Synthetic Studies toward the Natural Product Tripartin, the First Natural Histone Lysine Demethylase Inhibitor

Abstract

An efficient synthesis of dimethyl tripartin as a synthetic precursor of natural product tripartin, the first natural specific inhibitor of histone H3 lysine 9 demethylase KDM4, is described. The synthesis of dimethyl tripartin was achieved in a six-step longest linear sequence starting from commercially available 3,5-dimethoxy benzaldehyde with 21% overall yield, using ClTi(OⁱPr)₃-mediated dichloromethine insertion as the key step.

Introduction

Tripartin (1), a dichlorinated indanone natural product, was isolated in 2013 by Oh group from the culture broth of the Streptomyces sp. associated with larvae of the dung beetle Copris tripartitus Waterhouse.¹ It has a tertiary hydroxyl group and a dichloromethine group attached to the C-3 position. In fact, it is the first ever indanone system reported to possess such unique dichlorinated functionality. A total synthesis of tripartin has not been achieved so far (Figure 1).

Figure 1.

Tripartin.

Dynamic methylation and demethylation of arginine and lysine residues of histone protein is a very important biological phenomenon because methylation of different sites can activate or repress genes and therefore regulates transcription.² Methylation of specific lysine residues is carried out by enzymes known as histone methyltransferases, while the demethylation is carried out by histone demethylases (KDMs). Among the KDM subfamily, humans possess KDM2/7, KDM3, KDM4, KDM5, and KDM6, and these KDMs are often targets for treatment of diseases like leukemia, breast cancer, prostate cancer,³ and inflammation.⁴ Tripartin is the first natural specific inhibitor of histone H3 lysine 9 demethylase KDM4. Very few KDM selective inhibitors are reported in the literature⁵ and among those the KDM4 inhibitors are least known, which highlights the unique property of tripartin.

Results and Discussion

Careful observation of the structure of tripartin reveals that it has a very labile moiety at the C-3 position. The site contains a tertiary hydroxy group which is also a benzylic hydroxy group, making it very prone toward elimination. Two types of acidic protons one at α-position of the carbonyl group and another on the dichloromethine group are adjacent to the hydroxyl group, suggesting that the molecule might be quite sensitive toward acidic and basic conditions. This foresight of the problems challenged us to accept the total synthesis of tripartin. In this communication, we report our efforts toward the synthesis of tripartin.

The retrosynthetic analysis of tripartin is shown in Scheme 1. It was envisioned that natural product tripartin 1 could be obtained from the tertiary alcohol 2 by successive deprotections of dithiane and methoxy groups. Compound 2 was planned to be synthesized from indanone derivative 3 by insertion of the dichloromethine group. Compound 3 could be accessed from acid 4, which might be easily obtained from commercially available 3,5-dimethoxy benzaldehyde 5 via 6.

Scheme 1. Retrosynthetic Analysis.

As shown in Scheme 2, the starting point of our synthesis was β-keto ester 6 which was prepared from commercially available 3,5-dimethoxy benzaldehyde by a known two-step protocol.⁶ Protection of the ketone group using 1,3-propane dithiol followed by saponification of ester 8 gave acid 4, which set the stage for Friedel–Crafts intramolecular cyclization. Several Friedel–Crafts cyclization conditions were employed such as triflic acid, MeSO₃H, Tb(OTf)₃, Yb(OTf)₃, and AlCl₃ to cyclize the acid 4 to get indanone 3. Unfortunately, all these attempts were unsuccessful. Interestingly, when the acid chloride 9 was treated with AlCl₃, instead of the expected indanone derivative 3, it generated 8-membered ring compound 10 containing two S atoms from the dithiane moiety.

Scheme 2. Synthesis of Compound 10.

Because the dithiane protecting group was interfering with the Friedel–Crafts cyclization, it was decided to use benzyl protection. Unfortunately, benzyl protection of the secondary alcohol 7 was unsuccessful, under various conditions such as NaH/PhCH₂Br/–78 °C, CaSO₄/Ag₂O/PhCH₂Br, and Cl₃CC(NH)OCH₂Ph/BF₃·OEt₂, in all of the cases either the starting material was recovered or the hydroxyl elimination product was obtained.

It was thought that introduction of ketone functionality could be delayed rather than installing it at the beginning of the synthesis to avoid the complications. Reaching up to the indanone 12 stage seemed easy this way (Scheme 3).

Scheme 3. Retrosynthetic Analysis.

As anticipated, the indanone 12 was accessed without much difficulty starting from 3,5-dimethoxy benzaldehyde 5 using a four-step protocol. Wittig olefination followed by Pd–C catalyzed reduction furnished required ester 15 in excellent yield. Saponification of ester 15 by using LiOH provided acid 13, which was subsequently treated with CH₃SO₃H to generate required indanone 12 in 85% yield (two steps) (Scheme 4).

Scheme 4. Synthesis of Compound 12.

It was thought that methoxy groups should be deprotected before installing the sensitive tert-hydroxyl group and dichloromethine functionality. Keeping the upcoming sensitive intermediates in mind, deprotection of the methoxy groups of indanone 12 was planned at this stage. Accordingly, indanone 12 on treatment with BBr₃ afforded dihydroxy indanone derivative 16. Unfortunately dichloromethine insertion reaction was unsuccessful under basic conditions as shown in Scheme 5. The failure of this reaction might be due to the phenolic hydroxyl group, by decreasing the electrophilic character of the ketone group and rendering it inert toward the nucleophilic attack. Next, the reaction of indanone 12 with dichloromethine anion generated from dichloromethane and n-BuLi resulted in formation of compound 11 in 18% yield. The yield was further improved to 58% using ClTi(OⁱPr)₃ to activate the ketone.⁷

Scheme 5. Synthesis of Compound 11.

