Synthesis and computational analysis of conformationally restricted [3.2.2]- and [3.2.1]-3-azabicyclic diamines
نویسندگان
چکیده
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. 2017 Elsevier Ltd. All rights reserved. amines. 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. 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. 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 1b and Gosling et al. reported the synthesis and use of (±)-endo-3azabicyclo[3.2.1]octane-6-amine 2 to study adenosine receptor interactions (Fig. 1). 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 (Fig. 2). The oxygen-containing analogs represent conformationally restricted morpholine rings. Morpholine has been explored as a catalyst for a number of organic transformations. 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 1,3diaminopropane. 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 saponification and stereospecific Curtius rearrangement. Endo/exo stereochemistry in each ester intermediate was established by comparison to the NMR spectra of each compound in the literature Fig. 2. Bicyclic diamine target molecules. Scheme 1. Synthesis of [3.2.n]-bicyclodiamines. Fig. 3. Conformational mobility of bicyclic diamines. 4088 S.R. Tummalapalli et al. / Tetrahedron Letters 58 (2017) 4087–4089 and confirmed following base-mediated hydrolysis to known acids 9–12. 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, -78 C, acetic acid quench at 0 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 Nmethylmorpholine-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. 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 Fig. 3. The benzyl group was replaced by hydrogen (R = H in Fig. 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 Fig. 3 (i.e. 13–14 and 15–16). 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 Fig. 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 Fig. 4. Stick representations of 3 (blue, without benzyl substituent) and 1,3diaminopropane (red) overlapped to show extent of deviation. 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 (see Supporting Information for computational details). Structure Relative Energy (kcal/mol) [3.2.1] DFT RPA 2 chair-like 0.2 0.3 2 boat-like 5.5 5.7 3 chair-like 0 0
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