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Synlett 2023; 34(05): 477-482
DOI: 10.1055/a-1914-1799
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Special Edition Thieme Chemistry Journals Awardees 2022

Synthesis of Enantioenriched Azaborole Helicenes by Chirality Transfer from Axially Chiral Biaryls

Felix Full
,
Martijn J. Wildervanck
,
Daniel Volland
,
Agnieszka Nowak-Król  ∗

This research was funded by the German Research Foundation (DFG) within the Emmy-Noether Programme (NO 1459/1-1) and by the Hector Fellow Academy.
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Dedicated to Professor Holger Braunschweig on the occasion of his 60th birthday

Abstract

We report the enantioselective synthesis of azaborole helicenes from enantioenriched axially chiral precursors. The borylation/metal-exchange reaction sequence affords the target compounds with full transfer of chirality from the corresponding biaryls. Experimental studies provided insights into the configurational stability of the heterobiaryls and their (chir)optical properties. The structure of the ­phenyl-substituted helicene was unambiguously confirmed by single-crystal X-ray analysis.


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Key words

axial chirality - azaboroles - borylation - chirality transfer - helicenes - configurational stability

The chirality of all-carbon or heteroatom-doped polycyclic aromatic hydrocarbons (PAHs) gives rise to fascinating properties and enables new functions.[1] The preparation of such systems is vital for asymmetric catalysis and applications in materials chemistry.[2] The archetypal representatives of PAHs are carbo- and heterohelicenes featuring inherent helical chirality that originates from their screw-shaped structures. Considerable effort has been devoted to developing strategies that provide access to enantioenriched helicenes in appreciable quantities,[3] which would permit investigation of their properties and their implementation as functional materials in diverse fields, including molecular recognition and organic electronics.[4] Despite considerable progress in this area, the optical resolution of racemates by chiral high-performance liquid chromatography (HPLC) remains the predominant method for obtaining enantiomerically pure helicenes. Despite its significant challenges, direct asymmetric synthesis of helicenes and helicenoids from achiral precursors arises as the most appealing approach. To this end, metal-catalyzed reactions have emerged as versatile tools, the most prominent and well-established being transition-metal-catalyzed [2+2+2]-cycloaddition reactions using chiral ligands.[5] This research area has also benefited from important contributions by Tanaka and others, with the development of enantioselective Au-catalyzed intramolecular hydroarylation of alkynes.[6] A conceptually different realization of this approach is the elegant organocatalytic preparation of azahelicenes through a Fischer indole synthesis developed by List and co-workers.[7] This pioneering work was followed by the development of other metal-free approaches leading to dioxa- and carbo[6]helicenes.[8] Another possibility for accessing optically active helicenes and helicene-like molecules is the relay of stereochemical information from nonhelical enantioenriched precursors, which can be accomplished either by point-to-helical[5a] [9] or axial-to-helical chirality transfer. The latter relies on the construction of a chiral biaryl axis[5f] or the synthesis of enantioenriched axially chiral compounds through kinetic resolution of racemic biaryls, as demonstrated recently by the Ackermann group.[10] Alternatively, optical resolution of biaryl compounds can be proceeded by chiral HPLC[11] or by their derivatization to diastereomers followed by separation through achiral chromatography[12] or fractional crystallization.[13]

Such enantioenriched axially chiral compounds are then converted in one or more steps into the target helicenes. An earlier demonstration of this approach was reported by the Nozaki group. The method capitalized on the resolution of the optically active (1S)-10-camphorsulfonyl ester of 4,4′-biphenanthrene-3,3′-diol, an intermediate in the stereospecific synthesis of heterohelicenes through Pd-catalyzed N- and O-arylation. The method was also used to prepare nonracemic carbohelicenes in several steps through a benzylic-type coupling[14] or amide-containing helicenes through a Curtius rearrangement.[13b] Notably, all these examples describe biaryls bearing at least one substituent in an ortho-position to the C–C atoms of the chiral axis, increasing the configurational stability of the compound.