Compound 11 was found to be very unstable with highly labile tertiary alcohol moiety which readily underwent aerial oxidation to generate an epoxide 18 when kept at rt for 6 h. The structure of this epoxide molecule was further confirmed by single-crystal X-ray analysis.⁸ It was also noticed that the tertiary alcohol 11 undergoes dehydration when stored in CDCl₃ for 5 min (Scheme 6).

Scheme 6. Synthesis of Compounds 18 and 19.

After having tertiary alcohol 11 in hand, our next task was benzylic oxidation to install the ketone functionality. Toward this goal, various known oxidation conditions were screened such as NaOCl/t-BuOOH, t-BuOOH/MnO₂, KMnO₄, and t-BuOOH/Mn(OAc)₂, but unfortunately, we observed decomposition of the starting material. Interestingly, compound 11 on treatment with IBX in dimethyl sulfoxide (DMSO) at 80 °C for 12 h afforded compound 20. To our delight, the required keto compound 21 was obtained by employing a KMnO₄/MnO₂ reagent combination in 46% yield (Scheme 7). As anticipated earlier, the deprotection of methoxy groups proved to be most challenging task at this stage. Various reagents (BBr₃, EtSNa, AlCl₃, HBr, and dl-methionine/MeSO₃H, BCl₃) known in the literature for deprotection of methoxy groups were screened. Decomposition of the starting material was the common result of all such attempts.

Scheme 7. Synthesis of Compounds 20 and 21.

It was envisioned that benzyl protection would be more suitable instead of methoxy groups, as it can be removed selectively under hydrogenation conditions. Accordingly, compound 22 was obtained by benzyl protection of the 3,5-dihydroxy indanone 16 in 92% yield. When the dibenzylated indanone 22 was subjected to dichloromethine anion generated from dichloromethane and n-BuLi, the reaction went very smoothly without any difficulty and afforded compound 23 in 51% yield. But contrary to our assumption, deprotection of the benzyl groups was proved to be problematic. Under different types of hydrogenation conditions such as Pd/C/EtOAc, Pd/C/CH₂Cl₂, Pd/C/MeOH, Pd(OH)₂/MeOH, and Pd/C/TBAC/EtOAc, all chlorine atoms, tertiary hydroxyl group, and the benzyl groups were hydrogenated within 5 min. Next, we employed tetrabutylammonium chloride (TBAC)-mediated selective debenzylation in the presence of aromatic chlorine developed by Li group,⁹ but under this condition compound 25 was isolated, in which chlorine atoms and the tertiary hydroxyl group were hydrogenated and benzyl groups were intact (Scheme 8). Similar results were obtained when catalytic amount of water was added to decrease the reactivity of Pd/C in MeOH. This explains that the hydrogenation of chlorine atoms and hydroxyl group was much faster than the benzyl deprotection.

Scheme 8. Synthesis of Compounds 24 and 25.

Next, hydroxyl groups of indanone 16 were protected as its TBS-ether. Compound 26 was obtained in 82% yield after reaction of the 3,5-dihydroxy indanone 16 with TBSCl and imidazole in dimethylformamide (DMF). When compound 26 was subjected to dichloromethine insertion, the reaction went smoothly to afford compound 27 in 53% yield. To our disappointment, again deprotection of TBS groups using reagents such as HF/Py and TBAF did not afford the desired compound, instead we observed complete decomposition of the starting material. Under LiOAc·2H₂O condition, one of the TBS group was cleaved within 1 h to give a hydroxyl compound 28. Unfortunately, the compound was highly unstable, it got decomposed even at 40 °C while evaporating on rotavapor. Benzylic oxidation of compound 28 using KMnO₄/MnO₂ condition did not yield the expected product this time, and decomposition of the starting material was observed (Scheme 9).

Scheme 9. Synthesis of Compound 28.

As an alternative, acetyl protection was thought to be more suitable anticipating a smooth dichloromethine insertion using excess n-BuLi and CH₂Cl₂. It was logically assumed that more reactive ketone function would be attacked first by the dichloromethine anion to give tertiary alcohol. Then, the excess dichloromethine anion would attack the carbonyl carbons of two acetyl groups, resulting in their deprotection. Accordingly, compound 29 was synthesized by acetyl protection of the 3,5-dihydroxy indanone 16 in 96% yield. Unfortunately, the successive reaction could lead to an uncharacterizable complex reaction mixture but not the anticipated product (Scheme 10).

Scheme 10. Synthesis of Compound 29.

Next, hydroxyl groups of indanone 16 were protected with allyl groups. Compound 31 was obtained in 90% yield after reaction of the 3,5-dihydroxy indanone 16 with allyl bromide and K₂CO₃ in DMF. When compound 31 was subjected to dichloromethine insertion, the reaction went smoothly to afford compound 32 in 50% yield. To our disappointment benzylic oxidation of compound 32 using KMnO₄/MnO₂ condition did not yield the expected product, and decomposition of the starting material was observed. Unfortunately, allyl deprotection of compound 32 was unsuccessful, under various conditions such as Pd(PPh₃)₄/LiBH₄, Pd(PPh₃)₄/K₂CO₃, Pd/C/KOH, and SmI₂/H₂O/i-PrNH₂, in all of the cases either starting material was recovered or decomposed (Scheme 11).

