A Concise Enantioselective Synthesis of (+)-L-733,060 and (+)-T-2328 via Sequential Proline Catalysis

Abstract

A new, sequential proline-catalyzed approach to the synthesis of (+)-L-733,060 and (+)-T-2328 in high optical purity (93% ee) is described starting from phenyl N-Boc imine. The strategy involves proline-catalyzed Mannich reaction of an arylimine with acetaldehyde followed by α-aminoxylation/Wittig olefination in a sequential fashion as the key steps.

Key words

imine - Mannich reaction - aminoxylation - olefination - sequential

• References

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• 21 α-Aminoxylation/Wittig Olefination To a stirred precooled (–10 °C) MeCN (15 mL) solution of β-aminoaldehyde 6 (1 g, 4.01 mmol) and nitrosobenzene (360 mg, 3.34 mmol) was added l-proline (77 mg, 20 mol%). The mixture was allowed to stir at the same temperature for 20 h followed by the addition of Ph₃P=CHCO₂ t-Bu (1.91 g, 5.01 mmol) to the reaction mixture, which was stirred for a further 6 h at 0–25 °C. After addition of phosphate buffer, the resulting mixture was extracted with EtOAc (3 × 30 mL) and the combined organic phases were dried over anhyd Na₂SO₄, filtered and concentrated to give the crude aminoxy unsaturated ester that was directly taken to the next step without purification. To a MeOH (20 mL) solution of the above crude aminoxy unsaturated ester was added Cu(OAc)₂·2H₂O (140 mg, 0.67 mmol) at 25 °C and the reaction mixture was allowed to stir for 10 h at the same temperature. After addition of phosphate buffer, the resulting mixture was extracted with CHCl₃ (3 × 30 mL) and the combined organic phases were dried over anhyd. Na₂SO₄, filtered and concentrated. The crude residue was purified by column chromatography over silica gel using PE–EtOAc (7.5:2.5) to give syn-aminohydroxycinnamic ester 5. Yield: 1.02 g (70%); colorless liquid; [α]_D ²⁵ +11.5 (c 1.0, CHCl₃); ee = 93% [chiral HPLC analysis (Chiracel AD-H 250 × 4.6 mm), n-hexane/i-PrOH, (80:20) 0.5 mL/min, 254 nm), t _R = 27.200 min (minor), t _R = 30.607 min (major). IR (CHCl₃): 1322, 1463, 1522, 1621, 1719, 3342 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 1.41 (s, 9 H), 1.47 (s, 9 H), 2.51 (br s, 1 H), 4.51–4.58 (m, 1 H), 4.72–4.80 (m, 1 H), 5.30 (d, J = 8.1 Hz, 1 H), 6.06 (dd, J = 1.9, 15.7 Hz, 1 H), 6.80 (dd, J = 4.9, 15.7 Hz, 1 H), 7.30–7.37 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃): δ = 28.1, 28.3, 58.8, 74.3, 80.1, 80.5, 124.1, 126.8, 127.9, 128.8, 145.1, 156.1, 165.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₉NNaO₅: 386.1938; found: 386.1919.
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• 23 (+)-L-733,060 (1) Yield: 98 mg (95%); colorless liquid; [α]_D ²⁵ +31.99 (c 1.32, CHCl₃) {lit.^9b [α]_D ²⁵ +34.29 (c 1.32, CHCl₃)}. IR (CHCl₃): 660, 877, 1123, 1170, 1370, 1577, 2950 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.54 (d, J = 13.9 Hz, 1 H), 1.66–1.75 (m, 1 H), 1.84–1.93 (m, 1 H), 2.85 (td, J = 2.7, 12.2 Hz, 1 H), 3.29 (d, J = 12.0 Hz, 1 H), 3.68 (s, 1 H), 3.86 (s, 1 H), 4.14 (d, J = 12.7 Hz, 1 H), 4.53 (d, J = 12.7 Hz, 1 H), 7.28–7.37 (m, 5 H), 7.44 (s, 2 H), 7.69 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.4, 28.4, 47.0, 64.2, 70.0, 121.2 (m), 124.6 (q, J = 270 Hz), 126.8, 127.2, 127.5, 128.2, 131.2 (q, J = 33.1 Hz), 141.1, 141.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₀ONF₆: 404.1444; found: 404.1429.
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• 27 (+)-T-2328 Dihydrochloride Salt (3) Yield: 38 mg (quant.); colorless solid; mp 279–281 °C (lit.^4a 280–281 °C); [α]_D ²⁵ +70.1 (c 0.6, H₂O). IR (CHCl₃): 680, 889, 1128, 1250, 1370, 1556, 2923, 3350 cm^–1. ¹H NMR (400 MHz, D₂O): δ = 2.07 (s, 2 H), 2.25 (d, J = 7.8 Hz, 1 H), 2.46 (d, J = 14.9 Hz, 1 H), 3.29 (quin, J = 7.3 Hz, 1 H), 3.60 (s, 3 H), 3.66–3.72 (m, 1 H), 4.02 (dd, J = 3.4, 16.1 Hz, 2 H), 4.29 (d, J = 13.2 Hz, 1 H), 4.92 (d, J = 2.9 Hz, 1 H), 7.25 (d, J = 6.6 Hz, 2 H), 7.32 (s, 1 H), 7.44 (d, J = 7.1 Hz, 3 H), 7.49–7.58 (m, 4 H). ¹³C NMR (100 MHz, D₂O): δ = 16.8, 22.7, 43.3, 47.5, 55.3, 55.6, 58.0, 110.9, 111.6, 117.2, 118.4, 119.9 (d, J = 27.0 Hz), 126.2, 126.4, 128.9 (d, J = 3.1 Hz), 129.8, 130.0, 130.4, 131.2, 132.0, 132.6 (d, J = 3.1 Hz), 132.7, 157.4, 157.7 (d, J = 248 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇ON₃F: 416.2133; found: 416.2114.