Procedure for the Oxidation of β-Amino Alcohols to α-Amino Aldehydes

Abstract

A novel procedure for the mild oxidation of β-amino alcohols to α-amino aldehydes using commercially available manganese(IV) oxide is reported. There are several important advantages of the new method, such as high enantiopurity of the reaction and the absence of either over-oxidation or any reaction by-products during the process. A number of N-protected l-α-amino aldehydes was obtained. All new compounds were characterized by their NMR spectra and optical rotation data.

amino alcohols - amino aldehydes - enzymes - manganese - oxidations

References

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Caution: pure aminoaldehydes may cause acute allergic reaction on contact with skin or upon inhalation.

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Representative Experimental Procedure for the Synthesis of Aldehydes 1h and 1f. An aminoalcohol 2h or 2f (0.05 µmol) was dissolved in 2 mL of CHCl₃ and MnO₂ (0.2 µmol) was added in one portion. The mixture was stirred vigorously at r.t. for 12-24 h. The reaction was monitored by TLC on silica gel plates eluting with EtOAc-hexane 5:1. The resulting aldehyde was dried in a dark vacuum desiccator at -20 °C. Aldehydes should be stored in dark place at about -20 °C.
N -Boc-leucinal ( 1h).
The reaction was carried out over 18 h, the product was purified by silica gel flash chromatography eluting with CHCl₃, then CHCl₃-MeOH 1:1; the title compound was obtained as colorless crystals; mp 64-66 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.80-0.90 (dd, J = 5.21 Hz, 6 H, 2 × CH₃), 1.30 (m, J = 10.35 Hz, 2 H, -CH₂-i-Pr), 1.60 (s, 9 H, Boc), 2.00-2.10 (m, J = 6.60 Hz, 1 H, -CHMe₂), 4.20 (m, J = 6.89 Hz, 1 H, C*H asymm.), 4.89 (br s, 1 H, -NH-), 10.30 (dd, J = 2.33 Hz, 1 H, -CHO) ppm. [α]_D ²³ -41 (c 2.5, MeOH). SALDI-MS [M - Boc]⁺: 114.2.
N -Boc- O - tert -butyl-asparaginal ( 1f). The reaction was carried out over 12 h, the product was purified by silica gel flash chromatography eluting with CHCl₃, then CHCl₃-MeOH 1:1; the title compound was obtained as a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.40-1.50 (s, 18 H, Boc + t-Bu), 2.91-3.30 (m, J = 16 Hz, 2 H, -CH₂-COOt-Bu), 4.90 (m, J = 10.45 Hz, 1 H, C*H asymm.), 6.22 (br s, 1 H, -NH-), 8.40 (d, J = 2.33 Hz, 1 H, -CHO) ppm. [α]_D ²³ -38 (c 1, MeOH). SALDI-MS [M - Boc - t-Bu]⁺: 115.2.

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Synthesis of N -Boc-O- tert -butyl-asparaginal-semicarbazone ( 5). To a stirred solution of NaOAc (1.3 equiv) and semicarbazide hydrochloride (1.3 equiv) in 70% EtOH the solution of Boc(Ot-Bu)-asparaginal (1f) in 3 mL of EtOH was added. The reaction mixture was heated at 80 °C for 2 h and then at r.t. overnight. The reaction product was purified by silica gel flash chromatography, eluting with EtOAc-hexane 5:1. Yield 67%. ¹H NMR (400 MHz, CDCl₃): δ = 1.40 (dd, J = 5.23 Hz, 18 H, 6 × CH₃), 2.40-2.60 (m, J = 3.41, 9.57 Hz, 2 H, -CH₂-), 8.00 (br s, 1 H, -NH-amino acid), 4.20 (m, J = 5.53 Hz, 1 H, C*H asymm.), 6.00 (m, 3 H, -NH₂ and -NH-Sem.), 9.83 (dd, 1 H, -CH=N) ppm.

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Synthesis of Asparaginal-semicarbazone ( 6). TFA (10 equiv) was added to a stirred solution of protected semicarbazone 5 in CH₂Cl₂. The reaction mixture was stirred at r.t. for 12 h and the solvent with an excess of TFA were vacuum distilled. The resulting product was rinsed with Et₂O and recrystallized from EtOH-H₂O 2:1. The title compound was obtained as white amorphous solid. Yield 96%. ¹H NMR spectra were consistent with the structure.