3-Pyrroline-1-carbonyl (Pyroc) Group: A Removable Protecting Group for the Kinetic Resolution of Racemic Carboxylic Acids and Alcohols through Catalytic Asymmetric Acylation

Abstract

The O-3-pyrroline-1-carbonyl (O-Pyroc) group and 3-pyrrolinamide are useful removable protecting groups for the kinetic resolution of racemic α-hydroxycarboxylic acids, β-hydroxy­carboxylic acids, 1,2-dicarboxylic acids, and 1,2-diols using the l-histidine-derived bifunctional catalysts. The Pyroc group can be easily introduced from Pyroc chloride. Selective deprotection of the Pyroc group and 3-pyrrolinamide can be carried out via DDQ oxidation followed by hydrolysis using sodium hydroxide, without epimerization.

Key words

kinetic resolution - 3-pyrroline-1-carbonyl (Pyroc) - asymmetric acylation - protective and removable - l-histidine framework

References and Notes

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6

Reduction with lithium aluminium hydride (4 equiv) gave the corresponding 1,2-diol in high yield without epimeri-zation.^²

11

Experimental Procedure for the Deprotection of Pyroc Group in 6a
To a solution of 6a (0.1 mmol) in dioxane (1 mL) was added DDQ (0.15 mmol), and the mixture was stirred at 85 ˚C for 2 h. After the reaction mixture was cooled to ambient temperature, dioxane was removed under reduced pressure. The residue was purified by column chromatography on SiO₂ to give 7a in 98% yield.
Compound 7a: ^¹H NMR (400 MHz, CDCl₃): δ = 1.05 (s, 9 H), 1.49 (s, 9 H), 4.02 (dd, J = 2.3, 11.0 Hz, 1 H), 4.21 (dd, J = 4.1, 11.0 Hz, 1 H), 5.22 (dd, J = 2.3, 4.1 Hz, 1 H), 6.26 (dd, J = 1.8, 2.3 Hz, 2 H), 7.29 (dd, J = 1.8, 2.3 Hz, 2 H), 7.30-7.48 (m, 6 H), 7.60-7.74 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 19.2, 26.5, 28.0, 63.3, 76.0, 82.9, 112.6, 120.2, 127.8, 129.9, 132.7, 132.8, 135.4, 135.5, 149.9, 166.2.
To a solution of 7a (0.085 mmol) in THF (0.17 mL) and MeOH (0.17 mL) was added 1.5 M aq NaOH (0.085 mL, 0.13 mmol) at 0 ˚C, and the mixture was stirred at 0 ˚C for 0.5 h. The reaction mixture was quenched with 1 M aq HCl and diluted with EtOAc. The organic layer was separated, washed with brine, dried with Na₂SO₄, and concentrated. The residue was purified by column chromatography on SiO₂ to give 8a in 93% yield.
Compound 8a: ^¹H NMR (400 MHz, CDCl₃): δ = 1.04 (s, 9 H), 1.51 (s, 9 H), 3.88 (dd, J = 2.8, 10.6 Hz, 1 H), 3.99 (dd, J = 2.3, 10.6 Hz, 1 H), 4.10 (dd, J = 2.3, 2.8 Hz, 1 H), 7.31-7.47 (m, 6 H), 7.61-7.74 (m, 4 H).