During our work on chiral PAHs, we realized that the synthesis of helicene EH3-Me2 proceeds via atropisomeric biaryl BA3 (Scheme [1c]).[15] Previously, we had used its nonextended derivative, biaryl NE-BA3, to synthesize racemic azaborole helicenes bearing alkyl and aryl substituents on boron.[16] Intriguingly, this compound served as a configurationally labile intermediate in the synthesis of azoniahelicenes and olefinated biaryls (Scheme [1a]).[17] High stereocontrol of these transformations was achieved by in situ epimerization of NE-BA3 in the presence of chiral Rh(III)-catalysts that mediated atroposelective reaction outcomes at 80–120 °C. Considering that a relatively low atropoisomerization barrier is a prerequisite for deracemization of a biaryl by dynamic kinetic resolution[18] and the fact that our biaryls lack substituents at the N and 3-C ­atoms, the feasibility of resolving enantiomers of π-extended BA3 came as a surprise.

Zoom Image
Scheme 1 (a) Enantioselective syntheses of azoniahelicenes and olefinated biaryls by dynamic kinetic resolution.17 (b) π-Extended azabora[6]- or -[7]helicenes EH2-Me2 and EH3-Me2 ,15 and (c) enantioselective synthesis of EH3 by axial-to-helical chirality transfer reported in this work.

Herein, we disclose the resolution of this axially chiral compound and experimental studies of its configurational stability. The stereodynamic nature of this biaryl is contrasted with that of a shorter homologue. Finally, we demonstrate the synthetic utility of this scaffold in a divergent synthesis of enantioenriched π-extended azaborole helicenes through an axial-to-helical chirality transfer that proceeds with a full retention of chiral information.

Recently, we reported the synthesis of compounds BA2 (see Scheme [2], below) and BA3 from nitrogen polyheterocycles and 1-dibenzo[g,p]chrysene building blocks.[15] These racemic compounds were used as starting materials in the synthesis of π-extended helicenes EH2 and EH3 bearing methyl substituents on boron (Scheme [1b]). Interestingly, we observed a separation of enantiomers in chromatograms of BA2 and BA3 at room temperature [see Supporting Information (SI), Figure S10]. The resolution of racemic BA3 on a chiral stationary phase proved facile due to the considerable differences in retention times, affording (S a)- and (R a)-enantiomers in 96–97% and 96–98% ee, respectively. The configuration of the first and the second fractions was assigned by comparison of the experimentally obtained electronic circular dichroism (ECD) spectra with the computed ones (for details, see SI). Even though the chromatogram of BA2 showed two distinct peaks, attempts to resolve this biaryl into its enantiomers were unsuccessful. To understand the behavior of both compounds, we investigated their configurational stability by dynamic temperature-dependent HPLC (DHPLC) measurements on a chiral stationary phase. To this end, racemic mixtures of respective biaryls were heated during elution at temperatures between 283 and 333 K. The development of the elution profiles with the temperature is shown in Figure S10 of the SI. The formation of a plateau between the peaks of BA2 can already be observed at room temperature, whereas BA3 shows a perfect baseline separation. Upon heating, the peaks for BA2 move toward each other to coalescence at 328 K, while the peaks of BA3 remain nearly separated. This implies BA2 has a lower configurational stability than BA3.

