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Synlett 2016; 27(09): 1339-1343
DOI: 10.1055/s-0035-1561346
DOI: 10.1055/s-0035-1561346
letter
A Concise Enantioselective Synthesis of (+)-L-733,060 and (+)-T-2328 via Sequential Proline Catalysis
Further Information
Publication History
Received: 23 November 2015
Accepted after revision: 11 January 2016
Publication Date:
04 February 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201609/lookinside/thumbnails/st-2015-d0906-l_10-1055_s-0035-1561346-1.jpg)
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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561346.
- Supporting Information
-
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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.