A synthesis of (±)-thia-calanolide A, its resolution and in vitro biological evaluation

Anil U. Chopade; Manojkumar U. Chopade; Bhanu M. Chanda; Dilip D. Sawaikar; Kiran B. Sonawane; Mukund K. Gurjar

doi:10.1016/j.arabjc.2012.04.027

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Original article

9 (

2_suppl

); S1597-S1602

doi:

10.1016/j.arabjc.2012.04.027

A synthesis of (±)-thia-calanolide A, its resolution and in vitro biological evaluation

Anil U. Chopade^{^a,⁎}, Manojkumar U. Chopade^{^b}, Bhanu M. Chanda^{^a}, Dilip D. Sawaikar^{^a}, Kiran B. Sonawane^{^a}, Mukund K. Gurjar^{^a,1}

a Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India

b Department of Chemistry, University of Pune, Pune 411007, India

⁎Corresponding author. Tel.: +91 20 25902576; fax: +91 20 25902629. chopadeau@yahoo.co.in (Anil U. Chopade)

Received: 2011-7-22, Accepted: 2012-4-21, Published: 2012-11-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

1 Present address: Emcure Pharmaceuticals Ltd., Pune 411057, India.

Abstract

A synthesis of (±)-thia-calanolide A 3 has been successfully accomplished starting from 3,5-dimethoxythiophenol 4, in six steps in an overall yield of 4.5%. The key reaction involved Friedel–Crafts tigloylation of 5,7-dihydroxy-4-n-propyl thiocoumarin 6 employing an appropriate solvent of CS₂–PhNO₂ in a ratio of 7:3. In its biological evaluation for anti-HIV activity, (±)-thia-calanolide A 3 demonstrated comparatively less activity with calanolide A and its synthetic analogue aza-calanolide. Further, (±)-3 has been resolved by chiral HPLC to (+) and (−)-3.

Keywords

Thiocoumarin

Thia-calanolide A

Anti-HIV activity

Resolution via chiral HPLC

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1 Introduction

(+)-Calanolide A [(+)-1], non-nucleoside reverse transcriptase inhibitor (NNRTI) and few new coumarin derivatives were isolated from Calophyllum langerum (Kashman et al., 1992) which showed promising activity towards human immunodeficiency virus (HIV-1) reverse transcriptase (Currens et al., 1996a,b). It is also active against many strains of Mycobacterium tuberculosis including those resistant to the standard antitubercular drugs (Xu et al., 2004) and is reported through molecular dynamics simulation of SARS-CoV to be a potent proteinase inhibitor (Lee et al., 2003). Calanolide A is in clinical testing phase II as anti-HIV drug; (Buckheit et al., 2000; Cragg and Newman, 2003) interest therefore arose particularly in developing its analogues. So far, most of the analogues were either less potent or devoid of any anti-HIV activity (Galinis et al., 1996; Zhou et al., 1999; Zembower et al., 1997; Xu et al., 1998; Newman et al., 1998 ); however, aza-calanolide A [(±)-2] (Sharma et al., 2003) exhibited enhanced in vitro anti-HIV reverse transcriptase activity. These findings prompted us to undertake the total synthesis of thia-calanolide A 3 by replacing oxygen in ring B with a sulphur atom, which might exhibit better activity. Herein, we describe the first synthesis, optical resolution and in vitro biological evaluation of (±)thia-calanolide A 3 (Fig. 1).

2 Results and discussion

Thiophenol 4, obtained from phloroglucinol (Wolfers et al., 1975) or from 3,5-dimethoxyaniline by diazotization followed by reaction with Na₂S + S or NaSH (Allen and Mackay, 1943) was subjected to Pechmann condensation with ethylbutyrylacetate in the presence of sulphuric acid (Sethna and Phadke, 1953). However, it yielded the undesired 7-hydroxy-5-methoxy-2-propyl-4H-thiochromen-4-one. The required 5,7-dimethoxy-4-propyl-2H-thiochromen-2-one 5 was obtained by a modified Pechmann method where triflic acid was used instead of H₂SO₄. Demethylation with AlCl₃ yielded 5,7-dihydroxythiocoumarin 6. Friedel–Crafts acylation (Olah, 1964) of 6 with tigloyl chloride yielded a 3:1 mixture of 5,7-ditigloyloxy thiocoumarin 7a and 5-hydroxy-7-tigloyloxy thiocoumarin 7b instead of the required C-8 tigloyl coumarin 7 (Scheme 1).