The activation parameters ΔH ‡ and ΔS ‡ were derived from the slope and intercept of the Eyring plots (SI, Figures S11 and S12), respectively, and were used to calculate ΔG ‡ e(T) at 298 °K. Rate constants for the racemization processes at certain temperatures were determined by using the DCXplorer software,[19] developed by Trapp (for details, see SI). These studies provided a ΔG ‡ exp (298 K) of 89.5 kJ mol–1 for BA2. This means that the barrier of the shorter homologue is too low to permit resolution of the enantiomers, as the minimal barrier required is ~95 kJ mol–1 at 300 K.[20] On the other hand, BA3 with a ΔG ‡ exp of 97.4 kJ mol–1 and a half-life of 110 min at 298 K proved to be configurationally stable. We confirmed the value of the barrier obtained from DHPLC by a thermal racemization experiment for an enantioenriched sample of (R a)-BA3 at 75 °C in 1,2-dichlorobenzene, followed by monitoring the enantiomeric decay by chiral HPLC to obtain a ΔG ‡ exp (348 K) of 104.3 kJ mol–1. Thus, the removal of the boron bridge reduces the configurational stabilities of BA3 and BA2 by ~35–40 and 15 kJ mol–1, respectively, in comparison with those of corres­ponding helicenes EH3 and EH2. Notably, the R a–S a inversion processes are significantly more complex for BA2 and BA3 than for the analogous helicenes. The rotational freedom around the C–C single bond offers the possibility of generating a multitude of conformers and increases the number of plausible transition states when compared with helicenes in which the mutual orientation of the N-heterocycle and the dibenzochrysene core is fixed. Accordingly, rotation about the biaryl axis can proceed in either sense leading to alternative interconversion pathways. As found for other biaryls,[21] the more feasible scenario would involve a transition state in which the steric clash is built by benzene ring A of the dibenzochrysene core and an N-heteroaryl moiety, while the nitrogen atom is pointing toward ring B (see BA2, Scheme [2]), rather than an energetically more demanding puckered transition state, typical of helicenes. A lower steric demand of the first type of transition state, inaccessible for helicenes, would explain the particularly high difference in ΔG ‡ between BA3 and EH3.

Zoom Image
Scheme 2 (a) Molecular structure of BA2 and enantioselective synthesis of boron-containing helicenes starting from configurationally stable enantioenriched biaryl precursors (S a)- and (R a)-BA3. The (P)- and (M)-enantiomers of the respective helicenes EH3-Me2 and EH3-Ph2 were synthesized without any loss of enantiomeric purity. (b) Molecular structure of rac-EH3-Ph2 determined by X-ray analysis at 100 K. Only the (M)-enantiomer is depicted. ORTEP drawings are shown with 50% probability.

These investigations indicate that only axially chiral BA3 is a suitable candidate for further derivatization through chirality transfer. Having enantioenriched (R a)- and (S a)-BA3 in hand, we attempted an enantioselective synthesis of the target helicenes. To this end, the enantiomers were reacted with BBr3 to establish a boron bridge between both biaryl subunits. The reaction carried out in the presence of N,N-diisopropylethylamine (DIPEA) at room temperature afforded bromide complexes. A subsequent exchange of the bromo substituents on boron with alkyl groups at room temperature afforded the target compounds in 34–35% yield.[22] To our delight, the reactions proceeded with a complete transfer of chirality. As verified by analytical HPLC, (P)- and (M)-enantiomers of EH3-Me2 were obtained with 96 and 97% ee, respectively (Figure [1]). Thus, electrophilic borylation with BBr3 followed by the ligand exchange proved highly effective for the preparation of enantioenriched alkyl-substituted derivatives. Next, we tested the expediency of this approach to the synthesis of aryl derivatives, which needs to be carried out at elevated temperatures. In the first step, we synthesized racemic EH3-Ph2 . Boron-bridging and the subsequent reaction with AlPh3 at 90 °C afforded the target compound in 56% yield. The formation of EH3-Ph2 was unambiguously confirmed by single-crystal X-ray analysis (Scheme [2]b and SI).[23] The enantiomers of EH3-Ph2 were resolved by chiral HPLC[].

Zoom Image
Figure 1 Chromatograms of BA3 (left), EH3-Me2 (middle) and EH3-Ph2 (right): racemates (top), (S a)- or (M)- (middle), and (R a)- or (P)-enantiomers (bottom).

Enantiomerically enriched (R a)- and (S a)-BA3 were then converted into (M)- and (P)-EH3-Ph2 in 57% and 50% yield with 98 and 96% ee, respectively.[24] Even though the configurational stability of BA3 is relatively low, this reaction sequence was successfully used to synthesize the analogues bearing phenyl substituents. Since the first critical step, i.e., borylation, is performed at –78 °C to room temperature, the positive outcome of this approach relies entirely on the configurational stability of the boron-bridged scaffolds under the reaction conditions of the second step. As we demonstrated previously for the methyl derivative of EH3, its stability is significantly higher, permitting the introduction of aryl substituents without any deterioration of enantiomeric excess.

