A Family of Bisnaphthyl C2-Symmetric and Asymmetric Clefts: Synthesis, Solid-State Structure, and Calculation of the Interplanar Angle

The synthesis of a new family of naphthalenoid C2-symmetric clefts has been realized through a four-step synthetic sequence giving three C2-symmetric clefts and a rare nonsymmetric example. Subsequently, stereoselective reduction of the carbonyl groups at C-8 and C-16 then provides cleft molecules with hydrogen bonding potential. Using single-crystal X-ray and computational analysis, the cleft angle of the dione has been determined.

3.1]nona-5a,6a-diene-6,12-dione (1) is a C 2 -symmetric molecule with a distinctive 3D cleft shape, a consequence of three contiguous bridgehead sp 3 hybridized carbons that "fix" the conformation of the molecule (Scheme 1A). 1,2 The C 2 -symmetric axis, together with its unique topography, provides a unique chiral cavity that can be exploited in supramolecular interactions. 3−5 Unlike its structural equivalent Trogers base (TB, 2), 6,7 its carbocyclic skeleton provides immunity to racemization in acidic media while also offering extra functionality through the two carbonyl groups at C-6 and C-12, respectively. However, it must be emphasized that TB (2) has been extensively functionalized 7 and is an exemplar chiral cleft for dione 1 to aspire to in terms of flexibility and synthetic potential.
The synthesis of 1, and its analogues, is achieved through a double Friedel−Crafts cyclization of a diacid 3 (Scheme 1B). This route provides 1a, as well as the methyl-(1b) and bromoanalogue (1c) derivatives. 8 Alternatively, analogues of 1 can be accessed through direct chemoselective manipulation of the two aromatic rings (1d and 1e). 9 Functionalization of the two aromatic rings is important, as it directly affects the cleft angle (θ) and can provide predictability in their positioning. Importantly, the two carbonyl groups at positions C-6 and C-12 of 1 can be stereoselectively reduced, providing anchor points for the introduction of host−guest recognition features. 10−16 However, in contrast to its structural equivalent TB (2), there are very few examples of 1 possessing extended aromaticity, 17 even though this structural feature is known to enhance host−guest interactions and physicochemical properties. 18 The importance of extended aromaticity in naphthalenoid TB analogues has led to the development of molecular tweezers, 19−21 analogues that exhibit high specific rotations 22 and ligands that interact selectively with biomolecules such as DNA. 23−25 Consequently, presented with the benefits of extended aromaticity together with the structural deficiencies of TB, the synthesis of naphthalenoid analogues of 1 would be welcomed.
Therefore, in this disclosure we report the synthesis of a naphthyl family of carbocyclic dione clefts. Their 3D structure is fully characterized and supported by single-crystal X-ray crystallography, which then permits an analysis of the cleft angles of each naphthalenoid isomer.
Three C 2 -symmetric naphthalenoid clefts were targeted for synthesis (5a−c), all of which possess increased aromatic surface compared with the parent cleft 1 (Scheme 2). The synthesis of 5a is conceivable by a Friedel−Crafts cyclization on diacid 4a through the 2-naphthyl carbon. The clefts 5b and 5c can also be synthesized through a Friedel−Crafts cyclization on diacid 4b, with 5b being accessed through the 1-naphthyl carbon and 5c through the 3-naphthyl carbon.
The synthesis of the first naphthyl ligand 5a began with 1acetonitrilenaphthalene (6a) and diiodomethane using an adapted procedure of Tatemitsu (Scheme 3). 1 Condensation of 6a and CH 2 I 2 in the presence of potassium hydroxide provided a crude dinitrile that was subsequently hydrolyzed to give 4a, as a mixture of its meso and (±)-isomers, in a 51% yield over these two steps. Treatment of this mixture with concentrated sulfuric acid then effected a double Friedel− Crafts cyclization, giving (±)-5a in an isolated yield of 4% (conditions A). The structure of the C 2 -symmetric naphthalenoid dione (±)-5a was fully established through 1 H and 13 C NMR spectroscopy and further supported by single-crystal X-ray analysis, with the molecular structure also shown in Scheme 3.
The yield of (±)-5a using conditions A was very low and significantly depressed compared with the cyclization of diacid 3a, which provides the parent dione 1a in ca. 40% isolated yield. 9 We suspected the depressed yield in the formation of (±)-5a was due to the sulfonation of the naphthyl ring under the sulfuric acid-mediated Friedel−Craft cyclization condi-tions. We therefore sought an alternate method that would circumvent the sulfonation of either the starting diacid 4a, the product dione (±)-5a, or both. An improvement in the synthesis was found by the treatment of the diacid mixture 4a with (COCl) 2 to provide the diacid chloride, whose cyclization to the dione (±)-5a could then be effected with AlCl 3 (conditions B). This reaction sequence provided (±)-5a in an improved isolated yield of 61%. The physical data of (±)-5a using these improved conditions were identical to those of the product obtained using conditions A.
The naphthalenoid dione targets 5b and 5c were synthesized from 2-acetonitrilenaphthalene (6b) (Scheme 4). Again, condensation of 6b and CH 2 I 2 in the presence of potassium hydroxide, followed by immediate saponification of the mixture, gave 4b in a 38% yield over two steps. The cyclization of this diacid mixture using concentrated sulfuric acid (condition A) yielded one identifiable product in an isolated yielded of 6%. Subsequently, 1 H and 13 C NMR analysis showed this product to be the naphthalenoid dione (±)-5b. 17 Employing conditions B to achieve the cyclization of the diacid 6b provided three products after purification. Detailed
