Enantioselective gold(I)-catalysed alkyne hydroarylations for inherently chiral calix[4]arenes

Abstract

We report enantioselective gold(I)-catalysed hydroarylation of alkynes to access inherently chiral calix[4]arenes. This method delivered a family of macrocycles, embedded with phenanthrene motifs, with good yields and enantioselectivities. Investigations of the photophysical and chiroptical properties revealed interesting fluorescence features, suggesting potential applications in materials science and devices.

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Hydroarylation reactions represent a powerful tool to construct organic molecules with many applications in the field of organic chemistry.¹ In this context, gold catalysis has been established as a versatile method able to transform modular alkyne derivatives into useful building blocks or materials in the most atom- and step-economical manner.² In particular, enantioselective gold-catalysed hydroarylation of alkynes has been applied for the synthesis of chiral compounds characterised by non-trivial axial,³ planar⁴ or helical⁵ stereogenic elements (Scheme 1a and b). Recently, the scientific community has witnessed an increased interest in developing asymmetric catalytic methods to synthesize inherently chiral compounds.⁶ This type of chirality arises from the introduction of “a curvature in an ideal planar structure that is devoid of symmetry axes in its bidimensional representation”.⁷ Among such organic compounds, inherently chiral calix[4]arenes (ICCs) are now in high demand.⁸ This is demonstrated by numerous enantioselective catalytic methods that have been developed recently for the construction of such macrocycles in an asymmetric manner.⁹ ICCs find many applications in chemosensory, medicinal chemistry, or materials science.¹⁰ Moreover, their unique features have been employed to build synthetic molecular receptors¹¹ and catalysts.¹² Based on precedent studies,¹³ we now exploit enantioselective gold catalysis for the construction of inherent chirality. The functionalisation of 1 at its meta position,^8b via gold-catalysed hydroarylation of alkynes,^13b results in the desymmetrisation of the macrocycle, producing the targeted inherently chiral calix[4]arene 2 (Scheme 1c).

Scheme 1 “State-of-the-art” for enantioselective gold-catalysed hydroarylations of alkynes: (a) synthesis of axial, planar and (b) helical chiral compounds; (c) our work.

Calix[4]arenes are known to adopt several distinct conformations beyond the most common cone (i.e. partial cone, 1,3-alternate and 1,2-alternate). The latter arise from the rotation of the phenolic rings around the methylene bridges. However, the well-defined cone conformation offers an ideal platform to develop enantioselective catalytic desymmetrisations.^9b–j Hence, it gives a rigid bowl-shaped geometry that helps the catalysts to discriminate the enantiotopic faces. In contrast, in non-cone conformations, the spatial arrangement is less defined, rendering asymmetric catalytic reactions more challenging. For this reason, we began our investigation with the synthesis of model calix[4]arene 1a, “frozen” in a cone conformation.¹⁴ The presence of bulky propyl groups at the lower-rim of the macrocycle is necessary to make calix[4]arenes 1a and 2a configurationally stable, thus preventing the “oxygen-through the annulus” rotation.¹⁵ We then focused on optimising the enantioselective cyclisation reaction by screening a series of chiral gold(I) catalysts (Table 1; see the SI for full screening).

Table 1 Optimisation of the reaction conditions^a

Entry	[Au]	AgX	2^b (%)	e.r^c
a Reaction conditions: 1a (0.065 mmol), [Au] (2.5 or 5 mol%), AgNTf2 (5 mol%) in anhydrous 1,2-DCE (0.65 ml, 0.1 M) at rt for 1 h.b Isolated yield.c Enantiomeric ratios (e.r.) were determined by chiral HPLC. See the SI for full experimental details.d Toluene (0.1 M) as the solvent.e CH2Cl2 (0.1 M) as the solvent.f Reaction performed at 0 °C for 18 hours.
1	[L1AuCl]	AgNTf2	99	74 : 26
2	[L2AuCl]	AgNTf2	89	57 : 43
3	[L3(AuCl)2]	AgNTf2	89	43 : 57
4	[L4(AuCl)2]	AgNTf2	87	72 : 28
5	[L5(AuCl)2]	AgNTf2	91	70 : 31
6	[L6(AuCl)2]	AgNTf2	91	86 : 14
7	[L6(AuCl)2]	AgSbF6	87	87 : 13
8	[L6(AuCl)2]	AgBF4	80	86 : 14
9	[L6(AuCl)2]	AgOTf	87	86 : 14
10^d	[L6(AuCl)2]	AgSbF6	65	48 : 52
11^e	[L6(AuCl)2]	SbF6	99	90 : 10
12^e^f	[L6(AuCl)2]	SbF6	95	93 : 7

