Regio- and Diastereoselective Synthesis of a Primary β-Azidoalcohol via Stereoselective Epoxidation of a Highly Functionalised di-o,o′-Substituted Styrene: Toward a New Total Synthesis of (-)-Quinocarcin

Abstract

Diastereoselective epoxidation of a highly functionalised di-o,o′-substituted styrene combined with subsequent regioselective epoxide ring-opening afforded the corresponding primary β-azidoalcohol, which is the required key intermediate for a new total synthesis approach toward (-)-quinocarcin and various unnatural d-ring modified analogues.

Key words

asymmetric synthesis - epoxidations - azides - regio­selectivity - natural products

References

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18

Synthesis of Epoxide 9.
MCPBA (104 mg, 0.6 mmol) was added by portion over a period of 2 min to a -78 °C stirred solution of styrene 5b (86 mg, 0.3 mmol), NMO (176 mg, 1.5 mmol) and Jacobsen’s catalyst (R,R)-8 (20 mg, 0.03 mmol) in CH₂Cl₂ (1 mL). The reaction was vigourously stirred during 2 h at -78 °C. Then a solution of DMS (-78 °C, 186 mg, 3 mmol) in CH₂Cl₂ (1 mL) was added dropwise and the reaction mixture was warmed to r.t. The mixture was then washed with brine (3 × 30 mL) and the aqueous layers were extracted with 30 mL of CH₂Cl₂. The organic layers were combined and dried over Na₂SO₄. After removal of the solvents, the residue was chromatographed over silica gel (eluent: cyclohexane-EtOAc, 95:5 to 75:25) to afford epoxide 9 (de 82%; major isomer: 89 mg, 0.21 mmol; minor isomer: 9 mg, 0.02 mmol) as a colourless oil. Major diastereomer : [α]_D ²⁰ -48.1 (c 1.0, C₆H₆). ¹H NMR (CDCl₃): δ = 2.24-2.40 (dd, J = 5.3, 13.6 Hz 1 H, CH₂ ^Bn), 2.74 (dd, J = 2.9, 5.9 Hz, 1 H, CH₂-O-CH), 2.95-3.15 (m, 1 H, N^Troc-CH₂-CH-C=O^ketone), 3.24 (dd, J = 4.2, 5.9 Hz, 1 H, CH₂-O-CH), 3.35 (dd, J = 3.5, 13.6 Hz, 1 H, CH₂ ^Bn), 3.62-3.79 (m, 4 H, N^Troc-CH₂-CH-C=O^ketone, N^Troc-CH₂-C=O^ketone), 3.72 (s, 3 H, O-CH₃), 3.86 (dd, J = 2.9, 4.2 Hz, 1 H, CH₂-O-CH), 4.79 (s, 2 H, CH₂ ^Troc), 7.19-7.60 (m, 3 H, 3 × CH^Ar). ¹³C NMR (CDCl₃): δ = 32.2 (CH₂ ^Bn), 48.1 (N^Troc-CH₂-CH-C=O^ketone), 50.5 (N^Troc-CH₂-CH-C=O^ketone), 51.2 (CH₂-O-CH), 51.7 (CH₂-O-CH), 52.1 (N^Troc-CH₂-C=O^ketone), 55.9 (O-CH₃), 75.1 (CH₂ ^Troc), 95.1 (CCl₃ ^Troc), 128.6 (CH^Ar), 130.1 (CH^Ar), 130.9 (CH^Ar), 134.1 (C^Ar), 135.6 (C^Ar), 138.0 (C^Ar), 152.9 (C=O^Troc), 210.1 (C=O^ketone). IR (film): 3053, 3028, 2854, 1745, 1694, 1609, 1497, 1255, 1132, 909, 804, 790, 686 cm^-1.

19

Synthesis of β-Azidoalcohol 4a.
A mixture of enantiopure styrene oxide 9 (211 mg, 0.5 mmol), NaN₃ (65 mg, 1.0 mmol) and NH₄Cl (67 mg, 1.25 mmol) in EtOH (1 mL)-H₂O (0.25 mL) was refluxed during 24 h. The reaction mixture was cooled to r.t., H₂O (4 mL) was added. The aqueous layer was then extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: cyclohexane-EtOAc, 90:10 to 50:50) to afford β-azidoalcohol 4a (de 85%; major isomer: 118.5mg, 0.26 mmol; minor isomer: 9.5 mg, 0.02 mmol) as a pale yellow oil. Major diastereomer: [α]_D ²⁰ +47.9 (c 1.0, C₆H₆). ¹H NMR (CDCl₃): δ = 2.15 (s, 1 H, CH₂-OH), 2.21-2.40 (dd, J = 5.2, 13.7 Hz, 1 H, CH₂ ^Bn), 2.90-3.06 (m, 1 H, N^Troc-CH₂-CH-C=O^ketone), 3.26 (dd, J = 3.5, 13.7 Hz, 1 H, CH₂ ^Bn), 3.70-4.12 (m, 6 H, N^Troc-CH₂-CH-C=O^ketone, N^Troc-CH₂-C=O^ketone, CH₂-OH), 3.80 (s, 3 H, O-CH₃), 4.81 (s, 2 H, CH₂ ^Troc), 4.95 (t, J = 6.3 Hz, 1 H, CH-N₃), 7.20-7.51 (m, 3 H, 3 × CH^Ar). ¹³C NMR (CDCl₃): δ = 32.2 (CH₂ ^Bn), 47.9 (N^Troc-CH₂-CH-C=O^ketone), 50.5 (N^Troc-CH₂-CH-C=O^ketone), 52.2 (N^Troc-CH₂-C=O^ketone), 56.0 (O-CH₃), 63.8 (CH-N₃), 66.3 (CH₂-OH), 75.0 (CH₂ ^Troc), 95.2 (CCl₃ ^Troc), 128.6 (CH^Ar), 129.8 (CH^Ar), 130.9 (CH^Ar), 134.1 (C^Ar), 135.6 (C^Ar), 137.7 (C^Ar), 153.0 (C=O^Troc), 209.8 (C=O^ketone). IR (film): 3396, 3030, 2946, 2859, 2097, 1737, 1693, 1606, 1499, 1354, 1082, 803, 690 cm^-1. Anal. Calcd for C₁₇H₁₉Cl₃N₄O₅: C, 43.84; H, 4.11; N, 12.03. Found: C, 44.10; H, 3.93; N, 11.85.