Synthesis of Pentacycloundecane (PCUD) Based Spiro-Pyrano-Cage Framework via Ring-Closing Metathesis

: Here, we demonstrate a short synthetic route to pyrano cage systems containing pen-tacycloundecane units by employing ring-closing metathesis (RCM) as a key step. These cage systems were constructed starting with readily available starting materials by adopting atomic economic processes such as cycloadditions (Diels-Alder reaction and [2+2] cycloaddition), Grignard addition, and oleﬁn metathesis. The key building block, such as hexacyclic cage dione, was prepared from 1,4-naphthoquinone derivative and freshly cracked 1,3-cyclopentadiene. Some of these heterocyclic motifs are useful in biological chemistry and valuable as key synthons for high-energy-density materials.


Introduction
Heterocycles have attracted interest from the scientific community because of their biological activities against various diseases [1].They are considered promising candidates that are available from natural sources, show applications in medicinal chemistry and pharmaceutics, play a prominent role in the synthesis of agrochemicals, and act as key synthons for the design of pharmacophores in modern drug chemistry [2].Amongst the known heterocyclic compounds, cage-containing heterocyclic scaffolds are found in applications of bioorganic chemistry, material science, and supramolecular chemistry [3][4][5].Cage polycycles bearing heteroatoms in their molecular architecture act as ligands and are also suitable for chelation with metal ions [6].These are also considered core frameworks for energetic and photonic/electronic materials [7].Furthermore, functionalized hetero cages exhibit medicinal properties and act as valuable candidates for pharmaceutical applications [8,9].Additionally, some of the cage scaffolds (1)(2)(3)(4)(5)(6) depicted in Figure 1 were constructed by employing novel synthetic approaches.These heterocyclic cages are used as chiral ligands (1) [10] and supramolecules (2)(3) [11,12], and some of those (4-6) display interesting activities against tuberculosis, anti-Parkinson activity, and neurodegenerative diseases [13][14][15].
In view of the literature reports and valuable applications of cage polycycles, we are actively involved in developing new methods and simple synthetic strategies for cage frameworks.During the last two decades, we have demonstrated various new synthetic routes to diverse and functionalized cage molecules by employing cycloaddition and olefin metathesis protocols as key steps [16].Several reports are available for the synthesis of oxa-cage molecules in the literature [17].Some of these strategies to create heterocages rely on tandem cyclization, transannular cyclization, base-promoted rearrangement, dehydration of diols, intramolecular, and alkene-oxirane photocycloaddition [17].As part of our ongoing research focused on designing intricate molecules based on metathesis, here we conceived a ring-closing metathesis (RCM) approach to construct functionalized hetero-cage systems [18][19][20].In this regard, we identified cage dione 13 [21,22] as a useful starting material for the design of a target compound such as 17.

Results and Discussion
Our journey towards the synthesis of the hexacyclic dione 13 [21,22] began with the preparation of the DA precursor, such as the dihydronaphthalene-1,4-dione 11, from inexpensive and commercially available hydroquinone 7 (Scheme 1).In this context, the [4+2] cycloaddition of 1,4-benzoquinone 8 prepared from the hydroquinone 7 was treated with 2,3-dimethyl 1,3-butadiene under reflux conditions in anhydrous benzene to give the cycloadduct 9. Aromatization of cycloadduct 9 in the presence of dil.HCl at room temperature furnished the diol 10.

Results and Discussion
Our journey towards the synthesis of the hexacyclic dione 13 [21,22] began with the preparation of the DA precursor, such as the dihydronaphthalene-1,4-dione 11, from inexpensive and commercially available hydroquinone 7 (Scheme 1).In this context, the [4+2] cycloaddition of 1,4-benzoquinone 8 prepared from the hydroquinone 7 was treated with 2,3-dimethyl 1,3-butadiene under reflux conditions in anhydrous benzene to give the cycloadduct 9. Aromatization of cycloadduct 9 in the presence of dil.HCl at room temperature furnished the diol 10. hetero-cage systems [18][19][20].In this regard, we identified cage dione 13 [21,22] as a useful starting material for the design of a target compound such as 17.

