Unexpected Inversion of Configuration During the Carbamoylation of 1-Azaflavaglines

Abstract

The acylation of 8-demethoxy-1-azaflavaglines by dimethylcarbamoyl chloride was found to operate with an inversion of configuration, which is rationalized by the occurrence of styrylurea intermediate. The configuration-reversed products were not observed when the substrate was substituted by a methoxy in position 8, suggesting that an overstabilization of the carbocationic intermediate prevents this reaction to take place.

Key words

inversion of configuration - amino alcohol - flavaglines

Publication History

Received: 19 July 2020

Accepted after revision: 13 August 2020

Article published online:
18 September 2020

• References and Notes

• 1 Basmadjian C, Thuaud F, Ribeiro N, Désaubry L. Future Med. Chem. 2013; 5: 2185
• 2 Thuaud F, Bernard Y, Türkeri G, Dirr R, Aubert G, Cresteil T, Baguet A, Tomasetto C, Svitkin Y, Sonenberg N, Nebigil CG, Désaubry L. J. Med. Chem. 2009; 52: 5176
• 3 Thuaud F, Ribeiro N, Gaiddon C, Cresteil T, Désaubry L. J. Med. Chem. 2011; 54: 411
• 4 Ribeiro N, Thuaud F, Bernard Y, Gaiddon C, Cresteil T, Hild A, Hirsch EC, Michel PP, Nebigil CG, Désaubry L. J. Med. Chem. 2012; 55: 10064
• 5 Diedrichs N, Fahrig T, Gerlach I, Ragot J, Schumacher J, Thede K, Horvath E. US8030347, 2011
• 6 Diedrichs N, Ragot J, Thede K, Horvath E. Eur. J. Org. Chem. 2005; 1731
• 7 General All commercial reagents were used without purification. All the anhydrous solvents are commercially available and were conserved on molecular sieves. All reactions sensitive to moisture or oxygen were carried out under argon atmosphere and in flasks dried at 110 °C. Reactions were stirred with a magnetic stirrer. Temperatures for the reactions refer to bath temperatures. Reactions were monitored by TLC (0.2 mm, Merck DC Platten Kieselgel 60 F254) with detection by UV light (λ = 254 nm) and treatment with anisaldehyde and potassium permanganate stain. Melting points were recorded on an electrothermal melting point apparatus and are uncorrected. NMR spectra were acquired on a Bruker DRX-400 spectrometer in CDCl₃ (referenced to 7.26 ppm for ¹H and 77.16 ppm for ¹³C) or (CD₃)₂SO (referenced to 2.50 ppm for ¹H and 39.5 ppm for ¹³C) as solvents. Coupling constants (J) are in Hz. Chemical shifts are reported in parts per million (ppm). The multiplicities of the signals are described using the following abbreviations: s = singlet, d = doublet, t = triplet, m = multiplet. High-resolution mass spectra were recorded on a Bruker MicroTOF-Q (ESI Q-TOF) spectrometer.
• 8 (3S,3aR,8bS)-1-Amino-6-(2-Chloroethoxy)-3a-(4-chlorophenyl)-3-phenyl-1,2,3,3a-tetrahydro-8bH-cyclopenta[b]benzofuran-8b-ol (4 and 5) Ketone 3 (390 mg, 0.86 mmol) and O-methylhydroxylamine hydrochloride (358 mg, 4.28 mmol) were diluted in absolute ethanol (15.6 mL) and distilled pyridine (15.6 mL). The reaction was heated up to reflux 3 h, then the volatiles were removed, and the crude product was extracted with EtOAc. The organic phase was washed twice with HCl (1 M), a saturated