In an alternate route (Sekino et al., 2004) thiocoumarin 5 was subjected to Friedel–Crafts reaction with tigloylchloride to yield 5-methoxy-7-hydroxy-8-tigloylthiacoumarin 8. Intramolecular oxo-Michael addition (IMA) of the latter furnished the chromanone 9. Subsequent demethylation of 9 with various reagents like BBr₃/CH₂Cl₂ at −70 °C (Vickery et al., 1979), BBr₃-SMe₂/CH₂Cl₂ (Williard and Fryhle, 1980), BF₃-Et₂O/CH₂Cl₂ (Preston et al., 1983), AlCl₃/PhCl at 120 °C (Chenera et al., 1993), and MgI₂/K₂CO₃/PhH (Sekino et al., 2004) under reflux for 15 days did not proceed satisfactorily to yield the expected demethylated product. With BBr₃/CH₂Cl₂, compound 8 was regenerated, whereas the starting thiocoumarin 9 was recovered unchanged with other reagents (Scheme 2).

Successful tigloylation was achieved via Friedel–Crafts reaction from compound 6 employing an appropriate solvent in a ratio CS₂–PhNO₂ (7:3). The product 7 thus formed was cyclized with K₂CO₃ and yielded the desired 8,9-dimethyldihydrothiopyranones 10 as an 1:1 epimeric mixture. The required ‘C’ ring was constructed from 10 by reaction with 3-chloro-3-methyl-1-butyne to yield chromene-chromanone–thiacoumarins 11 and 12 in a 1.8:1 ratio and in an overall yield of 34% (Scheme 3).

Both the ketones 11 and 12 were separately reduced with NaBH₄ to afford (±)-3 and (±)-thia-calanolide C 14 in 44% and 71% yields, respectively. Reduction of 11 with NaBH₄–CeCl₃ under Luche condition resulted in a 3:2 mixture of (±)-3 and (±)-thia-calanolide B (±)-13, respectively (Scheme 4).

For the first time, in the calanolide series, especially in the thia-calanolide A synthesis, application of HPLC method for the determination and separation of small quantities of the intermediates in the total synthesis of (+)-thia-calanolide has been developed. Resolution of a mixture of cis and trans of 10 was found to be excellent using Bondapak silica porasil 30 cm column.

Resolution of (±)-3 was achieved by chiral HPLC (Chiralcel (OD), 9:1 hexane–isopropanol, 1 mL/min) to afford the two isomers (+)-3 and (–)-3 having optical rotation [α]_D + 54.3° (c 0.5, CHCl₃) and [α]_D −49.8° (c 0.3, CHCl₃), respectively (Scheme 5).

2.1

2.1 Anti-HIV activity assays

Compound (±)-3 was evaluated for anti-HIV reverse transcriptase activity by following HIV-1 p24 antigen capture ELISA (Perkin Elmer NEN) as per manufacturer’s protocol. Briefly, CEM cells were infected with HIV-1 NL4.3 isolate for 4 h in the presence of Poltbrene in complete medium. The infected cells were kept for 7–10 days in culture before the supernatant was used for HIV-1 p24 antigen capture. The percentage inhibition of virus production was calculated based on p24 values of untreated control. (±)-3 was found to be 28% inhibitory as compared to synthetic (±)-1 which was found to exhibit 99.7% inhibition of virus production.

3 Conclusion

The first synthesis of (±)-thia-calanolide 3 has been successfully accomplished. It has also been resolved by chiral HPLC to the (+) and (−) enantiomers which have been fully characterized. Biological evaluation for anti-HIV activity revealed that 3 is not as achieved as the natural calanolide A and its synthetic analogue aza-calanolide A. The amphoteric and bulkier nature of sulphur in 3 could be one of the reasons for diminished activity.