Results and Discussion
Our journey towards the synthesis of the hexacyclic dione 13 [21,22] began with the preparation of the DA precursor, such as the dihydronaphthalene-1,4-dione 11, from inexpensive and commercially available hydroquinone 7 (Scheme 1).In this context, the [4+2] cycloaddition of 1,4-benzoquinone 8 prepared from the hydroquinone 7 was treated with 2,3-dimethyl 1,3-butadiene under reflux conditions in anhydrous benzene to give the cycloadduct 9. Aromatization of cycloadduct 9 in the presence of dil.HCl at room temperature furnished the diol 10.In view of our interest in designing new polycyclic systems containing heteroatoms via metathesis and other protocols [23][24][25][26][27][28][29], we intended to synthesize our target compound 17.In this regard, the cage dione 13 was treated with the commercially available allyl magne- a 125 W-homemade lamp, producing the hexacyclic cage dione 13 (Scheme 1).The structure of cage dione 13 was confirmed by 1 H NMR and 13 C NMR data.
In view of our interest in designing new polycyclic systems containing heteroatoms via metathesis and other protocols [23][24][25][26][27][28], we intended to synthesize our target compound 17.In this regard, the cage dione 13 was treated with the commercially available allyl magnesium bromide in dry ether to deliver the diallyl cage diol 14 along with another hemiketal derivative 15 by transannular cyclization.Next, the cage diol 14, on allylation with the NaH in the presence of allyl bromide in dry DMF, gave the triallyl cage compound 16 (Scheme 2).Subsequent ring-closing metathesis of triallyl compound 16 with the G-I catalyst under rt conditions produced the cage derivative 17.Finally, hydrogenation of the compound 17 with hydrogen in the presence of 10% palladium on activated charcoal in dry EtOAc gave the saturated cage system 18 with a 90% yield (Scheme 2).The structures of cage heterocycles 17 and 18 were fully characterized on the basis of 1 H NMR, 13 C NMR, and DEPT-135 NMR spectroscopic data and finally supported by the mass spectra HRMS values.The 1 H NMR spectrum of the cage spiro-pyran derivative 17 displayed the presence of one singlet (-OH proton) at δ 6.96 (1H), which indicates the proton of alcohol, one doublet at δ 5.66 (1H), and three multiplets at δ 5.06 (2H), δ 5.80 (1H), and δ 6.01 (1H), which represents the olefinic proton of allylic carbon and the spiro-pyran ring.In addition, the 13 C NMR spectrum of 17 shows the four characteristic peaks (olefinic carbon) at δ 135.1, 123.9, 123.8, and 116.2 ppm of allyl carbon, and the spiro-pyran ring system represents the -CH and -CH2 carbon (Figure 2).In the 1 H NMR spectrum of compound 18, the one singlet (-OH proton) at δ 6.96 (1H) indicates the proton of alcohol, and the multiplet at δ 0.91 (4H) represents two -CH2 carbons adjacent to the quaternary carbon of -OH.In addition, the 13 C NMR spectrum of compound 18 also shows two peaks at δ 81.6 and 76.8 that represent the quaternary carbon and at δ 65.1 that represent the -CH2 carbon adjacent to the oxygen in the spiro-pyrane ring.In the spectra of cage spiro-pyran derivative 18, it shows the two olefinic peaks of the cyclohexane ring, and the other peaks of the allyl carbon and spiro-pyran rings are missing, which shows the reduction of double bonds.So, we clearly identified cage spiro-pyran derivative 17 and hydrogenated spiro-pyrane product 18 based on chemical shift values ( 1 H and 13 C).The NMR spectra of all of these are provided in the Supplementary Materials.The 1 H NMR spectrum of the cage spiro-pyran derivative 17 displayed the presence of one singlet (-OH proton) at δ 6.96 (1H), which indicates the proton of alcohol, one doublet at δ 5.66 (1H), and three multiplets at δ 5.06 (2H), δ 5.80 (1H), and δ 6.01 (1H), which represents the olefinic proton of allylic carbon and the spiro-pyran ring.In addition, the 13 C NMR spectrum of 17 shows the four characteristic peaks (olefinic carbon) at δ 135.1, 123.9, 123.8, and 116.2 ppm of allyl carbon, and the spiro-pyran ring system represents the -CH and -CH 2 carbon (Figure 2).In the 1 H NMR spectrum of compound 18, the one singlet (-OH proton) at δ 6.96 (1H) indicates the proton of alcohol, and the multiplet at δ 0.91 (4H) represents two -CH 2 carbons adjacent to the quaternary carbon of -OH.In addition, the 13 C NMR spectrum of compound 18 also shows two peaks at δ 81.6 and 76.8 that represent the quaternary carbon and at δ 65.1 that represent the -CH 2 carbon adjacent to the oxygen in the spiro-pyrane ring.In the spectra of cage spiro-pyran derivative 18, it shows the two olefinic peaks of the cyclohexane ring, and the other peaks of the allyl carbon and spiro-pyran rings are missing, which shows the reduction of double bonds.So, we clearly identified cage spiro-pyran derivative 17 and hydrogenated spiro-pyrane product 18 based on chemical shift values ( 1 H and 13 C).The NMR spectra of all of these are provided in the Supplementary Materials.

