Exceptional reactivity of the bridgehead amine on bicyclo[1.1.1]pentane

Bicyclo[1.1.1]pentane (BCP) has received substantial interest in the field of synthetic chemistry recently for its potential use as a benzene isostere in medicinal chemistry. Whereas bicyclo[2.2.2]octane (BCO) has also been used as a bioisostere of benzene, the condensation of BCP-amine with nadic anhydride is significantly easier than that of BCO-amine. Analyses of the geometries and the frontier molecular orbitals of these amines suggest that the low steric hindrance and high intrinsic nucleophilicity of BCP-amine together contribute to its exceptional reactivity.


Introduction
Bicyclo [1.1.1]pentane7][18][19] Similar to bicyclo[2.2.2]octane (BCO), [20][21][22][23] the fully sp 3 -hybridized BCP is a hydrophobic group ideal for filling enzyme pockets wherein π-π interaction is not needed.We sought to explore the possibility of using BCP or BCO to improve the drug properties of IWR1 (1), a highly selective tankyrase inhibitor (TNKSi) 24 that binds to the adenosine (AD) site of tankyrase (TNKS) to induce a D-loop conformation change of this unique PARP family protein to prevent poly(ADP-ribosylation) of its substrates. 25owever, 1 has low aqueous solubility and poor metabolic stability. 26During the synthesis of the BCP and BCO analogs of 1, we found that the BCP-amine reacted with nadic anhydride easily but the BCO-amine sluggishly.Analyses of the geometries and the frontier molecular orbitals of these amines provided an explanation to the reactivities of these structurally unique primary amines.A combination of low steric hindrance and high intrinsic nucleophilicity of the BCP-amine contributes to its exceptional reactivity.

Results and Discussion
1,3-Disubstituted BCP is a bioisostere of 1,4-disubstituted benzene.Docking experiments suggest that substituting the benzene ring of 1 with BCP would not affect its affinity to TNKS (Figure 1).We thus prepared IWR1-BCP (2) using a simple 5-step procedure (Figure 2).Coupling BCP-acid 3 with 8-aminoquinoline (4) followed by hydrolyzing its ester group gave 5. Subsequent Curtius rearrangement in tert-butanol yielded 6, a carbamate that could also be prepared directly from coupling the more expensive BocNH-BCP-COOH with 4. After removing the Boc group, condensing the resulting amine with endo-nadic anhydride (7) afforded 2 with a good overall yield.To further evaluate the steric tolerance of the AD pocket of TNKS wherein the benzene ring of 1 sits, we prepared IWR1-BCO (8) in a similar manner as 1,3-disubstituted BCO is also a commonly used 1,4benzene bioisostere. 27,28However, the norendimide condensation proceeded with a poor yield.To understand the observed reactivity difference, we also synthesized IWR1-BCHx (9) and IWR1-BCHp (10) analogously and found that the condensation efficiency gradually decreased as the size of the bicyclic ring system increases (BCP-2: 97% → BCHx-9: 49% → BCHp-10: 37% → BCO-8: 7%).To probe the dramatic difference in the condensation efficiency of these bicyclic amines, we assessed the nucleophilicity of 11─14 computationally to determine the contribution of the stereoelectronic effects of the ring system to the reactivity of the attached primary amine.We first calculated the equilibrium geometries of 8 primary amines (n-propyl, n-butyl, allyl, benzyl, 2-hydroxyethyl, i-propyl, t-butyl, and trifluoroethyl) and the corresponding ammonium ions by DFT at the B3LYP/6-311G+(d,p) level.We then used their HOMO and LUMO energies to evaluate various methods of nucleophilicity prediction. 29,30We found that the energy difference between the HOMO of the amine and the LUMO of the ammonium ion correlates well with the experimental data obtained in acetonitrile, 31 and the single-point energies calculated with the 6-311G+(d,p) basis set provided significantly better prediction than def2-TZVP.Adding the SMD solvation energy calculated at the 6-31G(d) level further improved the correlation (Figure 3).We thus used this model to estimate the intrinsic nucleophilicity of 11─14.Interestingly, introducing ring strains increases the s-character of the C─N bond (14: 27% → 13: 28% → 12: 30% → 11: 34%) 32 but does not attenuate their nucleophilicity.Amines 11─14 are all predicted to be more nucleophilic than aniline (N = 12.64).In particular, 11 has significantly higher nucleophilicity than aniline despite nearly sp 2 -hybridized at the bridgehead position.However, 11 is predicted to have lower nucleophilicity than 12 and 13.The nucleophilicities of 12 and 13 are expected to be close to that of n-propylamine, 11 to be equivalent to allylamine and benzylamine, and 14 to reside between isopropylamine and tert-butylamine.
To further understand the exceptional reactivity of BCP-amine, we assessed the steric hindrance of 11─14 by calculating the cone angles of these amines.As expected, the cone angle gradually increases as the ring size increases, with 12 close to iso-propylamine (90°) and 14 close to tert-butylamine (106°).Moreover, the distance between the nitrogen atom and the nearest hydrogen atom that blocks the approach of the electrophile is the longest for BCP and the shortest for BCO.This rather subtle steric effect apparently further tunes the reactivity of the amino group attached to the bridgehead position of these bicyclic systems.As such, the unique size of BCP-amine granted it exceptional reactivity toward nucleophilic reactions.

Conclusions
The nucleophilicity of a series of primary amines can be approximated by the energy difference between the HOMO of the amine and the LUMO of its ammonium ion, and this prediction can further be improved by including solvation energies.Despite nearly sp 2 -hybridized at the bridgehead position, 11 is expected to be significantly more nucleophilic than aniline.Additionally, the difference in the norendimide condensation efficiency of 2, 8, 9, and 10 cannot be explained simply by the electronic properties of these primary amines.A combination of low steric hindrance and high intrinsic nucleophilicity of the BCP-amine contributes to its exceptional reactivity.

Experimental Section
General.All solvents for the synthesis were purified by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns.Reactions were monitored by TLC or LC-MS and the products were purified by flash column chromatography unless otherwise mentioned.NMR spectra were recorded on a Bruker AN400 or AN600 instrument.The chemical shifts for 1 H and 13 C NMR spectra are reported in ppm (δ) relative to the 1 H and 13 C signals in the solvent (CDCl3: δ 7.26, 77.16 ppm; CD3CN: δ 1.94, 118.26 ppm; CD3OD: δ 3.31, 49.00 ppm) and the multiplicities are presented as follows: s = singlet, d = doublet, t = triplet, m = multiplet.LC-MS was performed on an Agilent 1260 HPLC machine coupled to a 6120 single quadrupole MS detector using an Agilent Eclipse XDB-C18 5 μm 4.6×150 mm column.

Figure 2 .
Figure 2. The synthesis of 2 and the structures of 8-10.