4 Experimental section

4.1

4.1 General

NMR spectra were recorded on a Bruker MSL-300 spectrometer operation at 300 MHz for ¹H and 75 MHz for ¹³C and Bruker AV-200 spectrometer operation at 200 MHz for ¹H and 50 MHz for ¹³C. Spectra were obtained at 25 °C in CDCl₃, DMSO-d₆ and Acetone-d₆ solution and were referenced to the CHCl₃ peak (δ 7.26), DMSO (δ 2.50) for ¹H or to the centre line of the CDCl₃, DMSO-d₆, acetone-d₆ at δ 77, 39.70, 29.8, respectively, for ¹³C, all chemical shifts are given as δ values (in ppm) relative to TMS. IR spectra were recorded on Perkin-Elmer FT IR instrument. Optical rotations were measured as CHCl₃ solution using Jasco P-1020 digital polarimeter. Microanalyses were performed on a Flash EA-1112 Thermo Finnigan Elemental Analyser. Chiral HPLC was performed on a SHIMADZU Class-VP using a Chiracel OD column. Melting points were determined by using a Yanco Micro Melting point apparatus and were uncorrected.

Reactions with moisture-sensitive chemicals were performed under nitrogen in flame-dried reaction flasks. Solvents were dried by standard methods. Column chromatography was carried out using 60–80 mesh and 230–400 mesh silica gel. Phloroglucinol, dimethylthiocarbamoyl chloride, trifluoromethanesulfonic acid, ethyl butyrylacetate, tiglic acid, 3-chloro-3-methyl-1-butyne were purchased from Aldrich and were used without purification.

4.1.1

4.1.1 5,7-Dimethoxy-4-n-propyl-2H-thiochromen-2-one (5)

A mixture of 4 (0.540 g, 3.17 mmol) and ethylbutyrylacetate (0.527 g, 3.3 mmol) was added dropwise to cold (5 °C) trifluoromethanesulfonic acid (0.55 mL, 6.34 mmol) over a 10 min period and the reaction mixture was warmed to 25 °C and stirred for 17 h. After quenching with ice water (10 mL), the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried (Na₂SO₄) and concentrated. The residue was subjected to chromatographic purification (EtOAc–pet-ether, 2:8) to give 5 as lemon yellow crystals (0.301 g, 36%). Mp 110–112 °C, IR (CHCl₃) 3016, 2965, 1630, 1593 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J = 7.3 Hz, 3H), 1.58 (m, 2H), 2.90 (t, J = 7.3 Hz, 2H), 3.82 (s, 3H), 3.86 (s, 3H), 6.20 (s, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 24.0, 41.8, 55.5, 55.6, 98.2, 101.8, 111.5, 122.7, 142.4, 156.9, 160.7, 160.8, 184.1. Anal. Calcd for C₁₄H₁₆O₃S: C, 63.61; H, 6.10; S, 12.13. Found: C, 63.61; H, 6.21; S, 11.07.

4.1.2

4.1.2 5,7-Dihydroxy-4-n-propyl-2H-thiochromen-2-one (6)

To a stirred solution of 5 (1 g, 3.78 mmol) in chlorobenzene (10 mL) was added AlCl₃ (2.5 g, 1.89 mmol) in portions over a period of 15 min and the reaction mixture was heated to 100 °C under stirring for 12 h. The mixture was then cooled to room temperature and poured on crushed ice (20 g) and stirred well for 30 min. The solid precipitated was filtered, washed with water (50 mL) till neutral, then washed with hexane (5 mL) and dried in vacuum to give 6 (0.849 g, 95%) as a dark brown solid. Mp 230–235 °C (decomp.): IR (CHCl₃) 3159, 1600 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆) δ 0.95 (t, J = 7.3 Hz, 3H), 1.60 (m, 2H), 2.97 (t, J = 7.3 Hz, 2H), 6.04 (s, 1H), 6.39 (s, 2H), 9.70 (s, 1H), 10.02 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.0, 24.0, 40.7, 102.6, 104.4, 108.2, 120.3, 140.9, 158.1, 159.7, 159.9, 182.6; Anal. Calcd for C₁₂H₁₂O₃S: C, 61.00; H, 5.12; S, 13.57. Found: C, 60.75; H, 4.98; S, 12.38.