solution of Na₂CO₃, and brine. Then, the organic phase was dried over MgSO₄ and concentrated to dryness to give quantitatively the desired oxime ether (414 mg, mixture of two isomers) as a white solid, which was used in the next step without purification. To a stirred solution of methylether oxime (340 mg, 0.70 mmol) in dry THF (25 mL), BH₃–THF complex (9.8 mL, 1 M) was added dropwise at 0 °C. After addition, the reaction was heated to 65 °C overnight. After cooling to room temperature, a solution of 3 M NaOH was added to stop the reaction, and the aqueous phase was extracted twice with EtOAc. The cumulated organic phase was washed with brine, dried over MgSO₄, and then purified by column chromatography on silica gel using DCM/MeOH (95:5) as eluent to give trans-α-hydroxy amine 4 (180 mg, 56%) and cis-α-hydroxy amine 5 (50 mg, 16%) as white solids. trans-α-hydroxy amine 4 is described (¹H NMR and MS) in literature.⁵ Compound 4: mp 102–105 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.83 (1 H, br s), 2.28 (1 H, m), 2.96 (1 H, m), 3.42 (1 H, br s), 3.83 (2 H, t, J = 5.6 Hz), 3.88 (1 H, dd, J = 6.4, 7.5 Hz), 4.08 (1 H, m), 4.25 (2 H, t, J = 5.6 Hz), 4.35 (1 H, br s), 6.58–6.62 (2 H, m), 6.94 (2 H, d, J = 8.7 Hz), 6.95–6.98 (2 H, m), 7.04 (2 H, d, J = 8.7 Hz), 7.10–7.16 (3 H, m), 7.20 (1 H, d, J = 8.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 31.4, 41.7, 53.7, 67.7, 68.6, 91.5, 98.2, 103.3, 109.3, 118.0, 125.7, 127.0, 127.5, 128.3, 128.7, 129.2, 133.3, 133.9, 137.7, 160.5, 162.2. Compound 5: mp 79–82 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.78 (2 H, br s), 1.88 (1 H, m), 2.60 (1 H, m), 3.83 (2 H, t, J = 5.8 Hz), 3.94 (2 H, m), 4.24 (2 H, t, J = 5.8 Hz), 6.55 (1 H, dd, J = 2.1, 8.2 Hz), 6.58 (1 H, d, J = 2.1 Hz), 6.96–7.13 (9 H, m), 7.21 (1 H, d, J = 8.3 Hz). ¹³C NMR (100 MHz, CDCl₃). δ = 36.6, 41.9, 53.7, 61.5, 68.4, 92.9, 97.3, 103.3, 108.3, 120.5, 126.5, 126.6, 127.2, 128.0, 128.6, 129.1, 133.1, 134.7, 139.2, 160.3, 161.1. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₅H₂₄Cl₂NO₃: 456.1133; found: 456.1119.
• 9 3-[(1R,3S,3aR,8bS)-6-(2-Chloroethoxy)-3a-(4-chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl]-1,1-dimethylurea (6) To a stirred solution of trans-α-hydroxy amine 4 (50 mg, 0.11 mmol) in dry DCM (1.7 mL) was added triethylamine (50 μL, 0.36 mmol), followed by dimethylcarbamoyl chloride (25 μL, 0.27 mmol) at room temperature under argon atmosphere. The resulting reaction mixture was stirred at reflux over 40 h. After cooling to room temperature, the mixture was concentrated and then purified by column chromatography on silica gel using pentane/Et₂O (9:1 to 3:7) as eluent to give trans-α-hydroxy urea 6 (43 mg, 75%) as a white solid; mp 171–174 °C. ¹H NMR (400 MHz, (CD₃)₂SO): δ = 2.12 (1 H, m), 2.36 (1 H, m), 2.92 (6 H, s), 3.81 (2 H, t, J = 5.9 Hz), 3.99 (1 H, dd, J = 3.1, 7.5 Hz), 4.21 (2 H, t, J = 5.9 Hz), 4.35 (1 H, d, J = 6.7 Hz), 4.94 (1 H, m), 5.45 (1 H, br s), 6.44 (1 H, d, J = 2.3 Hz), 6.52 (1 H, dd, J = 2.3, 8.3 Hz), 7.04 (2 H, d, J = 8.7 Hz), 7.08 (1 H, d, J = 8.3 Hz), 7.14–7.18 (7 H, m). ¹³C NMR (100 MHz, (CD₃)₂SO): δ = 30.5, 35.0, 36.6, 42.0, 53.3, 63.0, 68.4, 91.0, 96.9, 103.2, 108.1, 122.3, 126.0, 126.6, 127.3, 128.2, 129.2, 129.8, 133.4, 135.0, 140.1, 159.7, 159.8, 160.6. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₈H₂₈Cl₂N₂NaO₄: 549.1324; found: 549.1346.