Figure [2] shows UV/vis absorption spectra of BA3 alongside the spectra of the methyl and phenyl derivatives of EH3. The spectra reflect a distinct perturbation of electron density upon introduction of the boron bridge. The lowest-energy absorption band of BA3 is positioned at 385 nm. As expected, the corresponding transitions of EH3-Me2 and EH3-Ph2 are bathochromically shifted to 439 and 446 nm, respectively, with the shift accompanied by an increase in the molar absorptivity of the compounds (SI, Table S7). Evident differences between the axially and helically chiral compounds are also apparent in their ECD spectra. (S a)-BA3 exhibits a negative Cotton effect (CE) in the range of 330 to ~400 nm (Δε = –9 M–1 cm–1 at 358 nm) and a positive CE can be observed from 270 to 330 nm (Δε = +42 M–1 cm–1 at 285 nm).

Zoom Image
Figure 2 Absorption spectra of racemic mixtures of BA3, EH3-Me2 and EH3-Ph2 (c = 4.7 × 10–5 to 1.2 × 10–4 M) in CH2Cl2 (293 K).

The profile of the ECD spectrum of (P)-EH3-Ph2 resembles that of (P)-EH3-Me2 with negative CEs for the lowest-energy CD band between 400 and 500 nm (Δε = –13 m –1 cm–1 at 447 nm) and a band below 313 nm (Δε = –18 m –1 cm–1 at 292 nm) (Figure [3]). In addition, a broad positive band of a moderate intensity (Δε = +44 m –1 cm–1 at 360 nm) was recorded between 314 and 403 nm. While EH3-Me2 shows a stronger CD response in this region, EH3-Ph2 exhibits a more intense band below 300 nm. The absorption dissymmetry factors (|g abs|) of these helicenes (3.0 × 10–3 at 373 nm and 3.3 × 10–3 at 373 nm for EH3-Ph2 and EH3-Me2 , respectively) are larger than that of BA3 (2.0 × 10–3 at 285 nm).

Zoom Image
Figure 3 ECD (BA3: c = 5.0 × 10–5 M, EH3-Me2 : c = 2.7 × 10–5 M, EH3-Ph2 : c = 4.4 × 10–5 M) spectra of BA3, EH3-Me2 and EH3-Ph2 in CH2Cl2 (293 K).

In conclusion, we have developed a stereoselective synthesis of azaborole helicenes via chirality transfer from axially chiral biaryls. Enantiomers of atropoisomeric BA3 proved configurationally stable and can serve as chiral platform molecules for ligands in enantioselective catalysis. Utilization of these intermediates allowed the divergent synthesis of helicenes through introduction of various types of boron substituents. We demonstrated that the azaborole ring formation with BBr3 and the consecutive exchange of substituents on boron afford the target molecules with full retention of chiral information.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1914-1799.
  • Supporting Information