4.1.3

4.1.3 (E)-5,7-Dihydroxy-8-(2-methylbut-2-enoyl)-4-n-propyl-2H-thiochromen-2-one (7)

A mixture of 6 (0.5 g, 2.11 mmol), AlCl₃ (1.4 g, 10.59 mmol) and CS₂ (7 mL) was heated at 50 °C while stirring for 30 min PhNO₂ (2 mL) was added dropwise and stirred for additional 30 min to get a homogeneous mixture. Tigloyl chloride (0.262 g, 2.21 mmol) in PhNO₂ (1 mL) was then added dropwise and the reaction mixture was stirred at 50 °C for 24 h. It was then cooled to room temperature and quenched with crushed ice and dil. HCl before extracting with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (3 × 20 mL), dried (Na₂SO₄) and concentrated. The residue obtained was purified by column chromatography on silica gel (EtOAc–pet-ether, 4:6) to furnish 7 (0.437 g, 65%) as a brown solid. Mp 162–164 °C: IR (CHCl₃) 3263, 3019, 1720, 1610 cm⁻¹; ¹H NMR (200 MHz, DMSO-d₆) δ 0.99 (t, J = 7.2 Hz, 3H), 1.62 (m, 2H), 1.84 (d, J = 7.0 Hz, 3H), 1.87 (s, 3H), 3.04 (t, J = 7.5 Hz, 2H), 6.17 (s, 1H), 6.49 (q, J = 7.0 Hz, 1H), 6.64 (s, 1H), 10.69 (s, 1H), 11.03 (s, 1H); ¹³C NMR (50 MHz, DMSO-d₆) δ 10.5, 14.0, 14.9, 24.1, 41.1, 102.1, 107.9, 117.4, 120.1, 137.9, 138.1, 142.4, 156.7, 158.4, 159.9, 181.6, 196.2; Anal. Calcd for C₁₇H₁₈O₄S: C, 64.13; H, 5.70; S, 10.07. Found: C, 63.65; H, 5.58; S, 9.53.

4.1.4

4.1.4 5-Hydroxy-8,9-dimethyl-4-n-propyl-8,9- dihydrothiopyrano[2,3-f]chromene-2,10-dione (10)

To a solution of 7 (0.4 g, 1.25 mmol) in 2-butanone (5 mL), anhydrous K₂CO₃ (0.520 g, 3.77 mmol) was added and the mixture was refluxed for 1.5 h. It was then cooled to room temperature, acidified (pH 2) with dil. HCl and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (3 × 10 mL), dried (Na₂SO₄) and concentrated. The residue was chromatographed on silica gel column (EtOAc–pet-ether, 3:7) to give a 1:1 mixture of isomeric chromanones 10 (0.360 g, 90%) as white solid, mp 243–245 °C: IR (Nujol) 3130, 3020, 1621 cm⁻¹; Anal. Calcd for C₁₇H₁₈O₄S: C, 64.13; H, 5.70; S, 10.07. Found: C, 63.86; H, 5.72; S, 9.05.

4.1.5

4.1.5 6,7-Dihydro-2H-1,5-dioxa-12-n-propyl-2,2,6,7- tetramethyl-9-thia-triphenylene-8,10-dione (11 trans and 12 cis)