• 10 (3S,3aR,8bR)-3a-(4-Chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-one (8) To a solution of cis-diol 7 ⁶ (360 mg, 0.95 mmol) in dry DMSO (2.9 mL) at 0 °C under argon, a solution of SO₃·Py (454 mg, 2.85 mmol) in dry DMSO (1.7 mL) was added slowly. The mixture was stirred at room temperature overnight. The reaction was treated with a saturated cold solution of NH₄Cl, and then the liquid phase was eliminated by filtration. The obtained solid was diluted with DCM. The organic phase was washed with water, dried over anhydrous MgSO₄, filtered, concentrated, and purified by column chromatography on silica gel using pentane/DCM (3:7) as eluent to give ketone 8 (310 mg, 87%) as a white solid; mp 88–91 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.80 (1 H, s), 2.93–3.12 (2 H, m), 3.80 (1 H, dd, J = 9.4, 13.1 Hz), 6.93–6.96 (2 H, m), 7.03–7.20 (9 H, m), 7.43–7.47 (2 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 40.1, 48.5, 77.4, 88.3, 100.2, 112.4, 122.6, 125.2, 126.7, 127.4, 127.9, 128.0, 128.3, 128.4, 132.5, 133.8, 136.4, 158.4, 210.9. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₃H₁₇ClNaO₃: 399.0764; found: 399.0746.
• 11 (3S,3aR,8bS)-1-Amino-3a-(4-chlorophenyl)-3-phenyl-1,2,3,3a-tetrahydro-8bH-cyclopenta[b]benzofuran-8b-ol (10 and 11) Ketone 8 (300 mg, 0.80 mmol) and O-methylhydroxylamine hydrochloride (333 mg, 4 mmol) were diluted in absolute ethanol (15 mL) and distilled pyridine (15 mL). The reaction was heated up to reflux overnight, then the volatiles were removed, and the crude product was extracted with EtOAc. The organic phase was washed twice with HCl (1 M), a saturated solution of Na₂CO₃, and brine. Then, the organic phase was dried over MgSO₄ and concentrated to dryness to give quantitatively the desired oxime ether 9 (320 mg, mixture of two isomers) as a white solid, which was used in the next step without purification. To a stirred solution of methylether oxime 9 (310 mg, 0.76 mmol) in dry THF (24 mL), BH₃–THF complex (10.7 mL, 1 M) was added dropwise at 0 °C. After addition, the reaction was heated to 65 °C overnight. After cooling to room temperature, a solution of 3 M NaOH was added to stop the reaction, and the aqueous phase was extracted twice with EtOAc. The cumulated organic phase was washed with brine, dried over MgSO₄, and then purified by column chromatography on silica gel using DCM/MeOH (95:5) as eluent to give cis-α-hydroxy amine 10 (106 mg, 43%) and trans-α-hydroxy amine 11 (17 mg, 6%) as white solids. Compound 10: mp 89–92 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.96 (1 H, m), 2.67 (1 H, m), 4.02 (2 H, m), 6.96–7.15 (11 H, m), 7.31–7.37 (2 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 36.9, 53.9, 61.8, 93.4, 102.4, 110.7, 121.4, 126.0, 