Synthesis of cis-Oriented Vicinal Diphenylethylenes through a Lewis Acid-Promoted Annulation of Oxotriphenylhexanoates

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.


■ INTRODUCTION
Cyclic compounds possessing adjacent C(sp 3 )−aryl moieties are widely present in nature. While in most cases these compounds have a trans-vic-diphenylethylene moiety such as indanone 1−7 and reservatrol-based natural products, 8−19 the cis-vic-diphenylethylene motif has been explored less. Nevertheless, these interesting substances still show biological activity, and representative examples include both pharmaceuticals 20 and natural products (Figure 1a). 21−34 For example, the rocaglates, rocaglamide, and silvestrol have received widespread attention as they have been investigated for therapeutic targets such as cancer 21,34,35 and recently viruses like the coronavirus, 36 the Ebola virus, 37 and the hepatitis E virus. 38 Thus, synthetic strategies leading to the formation the cis-vic-diphenylethylene are attractive. However, there are only a limited number of general methods for direct stereoselective formation of cyclic compounds possessing the cis-vic-diphenylethylene moiety. It is also worth noting that a majority of these syntheses are devoted to the diphenyl dihydrobenzofuran moiety found in the rocaglates. 21,23,24,34,39−51 A practical way to prepare the cis-vic-configured C(sp 3 )−aryl could potentially be a ring closure of an acyclic starting material with a preset configuration on the carbons bearing the aryl substituents. We envisioned that a Dieckmann type condensation of a 1,6-ketoester such as the oxotriphenylhexanoate (OTHO) 52−56 would be ideal for this type of transformation. The OTHO has an enolizable ketone and an ester moiety and can, after cyclization, generate a fivemembered diketo compound. Furthermore, one very interesting feature of the OTHO is that the synthesis of the OTHO proceeds with exclusive formation of the trans-vic-diphenylethylene. Used as a starting material in the Dieckmann condensation would thus ensure total control of the cis-vicdiphenylethylene buildup (Figure 1b).

■ RESULTS AND DISCUSSION
Our studies commenced with screening of different Lewis acids for the cyclization of 1a (Table 1) because Lewis acids were already reported to be useful promoters in the Dieckmann type cyclization. 57 Initial attempts showed that the cyclization reaction was highly dependent on the Lewis acid used. Only BBr 3 and BCl 3 delivered the corresponding cyclized product 2a in good yield after 24 and 48 h, respectively (Table 1, entries 2 and 3, respectively). Single-crystal X-ray analysis of compound 2a confirmed that the vicinal aromatic rings were in the cis orientation ( Table 2, entry 2a). Other Lewis acids failed even after prolonged reaction times (Table 1, entries 1 and 4−9). Generally basic conditions were not efficient in promoting the cyclization; only NaH in THF as a solvent successfully afforded 2a in 45% yield (Table1, entry 10). Investigating the loading of BBr 3 showed that 1.5 equiv of BBr 3 is sufficient to reach full conversion within 3 h and produce a yield of 80% (Table 1, entry 11). Higher loadings of BBr 3 (2−3 equiv) resulted in a significant decrease in the level of formation of 2a, and the polycyclization reaction of 1a afforded tricyclic compound 3 (Table 1, entries 12 and 13). 58 At substoichiometric loadings of BBr 3 , the cyclization reaction does not proceed efficiently. For instance, in the presence of 0.25 equiv of BBr 3 , the reaction reaches 25% conversion and stops (Table 1, entry 14). The reaction performs best in chlorinated solvents such as dichloromethane and chloroform; additionally, toluene is shown to promote the reaction efficiently (Table 1, entries 11, 15, and 16).