To a stirred solution of 10 (0.5 g, 1.57 mmol) in a mixture containing 2-butanone: DMF (10 mL, 9:1), at room temperature, anhydrous K₂CO₃ (0.65 g, 4.71 mmol), 3-chloro-3-methyl-1-butyne (0.8 g, 7.85 mmol), n-Bu₄NI (0.49 g, 1.22 mmol) were added successively. The reaction mixture was heated at 60 °C for 1 h, and then anhydrous ZnCl₂ (0.278 g, 2.04 mmol) was added. The resultant mixture was further heated to 70 °C for 20 h. It was cooled to room temperature and quenched with saturated aq. solution of NH₄Cl (3 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layer was washed with brine (20 mL), dried (Na₂SO₄) and concentrated. The residue obtained was purified through column chromatography on silica gel (230–400 mesh, EtOAc–pet-ether, 1:9) to afford (±)-11 (0.132 g, 22%) as a white solid. Mp 143–144 °C: IR (CHCl₃) 1670, 1627, 1201 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 1.01 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.53 (d, J = 6.5 Hz, 3H), 1.58 (s, 6H), 1.67 (m, 2H), 2.60 (m, J = 6.8, 11.5 Hz, 1H), 2.98 (t, J = 7.2 Hz, 2H), 4.28 (dq, J = 6.3, 11.5 Hz, 1H), 5.64 (d, J = 10.1 Hz, 1H), 6.37 (s, 1H), 6.67 (d, J = 10.1 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 10.2, 13.9, 19.5, 24.2, 27.7, 28.1, 42.0, 46.5, 78.8, 79.4, 107.5, 109.0, 112.9, 115.8, 123.9, 128.0, 143.9, 156.0, 158.3, 158.8, 186.3, 192.5; Anal. Calcd for C₂₂H₂₄O₄S: C, 68.72; H, 6.29; S, 8.34. Found: C, 68.36; H, 6.32; S, 7.99; and (±)-thia-calanolide D (±)-12 (0.072 g, 12%) as a syrup liquid; IR (CHCl₃) 1670, 1627, 1201 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ1.02 (t, J = 7.1 Hz, 3H), 1.20 (d, J = 7.3 Hz, 3H), 1.43 (d, J = 5.8 Hz, 3H), 1.56 (s, 6H), 1.64 (m, 2H), 2.70–2.75 (m, J = 3.6, 7.3 Hz, 1H), 2.96 (t, J = 7.2 Hz, 2H), 4.70 (m, J = 2.9, 6.6 Hz, 1H), 5.65 (d, J = 9.5 Hz, 1H), 6.39 (d, 1H), 6.69 (d, J = 9.5 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 10.4, 13.9, 19.5, 24.3, 27.9, 28.2, 42.0, 46.7, 77.7, 78.9, 79.4, 96.1, 107.5, 116.0, 124.1, 127.9, 144.4, 155.7, 158.1, 158.8, 186.0, 192.1; Anal. Calcd for C₂₂H₂₄O₄S: C, 68.72; H, 6.29; S, 8.30. Found: C, 68.88; H, 6.33; S, 8. 29.

4.1.6

4.1.6 (±)-6,7-Dihydro-2H-1,5-dioxa-8-hydroxy-12-n-propyl-2,2,6,7-tetramethyl-9-thia-triphenylene-10-one (3, 13)

To a solution of (±)-11 (0.020 g, 0.052 mmol) in EtOH (2 mL) at 0 °C, was added NaBH₄ (0.003 g, 0.083 mmol) and the reaction temperature was allowed to rise to 25 °C over a period of 1 h. After completion of the reaction 2–3 drops of water were added and the reaction mixture was extracted with EtOAC (3 × 3 mL), the combined organic layer was washed with brine, dried with Na₂SO₄ and concentrated. The residue obtained was purified through flash column chromatography (EtOAc–pet-ether, 2:8) to give (±)-thia-calanolide A (±)-3 (0.009 g, 44%) as a white solid. Mp 158–160 °C: IR (CHCl₃) 3410, 1619, 1215 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 1.01 (t, J = 7.3 Hz, 3H), 1.12 (d, J = 7 Hz, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.52 (s, 6H), 1.64 (m, 2H), 2.05 (sext, J = 6, 13.4 Hz, 1H), 3.01 (dq, 3.4, 8.0, 2H), 4.02 (quin, J = 6.6, 13.1 Hz, 1H), 4.55 (d, J = 5.9 Hz, 1H), 5.60 (d, J = 9.9 Hz, 1H,), 6.3 (s, 1H), 6.66 (d, J = 9.9 Hz, 1H); ¹³C NMR (CDCl₃, 75 MHz, δ 14.0, 15.9, 19.2, 24.5, 27.5, 27.9, 41.7, 42.1, 68.2, 77.8, 108.9, 112.0, 112.7, 116.8, 122.5, 128.0, 140.9, 151.5, 153.3, 157.9, 183.6; ¹³C NMR (75 MHz, Acetone-d₆) δ 14.5, 15.9, 19.7, 25.6, 27.7, 28.3, 42.8, 43.6, 69.0, 77.7, 78.8, 109.7, 112.5, 115.0, 117.6, 123.4, 129.4, 142.5, 153.7, 154.0, 157.9, 184.2. Anal. Calcd for C₂₂H₂₆O₄S: C, 68.37; H, 6.78; S, 8.30. Found: C, 68.81; H, 6.87; S, 8.03; and (±)-thia-calanolide B (±)-13 (0.003 g, 14%) as a white solid mp 156–158 °C: IR (CHCl₃) 3400, 1621, 1533, 1122 cm⁻¹; ¹H NMR (200 MHz, CDCl₃) δ 1.03 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.41 (d, J = 6.3 Hz, 3H), 1.49 (s, 6H), 1.65 (m, 2H), 2.30 (m, J = 5.8,12.7 Hz, 1H), 3.01 (m, 2H), 4.49 (m, J = 6.8, 13.7 Hz, 1H), 4.82 (d, J = 6 Hz, 1H), 5.63 (d, J = 9.8 Hz, 1H), 6.31 (s, 1H), 6.70 (d, J = 9.8 Hz, 1H).