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Initially, chiral phosphoramidite–gold complexes [L₁AuCl] (bearing a 2-naphthyl group at the C3/C′3 positions) and [L₂AuCl] (9-pyrenyl) were tested. While both gave excellent yields of 2a (99% and 89%, respectively), the enantioselectivities were modest or low (e.r. = 74 : 26 and 57 : 43, respectively; entries 1 and 2). We next explored bidentate chiral ligands, such as L₃ and L₄, belonging to the BIPHEP family. [L₃(AuCl)₂] afforded 2a in an 89% yield but with poor enantiocontrol, while [L₄(AuCl)₂] gave slightly improved enantioselectivity (e.r. = 72 : 28), though still unsatisfactory (entries 3 and 4). The (R)-DTBM-Segphos complex [L₅(AuCl)₂] performed similarly to L₄ (entry 5), whereas (R)-DM-Segphos [L₆(AuCl)₂] delivered 2a in a 91% yield and a promising e.r. of 86 : 14 (entry 6). With L₆ as the most effective ligand, we examined the influence of the counterion. The use of AgSbF₆ resulted in a slight improvement in enantioselectivity (entry 7). Other counterions tested in the gold(I)-catalysed hydroarylation proved less effective (entries 8 and 9). In contrast, switching the solvent to toluene negatively affected the reaction, giving racemic 2a in a 65% yield. Dichloromethane, on the other hand, improved both the yield and the enantiomeric ratio (99%, e.r. = 90 : 10), and was selected as the optimal reaction medium (entry 11). Finally, performing the reaction at 0 °C for 18 hours led to a satisfactory e.r. of 93 : 7 and a 95% yield (entry 12). With the optimized reaction conditions, we next evaluated the generality of the transformation by testing a series of functionalized calix[4]arenes 1b–p (Scheme 2).

Scheme 2 Scope of the reaction. Reaction conditions: 1b–p (0.065 mmol), [L₆(AuCl)₂] (2.5 mol%), AgSbF₆ (5 mol%) in anhydrous CH₂Cl₂ (0.1 M) at 0 °C for 18 hours. Isolated yields are reported. ^gAt room temperature.

At the outset, modifications at the lower rim of the calix[4]arene core were examined. Tetrahexyl- and tetraoctyloxy-substituted calix[4]arenes 1b and 1c afforded the corresponding hydroarylated products 2b and 2c in high yields (81% and 85%) with enantiomeric ratios of 89 : 11 and 90 : 10, respectively. An even higher yield was obtained using the ethoxylated scaffold 1d, which delivered 2d in a 94% yield, albeit with a slightly lower enantioselectivity (e.r. = 87 : 13). Keeping the tetrapropyl alkyl chain at the lower rim, we then introduced substituents with various electronic properties in the phenylacetylene ring. The reaction proved tolerant to a range of electron-withdrawing groups (F, Cl, CF₃, CO₂Me, NO₂) at the meta-position with respect to the alkyne moiety, affording the corresponding products 2e–i in yields ranging from 71% to 99% and enantiomeric ratios of up to 93 : 7.

Similar results were obtained with halogens at the para-position: fluoro-, chloro- derivatives 2j and 2k were isolated in 87% and 79% yields, respectively, both with an e.r. of 90 : 10. In contrast, the methoxycarbonyl-substituted product 2l showed lower reactivity and selectivity (48%, e.r. = 71 : 29). Likewise, difluoro-calix[4]arene 1m was less reactive, giving 2m in a 61% yield and an e.r. of 88 : 12. Electron-donating groups were also tolerated at various positions of the calix[4]arene scaffold. Hence, meta-OMe and para-OBn afforded the corresponding products 2n and 2o in moderate to excellent yields (68 and 94%, respectively). However, these reactions required higher temperatures (room temperature instead of 0 °C), and enantiocontrol was slightly reduced (e.r. = 86 : 14 and 88 : 12, respectively). Finally, thiophene-containing product 2p could also be synthesized, albeit with modest yield (51%) and poor enantioselectivity. The structure and absolute configuration of the ICCs were further elucidated through X-ray single-crystal diffraction analysis of calix[4]arene 2f and 2k.

