Stereoselective synthesis of linear oxa-triquinanes and oxa-diquinanes via Lewis acid mediated nucleophilic addition to oxonium ions: study of nucleophile-dependent selectivity

A simple and reliable approach was developed for the stereoselective construction of symmetrical linear dioxatriquinanes and oxadiquinanes via Lewis acid mediated nucleophilic addition to oxonium ion intermediate for etherification of dimethyl acetals. The precursors of linear triquinanes are obtained from the Diels – Alder adducts via ozonolysis in MeOH followed by reductive work-up and subsequent treatment with catalytic H 2 SO 4 to furnish the dimethyl acetal. Further, the stereochemistry of synthesized oxa-bowls was unambiguously established by single crystal X-ray diffraction studies on its derivative


Introduction
Triquinanes have attracted considerable attention from organic chemists due to their unique and synthetically challenging framework, which is also present in many natural products. [1][2][3][4] Generally, triquinanes are classified into three types depending on the stereochemical arrangement of the fused five-membered rings present, namely, linear-, angular-, and propellane-type ( Figure 1). In addition, many of these linear triquinanes, which belong to the sesquiterpenoid family, have aroused intense interest in the recent past due to their novel molecular architecture and wide spectrum of biological activities. After the discovery and synthesis of the first polyquinane natural product, hirsutic acid C, significant progress has been made on the synthesis of carbocyclic polyquinanes. As a result, several strategies have been employed for the synthesis of linear triquinanes Cnorcardanolide and Isogenine steroid based natural products. 5,6 The oxygen analogues of linear triquinanes have shown promising biological activity and proved to be useful for the treatment of leukemia, osteosarcoma, breast cancer and ovarian cancer. 7,8  Substantial efforts have been directed towards the synthesis of carbocyclic triquinane frameworks as they constitute the core of many sesquiterpene natural products. In contrast, the heteroatom-substituted triquinanes have attracted considerably less attention from synthetic chemists. The majority of the strategies developed in past few decades give access to unsymmetrical aza-and oxa-triquinanes. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] Far less attention has been paid to develop strategies that would incorporate symmetrical dioxa-linear-triquinane. In continuation of our interest in the synthesis of oxa-, aza-bowls, cages and triquinanes, herein we describe an efficient approach to symmetrical linear dioxatriquinanes and oxadiquinanes through the stereoselective addition of nucleophiles to oxonium ion intermediate. [25][26][27][28][29][30]

Results and Discussion
A Lewis acid mediated etherification reaction based strategy conceived for the construction of symmetrical, linear oxa-triquinane structures is outlined in the Figure 2. It was envisaged that the oxa-triquinanes 7 could be readily prepared by addition of an appropriate nucleophile to the bis-oxonium ion 8 derived from the acetal 9 in the presence of Lewis acid. It was further argued that the nucleophile would preferentially add to the oxonium ion 8 from the less hindered convex face. The dimethyl acetal 9 could in turn be obtained from the diol 10 after ozonolysis. The diol 10 could be readily obtained from the reduction of Diels-Alder adduct formed between cyclopentadiene and maleic anhydride.
In order to test the feasibility of the proposed ozonolysis/Lewis acid mediated etherification strategy for the synthesis of linear dioxatriquinanes, acetal 9 was chosen as an appropriate precursor. Synthesis began with the Diels-Alder reaction between cyclopentadiene and maleic anhydride, which furnished the endo-adduct 11 in good yield with excellent diastereoselectivity. Reduction of the anhydride 11 using LAH in refluxing THF gave the diol 10. The diol 10 was subjected to ozonolyzis, followed by reductive workup with dimethyl sulphide and the reaction mixture was treated with catalytic amount of H2SO4 in methanol to furnish the dimethyl acetal 9 in 90% yield (Scheme 1). Having the acetal 9 in hand, it was subjected to reductive etherification using triethylsilane and TMSOTf in CH2Cl2 at 0 °C. Gratifyingly, the reaction resulted in the formation of dioxatriquinane 7a in 89% yield.