  • References and Notes

  • 7 Kötzner L, Webber MJ, Martínez A, De Fusco C, List B. Angew. Chem. Int. Ed. 2014; 53: 5202
    CrossrefPubMedSearch in Google Scholar
  • 10 Dhawa U, Tian C, Wdowik T, Oliveira JC. A, Hao J, Ackermann L. Angew. Chem. Int. Ed. 2020; 59: 13451
    CrossrefPubMedSearch in Google Scholar
  • 12 Nakano K, Hidehira Y, Takahashi K, Hiyama T, Nozaki K. Angew. Chem. Int. Ed. 2005; 44: 7136
    CrossrefPubMedSearch in Google Scholar
  • 14 Terrasson V, Roy M, Moutard S, Lafontaine M.-P, Pèpe G, Félix G, Gingras M. RSC Adv. 2014; 4: 32412
    CrossrefSearch in Google Scholar
  • 15 Full F, Wölflick Q, Radacki K, Braunschweig H, Nowak-Król A. Chem. Eur. J. 2022; in press; DOI
    CrossrefPubMedSearch in Google Scholar
  • 16 Full J, Panchal SP, Götz J, Krause A.-M, Nowak-Król A. Angew. Chem. Int. Ed. 2021; 60: 4350
    CrossrefPubMedSearch in Google Scholar
  • 19 Trapp O. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2008; 875: 42
    CrossrefPubMedSearch in Google Scholar
  • 20 Watson AA, Willis AC, Wild SB. J. Organomet. Chem. 1993; 445: 71
    CrossrefPubMedSearch in Google Scholar
  • 21 Tan JS. J, Paton RS. Chem. Sci. 2019; 10: 2285
    CrossrefPubMedSearch in Google Scholar
  • 22 (M)-EH3-Me2: Enantioselective SynthesisEnantioenriched (R a)-BA3 (96% ee) (16.0 mg, 31.6 μmol, 1.0 equiv) was dissolved in CH2Cl2 (1.5 mL) under argon. DIPEA (5.90 μL, 4.50 mg, 34.8 μmol, 1.1 equiv) was added and the mixture was cooled to –78 °C. A 1.0 M solution of BBr3 in CH2Cl2 (95.0 µL, 95.0 μmol, 3.0 equiv) was added dropwise, and the mixture was warmed to rt and stirred at rt for 22 h. The solvent was removed in vacuo and the resulting orange solid was washed with dry hexane (3 × 1 mL) under argon. The resulting residue was dissolved in CH2Cl2 (2 mL), and a 2.0 M solution of AlMe3 in toluene (46.7 μL, 93.3 µmol, 3.0 equiv) was added dropwise to the mixture under argon. The resulting mixture was stirred at rt for 1 h, then cooled to 0 °C. H2O (2 mL) was added and the mixture was extracted with CH2Cl2 (4 × 5 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica hexane/EtOAc (4:1)] to give a yellow solid; yield: 6.00 mg (11.0 μmol, 35%, 96% ee).HPLC: Reprosil Chiral-MIF, 250 × 4.6 mm, hexane–CH2Cl2 (87:13), 2 mL/min. 1H NMR (400 MHz, CD2Cl2): δ = 8.88 (d, J = 7.9 Hz, 1 H, Ar-H), 8.83–8.74 (m, 3 H, Ar-H), 8.59 (d, J = 7.7 Hz, 1 H, Ar-H), 8.55 (d, J = 5.8 Hz, 1 H, Ar-H), 8.17 (d, J = 8.2, 1 H, Ar-H), 8.10 (d, J = 7.8 Hz, 1 H, Ar-H), 7.98 (d, J = 8.7 Hz, 1 H, Ar-H), 7.83 (d, J = 5.8 Hz, 1 H, Ar-H), 7.82–7.74 (m, 3 H, Ar-H), 7.34–7.70 (m, 2 H, Ar-H), 7.67 (d, J = 7.9 Hz, 1 H, Ar-H), 7.52 (d, J = 8.3, 1 H, Ar-H), 7.37 (t, J = 8.2, 1 H, Ar-H), 7.26 (d, J = 8.2 Hz, 1 H, Ar-H), 6.99 (t, J = 7.2 Hz, 1 H, Ar-H), 6.59 (t, J = 7.2 Hz, 1 H, Ar-H), 6.38 (t, J = 7.2 Hz, 1 H, Ar-H), 0.37 (s, 3 H, CH3), 0.20 (s, 3 H, CH3).The synthesis of (P)-EH3-Me2 from (S a)-BA3 is described in the SI.
  • 23 CCDC 2182824 contains the supplementary crystallographic data for compound EH3-Ph2 . The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
  • 24 (M)-EH3-Ph2: Enantioselective SynthesisEnantioenriched (R a)-BA3 (98% ee) (6.00 mg, 11.9 μmol, 1.0 equiv) was dissolved in CH2Cl2 (0.75 mL) under argon. DIPEA (2.20 μL, 1.69 mg, 13.1 μmol, 1.1 equiv) was added and the mixture was cooled to –78 °C. A 1.0 M solution of BBr3 in CH2Cl2 (35.6 μL, 35.6 μmol, 3.0 equiv) was added dropwise, and the mixture was warmed to rt and stirred at rt for 22 h. The solvent was then removed in vacuo and the resulting orange solid was washed with dry hexane (3 × 0.5 mL) under argon. The residue was dissolved in toluene (0.75 mL) and a 1.0 M solution of AlPh3 in Et2O (35.5 μL, 35.5 µmol, 3.0 equiv) was added dropwise under argon. The resulting mixture was stirred at 90 °C for 4 h, then cooled to 0 °C. H2O (1.5 mL) was added and the mixture was extracted with EtOAc (4 × 3 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica , cyclohexane/CH2Cl2 (3:1)] to give a yellow solid; yield: 4.50 mg (6.72 μmol, 57%, 98% ee). HPLC: Reprosil Chiral-MIF, 250 × 4.6 mm, hexane–CH2Cl2 (87:13), 2 mL/min (For details, see SI). 1H NMR (400 MHz, CD2Cl2) δ = 8.89 (d, J = 8.0 Hz, 1 H, Ar-H), 8.81–8.69 (m, 3 H, Ar-H), 8.61–8.57 (m, 1 H, Ar-H), 8.56 (d, J = 5.9 Hz, 1 H, Ar-H), 8.18 (d, J = 8.5 Hz, 1 H, Ar-H), 8.14 (d, J = 8.0 Hz, 1 H, Ar-H), 8.03 (d, J = 8.6 Hz, 1 H, Ar-H), 7.82 (d, J = 5.9 Hz, 1 H, Ar-H), 7.81–7.63 (m, 6 H, Ar-H), 7.60 (d, J = 8.5 Hz, 1 H, Ar-H), 7.56–7.52 (m, 2 H, Ar-H), 7.41 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, Ar-H), 7.38–7.27 (m, 5 H, Ar-H), 7.26–7.20 (m, 1 H, Ar-H), 7.16–7.07 (m, 3 H, Ar-H), 7.02 (ddd, J = 8.3, 7.1, 1.4 Hz, 1 H, Ar-H), 6.64 (ddd, J = 8.4, 6.9, 1.2 Hz, 1 H, Ar-H), 6.43 (ddd, J = 8.3, 7.1, 1.2 Hz, 1 H, Ar-H).The syntheses of (P)-EH3-Ph2 from (S a)-BA3 and of rac-EH3-Ph2 from rac-BA3 are described in the SI.