Scheme 11. Synthesis of Compound 32.

Conclusion

In conclusion, the first synthetic effort toward the synthesis of tripartin has been reported. A short route to dimethyl tripartin was accomplished in six steps with 21% overall yield starting from commercially available 3,5-dimethoxy benzaldehyde using ClTi(OⁱPr)₃-mediated dichloromethine insertion as a key step.

Experimental Section

General Information

Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. NMR spectra were recorded on either a Bruker AVANCE 200 (¹H: 200 MHz, ¹³C: 50 MHz), Bruker AVANCE 400 (¹H: 400 MHz, ¹³C: 100 MHz), Bruker AVANCE 500 (¹H: 500 MHz, ¹³C: 125 MHz), or JEOL ECX 500 (¹H: 500 MHz, ¹³C: 125 MHz). Mass spectrometric data were obtained using WATERS-Q-Tof Premier-ESI-MS.

The single crystal X-ray diffraction intensity data collection for the crystals of compound 18 was carried out on a Bruker APEX-II CCD detector system with Mo-sealed Siemens ceramic diffraction tube (λ = 0.7107 Å) and a highly oriented graphite monochromator operating at 50 kV and 30 mA. The data were collected in a hemisphere mode and processed with Bruker SAINT. Empirical absorption correction was made using Bruker SADABS. The structure was solved by using SHELXL package and refined by full matrix least-squares method based on F2 using SHELX-2017 program (Sheldrick 2017). Hydrogens were fixed geometrically, treated as riding on their nonhydrogens, and refined isotropically, while all nonhydrogens were subjected to anisotropic refinement.

The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of a doublet of a doublet, dm = doublet of a multiplet, m = multiplet, and br = broad.

Ethyl 2-(2-(3,5-Dimethoxyphenyl)-1,3-dithian-2-yl)acetate (8)

BF₃·OEt₂ (0.6 mL, 5 mmol) was slowly added to the mixture of β-keto ester 6 (500 mg, 2 mmol) and 1,3-propane dithiol (0.8 mL, 8 mmol) in CH₂Cl₂ at 0 °C. After being stirred at 0 °C for 1 h and room temperature for 12 h, the reaction was quenched by adding 1 M NaOH and the mixture was extracted with Et₂O three times. The organic phase was washed with 1 M NaOH three times and dried over MgSO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 8 (651 mg, 96%) as a colorless liquid; R_f = 0.4 (EtOAc–hexane 1:19); IR (neat) ν_max/cm^–1: 2936, 2906, 2835, 1734, 1594, 1455, 1422, 1307, 1286, 1203, 1191, 1155, 1067, 838, 697; ¹H NMR (400 MHz, chloroform-d): δ 7.12 (d, J = 2.2 Hz, 2H), 6.37 (t, J = 2.2 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 3.78 (s, 6H), 2.99 (s, 2H), 2.78–2.71 (m, 4H), 1.96–1.89 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, chloroform-d): δ 167.8, 160.8, 143.2, 106.7, 99.2, 60.5, 55.4, 55.3, 49.1, 27.9, 24.3, 13.8; HRMS-ESI m/z: calcd for C₁₆H₂₃O₄S₂ [M + H], 343.1038; found, 343.1039.

(Z)-4-(3,5-Dimethoxyphenyl)-7,8-dihydro-1,5-dithiocin-2(6H)-one (10)

To a solution of ester 8 (100 mg, 0.3 mmol) in tetrahydrofuran (THF) (8 mL), an aqueous solution (2 mL) of LiOH (35 mg, 1.5 mmol) was added. The reaction was monitored using TLC and on completion was quenched with 1 N HCl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give the acid 4. To a solution of crude acid 4 in CH₂Cl₂ at 0 °C was added oxalyl chloride (0.4 mL, 0.5 mmol) slowly, followed by 2–3 drops of DMF. The resulting mixture was stirred at 0 °C for 1 h. After concentration of the reaction mixture, the crude residue was dissolved in CH₂Cl₂, cooled to 0 °C, and AlCl₃ (42 mg, 0.3 mmol) was added in portion wise. After stirring for 1 h, the reaction mixture was quenched with aq NaHCO₃ and the layers were separated. The aqueous layer was extracted with Et₂O and the combined organic extracts were washed with H₂O, saturated NaHCO₃, and brine and dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on silica gel column furnished the product 10 (52 mg, 55%) as a colorless liquid; R_f = 0.5 (EtOAc–hexane 1:19); IR (neat) ν_max/cm^–1: 2927, 2838, 1592, 1454, 1422, 1344, 1321, 1297, 1258, 1205, 1155, 1107, 1064, 839, 803; ¹H NMR (400 MHz, chloroform-d): δ 6.67 (dd, J = 1.4, 2.3 Hz, 2H), 6.53–6.45 (m, 1H), 6.18 (s, 1H), 3.81 (s, 6H), 3.54 (br s, 2H), 3.29 (br s, 2H), 2.27 (quin, J = 5.6 Hz, 2H); ¹³C NMR (125 MHz, chloroform-d): δ 197.1 (C=O), 160.7 (C), 149.2 (C), 141.9 (C), 121.8 (CH), 105.5 (CH), 101.6 (CH), 55.5 (CH₃), 33.0 (CH₂), 30.5 (CH₂), 28.8 (CH₂); HRMS-ESI m/z: calcd for C₁₄H₁₇O₃S₂ [M + H], 297.0619; found, 297.0610.