With our optimized conditions in hand, we first decided to verify the effectiveness of the reaction on a larger scale. It was shown that the reaction of 1a on a 1 mmol scale proceeds with only small decrease in the yield and the corresponding compound 2a could be isolated in 76% yield. Next, we turned our attention to the scope of the reaction ( Table 2). The effect of aromatic ring 3 (Ar3) on the course of cyclization was investigated first. This revealed that the reaction tolerates a broad scope of substituents. For example, OTHOs substituted with halogens in the para position delivered the corresponding products 2b−d in good yields (81−90%). Similarly, OTHOs with a sterically demanding bromine in the meta and ortho positions on Ar3 could also be employed in the cyclization reaction. However, a decrease in the yield could be observed for compounds 2e and 2f (69% and 67%, respectively) compared to that para-substituted derivative 2d (81%). Substrates with an electron rich Ar3 are tolerated by the reaction, as well. For instance, OTHO with a methyl group at the para position on Ar3 provides the corresponding product 2g in high yield (90%). A slight decrease in the yield was observed when OTHO substituted with methyl groups at both Ar2 and Ar3 was used. Corresponding derivative 2h was  isolated in a good yield (76%). Introduction of a methoxy group at the para position of Ar3 decreased the yield of the corresponding product 2i to 50%. The lower yield can be explained by the formation of a demethylated OTHO (1i′) as a side product in 25% yield. The influence of a strong electronwithdrawing group was also verified, and BBr 3 applied on OTHO substituted with a methyl ester group at the para position of Ar3 led to the formation of product 2j in 50% yield. Next, we investigated the effect of aromatic ring 2 (Ar2) in the cyclization reaction. The results showed lower reactivity compared to that of OTHOs substituted at Ar3. This was demonstrated on OTHOs substituted with chlorine or bromine at the para position on Ar2 where the corresponding diketones 2k and 2l could be isolated in 59% and 72% yields, respectively. OTHO substituted with a methyl at the para position of Ar2 led to the formation of 2m; however, the isolated yield was lower (70%) than that of derivative 2g (90%). Also, the effect of the electron-withdrawing cyano group at the para position of OTHO on Ar2 was successfully investigated, isolating the corresponding product 2n in 79% yield. Finally, substituent effects at Ar1 of the OTHOs were investigated. Both p-chloro and p-bromo are well tolerated, and the corresponding diketones 2o and 2p were isolated in good yields (56−75%). A comparable result was obtained with OTHO substituted with a methyl group yielding derivative 2q in 58% yield. In addition, OTHOs substituted with electronwithdrawing methyl ester and cyano groups at the para position on Ar1 were successfully employed in the cyclization reaction; however, the yields of corresponding compounds 2r and 2s were lower (41% and 60%, respectively) than those of derivatives 2j and 2n. Notably, the ester group and the cyano group can be readily transferred to carboxylic acid and amide or amine, respectively, and thus, these substrates open up for the preparation of potentially biologically active compounds with hydrogen bond donor and acceptor capabilities. Expanding the scope by replacing the aryl moieties with an alkyl group is difficult as the synthesis of 1 is not compatible with alkyl substituents. Mechanistically, we propose that the reaction starts with enolization of OTHO 1 promoted by BBr 3 leading to intermediate I (Scheme 1). In the next step, the ester carbonyl is intramolecularly activated by boron leading to the borontethered species (II). In intermediate II, the enol reacts with the ester in an intramolecular fashion, resulting in boroncontaining cyclic transition intermediate III. 59 At the end of the reaction, an excess of isopropanol is added to quench intermediate III, generating compound 2, which is stabilized in the enol form.
To demonstrate the versatility of this methodology, we used 2a as a building block in various transformations (Scheme 2).
At first, we focused on bromination reactions. When 2a was subjected to N-bromosuccinimide, 60 α-bromo derivative 5 was isolated in 84% yield as a single diastereoisomer. Interestingly, when 2a was treated with pyridinium tribromide, δ-brominated regioisomer 4 was isolated in high yield (97%). This bromination strategy offers a route toward compounds that can be used as building blocks in, for example, the Reformatsky type cyanation reaction mediated by samarium salts 61 or in organocatalytic cyclopropanation reactions. 62 Remarkably, compound 4 was like derivative 5 isolated as a single diastereoisomer with an anti orientation of bromine and both aromatic rings. This relative configuration of substituents on the cyclopentanone ring was confirmed by X-ray diffraction of both derivatives 4 and 5 (see the Supporting Information).
Apart from bromination, we also showed that 2a can be regioselectively substituted with phenylselenium on either C-2 or C-5 of cyclopentanone based on the used conditions. When 2a was subjected to N-(phenylseleno)phthalimide in the presence of 2 equiv of LDA, prepared in situ, selenylated product 11 was isolated in 76% yield as a single diastereoisomer, whereas selenylation with N-(phenylseleno)phthalimide without a base led to the selenylation on C-2 of 2a. The corresponding intermediate was unstable upon isolation, but after the crude mixture had been treated with hydrogen peroxide, the elimination reaction took place and unsaturated derivative 6 was isolated in 70% overall yield. The same reaction conditions were also used on compound 11. Unfortunately, elimination did not proceed, and decomposition of the starting material was observed. On the contrary, corresponding unsaturated derivative 12 was isolated in good yield (85%) after treatment of 4 with 1, 4 octane (DABCO) in THF at room temperature. Furthermore, diastereoselective hydroxylation of 2a was developed in the presence of m-CPBA and hydroxylated diketone 7 could be isolated in 45% yield. Next, the possibility of C−C bond formation on C-2 and C-5 of 2a was investigated. When 2a was treated with iodomethane in the presence of potassium carbonate, methylated product 9 was isolated as a single diastereoisomer in a good yield of 70%, however, as a mixture of regioisomers (4:1 keto:enol). On the contrary, when 2 equiv of in situ-generated LDA was used in the presence of 2a and benzophenone as an electrophile, 63 the corresponding product 10 was isolated in 65% yield as a single diastereomer. These examples nicely illustrate the influence of both cis-oriented aromatic rings on stereoselective addition of electrophiles to both C-2 and C-5 to the unhindered side of the cyclic keto ester. We were also able to show that 2a can be transformed into pyrazole derivative 8 upon being treated with hydrazine hydrate in ethanol under reflux conditions. 64 To validate whether our diastereoselective synthesis of cisvic-diphenylethylene dicarbonyl compounds could be useful for the synthesis of compounds that are structurally similar to rocaglamide or silvestrol, a superimposition was made between compound 2t and rocaglamide. As it turns out, the superimposition shows an unambiguous match between both cisoriented neighboring Ar of 2t and the rocaglamide aromatic rings ( Figure 2). This provides evidence that the geometry of the diphenylethylene moiety found in the series of compound 2 mimics the diphenylethylene found in natural products such as rocaglamide and silvestrol.

