Staircase chirality – a novel 3D chirality pattern

In the past several decades, significant progress has been made in controlling molecular chirality, as evidenced by the several Nobel Prizes in chemistry awarded in this area, particularly for advancements in the asymmetric catalytic synthesis of molecules with central and axial chirality. However, the exploration of new types of chirality has been largely stagnant for more than half a century, likely due to the complexity and challenges inherent in this field. Prof Li and Liang’s groups at Texas Tech University present the discovery of a novel type of chirality—staircase chirality.

It is well-known that molecular chirality is generally classified into several categories. At the small-molecule level, it includes central chirality, axial chirality, spiral chirality, sandwich chirality (metallic and organo) and turbo or propeller chirality, orientational chirality. At the macro and polymeric molecular level, it encompasses multilayer chirality (rigid helical and flexible folding), as well as topological and inherent chirality. Among these categories, orientational chirality is the most recent addition, defined by the C(sp²)-C(sp³) or C(sp)-C(sp³) axis with remotely anchored blockers. The orientational model exhibits three major energy barriers, contrasting with the six found in classic Felkin-Ahn or Cram models. This new form of chirality was revealed through authors’ study of multilayer chiral frameworks via asymmetric catalytic C-C bond formation (Scheme 1).

The above work led to the discovery of a new chirality pattern, which we are provisionally calling "staircase chirality”. This chirality is illustrated in Figure 1, featuring two symmetrical layers that slip in opposite directions. Two functional groups, represented by two spheres, may be identical or different. In this report, we present our preliminary findings on this novel chirality element.

In the asymmetric synthesis of this chirality framework, chiral amino acids were selected as the two auxiliaries at the para positions of the phenyl rings due to their potential for use in peptide drug design and synthesis. Another key factor in this choice was the likelihood of obtaining high-quality crystals suitable for X-ray diffraction analysis, which is critical for this project as the slipped isomeric structures are challenging to distinguish by other analytical methods. As shown in Figure 2, two diastereomers co-exist, each displaying two types of chirality: central chirality and staircase chirality. The two symmetrical phenyl rings exhibit asymmetric slippage; when the naphthyl anchor is positioned as shown in Figure 2, the top phenyl ring slips either to the right (Figure 2a) or to the left (Figure 2b). Since there is no established nomenclature for this new form of chirality, we propose a provisional naming system as follows: (1) Observe the "stairs" from the naphthyl anchor to the other end of the phenyl ring, which is attached to the auxiliaries. (2) Imagine climbing the stairs from the bottom to the top. (3) The P-configuration is assigned to rightward climbing, while the M-configuration is assigned to leftward climbing. Based on this temporary system, isomers a and b would be classified as P- and M-configurations, respectively. Thus, the full names of these diastereomers are P- and M-diethyl 2,2'-((4,4'-(naphthalene-1,8-diyl)bis(benzoyl))bis(azanediyl))(2S,2'S)-bis(4-methylpentanoate), respectively.

Authors next explored the stereoselective formation of single staircase isomers, rather than a mixture of M- and P-diastereomers. They designed and synthesized a new staircase target containing two pairs of combinational auxiliaries: (R)-valine amide and chiral sulfonimine-derived amine; chiral tertiary amino acid and (R)- or (S)-1-phenylethan-1-amine. They found that the asymmetric synthesis of staircase chirality is predominantly controlled by chiral amide auxiliary without being affected by chiral centers of C*(sp3) and S*(=O)tBu of sulfinamide auxiliary.

They performed quantum mechanical calculations using density functional theory (DFT) to evaluate the energies of an isolated staircase molecule in the vacuum and its stereoisomers with different center and staircase chirality. It is observed that in the crystal structure, the -NH moiety on the amide group is involved in the intermolecular hydrogen bonds across neighboring cells, which is absent in the calculations performed here for an isolated molecule in the vacuum. For this reason, the -NH moiety on the amide group was replaced with the -NCH3 moiety to simplify the energy comparison among different stereoisomers.

The computational results revealed that by changing from the (S,R,R)-(M) isomer to the (R,R,R)-(M) isomer, the energy increases by 2.7 kcal/mol (Figure 3). This result suggests that the staircase chirality influences the relative thermal stability of the chirality of the carbon atom adjacent to the NCH3 group. Additionally, changing from the (S,R,R)-(M) isomer to the (S,R,R)-(P) isomer features the large displacements of the two torsions connecting the naphthalene ring and the two benzyl rings (φ₁, φ₂, Figure 3), and an energy increase of 6.3 kcal/mol (Figure 3). This result suggests that the chirality of the carbon atom adjacent to the -NCH₃ group influences the thermal stability of the staircase chirality. Thus, the calculations are consistent with the crystal structures of the original compound with the amide group and support the experimentally observed coupling between the staircase chirality and the center chirality.

In summary, a novel chiral element—staircase chirality was discovered. Individual staircase isomers were selectively synthesized by simultaneously using two chiral auxiliaries: an amide and a sulfinamide. This chiral framework features two symmetrical phenyl rings bridged by a naphthyl core, with these phenyl rings asymmetrically displaced due to the chiral auxiliaries at their para positions. A nomenclature system was proposed for the staircase isomers, and one isomer was found to exhibit four distinct types of chirality elements: central, orientational, turbo, and staircase chirality—an unprecedented combination. This two layer-unit will be utilized to build higher staircase oligomers and polymers. This discovery is expected to pave the way for new research in asymmetric synthesis and catalysis, with broad implications for the fields of chemistry, medicinal chemistry, and material sciences.