Corresponding Author

Agnieszka Nowak-Król
Institut für Anorganische Chemie and Institute for Sustainable Chemistry and Catalysis with Boron, Universität Würzburg
Am Hubland, 97074 Würzburg
Germany   

Publication History

Received: 30 June 2022

Accepted after revision: 01 August 2022

Accepted Manuscript online:
01 August 2022

Article published online:
30 August 2022

© 2022. Thieme. All rights reserved

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  • References and Notes

  • 7 Kötzner L, Webber MJ, Martínez A, De Fusco C, List B. Angew. Chem. Int. Ed. 2014; 53: 5202
    CrossrefPubMedSearch in Google Scholar
  • 10 Dhawa U, Tian C, Wdowik T, Oliveira JC. A, Hao J, Ackermann L. Angew. Chem. Int. Ed. 2020; 59: 13451
    CrossrefPubMedSearch in Google Scholar
  • 12 Nakano K, Hidehira Y, Takahashi K, Hiyama T, Nozaki K. Angew. Chem. Int. Ed. 2005; 44: 7136
    CrossrefPubMedSearch in Google Scholar
  • 14 Terrasson V, Roy M, Moutard S, Lafontaine M.-P, Pèpe G, Félix G, Gingras M. RSC Adv. 2014; 4: 32412
    CrossrefSearch in Google Scholar
  • 15 Full F, Wölflick Q, Radacki K, Braunschweig H, Nowak-Król A. Chem. Eur. J. 2022; in press; DOI
    CrossrefPubMedSearch in Google Scholar
  • 16 Full J, Panchal SP, Götz J, Krause A.-M, Nowak-Król A. Angew. Chem. Int. Ed. 2021; 60: 4350
    CrossrefPubMedSearch in Google Scholar
  • 19 Trapp O. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2008; 875: 42
    CrossrefPubMedSearch in Google Scholar
  • 20 Watson AA, Willis AC, Wild SB. J. Organomet. Chem. 1993; 445: 71
    CrossrefPubMedSearch in Google Scholar
  • 21 Tan JS. J, Paton RS. Chem. Sci. 2019; 10: 2285
    CrossrefPubMedSearch in Google Scholar
  • 22 (M)-EH3-Me2: Enantioselective SynthesisEnantioenriched (R a)-BA3 (96% ee) (16.0 mg, 31.6 μmol, 1.0 equiv) was dissolved in CH2Cl2 (1.5 mL) under argon. DIPEA (5.90 μL, 4.50 mg, 34.8 μmol, 1.1 equiv) was added and the mixture was cooled to –78 °C. A 1.0 M solution of BBr3 in CH2Cl2 (95.0 µL, 95.0 μmol, 3.0 equiv) was added dropwise, and the mixture was warmed to rt and stirred at rt for 22 h. The solvent was removed in vacuo and the resulting orange solid was washed with dry hexane (3 × 1 mL) under argon. The resulting residue was dissolved in CH2Cl2 (2 mL), and a 2.0 M solution of AlMe3 in toluene (46.7 μL, 93.3 µmol, 3.0 equiv) was added dropwise to the mixture under argon. The resulting mixture was stirred at rt for 1 h, then cooled to 0 °C. H2O (2 mL) was added and the mixture was extracted with CH2Cl2 (4 × 5 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica hexane/EtOAc (4:1)] to give a yellow solid; yield: 6.00 mg (11.0 μmol, 35%, 96% ee).HPLC: Reprosil