(E)-Ethyl 3-(3,5-Dimethoxyphenyl)acrylate (14)

To a solution of aldehyde 5 (5 g, 30.1 mmol) in anhydrous CH₂Cl₂ was added dry Ph₃P=CHCO₂Et (12.6 g, 36.1 mmol) and stirred magnetically for 4 h at rt. Evaporation of the solvent and purification of the residue on silica gel column furnished the product 14 (7 g, 98%) as a colorless liquid; R_f = 0.3 (EtOAc–hexane 1:10); IR (neat) ν_max/cm^–1: 2939, 2840, 1712, 1640, 1593, 1460, 1282, 1177, 1158, 1207; ¹H NMR (400 MHz, chloroform-d): δ 7.61 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.3 Hz, 2H), 6.50 (t, J = 2.3 Hz, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.81 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, chloroform-d): δ 166.9, 161.0, 144.6, 136.3, 118.7, 105.9, 102.5, 60.5, 55.4, 14.3; HRMS-ESI m/z: calcd for C₁₃H₁₇O₄ [M + H], 237.1127; found, 237.1129.

Ethyl 3-(3,5-Dimethoxyphenyl)propanoate (15)

Compound 14 (6 g, 25.4 mmol) was dissolved in MeOH and 10% palladium on activated carbon was added. The reaction was stirred under H₂ at rt overnight, whereupon TLC showed that the reaction was complete. The solid was filtered off. Evaporation of the solvent and purification of the residue on silica gel column furnished the product 15 (5.8 g, 96%) as a colorless liquid; R_f = 0.3 (EtOAc–hexane 1:10); IR (neat) ν_max/cm^–1: 2939, 2839, 1732, 1597, 1463, 1430, 1206, 1154, 1069, 834, 692; ¹H NMR (400 MHz, chloroform-d): δ 6.37 (d, J = 2.3 Hz, 2H), 6.32 (t, J = 2.3 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.78 (s, 6H), 2.90 (t, J = 7.9 Hz, 2H), 2.61 (t, J = 7.9 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, chloroform-d): δ 172.9, 160.8, 142.9, 106.3, 98.2, 60.4, 55.2, 35.8, 31.2, 14.2; HRMS-ESI m/z: calcd for C₁₃H₁₉O₄ [M + H], 239.1283; found, 239.1287.

5,7-Dimethoxy-2,3-dihydro-1H-inden-1-one (12)

To a solution of ester 15 (5.5 g, 23.1 mmol) in THF (20 mL), an aqueous solution (5 mL) of LiOH (1.7 g, 69.3 mmol) was added. The reaction was monitored using TLC and on completion was quenched with 1 N HCl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give the acid 13. Crude carboxylic acid 13 and methanesulfonic acid (13 mL, 196 mmol) were combined and heated to 95 °C for 6 h. On completion of the reaction, which was monitored by TLC, the reaction mixture was poured over crushed ice. NaOH was added to neutralize methanesulfonic acid. The aqueous layer was extracted with ethyl acetate. The entire organic portion was washed with brine and dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on silica gel column furnished the product 12 (4.3 g, 85%) as a solid, mp 99–100 °C; R_f = 0.2 (EtOAc–hexane 1:1); IR (KBr) ν_max/cm^–1: 2945, 2839, 1691, 1601, 1471, 1326, 1215, 1155, 1086, 1021; ¹H NMR (400 MHz, chloroform-d): δ 6.47 (s, 1H), 6.29 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.03–2.98 (m, 2H), 2.66–2.60 (m, 2H); ¹³C NMR (100 MHz, chloroform-d): δ 203.1, 166.9, 160.4, 159.3, 119.4, 101.6, 97.3, 55.7, 55.6, 36.9, 25.9; HRMS-ESI m/z: calcd for C₁₁H₁₃O₃ [M + H], 193.0865; found, 193.0860.

1-(Dichloromethyl)-5,7-dimethoxy-2,3-dihydro-1H-inden-1-ol (11)

To a solution of dry CH₂Cl₂ (3 mL, 36.4 mmol) in dry THF (20 mL), n-BuLi (16 mL, 26.4 mmol, 1.6 M in hexane) was added very slowly under argon atmosphere at −100 °C. After the addition was complete, the mixture was stirred at −100 °C for 1 h. A mixture of compound 12 (1.0 g, 5.2 mmol) and TiCl(OⁱPr)₃ (1.2 mL, 5.2 mmol) in dry THF was added slowly and stirred at −100 °C for 2 h. After 2 h, the reaction mixture was allowed to warm to −20 °C and poured into an ice water. Et₂O was added and the layers were separated. The aqueous layer was extracted with ether (two times). The combined organic layers were dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 11 (833 mg, 58%) as a white solid; mp 53–55 °C; R_f = 0.3 (EtOAc–hexane 1:4); IR (neat) ν_max/cm^–1: 3380, 3010, 2942, 2843, 1601, 1493, 1464, 1340, 1216, 1153, 1080, 830, 790; ¹H NMR (400 MHz, DMSO-d₆): δ 6.60 (s, 1H), 6.39 (s, 1H), 6.36 (s, 1H), 5.82 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.97 (td, J = 8.2, 16.3 Hz, 1H), 2.79 (ddd, J = 2.7, 9.1, 16.3 Hz, 1H), 2.58 (ddd, J = 7.7, 9.1, 13.6 Hz, 1H), 2.08 (ddd, J = 2.7, 8.6, 13.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 161.9 (C), 156.6 (C), 147.1 (C), 123.0 (C), 100.9 (CH), 97.1 (CH), 87.2 (C), 78.3 (CH), 55.4 (CH₃), 55.3 (CH₃), 34.0 (CH₂), 29.5 (CH₂); HRMS-ESI m/z: calcd for C₁₂H₁₃Cl₂O₂ [M – OH]. 259.0293; found, 259.0294.

