An enantioselective synthesis of heteroaromatic N-tosyl α-amino acids

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Mogens Johannsen


Abstract

A new synthesis of optically active β-indolyl and pyrrolyl N-tosyl α-amino acids has been developed which uses readily available starting materials and proceeds with a high degree of enantioselection, giving the α-amino acids with up to 96% enantiomeric purity in 89% yield using 1–5 mol% of a chiral copper(I)–Tol-BINAP catalyst.


References

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  4. (R)-Tol-BINAP is the abbreviation for the commercial ligand (R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl.
  5. The optically pure heteroaromatic α-amino acids obtained this way are to the best of our knowledge all new compounds which are not easily accesible by any other synthetic route. They all give 1H and 13C NMR spectra in accordance with the assigned structures. It should be mentioned that a derivative of 3a has previously been prepard via an enzymatic resolution (ref. 12). For some excellent reviews on the synthesis of α-amino acids, see: R. M. Williams, Aldrichim. Acta, 1992, 25, 11 Search PubMed; R. M. Williams, Synthesis of Optically Active α-Amino Acids, Pergamon, New York, 1989 Search PubMed; R. O. Duthaler, Tetrahedron, 1994, 50, 1539 Search PubMed.
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  8. A representative experimental proceudre: Synthesis of (1H-indol-3-yl)tosylaminoacetic acid ethyl ester 3a. To a flame dried Schlenk tube was added CuPFb(MeCN)4(ref. 15)(7.5mg, 0.02 mmol) and (R)-Tol-BINAP (15 mg, 0.022 mmol) under N2. The solids were dried on the vacuum line for 1 h before 1.5 ml of dry THF was added via syringe. The clear yellow solution was stirred for 1 h before cooling down to –78 °C. Indole 1a(94 mg 0.80 mmol) and imino ester 2(ref. 16)(96 mg, 0.40 mmol) dissolved in 0.2 ml dry THF were added and the reaction was stirred overnight. The product was purified by flash column chromatography (30% EtOAc in pentane) giving 3a as a white solid in 89% yield (93 mg) and 96% ee detected by HLPC using a Chiralcel OD-H column (20% PriOH–80% hexane, 0.5 ml min–1); [α]rtD+102 (c 1.0, CHCl3); δH(500 MHz, CDCl3) 8.11 (br s, 1H, NH), 7.65 (d, 2H, J 8.0, Ar), 7.53 (d, 1H, J 8.0, Ar), 7.30 (d, 1H, J 8.5, Ar), 7.20–7.14 (m, 3H, Ar), 7.10–7.07 (m, 2H, Ar), 5.56 (d, 1H, J 8.0, CHNHTs), 5.34 (d, 1H, J 8.0, CHNHTs), 4.09–3.97 (m, 2H, OCH2CH3), 2.36 (s, 3H, ArCH3), 1.12 (t, 3H, J 7.0, CH2CH3); δc(75 MHz, CDCl3) 170.5, 143.2, 137.0, 136.2, 129.2, 127.2, 125.2, 123.4, 122.7, 120.2, 119.1, 111.3, 110.5, 62.0, 53.1, 21.5, 13.9.
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  13. The enantiomeric purities of 3d and 3e were determined by 1H NMR using a lanthanide shift reagent [Eu(hfc)3]. The ee values after recrystallisation are probably > 99%, but due to the limitations of 1H NMR have been given as > 98%, even though only one enantiomer was detected.
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