■ CONCLUSION
We have developed an intramolecular cyclization reaction of 1,6-ketoesters using boron tribromide as a Lewis acid promoter. This methodology provides straightforward access to 1,3-diketo compounds with a cyclopentane moiety having a cis-oriented vicinal diphenylethylene that is unique and difficult to obtain by known synthetic methods. We have also shown that the defined orientation of both vicinal aromatic rings has a directing effect on stereoselectivity in subsequent substitution reactions with bromine, selenium, or a carbon electrophile on C-2 or C-5 of the 1,3-diketones (Scheme 2). Also, regioselective elimination procedures were developed on the basis of the substitution at C-2 or C-5 providing access to two types of α,β-unsaturated carbonyl compounds. Moreover, successful transformation of a 1,3-diketo compound to a heterocyclic pyrazole derivative has been demonstrated showing the importance of 1,3-diketones as potential building blocks for druglike architectures. Additionally, the matching superimposition of 2t and rocaglamide indicates that the substructure found in compound 2 is a good starting point for the synthesis of a molecular library for probing biological activity. Compounds including cis-vic-diphenylethylene-oriented motifs such as rocaglamide and silverstrol have attracted considerable pharmaceutical interest, e.g., in cancer treatment and as antiviral agents. 21,36−38 The synthesis protocol presented here can easily be fine-tuned to achieve a wanted pharmacological profile and thus opens up new opportunities to further explore new analogues for the therapies mentioned above.
■ EXPERIMENTAL SECTION Molecular Modeling. To verify the hypothesis that the aromatic rings in 2t can mimic the corresponding rings in rocaglamide, molecular mechanics calculations were used. A conformational search was performed on both compounds using the Amber10:EHT force field, the Born aqueous solvation model, and the LowModeMD search methodology. The standard settings were applied, and the energy cutoff was set to 5 kcal/mol from their global minima. An ensemble of conformations of the two compounds (24 of rocaglamide and 14 of 2t) was achieved, and these were crosswise superimposed (336 combinations). The conclusion was that superimposition of 2t mimics rocaglamide very well, and among the top-scoring combinations were the global minima of rocaglamide and a lowenergy conformation of 2t, i.e., ΔE = 0 and 0.7 kcal mol −1 (Figure 2). The superimposition queries were aromatic rings 2 and 3, the methoxy oxygen, and C-3 and C-4 in the five-membered ring (see Scheme 2 for numbering). All molecular calculations were performed using tools implemented in MOE modeling software. 65 General Experimental Information. Column chromatography was performed on automated column chromatography Biotage Isolera Spektra One with Biotage SNAP-10g KP-sil columns. Thin layer chromatography (TLC) was performed on Merck TLC plates precoated with silica gel 60 F254 (Art 5715, 0.25 mm) and visualized with ultraviolet light (254 nm). The 1 H NMR (400 MHz) and 13 C NMR (101 MHz) spectra were recorded on a Varian 400 instrument, and 19 F NMR (470 MHz) spectra were recorded on a Varian 500 spectrometer. The chemical shifts are reported in parts per million (δ) relative to the residual solvent peak CDCl 3 : 1 H NMR at δ 7.26 and 13 C NMR at δ 77. 16. Coupling constants (J) are reported in hertz. Infrared (IR) spectra were recorded on a PerkinElmer series FT-IR spectrometer and are reported in wavenumbers (cm −1 ). Melting points were recorded on a Stuart Scientific Melting Point SMP1 instrument. Gas chromatographic studies were performed using an Agilent 7820A instrument equipped with a flame ionization detector and an Agilent HP-5 19091J-413 column. Crystallographic data were obtained using a Bruker D8 VENTURE Kappa Duo PHOTONIII instrument. The 1-ethyl-3-methylimidazolium acetate (EMIMAc) was purchased from Sigma-Aldrich (Stockholm, Sweden), produced by BASF ≥95%, and dried in vacuo with heating prior to use. All other solvents and reagents were purchased from commercial sources and used without further treatments.