Compound 18

Red color solid, mp 49–51 °C; R_f = 0.4 (EtOAc–hexane 1:9); IR (KBr) ν_max/cm^–1: 2927, 2852, 1673, 1604, 1461, 1228, 1152, 1070, 898, 823, 781, 764, 725; ¹H NMR (400 MHz, chloroform-d): δ 6.33 (s, 1H), 6.27 (s, 1H), 5.80 (d, J = 1.6 Hz, 1H), 3.83 (s, 3H), 2.62–2.51 (m, 4H); ¹³C NMR (100 MHz, chloroform-d): δ 186.6 (C=O), 164.2 (C), 156.6 (C), 126.7 (CH), 108.0 (CH), 78.9 (C), 69.0 (CH), 65.9 (C), 56.4 (CH₃), 24.8 (CH₂), 24.7 (CH₂); HRMS-ESI m/z: calcd for C₁₁H₁₁Cl₂O₃ [M + H], 261.0085; found, 261.0086.

3-(Dichloromethyl)-4,6-dimethoxy-1H-indene (19)

Colorless liquid; R_f = 0.3 (EtOAc–hexane 1:19); IR (neat) ν_max/cm^–1: 2966, 2925, 2851, 2839, 1605, 1575, 1486, 1433, 1465, 1455, 1328, 1298, 1213, 1154, 1093, 1072, 838, 814, 674; ¹H NMR (400 MHz, chloroform-d): δ 7.13 (d, J = 0.9 Hz, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 6.44 (d, J = 1.8 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.44 (s, 2H); ¹³C NMR (100 MHz, chloroform-d): δ 160.0, 154.1, 147.5, 143.4, 129.8, 122.4, 101.9, 97.4, 67.1, 55.6, 55.5, 38.2; HRMS-ESI m/z: calcd for C₁₂H₁₃Cl₂O₂ [M + H], 259.0293; found, 259.0296.

1-(Dichloromethyl)-5,7-dimethoxy-1H-inden-1-ol (20)

To a solution of compound 11 (30 mg, 0.1 mmol) in DMSO, IBX (45 mg, 0.2 mmol) was added and stirred at 80 °C for 12 h. The reaction was monitored by TLC on completion, the reaction mixture was cooled and diluted with ether. The organic layer was washed with saturated NaHCO₃ solution and with water, dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 20 (11 mg, 36%) as a yellow color solid, mp 46–48 °C; R_f = 0.5 (EtOAc–hexane 1:6); IR (neat) ν_max/cm^–1: 3434, 3097, 2944, 2843, 1615, 1594, 1467, 1369, 1309, 1105, 1078, 963, 837, 802, 713; ¹H NMR (400 MHz, chloroform-d): δ 7.36 (s, 1H), 6.87 (d, J = 5.5 Hz, 1H), 6.79 (dd, J = 1.6, 5.5 Hz, 1H), 6.54 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H); ¹³C NMR (125 MHz, chloroform-d): δ 161.3 (C), 156.0 (C), 145.5 (C), 141.2 (C), 133.0 (CH), 126.2 (CH), 121.2 (CH), 114.3 (C), 99.8 (CH), 96.2 (CH), 55.6 (CH₃), 55.2 (CH₃); HRMS-ESI m/z: calcd for C₁₂H₁₁Cl₂O₂ [M – OH], 257.0136; found, 257.0138.

3-(Dichloromethyl)-3-hydroxy-4,6-dimethoxy-2,3-dihydro-1H-inden-1-one (21)

To a solution of compound 11 (50 mg, 0.2 mmol) in CH₂Cl₂, finely ground KMnO₄/MnO₂ reagent (5:1 mole ratio) was added in small portions over a period of 15 min. The mixture was stirred vigorously at rt and while the progress of the reaction was monitored by TLC. After 5 days, the reaction mixture was filtered through a sintered glass funnel to remove spent oxidant. The residue was then washed with ethyl acetate. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 21 (24 mg, 46%) as a colorless liquid and also starting material (55 mg) was recovered; R_f = 0.3 (EtOAc–hexane 1:3); IR (neat) ν_max/cm^–1: 3432, 2928, 2842, 1719, 1614, 1492, 1347, 1313, 1206, 1153, 1037, 796; ¹H NMR (400 MHz, chloroform-d): δ 6.82 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.48 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.42 (d, J = 18.9 Hz, 1H), 2.81 (d, J = 18.9 Hz, 1H); ¹³C NMR (100 MHz, chloroform-d): δ 200.9 (C=O), 163.5 (C), 156.8 (C), 140.2 (C), 132.5 (C), 106.1 (CH), 96.9 (CH), 81.4 (C), 76.0 (CH), 56.0 (CH₃), 55.9 (CH₃), 47.3 (CH₂); HRMS-ESI m/z: calcd for C₁₂H₁₃Cl₂O₄ [M + H], 291.0191; found, 291.0190.