Scheme 1
The structure of the linear dioxatriquinane 7a rests secured from its spectral data. Presence of molecular ion peak at m/z 155.1068 (C9H15O2) in the mass spectrum suggested the formation of the product. In the 1 H NMR spectrum, presence of multiplets at δ 3.76-3.61, 2.81-2.77, 2.15-2.10 and 1.36-1.28 ppm established the structure of the product. Finally, five-line 13 C NMR spectrum with characteristic signals at δ 73.2 (CH2), 69.5 (CH2), 48.0 (CH), 46.9 (CH), 37.1(CH2) ppm confirmed the formation of the product.
After successful demonstration of the concept by trapping the bis-oxonium ion with hydride as a nucleophile, a systematic study towards enhancing the scope of the reaction was carried out. Various nucleophiles were screened for their reactivity with bisoxonium ion and their stereoselectivity were monitored closely. [31][32][33][34] Initial screening of the reaction of acetal with different nucleophiles using TMSOTf as the Lewis acid revealed that even though the reaction worked, it was sluggish in some cases. On the other hand using TiCl4 as the Lewis acid gave consistently good reactivity as well as selectivity and hence it was chosen as the Lewis acid to study the scope of the reaction with various nuclephiles. It was observed that 1,3,5-trimethoxybenzene was used as the nucleophile, trimethoxyphenyl substituted linear dioxatriquinane 7b was obtained in good yield and excellent diastereoselectivity. Single crystal X-ray diffraction studies (CCDC 1006760) ( Figure 3) on this triquinane 7b revealed that the aryl group had trapped the oxonium ions from the least hindered convex face. In another direction the bis-oxonium ion intermediate could be trapped with triethylphosphite leading to bis-phosphonate ester bearing triquinane 7d. TMSCN was found to be good nucleophile and gave the corresponding triquinane 7e and 7e', in good yields albeit with poor diastereoselectivity (cis:trans = 3:1) (Scheme 2). 35

Scheme 2
The structure of both the diastereomers 7e and 7e' could be unambiguously assigned based on the single crystal X-ray diffraction studies (CCDC 942151 and 1006761) ( Figure 4). The bis-substituted linear triquinanes such as bis-nitriles 7e and 7e' could be potentially used as ligands for the synthesis of metal complexes. It was observed that allenyltributyltin and allyltributylstannane could be used as nucleophiles to furnish the triquinanes 7f and 7c, respectively, in good yield and excellent diatereoselectivity. On the contrary, when TMSN3 was used as nucleophile the corresponding bis-azide 7g was obtained in very good yield as a single detectable diastereomer. A Lewis acid mediated etherification reaction-based strategy was also conceived for the construction of oxadiquinanes. Having gained access to the bis-azide triquinane 7g, it was decided to study its reactivity in 1,3dipolar cycloaddition reaction with an alkyne. Towards this end, the azide 7g was subjected to 'click' reaction with phenyl acetylene using copper(I) iodide in DMSO-H2O mixture as solvent. The reaction indeed gave the bistriazole 12 in 76% yield (Scheme 3). [36][37][38][39]

Scheme 3
After successfully demonstrating that the triazole 12 can be prepared following the click reaction protocol, it was decided to study if triquinanes could function as spacer between two cholesterol units and if such a system will display liquid crystalline behaviour. To test this idea, synthesis of a bis-cholesterol derivative 15 was envisaged. Thus, cholesterol 13 was reacted with NaH and propargyl bromide to furnish the propargyl ether 14 in 45% yield. 40 The bis-azide 7g was reacted with the alkyne 14 in DMSO and water (9:1) in the presence of 20 mol % of CuI at room temperature to furnish the triazole derivative 15 in good yield as a single regioisomer (Scheme 4).

Scheme 4
After synthesizing this cholesterol based triazole 15, optical polarizing micrographs were recorded at its melting point using optical polarizing microscope as shown in Figure 5, which is a powerful tool to identify liquid crystal behaviour. [41][42][43][44][45] In addition, the phase transitions were studied by differential scanning calorimetry (DSC) operated at a scanning rate of 10 o C/min and the phase transitions of the compound are shown in figure 6. The textural pattern coupled with the peaks in DSC traces suggested the occurrence of liquid crystal behaviour; in particular, the compounds are self-assembling into a smectic phase i.e. a fluid layer structure. Further explorations are under way to understand this system better. After successfully employing the ozonolysis followed by Lewis acid mediated etherification reaction for the synthesis of linear dioxa-triquinanes, study was also extended to using this method for the synthesis of oxadiquinanes. The synthesis of the requisite alcohol 17 began with SnCl4 catalyzed Diels-Alder reaction of cyclopentadiene with acrolein to furnish endo-adduct 16 contaminated with trace amounts of exo-adduct 16'. Mixture of aldehydes 16 and 16' was subjected to reduction using NaBH4 in MeOH to furnish mixture of the alcohols 17 and 17'. No efforts were made to separate the two isomers as it was anticipated that during ozonolysis followed by the acetal formation step, only the endo isomer would lead to the acetal. Indeed, when the alcohol was subjected to ozonolysis followed by reductive workup with Me2S followed by treatment with catalytic amount of H2SO4 in methanol, the acetal 18 was obtained as a single diasteromer in 90% yield (Scheme 5).