Synthesis of the Starting Material, OTHOs (1). OTHOs 1a−d, 1g, 1i−l, 1n, 1o, 1e, 1f, 1h, 1m, and 1p−s were synthesized according to previously published procedures. 52,58  Bromination of 2a with Pyridinium Tribromide. Diketo compound 2a (210 mg, 0.62 mmol, 1 equiv) was dissolved in DCM (18 mL) and cooled to 0°C. Then PyrHBr·Br 2 (220 mg, 90%, 0.62 mmol, 1 equiv) was added at once while the reaction mixture was vigorously stirred. The reaction mixture was then stirred overnight at room temperature. A saturated solution of NaHCO 3 was added; the organic phase was extracted and washed with water and dried, and the solvent was removed in vacuo. The crude mixture was purified by automated column chromatography with a 98:2 petroleum ether/ EtOAc eluent, yielding product 4 as a pale orange solid.
2-Benzoyl-2-bromo-3,4-diphenylcyclopentan-1-one (5 Synthesis of 6. To diketo compound 2a (60 mg, 0.176 mmol, 1 equiv) in DCM (3 mL) was added at rt a solution of N-(phenylseleno)phthalimide (90 mg, 90%, 0.26 mmol, 1.5 equiv). The reaction mixture stirred for 3 h until full conversion was achieved, and the solvent was removed in vacuo. The crude mixture was then dissolved in EtOAc (6 mL), and hydrogen peroxide (2 mL of 30% in water) was added. After 3 h, full conversion was achieved, the reaction mixture was diluted with water (1 mL), and the organic phase was collected and washed with saturated NaHCO 3 and water and dried over MgSO 4 . After filtration and evaporation of the solvent, the crude product was separated by automated column chromatography with a petroleum ether/EtOAc gradient (93:7 to 85:15), yielding product 6 as a transparent oil.
2-Benzoyl-3,4-diphenylcyclopent-2-en-1-one (6 According to the modified procedure, 55 diisopropylamine (91 μL, 2.20 equiv) was dissolved in dry tetrahydrofuran (5 mL), and after the mixture had cooled to 0°C, n-butyllithium (260 μL, 2.20 equiv, 2.5 M solution in n-hexane) was added. The reaction mixture was stirred at rt for 30 min followed by further cooling to 0°C. Diketone 2a (100 mg, 0.29 mmol, 1 equiv) was dissolved in dry tetrahydrofuran (3 mL) and slowly added to the solution of diisopropylamine and n-butyllithium, and the mixture was stirred. After 15 min, benzophenone (65 mg, 0.35 mmol, 1.20 equiv) was added and the reaction mixture stirred at 0°C for 30 min and then at rt overnight. After 16 h, TLC revealed full conversion; the reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride (1 mL) and water (10 mL), and EtAOc was then added. The organic phase was separated, and the aqueous phase extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine and dried over MgSO 4 , and the solvent was evaporated in vacuo. The crude material was purified by automated column chromatography with a petroleum ether/EtOAc gradient (95:5 to 92:8), yielding product 10 as a transparent oil. Selenylation of 2a. According to the modified procedure, 55 diisopropylamine (91 μL, 2.20 equiv) was dissolved in dry tetrahydrofuran (5 mL). After the mixture had cooled to 0°C, nbutyllithium (260 μL, 2.20 equiv, 2.5 M solution in n-hexane) was added and the reaction mixture was stirred at room temperature for 30 min. Then after the mixture had again cooled to 0°C, diketone 2a (100 mg, 0.29 mmol, 1 equiv) was dissolved in dry tetrahydrofuran (3 mL) and slowly added to the solution of diisopropylamine and nbutyllithium. The reaction mixture was stirred for 15 min followed by an addition of N-(phenylseleno)phthalimide (120 mg, 1.20 equiv); the subsequent mixture was stirred at 0°C for 30 min and then at rt for an additional 60 min when, according to TLC, full conversion was achieved. The reaction was then quenched by the addition of a saturated aqueous solution of NH 4 Cl (1 mL) and water (10 mL), and EtAOc (20 mL) was then added. The organic phase was separated, and the aqueous phase extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine and dried over MgSO 4 , and the solvent was evaporated in vacuo. The crude material was purified by automated column chromatography with a petroleum ether/EtOAc gradient (98:2 to 92:8), yielding product 11 as single diastereoisomer in the form of a thick yellow oil.