5,7-Bis(benzyloxy)-2,3-dihydro-1H-inden-1-one (22)

To a solution of compound 16(9) (500 mg, 3.0 mmol) in dry DMF, BnBr (2.2 mL, 18.3 mmol) and K₂CO₃ (2.5 g, 18.3 mmol) were added and stirred at 80 °C for 3 h. Cold H₂O was added, and the mixture was stirred until all of the carbonate dissolved. The solution was acidified with HCl and then extracted with EtOAc three times. The combined organic layers were washed with H₂O and dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 22 (965 mg, 92%) as a colorless liquid; R_f = 0.4 (EtOAc–hexane 1:2); IR (neat) ν_max/cm^–1: 3031, 2921, 1696, 1598, 1320, 1160, 736, 696; ¹H NMR (400 MHz, chloroform-d): δ 7.49 (d, J = 7.3 Hz, 2H), 7.44–7.33 (m, 7H), 7.31 (d, J = 7.3 Hz, 1H), 6.56 (s, 1H), 6.41 (d, J = 1.8 Hz, 1H), 5.23 (s, 2H), 5.07 (s, 2H), 3.06–2.98 (m, 2H), 2.70–2.62 (m, 2H); ¹³C NMR (100 MHz, chloroform-d): δ 202.7, 165.7, 160.2, 158.1, 136.3, 135.9, 128.6, 128.5, 128.2, 127.7, 127.5, 126.5, 120.0, 103.0, 99.7, 70.3, 69.9, 36.9, 25.8; HRMS-ESI m/z: calcd for C₂₃H₂₁O₃ [M + H], 345.1491; found, 345.1492.

5,7-Bis(benzyloxy)-1-(dichloromethyl)-2,3-dihydro-1H-inden-1-ol (23)

According to the procedure for the synthesis of compound 11, compound 22 (500 mg, 1.4 mmol), dry CH₂Cl₂ (0.6 mL, 10.2 mmol), n-BuLi (5.4 mL, 8.7 mmol, 1.6 M in hexane), and TiCl(OⁱPr)₃ (0.4 mL, 1.4 mmol) were used to furnish the product 23 (317 mg, 51%) as a colorless liquid; R_f = 0.5 (EtOAc–hexane 1:4); IR (neat) ν_max/cm^–1: 3561, 3063, 3031, 2929, 1602, 1453, 1325, 1218, 1148, 1069, 1028, 734, 696; ¹H NMR (400 MHz, DMSO-d₆): δ 7.51–7.46 (m, 2H), 7.45–7.30 (m, 8H), 6.56 (s, 1H), 6.51 (d, J = 2.7 Hz, 2H), 5.93 (s, 1H), 5.12 (s, 2H), 5.06 (s, 2H), 2.97 (td, J = 8.2, 16.2 Hz, 1H), 2.79 (ddd, J = 2.2, 9.3, 16.2 Hz, 1H), 2.62–2.52 (m, 1H), 2.08 (ddd, J = 2.4, 8.5, 13.7 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 160.8 (C), 155.4 (C), 147.3 (C), 137.1 (C), 137.0 (C), 128.5 (CH), 128.4 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.4 (CH), 123.4 (C), 102.1 (CH), 99.0 (CH), 87.2 (C), 78.2 (CH), 69.4 (CH₂), 34.0 (CH₂), 29.4 (CH₂); HRMS-ESI m/z: calcd for C₂₄H₂₁Cl₂O₂ [M – OH], 411.0919; found, 411.0925.

3-Methyl-2,3-dihydro-1H-indene-4,6-diol (24)

According to the procedure for the synthesis of compound 15, compound 23 (50 mg, 0.1 mmol) and 5% Pd/C were used to furnish the product 24 (12 mg, 65%) as a colorless liquid; R_f = 0.3 (EtOAc–hexane 1:4); IR (neat) ν_max/cm^–1: 3381, 2952, 2925, 2851, 1600, 1463, 1335, 1251, 1127, 1025, 836; ¹H NMR (400 MHz, chloroform-d): δ 6.30 (s, 1H), 6.14 (d, J = 1.8 Hz, 1H), 3.32–3.25 (m, 1H), 2.93 (td, J = 8.1, 16.0 Hz, 1H), 2.74 (ddd, J = 4.4, 9.0, 16.0 Hz, 1H), 2.32–2.23 (m, 1H), 1.71 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H); ¹³C NMR (100 MHz, chloroform-d): δ 155.6 (C), 152.6 (C), 147.2 (C), 126.3 (C), 104.1 (CH), 100.8 (CH), 36.2 (CH), 34.1 (CH₂), 31.5 (CH₂), 19.8 (CH₃); HRMS-ESI m/z: calcd for C₁₀H₁₃O₂ [M + H], 165.0916; found, 165.0920.

