Concise Synthesis of Anserine: Efficient Solvent Tuning in Asymmetric Hydrogenation Reaction

Abstract

A concise synthesis of anserine and related compounds was accomplished by Et-DuPhos-Rh-catalyzed asymmetric hydrogenation of dehydrohistidine derivatives in 2,2,2-trifluoroethanol, which played a key role in improving the yield and selectivity.

Key words

anserine - DuPhos - rhodium catalysis - asymmetric catalysis - hydrogenation - dehydrohistidine - trifluoroethanol

• References and Notes

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• 13 When TFE was used as the solvent, it was possible to decrease the hydrogen pressure and the temperature; a slight increase in the enantioselectivity was also observed. Asymmetric Hydrogenation of 6a; Typical Procedure (R,R)-Et-DuPHOS-Rh (7) (14 mg, 10 mol%) was added to a solution of 6a (63 mg, 0.20 mmol) in TFE (6 mL), and the mixture was pressurized with H₂ to an initial pressure of 300 psi. The mixture was then heated to 50 °C and stirred for 10 h. The solvent was evaporated in vacuo to give a crude product that was purified by preparative TLC (CHCl₃–MeOH, 10:1) to give 8a as a pale-yellow oil; yield: 58 mg (91%); optical purity >99% ee by chiral HPLC [CHIRALPAK-IC, hexane–EtOH–Et₂NH (60:40:0.1)]; IR (neat) 1059, 1263, 1529, 1715, 2955 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ = 3.11 (dd, J = 5.7, 15.3 Hz, 1 H), 3.14 (dd, J = 5.7, 15.3 Hz, 1 H), 3.50 (s, 3 H), 3.75 (s, 3 H), 4.61 (td, J = 5.7, 7.4 Hz, 1 H), 5.10 (dd, J = 11.9, 19.8 Hz, 1 H), 5.41 (d, J = 7.4 Hz, 1 H), 6.76 (s, 1 H), 7.33–7.37 (m, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 26.7, 31.3, 52.7, 53.4, 67.1, 126.4, 128.2, 128.3, 128.6, 134.1, 136.0, 138.5, 155.6, 171.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₀N₃O₄: 318.1448; found: 318.1451.
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• 16 Acylation of the HCl salt of histidine with 9 proceeded smoothly without any protection of the imidazole group. Boc protection was therefore selected in the case of carnosine synthesis.
• 17 The optically rotation of the synthesized carnosine (3) matched that of natural carnosine: [α]_D ²⁵ +21.0 (c 0.215, H₂O) [Lit.⁶ [α]_D ²⁵ +20.5 (c 2.0, H₂O)]. The asymmetric reduction of 11b therefore proceeded with high enantioselectivity.