The selective mono and difunctionalization of carbocyclic cleft molecules with pyridyl groups and X-ray crystallographic analysis

Abstract

Citation: JILKA, P. ... et al, 2010. The selective mono and difunctionalization of carbocyclic cleft molecules with pyridyl groups and X-ray crystallographic analysis. Tetrahedron, 66 (48) --- IntroductionMolecular recognition relies on the ability to design and synthesize appropriate substrates with predictable geometries and binding sites. 1 Towards this end Tröger's base 2 1 has been used to great effect by a number groups within the context of molecular recognition because it contains a rigid predictable structure, heteroatoms capable of binding events and importantly a chiral cavity.3,4 While Tröger's base has proved effective as a chiral cleft molecule, a number of carbocyclic and heterocyclic analogues have also been also investigated as possible surrogates.5 The carbocyclic cleft molecule 2 was initially reported in 1960 by Stetter 6 but was fully characterized and resolved in 1975 by Tatemitsu et al. 7 Significant advances in the functionalization of 2 have been developed by the Harding group 8 and an excellent review on its development/ uses has been published (Figure 1). Of particular interest to our group is the reduced version of 2. Treatment of 2 with excess reducing agent results in the formation of the bis-hydroxyl carbocycle 3, where both hydroxyl groups are directed into the chiral cavity. This potentially gives a ligand which can bind substrates via metal or Brønsted base / acid binding interactions within a chiral cavity (Scheme 1). Scheme 1. Reduction of 2 to give diol 3.To date the only reported functionalization of these hydroxyl groups has been the attachment of simple esters (bromobenzoate, acetate and menthoxy acetyl) and the synthesis of cyclic ethers.7,10 The dibromobenzoate and diacetate derivatives were synthesized for characterization reasons, the dimenthoxy acetate was synthesized for separation purposes and the cyclic ethers A R T I C L E I N F O A B S T R A C TArticle history: Received Received in revised form Accepted Available onlineThe diesterification and selective mono and dialkylation of carbocyclic analogues of Tröger's base with pyridyl groups has been achieved in high yield and good selectivity giving access to a novel range of cleft molecules capable of binding events. Reaction conditions for the selective functionalization of this carbocyclic cleft molecule are discussed as well as the solid state structures of these newly synthesized ligands.

Improved Procedures for Gram-Scale Synthesis of Galeterone 3β-Imidazole and Galeterone 3β-Pyridine Methoxylate, Potent Androgen Receptor/Mnk Degrading Agents

“…To improve on our reported low yield synthesis of compound 3 , , we initially attempted the synthesis following the procedure reported by Jilka et al where galeterone ( 1 ) in THF was treated with sodium hydride (NaH) at 0 °C and stirred at room temperature for 10 min followed by addition of 4-(bromomethyl)­pyridine hydrobromide solution [ 14 ; THF/DMF (1:1), TEA]. The product was isolated in low yields of 24% although it was 2-fold higher than our previously reported 12% yield. , In an effort to improve the product yield, DMF and DMSO were investigated as alternative reaction solvents to THF/DMF mixture, as well as addition of phase transfer catalyst (tetrabutylmmonium iodide), but insignificant product formation improvement was observed by TLC analysis and isolated product yields.…”

“…Synthesis of Galeterone 3β-Pyridine Methoxylate (3). To improve on our reported low yield synthesis of compound 3, 13,14 we initially attempted the synthesis following the procedure reported by Jilka et al 33 where galeterone (1) in THF was treated with sodium hydride (NaH) at 0 °C and stirred at room temperature for 10 min followed by addition of 4-(bromomethyl)pyridine hydrobromide solution [14; THF/ DMF (1:1), TEA]. The product was isolated in low yields of 24% although it was 2-fold higher than our previously reported 12% yield.…”

Synthesis and solid state structure of pyridyl diboroxines linked by a chiral spacer analogous to Tröger’s base

“…5 Consequently, taking 3a (1 equiv) with phenylboronic acid 5 (6 equiv) in CH 2 Cl 2 , we found that the boronic acid rapidly solubilised to give a homogenous reaction mixture (Scheme 3). Upon removal of the solvent the 1 H and 13 C NMR spectra of the crude white solid showed the formation of one discrete product which was assigned to 3a.6 2 .…”

“…To date, the only functionalization of these hydroxyl groups has been by esterification and alkylation; 1b,4 for example, we successfully demonstrated that the diol could be selectively transformed into the mono-and dipyridyl analogues, with the potential to interact with transition metals. 5 This type of interaction with transition metals is typical for pyridyl ligands of this kind, as demonstrated by Harding and co-workers who exploited such binding for the self-assembly of [2+2]-macrocycles. 3d However, we perceived an opportunity to use the pyridyl groups attached to these hydroxyl groups, in the selfassembly of boroxines.…”

Controlling the Assembly of C2-Symmetric Molecular Tectons Using a Thiocarbamate Appended Carbocyclic Cleft Molecule Analogous to Tröger’s Base

“…We have previously emphasized the practicality of 1 by appending the hydroxyl groups with pyridyl functionality, as well as highlighting the self-assembly of these pyridyl adducts with phenylboronic acid to yield bis-boroxine substrates, with the 4-pyridyl analogue being fully characterized by single crystal X-ray analysis emphasizing the chiral space. 14,15 The capacity to be able to confidently predict crystal packing to facilitate the design of new solids with sought-after physical properties has been central to the evolution of crystal engineering. 16−18 Furthermore, the ability to control secondary and tertiary structure within crystal packing has enormous potential in the development of new functional materials and devices.…”