4.1.7

4.1.7 (±)-6,7-Dihydro-2H-1,5-dioxa-8-hydroxy-12-n- propyl-2,2,6,7-tetramethyl-9-thia-triphenylene-10-one (14)

To a solution of 12 (0.050 g, 0.13 mmol) in EtOH (5 mL) at 0 °C was added NaBH₄ (0.009 g, 0.26 mmol) while stirring and the temperature was allowed to rise to 30 °C and the mixture was stirred further for 1 h. After completion of reaction, ice water (1 mL) was added and the reaction mixture was extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (5 mL), dried (Na₂SO₄) and concentrated. The residue obtained was purified through flash column chromatography on silica gel (230–400 mesh, EtOAc–pet-ether, 2:8) to give (±)-14 (0.036 g, 71%) as a white solid. Mp 167–168 °C: IR (CHCl₃) 3400, 1619, 1201 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J = 7.3 Hz, 3H), 1.21 (d, J = 7.3 Hz, 3H), 1.53 (d, J = 6.5 Hz, 3H), 1.55 (s, 3H), 1.58 (s, 6H), 1.67 (m, 2H), 2.62 (m, 1H), 3.46 (m, 2H), 4.28 (m, J = 2.2, 6.6 Hz, 1H), 4.79 (d, J = 3.6 Hz, 1H), 5.67 (d, J = 9.5 Hz, 1H), 6.37 (d, 1H), 6.70 (d, J = 9.5 Hz, 1H). Anal. Calcd for C₂₂H₂₆O₄S: C, 68.37; H, 6.78; S, 8.30. Found: C, 68.65; H, 6.91; S, 8.44.

Acknowledgments

A.U.C. thank the UGC-CSIR, New Delhi, for the award of a research fellowship. NCCS (Pune) is thanked for anti-HIV activity assays.

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Introduction

Results and discussion

Anti-HIV activity assays

Conclusion

Experimental section

General

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[1] Allen C.F.H., Mackay D.D., . Org. Synth. Coll. Vol.. 1943;2:580-582.

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A synthesis of (±)-thia-calanolide A, its resolution and in vitro biological evaluation

Abstract

Keywords

Thiocoumarin

Thia-calanolide A

Anti-HIV activity

Resolution via chiral HPLC

1 Introduction

2 Results and discussion

2.1 Anti-HIV activity assays

3 Conclusion

4 Experimental section

4.1 General

4.1.1 5,7-Dimethoxy-4-n-propyl-2H-thiochromen-2-one (5)

4.1.2 5,7-Dihydroxy-4-n-propyl-2H-thiochromen-2-one (6)

4.1.3 (E)-5,7-Dihydroxy-8-(2-methylbut-2-enoyl)-4-n-propyl-2H-thiochromen-2-one (7)

4.1.4 5-Hydroxy-8,9-dimethyl-4-n-propyl-8,9- dihydrothiopyrano[2,3-f]chromene-2,10-dione (10)

4.1.5 6,7-Dihydro-2H-1,5-dioxa-12-n-propyl-2,2,6,7- tetramethyl-9-thia-triphenylene-8,10-dione (11 trans and 12 cis)

4.1.6 (±)-6,7-Dihydro-2H-1,5-dioxa-8-hydroxy-12-n-propyl-2,2,6,7-tetramethyl-9-thia-triphenylene-10-one (3, 13)

4.1.7 (±)-6,7-Dihydro-2H-1,5-dioxa-8-hydroxy-12-n- propyl-2,2,6,7-tetramethyl-9-thia-triphenylene-10-one (14)

Acknowledgments

References

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