Synthesis and Self‐Aggregation of Enantiopure and Racemic Molecular Tweezers Based on the Bicyclo[3.3.1]nonane Framework

Abstract

A pair of molecular tweezers (syn-4) that consists of quinoline and pyrazine units fused to a bicyclic framework is presented. The tweezers were synthesised both as a racemic mixture (rac-4) and an enantiomerically pure form ((R,R,R,R)-4) starting from either racemic or enantiomerically pure bicyclo[3.3.1]nonane-2,6-dione (3). Homochiral dimers were observed in the solid state for rac-4. The self-association of both rac-4 and (R,R,R,R)-4 was studied in solution. A weak self-association constant in CDCl(3) was estimated by (1)H NMR spectroscopic dilution titration experiments in both cases, following several proton resonances. For this purpose, a general normalisation model for the accurate determination of association constants from multiple datasets was developed. In contrast to the solid state, no diastereomeric discrimination was observed for rac-4 in solution.

Synthesis of an Orthogonal Topological Analogue of Helicene

“…Amino aldehyde 3 was employed in the convergent synthesis of 1 from ketoacetal ( S , S )‐ 13 , as outlined in Schemes and . A Friedländer condensation between 3 and ( S , S )‐ 13 12a and subsequent acetal hydrolysis afforded ( R , S )‐ 8 in 83 % yield over two steps. A Friedländer condensation between ( R , S )‐ 6 12a and 3 afforded pyrido[3,2‐ d ]pyrimidine ( R , R )‐ 14 in 74 % yield.…”

“…A Friedländer condensation between 3 and ( S , S )‐ 13 12a and subsequent acetal hydrolysis afforded ( R , S )‐ 8 in 83 % yield over two steps. A Friedländer condensation between ( R , S )‐ 6 12a and 3 afforded pyrido[3,2‐ d ]pyrimidine ( R , R )‐ 14 in 74 % yield. Compound ( R , R )‐ 14 could also be reached (but in lower yield) by reacting ( R , S )‐ 8 with 2‐aminobenzaldehyde under basic conditions in MeOH 24.…”

“…Through our research based on the bicyclo[3.3.1]nonane (BCN) skeleton,9, 12 in which we have previously reported the synthesis of an enantiomerically pure pair of molecular tweezers that constitutes a half turn of a tubular helix (Scheme d),12a we realized that the BCN framework could be used as a backbone for the synthesis of a complete turn of a helix. Thus, we now report on the first covalent, tubular structure with an aromatic skeleton parallel to the axis of propagation making one turn of a helix—pentamer 1 (five BCN units, Scheme ).…”

“…The BCN framework has a structural advantage as a helical backbone compared to the very similar building block Tröger’s base (TB), which is used to make cleft compounds (Scheme e):13 the stereogenic centers of the BCN framework are configurationally stable and the synthetic manipulations used here will not cause racemization. Another advantage with our BCN approach over the current TB approach is that the synthesis of higher generations does not include the formation of new stereogenic centers, which avoids formation of competing diastereomeric structures 12a. By selection of the aromatic spacer and the number of BCN units, the synthetic strategy towards 1 allows for the control of important properties of the resultant tubular structure, such as diameter and length.…”

Fully Supramolecular Chiral Hydrogen-Bonded Molecular Tweezer

“…For instance, Zimmerman et al took a step further from the flexible Whitlock tweezer and synthesized a conformationally more restricted system to prevent mono intercalation into DNA (Figure a). , The newly designed tweezer equipped with an additional H-bonding site proved to be an efficient receptor for some important analytes, such as adenine . Further developments in the field by Klärner , (Figure a) and others − resulted in the creation of semirigid systems possessing a small yet tangible degree of conformational freedom. In this line of research, the work of Harmata et al is worthy of a special mention as they synthesized one of the first chiral molecular tweezers based on Kagan ether.…”