126.5, 127.3, 127.8, 128.0, 128.6, 129.2, 131.1, 133.2, 134.7, 139.3, 159.0. Compound 11: mp 95–98 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.81 (1 H, br s), 2.31 (1 H, m), 2.99 (1 H, m), 3.36 (1 H, m), 3.92 (1 H, m), 4.12 (1 H, m), 4.26 (1 H, br s), 6.93–7.18 (11 H, m), 7.28 (1 H, d, J = 7.4 Hz), 7.41 (1 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 31.4, 53.7, 67.8, 91.8, 102.4, 111.6, 122.4, 125.1, 125.4, 127.1, 127.5, 128.3, 128.7, 129.3, 132.5, 133.2, 133.9, 137.7, 159.0. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₃H₂₁ClNO₂: 378.1261; found: 378.1250.
• 12 3-[(3S,3aR,8bS)-3a-(4-Chlorophenyl)-8b-hydroxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl]-1,1-dimethylurea (12) To a stirred solution of cis-α-hydroxy amine 10 (120 mg, 0.32 mmol) in dry DCM (4.8 mL), was added triethylamine (0.12 mL, 0.82 mmol) followed by dimethylcarbamoyl chloride (59 μL, 0.63 mmol) at room temperature under argon atmosphere. The resulting reaction mixture was stirred at reflux over 24 h. After cooling to room temperature, the mixture was concentrated and then purified by column chromatography on silica gel using DCM/EtOAc (95:5) as eluent to give an inseparable mixture of two diastereomers, trans-α-hydroxy urea 12 and cis-α-hydroxy urea 13 in a 83/17 ratio (126 mg, 89%) as a white solid; mp (mixture) 191–194 °C. Compound 12: ¹H NMR (400 MHz, (CD₃)₂SO): δ = 2.07 (1 H, m), 2.53 (1 H, m), 2.78 (6 H, s), 3.98 (1 H, t, J = 8.2 Hz), 4.85 (1 H, dd, J = 7.5, 15.1 Hz), 6.11 (1 H, s), 6.25 (1 H, d, J = 7.4 Hz), 6.94–7.31 (13 H, m). ¹³C NMR (100 MHz, (CD₃)₂SO): δ = 33.6, 36.1, 52.8, 61.0, 91.7, 101.3, 109.9, 120.5, 126.1, 126.3, 126.5, 127.6, 128.2, 129.4, 129.7, 130.0, 131.2, 135.8, 139.6, 157.5, 159.0. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₆H₂₅ClN₂NaO₃: 471.1451; found: 471.1439.
• 13 3-[(1S,3S,3aR,8bS)-3a-(4-Bromophenyl)-8b-hydroxy-6,8-dimethoxy-3-phenyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl]-1,1-dimethylurea (1) To a stirred solution of cis-α-hydroxy amine 18 (50 mg, 0.10 mmol) in dry DCM (1.5 mL), was added triethylamine (37 μL, 0.27 mmol) followed by dimethylcarbamoyl chloride (19 μL, 0.21 mmol) at room temperature under argon atmosphere. The resulting reaction mixture was stirred at reflux over 24 h. After cooling to room temperature, the mixture was concentrated and then purified by column chromatography on silica gel using pentane/EtOAc (9:1) as eluent to give cis-α-hydroxy urea 1 (54 mg, 95%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ = 2.31 (1 H, m), 2.34 (1 H, s), 2.76 (1 H, m), 2.95 (6 H, s), 3.67–3.75 (4 H, m), 3.78 (3 H, s), 4.52 (1 H, m), 5.72 (1 H, d, J = 5.8 Hz), 6.00 (1 H, d, J = 1.9 Hz), 6.19 (1 H, d, J = 1.9 Hz), 7.03–7.12 (7 H, m), 7.21 (2 H, d, J = 8.7 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 30.4, 36.3, 36.8, 52.0, 55.5, 55.7 ; 57.6, 88.2, 88.9, 92.5, 102.4, 110.4, 121.3, 126.4, 127.9, 128.1, 129.4, 130.3, 135.3, 138.2, 157.8, 158.6, 159.9, 163.8. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₈H₂₉BrN₂NaO₅: 575.1158; found: 575.1136.