General Information
Allylmagnisium bromide, dicyclopentadiene, hydroquinone, and other essential reagents, chemicals, and solvents are used as such, obtained from commercial suppliers,

General Information
Allylmagnisium bromide, dicyclopentadiene, hydroquinone, and other essential reagents, chemicals, and solvents are used as such, obtained from commercial suppliers, without any further purifications.The reaction progress was monitored by thinlayer chromatographic technique (TLC; Type-A, B, or C) using appropriate mobile phase (EtOAc/petroleum ether), and observation was conducted by UV, iodine exposure, and immersion in KMnO 4 solution.In all cases, column purification was performed with 100-200 mesh silica gel with a suitable solvent system.All IR samples were recorded with DCM and chloroform as solvents on the Nicolet Impact-400 FTIR spectrometer.Nuclear magnetic resonance (NMR) spectra ( 1 H, 13 C and DEPT 135) have been recorded on 400 and 500 MHz spectrometers (Bruker), with CDCl 3 solvent and chemical shifts (δ ppm) reported to be relative to an internal standard such as TMS.The J values (coupling constants) are given in Hz.Mass spectra (HRMS) have been recorded in positive ion electrospray ionization (ESI, Q-TOF) mode.Compounds 11 and 13 were synthesized via the literature methods [21,22], and the spectral data are consistent with the reported values.

Synthesis of Cage Diol 14 via Grignard Addition
To a solution of cage dione 13 (200 mg, 0.78 mmol) in dry THF (10 mL), commercially available allylmagnesium bromide (1.0 M in THF, 6 equiv.)was added dropwise at 0 • C and the reaction mixture was stirred at rt for 1 h.After completion of the reaction (TLC monitoring), the reaction mixture was quenched with saturated aq.NH 4 Cl solution (5 mL) and the aqueous layer was extracted with EtOAc (3 × 10 mL).The solvent was removed reduced pressure, and the crude product was purified by column chromatography (100-200 silica gel) using 5-10% EtOAc-petroleum ether as an eluent to afford compound 15 (for data, see the supplementary material).Further elution of column chromatography afforded the desired compound 14.Off white solid; Yield: 186 mg (70%); M.P. 177-179

Molbank 2023 ,
2023, M1567 3 of 7 sium bromide in dry ether to deliver the diallyl cage diol 14 along with another hemiketal derivative 15 by transannular cyclization.Next, the cage diol 14, on allylation with the NaH in the presence of allyl bromide in dry DMF, gave the triallyl cage compound 16 (Scheme 2).Subsequent ring-closing metathesis of triallyl compound 16 with the G-I catalyst under rt conditions produced the cage derivative 17.Finally, hydrogenation of the compound 17 with hydrogen in the presence of 10% palladium on activated charcoal in dry EtOAc gave the saturated cage system 18 with a 90% yield (Scheme 2).The structures of cage heterocycles 17 and 18 were fully characterized on the basis of 1 H NMR,13 C NMR, and DEPT-135 NMR spectroscopic data and finally supported by the mass spectra HRMS values.