Four of the new ICCs were chosen for complete characterization of the (chiro-)optical properties, particularly 2a (the reference compound), 2f (meta chloride), 2h (meta CO₂Et) and 2i (meta nitro). Absorption, fluorescence and circular dichroism (CD) spectra were collected in two solvents of different polarity, hexane and dichloromethane (DCM). The main data in CH₂Cl₂ are reported in Fig. 1 (spectra in hexane in Fig. S1) and summarized in Table S1 (see the SI). All the compounds are characterized by strong absorption (ε ∼ 30 000–60 000 L mol⁻¹ cm⁻¹) in the UV. Compounds 2a, 2f and 2h show weakly allowed transitions (ε ∼ 100–1000 L mol⁻¹ cm⁻¹) around 330–340 nm, likely of charge transfer (CT) nature. Since fluorescence emission always stems from the lowest-energy excited state, the observed Stokes shifts are very large (Fig. 1 and Table S1). For calixarene 2i, the lowest-energy absorption band is quite intense and solvatochromic, moving from 345 nm in hexane to 360 in CH₂Cl₂, confirming the CT nature of the transition. Unfortunately, 2i has no detectable emission in hexane, while in CH₂Cl₂ a red-shifted, broad emission band is recorded, associated with the same CT transition. In general, quantum yields are higher, and fluorescence lifetimes are longer in CH₂Cl₂ than in hexane (Table S1). All the compounds show positive CD peaks in the region of the main absorption bands in the visible range, while the sign changes for the band in the UV. 2i also has a broad CD-active band at ∼350 nm, associated with the CT transition, while for the other compounds these low-energy bands are extremely weak, as already observed in absorption. The dissymmetry factors (g_abs = Δε/ε) are plotted in Fig. S2. The |g_abs| are in general about 10⁻³, indicating weak chiroptical activity, consistent with the small dimensions of the inherently chiral chromophore. The highest |g_abs| are observed for 2f, reaching values >2 × 10⁻³.

Fig. 1 Absorption (blue lines, left axes, molar extinction coefficient units), emission (green lines, arbitrary units) and CD spectra (red lines, right axes, Δε = ε_L − ε_R) of compounds 2a, 2f, 2h and 2i in CH₂Cl₂.

Finally, we investigated the origin of the observed enantioselectivity by means of DFT calculations (see the SI for details). We located twelve transition states (TSs) for each enantiomeric product, for the gold-catalysed C–C bond formation (see relative energies and the optimized structures of selected TSs in Fig. 2). The TS associated with the lowest energy (P_tilt_out_O2_C1) leads to the formation of the experimentally observed major enantiomer P, while the lowest energy TS leading to the enantiomer M (M_tilt_in_O2_C2) is only 0.6 kcal mol⁻¹ higher in energy. This energy difference would correspond to a 74 : 26 e.r. However, a few TSs are similar in energy, and would thus contribute to the product distribution. Boltzmann averaging all possible TS energies gives an 83 : 17 e.r., in good agreement with the experimental results. Regarding the origin of the enantioselectivity, comparing the lowest energy TSs suggests that P_tilt_out_O2_C1 is less sterically crowded than M_tilt_in_O2_C2. Moreover, the Au–Au interatomic distance is shorter in P_tilt_out_O2_C1 than in M_tilt_in_O2_C2 (3.13 vs. 3.28 Å), which could also contribute to the enantioselectivity of the reaction. In conclusion, we have developed the first enantioselective gold(I)-catalysed hydroarylation of alkynes for inherently chiral calix[4]arenes. Despite the intrinsic complexity of achieving high enantiocontrol in these sterically demanding alkynyl-functionalised macrocycles,¹⁶ the method is general, operationally simple, and affords a broad range of ICCs in good yields and moderate to good enantioselectivities. Complementary computational studies rationalised the observed selectivities, while detailed chiroptical and photophysical analyses revealed structural and electronic properties that influence the optical behaviour of the final products. This catalytic method paves the way for the gold catalysed enantioselective synthesis of other calix[n]arene macrocycles.

Fig. 2 Relative energies of the DFT-optimized transition states (top) and lowest energy transition states leading to the two enantiomers (bottom).

Dr Elisa Brambilla is gratefully acknowledged. Mass spectrometry analyses were performed at the MS facility of the Unitech COSPECT (University of Milan). We acknowledge the CINECA award under the ISCRA initiative, for the availability of high performance computing resources and support. This work has benefited from the equipment and framework of the COMP-HUB and COMP-R Initiatives, funded by the “Departments of Excellence” program of the Italian Ministry for University and Research (MIUR, 2018-2022 and MUR, 2023-2027). This project was funded by the Italian MIUR (PRIN 20227Z3BL8).

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary Information (SI). See DOI: https://doi.org/10.1039/d5cc04405g.

CCDC 2476429 (2f) and 2476430 (2k) contain the supplementary crystallographic data for this paper.^17a,b

Notes and references

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