Compared with (±)-5a−c, the 1 H NMR spectrum of the remaining unidentified product was atypical. Characteristically, the bridge protons of parent dione 1 and the naphthalenoid C 2 -symmetrical diones (±)-5a−c present as a triplet, typically in the region of δ 3.30−2.95 ppm. However, the 1 H NMR spectrum of the unidentified product exhibited increased complexity in this region, signifying that the product was no longer C 2 -symmetric. Further analysis indicated that the bridge protons were presenting as diastereotopic, at δ 3.21 and 3.05 ppm, respectively; this was further supported by the 13 C NMR spectra. Therefore, we proposed the structure of the unknown product to be that shown for (±)-5d. We were able to obtain crystals for all three clefts (±)-5b−d, and this further supported our NMR analysis, confirming their proposed structures; the molecular structure of (±)-5c is shown in Scheme 4. The naphthalenoid dione (±)-5d is a very rare example of an unsymmetrical cleft within this family of cleft molecules and should find relevance with the wider family of TB naphthalenoid derivatives. 19−22, 26 Previously we have reported that the reduction of 1a with NaBH 4 provides a diol with two hydroxy groups that are ideally positioned for chiral recognition. 14,15 Accordingly, the reduction of diones (±)-5a and (±)-5b was realized by treatment with methanolic NaBH 4 providing diols (±)-7a and (±)-7b in 51% and 47% yields, respectively (Scheme 5).
Detailed 1 H and 13 C NMR analysis of (±)-7a and (±)-7b indicated that, analogous with 1, the reduction is entirely stereospecific, with each hydroxyl group being directed into the cavity of the cleft. This observation was further confirmed by the single-crystal X-ray analysis performed on (±)-7a, whose molecular structure is shown in Scheme 5. This X-ray analysis also shows H-bonding of the diol with two molecules of methanol, therefore demonstrating the potential for this cleft class.
Pleasingly, the results above enabled an analysis of the interplanar "cleft" angles (θ) for each of the four diones (±)-5a−d and the diol (±)-7a (Table 1). This angle was calculated between the two aromatic rings directly attached to the saturated cleft; furthermore, this measure maybe useful in the rationale design of host−guest interactions within the cavity of the cleft. The interplanar "cleft" angle for naphthalenoid dione (±)-5a, was considerably higher, 105.2°, compared with those of diones (±)-5b−d. These later diones exhibited cleft angles in the range of 91−94°a pproximating that of TB (2). 27 The flexibility in the interplanar angle of this dione cleft family has been observed in previous studies, 8,9 with substitution on the benzene rings of 1 greatly affecting the interplanar angle. Electron-donating groups on the aryl ring of 1 have been shown to increase the interplanar angle, with the dimethyl ligand 1a exhibiting the largest angle (104.3°or 101.7°) to date; this value is now surpassed by (±)-5a. The cleft angles were also determined from the computational optimized structures of 5a−d and 7a. 28 Apart from 5a, there are discrepancies in these cleft angle values for 5b−d and 7a, and this most likely reflects the defined crystal packing and has been observed in the X-ray crystallographic data for related analogues of 1. 14,15 The mechanism for the formation of dione (±)-5a mirrors that of 1, occuring through initial oxonium formation to give I, which undergoes a Friedel−Crafts cyclization with the 2naphthyl carbon to give intermediate II; this cyclizes again, providing the bicyclic dione (±)-5a (Scheme 6A). Note that only (±)-I undergoes cyclization and that its meso isomer cannot due to geometrical constraints.
The formation of (±)-5b−d is more complicated given there are two potential nucleophilic sites on the oxonium III: the 1-naphthyl carbon and 3-naphthyl carbon, respectively (Scheme 6B). Cyclization of oxonium III via the 1-naphthyl carbon provides the oxonium intermediate IV, which in turn can cyclize via two subsequent pathways. Cyclization via the second 1-naphthyl carbon provides the C 2 -symmetric dione (±)-5b, whereas cyclization via the 3-naphthyl carbon provides the unsymmetrical dione (±)-5d. Alternatively, cyclization of oxonium III via the 3-naphthyl carbon provides oxonium intermediate VI. Again, this can cyclize via two pathways, with cyclization via the second 3-naphthyl carbon providing the C 2symmetric dione (±)-5c and cyclization via the 1-naphthyl carbon giving the unsymmetrical dione (±)-5d.  To conclude, in this study we have synthesized a new series of naphthalenoid C 2 -symmetric clefts possessing extended aromaticity. Additionally, a rare unsymmetrical naphthalenoid cleft could be accessed. The single-crystal X-ray structure data for the four diones provided an analysis of the interplanar cleft angle, with dione 5a exhibiting an angle of 105.2°, the largest yet reported for this family of cleft substrates. Given the structural advantages of dione 1 29 (e.g., immunity to racemization and carbonyl functionalization) compared with TB, these new C 2 -symmetric cleft molecules hold potential as scaffolds, given the historical success of TB analogues in medicinal chemistry. There exists significant scope in further developing this family of ligands by synthesizing each of their enantiomers using existing chemistry 15 and investigating the synthetic manipulation of the naphthyl rings. 9 Additionally, we are currently assessing the interactions of (±)-5a−d with biomolecules such as ct-DNA and will report these results in due course.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information
Experimental procedures, compound characterization, crystallographic data, computational tables, and copies of NMR spectra (PDF)

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We would like to acknowledge funding for G.E. (Libyan Cultural Attaché). The authors thank the EPSRC for underpinning funds (EP/P030599/1) and for X-ray diffraction data collection at the UK's National Crystallography Service at the University of Southampton for 5c and 5d.