5,7-Bis(benzyloxy)-1-methyl-2,3-dihydro-1H-indene (25)

To a magnetically stirred solution of compound 23 (50 mg, 0.1 mmol) in CH₂Cl₂ was added TBAC (161 mg, 0.6 mmol) and 5% palladium on activated carbon. The reaction was stirred under H₂ at rt overnight, whereupon TLC showed that the reaction was complete. The solid was filtered off. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 25 (18 mg, 45%) as a colorless liquid; R_f = 0.4 (EtOAc–hexane 1:19); IR (neat) ν_max/cm^–1: 3031, 2950, 2863, 1597, 1487, 1453, 1434, 1375, 1309, 1167, 1139, 1067, 734, 696; ¹H NMR (500 MHz, chloroform-d): δ 7.48–7.42 (m, 4H), 7.40 (dt, J = 1.7, 7.4 Hz, 4H), 7.37–7.31 (m, 2H), 6.49 (s, 1H), 6.45 (s, 1H), 5.06 (s, 2H), 5.03 (s, 2H), 3.43–3.35 (m, 1H), 2.99 (td, J = 8.0, 16.0 Hz, 1H), 2.83–2.76 (m, 1H), 2.34–2.25 (m, 1H), 1.75–1.70 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H); ¹³C NMR (125 MHz, chloroform-d): δ 159.4 (C), 155.9 (C), 146.2 (C), 137.4 (C), 137.3 (C), 129.1 (C), 128.6 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 127.5 (CH), 127.1 (CH), 102.1 (CH), 98.6 (CH), 70.3 (CH₂), 69.6 (CH₂), 37.1 (CH), 33.9 (CH₂), 31.8 (CH₂), 20.0 (CH₃); HRMS-ESI m/z: calcd for C₂₄H₂₅O₂ [M + H], 345.1855; found, 345.1861.

5,7-Bis(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-1-one (26)

To a solution of ketone 16 (500 mg, 3.0 mmol) dissolved in DMF, cooled to 0 °C, imidazole (1.1 g, 15.8 mmol) followed by TBDMSCl (1.2 g, 8 mmol) was added and stirred overnight. On completion of the reaction, DMF was evaporated, and the reaction mixture was quenched with water and extracted with CH₂Cl₂ (3 × 15 mL). The entire organic layer was washed with brine and dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 26 (980 mg, 82%) as a colorless liquid; R_f = 0.3 (EtOAc–hexane 1:19); IR (neat) ν_max/cm^–1: 2955, 2930, 2858, 1712, 1596, 1468, 1347, 1196, 1160, 832, 781; ¹H NMR (400 Mz, chloroform-d): δ 6.47 (s, 1H), 6.18 (d, J = 1.8 Hz, 1H), 3.00–2.92 (m, 2H), 2.61–2.55 (m, 2H), 1.05 (s, 9H), 0.99 (s, 9H), 0.24 (s, 12H); ¹³C NMR (100 MHz, chloroform-d): δ 202.7, 162.7, 158.9, 155.3, 122.4, 110.9, 110.8, 36.9, 25.7, 25.6, 25.4, 18.4, 18.3, −3.6, −4.3, −4.5; HRMS-ESI m/z: calcd for C₂₁H₃₇O₃Si₂ [M + H], 393.2281; found, 393.2285.

5,7-Bis(tert-butyldimethylsilyloxy)-1-(dichloromethyl)-2,3-dihydro-1H-inden-1-ol (27)

According to the procedure for the synthesis of compound 11, compound 26 (500 mg, 1.3 mmol), dry CH₂Cl₂ (0.6 mL, 8.9 mmol), n-BuLi (5 mL, 7.6 mmol, 1.6 M in hexane), and TiCl(OⁱPr)₃ (0.3 mL, 1.3 mmol) were used to furnish the product 27 (321 mg, 53%) as a colorless liquid; R_f = 0.5 (EtOAc–hexane 1:9); IR (neat) ν_max/cm^–1: 3352, 2930, 2858, 1592, 1471, 1346, 1256, 1152, 1057, 1006, 833, 782; ¹H NMR (400 MHz, acetonitrile-d₃): δ 6.57 (s, 1H), 6.37 (s, 1H), 6.18 (s, 1H), 3.73 (s, 1H), 3.02–2.93 (m, 1H), 2.83 (ddd, J = 3.8, 9.3, 16.3 Hz, 1H), 2.76–2.67 (m, 1H), 2.10 (ddd, J = 3.8, 8.9, 13.9 Hz, 1H), 1.03 (s, 9H), 0.97 (s, 9H), 0.30 (s, 3H), 0.29 (s, 3H), 0.20 (s, 6H); ¹³C NMR (125 MHz, acetonitrile-d₃): δ 158.8, 153.7, 149.3, 126.3, 110.4, 109.7, 88.9, 78.7, 35.3, 30.6, 26.3, 26.1, 19.0, 18.9, −3.7, −3.9, −4.1; HRMS-ESI m/z: calcd for C₂₂H₃₇Cl₂O₂Si₂ [M – OH], 459.1710; found, 459.1709.

7-(tert-Butyldimethylsilyloxy)-1-(dichloromethyl)-2,3-dihydro-1H-indene-1,5-diol (28)

To a solution of compound 27 (30 mg, 0.1 mmol) in DMF–H₂O (50:1, 2.0 mL) under argon, LiOAc dihydrate (19 mg, 0.2 mmol) was added, and the solution was stirred at rt until all of the starting material has been consumed. The mixture was cooled to rt, diluted with ether. The entire organic layer was washed with brine and dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 28 (9 mg, 42%) as a colorless liquid; R_f = 0.4 (EtOAc–hexane 1:4); IR (neat) ν_max/cm^–1: 3356, 2929, 2852, 1590, 1462, 1360, 1242, 1046, 1015, 845, 776; ¹H NMR (400 MHz, acetonitrile-d₃): δ 7.27 (s, 1H), 6.51 (s, 1H), 6.28–6.27 (m, 1H), 6.18–6.17 (m, 1H), 3.87 (s, 1H), 2.96–2.89 (m, 1H), 2.87–2.80 (m, 1H), 2.73–2.66 (m, 1H), 2.14–2.07 (m, 1H), 0.97 (s, 9H), 0.20 (s, 6H);¹³C NMR (125 MHz, acetonitrile-d₃): δ 156.5, 151.8, 149.1, 144.2, 131.3, 110.1, 106.8, 68.4, 38.8, 26.2, 26.1, 19.0, −4.2; HRMS-ESI m/z: calcd for C₁₆H₂₃Cl₂O₂Si [M – OH], 345.0845; found, 345.0851.

