2] templates the two orientations are very similar in
energy. When adding t-butyl carbamate to the primary amine only the chair-like
minimum is found for the [3.2.1] templates. Either the boat-like or chair-like orientation is
found for the [3.2.2] templates. The effect of a substituent on the secondary amine
depends on its electronic structure: phenyl removes the barrier between chair- and
boat-like orientation, whereas t-butyl has no significant effect.
Both the [3.2.1] and [3.2.2] templates can be overlaid on low energy
conformations of 1,3-diaminopropane with similar bond lengths and bond angles. This
observation is an important one, highlighting the value of these scaffolds to mimic low
energy conformations of the flexible diamine.
In view of the wide use of
conformationally restricted diamines in medicinal chemistry and the use of virtual
screening as a starting point for hit identification, these results offer medicinal chemists
new scaffolds for exploration. Given the comparative ease of synthesis, the ability to
adapt this to obtain optically active versions with high enantiospecificity, their relative
structural rigidity and similarity to low energy conformations of the flexible parent
diamine, these scaffolds can be more readily explored in both organic and medicinal
chemistry. Investigations toward these objectives are underway and will be reported in
due course.

ACKNOWLEDGMENTS
We thank Wayne Childers and Carlos Barrero for their assistance with high resolution
mass spectra. This research was supported by the Margaret and Herman Sokol
Endowment and Montclair State University.
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Synthesis and Computational Analysis of Conformationally Restricted [3.2.2]- and
[3.2.1]-3-Azabicyclic Diamines
Highlights
• Expeditious synthesis of five unknown bicyclic [3.2.n] diamines (n=1 and 2)
• In silico analysis flexibility reveals low barrier for boat-chair interconversion
• In silico analysis reveals substituents influence conformation in [3.2.2] scaffold
• Substantial overlap with low energy conformations of 1,3-diaminopropane

Graphical Abstract
Synthesis and Computational Analysis of Conformationally Restricted [3.2.2]- and
[3.2.1]-3-Azabicyclic Diamines
Sreedhar Reddy Tummalapalli, Rohit Bhat, Craig Waitt, Henk Eshuis*,
David P. Rotella*
Department of Chemistry and Biochemistry
Montclair State University
1 Normal Avenue
Montclair NJ 07043
2/3
6/7
4/5