Chiral-MIF, 250 × 4.6 mm, hexane–CH2Cl2 (87:13), 2 mL/min. 1H NMR (400 MHz, CD2Cl2): δ = 8.88 (d, J = 7.9 Hz, 1 H, Ar-H), 8.83–8.74 (m, 3 H, Ar-H), 8.59 (d, J = 7.7 Hz, 1 H, Ar-H), 8.55 (d, J = 5.8 Hz, 1 H, Ar-H), 8.17 (d, J = 8.2, 1 H, Ar-H), 8.10 (d, J = 7.8 Hz, 1 H, Ar-H), 7.98 (d, J = 8.7 Hz, 1 H, Ar-H), 7.83 (d, J = 5.8 Hz, 1 H, Ar-H), 7.82–7.74 (m, 3 H, Ar-H), 7.34–7.70 (m, 2 H, Ar-H), 7.67 (d, J = 7.9 Hz, 1 H, Ar-H), 7.52 (d, J = 8.3, 1 H, Ar-H), 7.37 (t, J = 8.2, 1 H, Ar-H), 7.26 (d, J = 8.2 Hz, 1 H, Ar-H), 6.99 (t, J = 7.2 Hz, 1 H, Ar-H), 6.59 (t, J = 7.2 Hz, 1 H, Ar-H), 6.38 (t, J = 7.2 Hz, 1 H, Ar-H), 0.37 (s, 3 H, CH3), 0.20 (s, 3 H, CH3).The synthesis of (P)-EH3-Me2 from (S a)-BA3 is described in the SI.
  • 23 CCDC 2182824 contains the supplementary crystallographic data for compound EH3-Ph2 . The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
  • 24 (M)-EH3-Ph2: Enantioselective SynthesisEnantioenriched (R a)-BA3 (98% ee) (6.00 mg, 11.9 μmol, 1.0 equiv) was dissolved in CH2Cl2 (0.75 mL) under argon. DIPEA (2.20 μL, 1.69 mg, 13.1 μmol, 1.1 equiv) was added and the mixture was cooled to –78 °C. A 1.0 M solution of BBr3 in CH2Cl2 (35.6 μL, 35.6 μmol, 3.0 equiv) was added dropwise, and the mixture was warmed to rt and stirred at rt for 22 h. The solvent was then removed in vacuo and the resulting orange solid was washed with dry hexane (3 × 0.5 mL) under argon. The residue was dissolved in toluene (0.75 mL) and a 1.0 M solution of AlPh3 in Et2O (35.5 μL, 35.5 µmol, 3.0 equiv) was added dropwise under argon. The resulting mixture was stirred at 90 °C for 4 h, then cooled to 0 °C. H2O (1.5 mL) was added and the mixture was extracted with EtOAc (4 × 3 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica , cyclohexane/CH2Cl2 (3:1)] to give a yellow solid; yield: 4.50 mg (6.72 μmol, 57%, 98% ee). HPLC: Reprosil Chiral-MIF, 250 × 4.6 mm, hexane–CH2Cl2 (87:13), 2 mL/min (For details, see SI). 1H NMR (400 MHz, CD2Cl2) δ = 8.89 (d, J = 8.0 Hz, 1 H, Ar-H), 8.81–8.69 (m, 3 H, Ar-H), 8.61–8.57 (m, 1 H, Ar-H), 8.56 (d, J = 5.9 Hz, 1 H, Ar-H), 8.18 (d, J = 8.5 Hz, 1 H, Ar-H), 8.14 (d, J = 8.0 Hz, 1 H, Ar-H), 8.03 (d, J = 8.6 Hz, 1 H, Ar-H), 7.82 (d, J = 5.9 Hz, 1 H, Ar-H), 7.81–7.63 (m, 6 H, Ar-H), 7.60 (d, J = 8.5 Hz, 1 H, Ar-H), 7.56–7.52 (m, 2 H, Ar-H), 7.41 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, Ar-H), 7.38–7.27 (m, 5 H, Ar-H), 7.26–7.20 (m, 1 H, Ar-H), 7.16–7.07 (m, 3 H, Ar-H), 7.02 (ddd, J = 8.3, 7.1, 1.4 Hz, 1 H, Ar-H), 6.64 (ddd, J = 8.4, 6.9, 1.2 Hz, 1 H, Ar-H), 6.43 (ddd, J = 8.3, 7.1, 1.2 Hz, 1 H, Ar-H).The syntheses of (P)-EH3-Ph2 from (S a)-BA3 and of rac-EH3-Ph2 from rac-BA3 are described in the SI.

