As screw-shaped compounds formally derived from ortho-annulated aromatic and/or hetero-aromatic rings, helically chiral molecules have fascinated synthetic chemists for more than 100 years owing to their esthetic architectures and unique chiroptical properties. Tremendous efforts have been devoted to developing the methodologies for the synthesis of enantiomerically pure helicenes, which have been demonstrated in the past decades to be highly promising for application in diverse fields, such as asymmetric catalysis, molecular recognition, molecular machines, material sciences and some biologically active agents. While approaches to optically pure point-chiral and axially chiral compounds have mushroomed enormously in the past decades, catalytic enantioselective synthesis of helicenes is still in its infancy, and corresponding literatures reported to date have been fairly limited1-4 (Fig. 1a).
Fig. 1 | Background introduction and our strategy for synthesizing optically pure helicenes.
To the best of our knowledge, current methods to construct such compounds almost entirely rely on catalytic enantiocontrolled fused-ring system extension5,6 (Fig. 1b-I). The scarcity of complementary assembly strategies has significantly hindered the on-demand synthesis of helicenes or helicene-like molecules through catalytic enantioselective methods. Therefore, the exploration of more innovative and practical concepts for obtaining optically pure helicenes with a wide structural diversity is highly desired. It should be noted that besides π-conjugated scaffold extension through arene formation, terminal peri-functionalization of the choreographed substrates could also generate configurationally stable [4]- and [5]helicenes. However, such a tactic has hitherto not been applied in the catalytic enantioselective synthesis of functionalized helicenes and their heteroanalogues (Fig. 1b-II). Thus, we directed our efforts toward designing and synthesizing suitable substrates and catalysts to realize this vision.
For this purpose, benzo[c]phenanthren-2-ol 1 with a substituent at its 12-position, in which the hydroxyl group could function as both a directing group and a binding site, was designed and synthesized (Fig. 2). We speculated that diverse functional groups could be incorporated at the 1-position in a catalytic helicoselective fashion by utilizing the nucleophilicity of the enol tautomer of substrate 1, thereby increasing the barrier to enantiomerization and giving access to enantioenriched 1,12-disubstituted [4]helicenes. Herein, highly reactive azo-compound 2 was employed to realize the functionalization of highly steric-hindered fjord-type area of polycyclic phenol 1. To the best of our knowledge, catalytic asymmetric amination reaction of phenols with azo-compounds represents one of flexible and versatile protocols for preparing functionalized molecules with different stereogenic elements. However, despite the conspicuous progresses of catalytic enantioselective amination reactions in constructing axially and centrally chiral compounds (Fig. 2a), the applications of similar chemical processes in helicenes synthesis have not yet been reported, even in a non-helicoselective version. To further extend the potential of Friedel-Crafts amination reactions in asymmetric synthesis and enrich the synthetic strategies of enantioenriched helicenes, we report herein an enantioselective terminal peri-amination strategy for the efficient synthesis of configurationally stable [4]- and [5]helicenes (Fig. 2b).
Fig. 2 | Diverse synthesis of compounds with different chiralities via catalytic enantioselective amination reactions of polycyclic phenols.
By screening different bifunctional organocatalysts and solvents, we established the optimal reaction conditions. It was noteworthy that extending the steric hindrance group of the catalyst availed to the long-range control of enantioselectivity. Then, we sought to investigate the substrate scope and limitations of this intermolecular amination reaction (Fig. 3). First, a variety of diazodicarboxamides 2 were examined. Pleasingly, aryl groups as well as alkyl substituents were all compatible with this protocol. Next, we targeted the exploration of substrate scope with respect to 2-hydroxybenzo[c]phenanthrenes 1. A variaty of substitutions at different sites of the terminal ring were recruited, and to our delight, all proved to be well tolerated. Encouraged by the above success, we then used this approach to construct stereochemically complex molecules featuring both helical and axial chiralities, which was challenging and has rarely been reported. Towards this goal, the reactions of diazodicarboxamides with a sterically bulky t-butyl group at the ortho-position of phenyl ring were further performed, and surprisingly, supplied the respective helically chiral products bearing a stereogenic C-N axis in good yields with excellent stereoselectivities. Remarkably, stereochemically complex [5]- and [6]-helicenes were also achievable with comparably high er values. The capacity of realizing remote axial enantiocontrol while controlling helical sense selectivity again confirmed the broad generality of this catalytic enantioselective approach to derive structurally diverse helically chiral [4]-, [5]- and [6]helicenes.
Fig. 3 | Substrate scope with respect to diazodicarboxamides, polycyclic phenols and scope of the synthesis of helicenes bearing a stereogenic C-N axis. Isolated yields based on 1 are shown.
To demonstrate the scalability and practicality of this protocol in the synthesis of helically chiral chemicals, 2.0 mmol scale preparations of [4]helicenes under standard conditions were conducted and there was no obvious erosion of yield and enantioselectivity to be observed, suggesting a potential for large-scale chemical production of this method (Fig. 4a). Furthermore, some representative transformations of the helically chiral products were exhibited, which further validated the synthetic value of this methodology (Fig. 4b).
Fig. 4 | Reaction scale-up and products transformations. Isolated yields based on the substrate are shown.
To gain insight into the reaction mechanism, density functional theory calculations were conducted and the computational outcomes matched with our experimental data very well (Fig. 5). The calculations revealed that catalyst brings the two reactants into close proximity via hydrogen bonding interactions and locks the relative orientation of the two substrates through hydrogen bonds and C-H---π interactions with the naphthalene skeleton and the pyrenyl substituent in the catalyst (Fig. 5a). With the favored activation model established, we next intended to unravel the origin of C-N axial chirality induction. It was found that the comparatively favored transition state TS-MS has lower free energy than the disfavored TS-MP, leading to the major (M,S)-configured product (Fig. 5b).
Fig. 5 | Mechanistic studies. Energy in kcal/mol and bond lengths in Å.
In conclusion, a terminal peri-functionalization strategy for the catalytic enantioselective preparation of helically chiral molecules was developed. The highly enantioselective synthesis of [4]carbohelicenes has been accomplished via an organocatalyzed intermolecular electrophilic aromatic amination reaction of 2-hydroxybenzo[c]phenanthrene derivates with diazodicarboxamides. The capacity of simultaneous control of helical and remote C-N axial chiralities made the current protocol especially intriguing, allowing for the construction of enantioenriched [4]-, [5]- and [6]helicenes featuring an urazole scaffold with both structural diversity and stereochemical complexity in good to excellent yields and enantioselectivities.
For more details of this work, please see our paper titled “Enantioselective Synthesis of [4]Helicenes by Organocatalyzed Intermolecular C-H Amination” in Nature Communications.
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