3-Oxo-2,3-dihydro-1H-indene-4,6-diyl Diacetate (29)

To a solution of ketone 16 (200 mg, 1.2 mmol) in CH₂Cl₂, triethylamine (0.85 mL, 6 mmol) was added. The mixture was stirred for 5 min at 0 °C then acetyl chloride (0.26 mL, 3.6 mmol) was added dropwise and was stirred overnight. The reaction was quenched with water, the organic layer was separated and aqueous layer was extracted with CH₂Cl₂ (2 × 20 mL). The entire organic layer was washed with brine and dried over Na₂SO₄, then concentrated, and purified using column chromatography to obtain the product 29 (289 mg, 96%); R_f = 0.6 (EtOAc–hexane 1:1); ¹H NMR (400 MHz, chloroform-d): δ 7.13 (s, 1H), 6.78 (s, 1H), 3.16–3.11 (m, 2H), 2.71–2.67 (m, 2H), 2.39 (s, 3H), 2.33 (s, 3H); ¹³C NMR (100 MHz, chloroform-d): δ 202.4, 168.8, 168.4, 157.9, 156.3, 148.2, 126.3, 117.2, 114.9, 36.8, 25.7, 21.1, 20.7; HRMS-ESI m/z: calcd for C₁₃H₁₃O₅ [M + H], 249.0763; found, 249.0757.

5,7-Bis(allyloxy)-2,3-dihydro-1H-inden-1-one (31)

To a solution of compound 16 (400 mg, 2.4 mmol) in dry DMF, allyl bromide (1.0 mL, 9.7 mmol) and K₂CO₃ (1.0 g, 7.3 mmol) were added and stirred at rt for 20 h. Cold H₂O was added and the mixture was stirred until all of the carbonate dissolved. The solution was acidified with HCl and then extracted with EtOAc three times. The combined organic layers were washed with H₂O and dried over Na₂SO₄. Evaporation of the solvent and purification of the residue on a silica gel column furnished the product 31 (535 mg, 90%) as a colorless liquid; R_f = 0.4 (EtOAc–hexane 1:4); ¹H NMR (400 MHz, chloroform-d): δ 6.45 (s, 1H), 6.30 (s, 1H), 6.10–5.96 (m, 2H), 5.48 (td, J = 1.1, 17.2 Hz, 1H), 5.40 (td, J = 1.4, 17.2 Hz, 1H), 5.29 (tdd, J = 1.1, 6.1, 10.6 Hz, 2H), 4.64 (dd, J = 1.4, 5.0 Hz, 2H), 4.56 (dd, J = 1.4, 5.0 Hz, 2H), 3.02–2.93 (m, 2H), 2.64–2.57 (m, 2H); ¹³C NMR (100 MHz, chloroform-d): δ 202.6, 165.5, 160.1, 158.1, 132.2, 119.7, 118.2, 117.8, 102.6, 99.1, 99.0, 69.0, 36.8, 25.8; HRMS-ESI m/z: calcd for C₁₅H₁₇O₃ [M + H], 245.1178; found, 245.1174.

5,7-Bis(allyloxy)-1-(dichloromethyl)-2,3-dihydro-1H-inden-1-ol (32)

According to the procedure for the synthesis of compound 11, compound 31 (318 mg, 1.3 mmol), dry CH₂Cl₂ (0.6 mL, 8.9 mmol), n-BuLi (5 mL, 7.6 mmol, 1.6 M in hexane), and TiCl(OⁱPr)₃ (0.3 mL, 1.3 mmol) were used to furnish the product 32 (210 mg, 50%) as a colorless liquid; R_f = 0.5 (EtOAc–hexane 1:9); ¹H NMR (500 MHz, chloroform-d): δ 6.47 (s, 1H), 6.38 (br s, 1H), 6.33 (br s, 1H), 6.14–5.96 (m, 2H), 5.41 (d, J = 17.2 Hz, 2H), 5.32 (dd, J = 10.9, 14.9 Hz, 2H), 4.59 (s, 2H), 4.51 (s, 2H), 3.14–3.00 (m, 2H), 2.99–2.81 (m, 2H), 2.22 (br s, 1H); ¹³C NMR (100 MHz, chloroform-d): δ 158.8, 153.0, 147.6, 143.4, 133.2, 133.0, 130.0, 122.7, 117.9, 117.8, 103.1, 99.1, 69.3, 69.2, 67.1, 38.1; HRMS-ESI m/z: calcd for C₁₆H₁₇Cl₂O₂ [M – OH], 311.0606; found, 311.0602.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01341.

• ¹H and ¹³C NMR spectra for all new compounds (PDF)

• (CIF)

The authors declare no competing financial interest.