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Scheme 1 (a) Enantioselective syntheses of azoniahelicenes and olefinated biaryls by dynamic kinetic resolution.17 (b) π-Extended azabora[6]- or -[7]helicenes EH2-Me2 and EH3-Me2 ,15 and (c) enantioselective synthesis of EH3 by axial-to-helical chirality transfer reported in this work.
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Scheme 2 (a) Molecular structure of BA2 and enantioselective synthesis of boron-containing helicenes starting from configurationally stable enantioenriched biaryl precursors (S a)- and (R a)-BA3. The (P)- and (M)-enantiomers of the respective helicenes EH3-Me2 and EH3-Ph2 were synthesized without any loss of enantiomeric purity. (b) Molecular structure of rac-EH3-Ph2 determined by X-ray analysis at 100 K. Only the (M)-enantiomer is depicted. ORTEP drawings are shown with 50% probability.
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Figure 1 Chromatograms of BA3 (left), EH3-Me2 (middle) and EH3-Ph2 (right): racemates (top), (S a)- or (M)- (middle), and (R a)- or (P)-enantiomers (bottom).
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Figure 2 Absorption spectra of racemic mixtures of BA3, EH3-Me2 and EH3-Ph2 (c = 4.7 × 10–5 to 1.2 × 10–4 M) in CH2Cl2 (293 K).
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Figure 3 ECD (BA3: c = 5.0 × 10–5 M, EH3-Me2 : c = 2.7 × 10–5 M, EH3-Ph2 : c = 4.4 × 10–5 M) spectra of BA3, EH3-Me2 and EH3-Ph2 in CH2Cl2 (293 K).