Scheme 5
After successfully synthesizing the acetal 18, it was treated with triethylsilane and TiCl4 in CH2Cl2 at 0 °C. The reaction resulted in the formation of the oxa-diquinane 19 in 47% yield (Scheme 6). The low yield is due to volatile nature of the compound. In fact, when allyltributylstannane was used as a nucleophile to trap the oxonium ion generated from the acetal 18 in the presence of TiCl4, the bis-allyl oxa-diquinane 20 was obtained in 76% yield as the only detectable diastereomer. However, the stereochemistry of the final product could not be ascertained completely.

Scheme 6
The reaction of acetal 18 with electron rich aromatic nucleophiles was found to be particularly interesting. When 1,3,5-trimethoxybenzene (21) was reacted with acetal 18 in the presence of TiCl4, rather than the oxadiaquinane 23, a substituted cyclopentane derivative 22 was obtained in 57% yield (Scheme 7).

Scheme 7
The structure of the cyclopentane derivative 22 rests secure from its spectral data. Presence of molecular ion peak at m/z 475.2335 (C26H35O8) in the mass spectrum and the presence of absorption band at 3055 and 1606 cm -1 suggested the formation of the product. In the 1 H NMR spectrum, presence of two singlets at δ 6.11 and 6.09 ppm due to aromatic protons established the structure of the product. Finally, twenty six-line 13   Formation of the product 22 can be explained based on the mechanism involving 1,5-hydride shift. When the acetal 18 is treated with Lewis acid, initially formed oxonium ion 24 which is trapped by 1,3,5trimethoxybenzene (21), leading to the formation of trimethoxyphenyl substituted oxadiquinane 23 (Scheme 7). The initially formed oxonium ion 24 further reacts with the Lewis acid, forming oxonium ion 25, which is trapped intermolecularly by 1,3,5-trimethoxybenzene (21) to lead to 25. At this stage, under the influence of the Lewis acid, benzylic methoxy group is eliminated to generate the oxonium ion 25. This stable benzylic carbocation 25 is trapped intramolecularly with hydride by 1,5-hydride shift leading to the formation of more stable oxonium ion 26. Trapping of this oxonium ion 26 by water molecule generates hemiacetal 27, which leads to the formation of the keto alcohol 22. [46][47][48][49][50] Scheme 8. Plausible mechanism for the formation of 22.
Further studies to expand the scope of this reaction and use it for the synthesis of diversely substituted cyclopentane derivatives are underway in our laboratory.

Conclusions
In conclusion, a new strategy for the stereoselective synthesis of symmetrically substituted linear dioxatriquinanes was developed based on the ozonolysis followed by Lewis acid mediated etherification strategy. The azide substituted dioxa triquinanes could be further elaborated using click chemistry to prepare cholesterol based liquid crystals. The method was extended to the synthesis of oxadiquinanes. An interesting 1,5-hydride shift was observed when electron rich aryl ring was used as a nucleophile leading to stereoselective synthesis of trisubstituted cyclopentane derivative. The bis-substituted linear triquinanes such as bis-nitriles 7e and 7e' could be potentially used as ligands for the synthesis of metal complexes.

Experimental Section
General. Melting points are recorded using Tempo melting point apparatus in capillary tubes and are uncorrected. IR spectra were recorded on Nicolet 6700 spectrophotometer and JASCO FT-IR-4100 spectrophotometer. 1 H (400 MHz, 500 MHz) and 13 C (100 MHz, 125 MHz) NMR spectrums were recorded on Bruker Avance 400 spectrophotometer and Bruker Avance 500 spectrophotometer, respectively. The chemical shifts (ppm) and coupling constants (Hz) are reported in the standard fashion with reference to chloroform. In the 13 C NMR spectra, the nature of the carbons (C, CH, CH2 or CH3) was determined by recording the DEPT-135 experiment and is given in parentheses. CHN analysis was carried out using Elemental analyzer VSM-VT. High resolution mass measurements were carried out using Micromass Q-ToF instrument using direct inlet mode. Analytical thin-layer chromatography (TLC) was performed on glass plates (7.5 × 2.5 and 7.5 × 5.0 cm) coated with Merck silica gel G containing 13% calcium sulfate as binder or on pre-coated 0.2 mm thick Merck 60 F245 silica plates and various combinations of ethyl acetate and hexanes were used as eluent. Visualization of spots was accomplished by exposure to iodine vapour and UV light. All compounds were purified using silica gel [Acme's silica gel (100-200 mesh)] column chromatography. All small-scale dry reactions were carried out using standard syringe septum technique. Syringe pump was used for slow rate of addition of the reagents. All the commercial reagents were used as such without further purification.