An Efficient Synthesis of 2,3-Aziridino-γ-lactones from Azetidin-2-ones

Abstract

An efficient synthesis of enantiopure 2,3-aziridino-γ-lactones from azetidin-2-ones is described. Acid-catalyzed tandem intramolecular azetidinone ring opening followed by aziridine ring formation via elimination of a mesylate group is the key step in this synthesis. 2,3-Aziridino-γ-lactones are important precursors for ­biologically important glutamic acid derivatives.

Key words

azetidin-2-ones - aziridines - lactones - glutamic acid

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14

A typical procedure for the synthesis of (1S,4S,5R)-6-benzyl-4-hydroxymethyl-3-oxa-6-aza-bicyclo[3.1.0]hexan-2-one(5a): Dihydroxyazetidin-2-one (4a; 0.5 g, 1.58 mmol) was dissolved in methanolic HCl (20%, 10 mL) and the reaction mixture was refluxed for 20 h. After the reaction was over (TLC), MeOH was removed under reduced pressure and sat. NaHCO₃ was added to the residue. It was then extracted with EtOAc (3 × 20 mL) and the combined organic extract was washed with brine (10 mL). It was then dried over anhyd Na₂SO₄ and the solvent was removed under reduced pressure to provide a thick oil, which was quickly purified by flash column chromatography (acetone-petroleum ether, 4:1) to furnish 5a (0.300 g, 86%) as a thick oil.

[α]_D ³⁰ -40 (c 1.5, CHCl₃); IR (CHCl₃): 3417, 1780 cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ = 7.34-7.38 (m, 5 H), 4.46-4.53 (m, 1 H), 3.78-3.94 (m, 2 H), 3.82 (d, J = 13.0 Hz, 1 H), 3.35 (d, J = 13.0 Hz, 1 H), 3.14 (dd, J = 3.1, 4.5 Hz, 1 H), 2.80 (d, J = 4.5 Hz, 1 H), 2.26 (br s, 1 H); ¹³C NMR (50.32 MHz, CDCl₃): δ =171.8, 136.8, 128.6, 127.8, 127.7, 79.3, 61.6, 60.8, 42.8, 40.0; MS (70 eV): m/z = 242 (M⁺); Anal. Calcd for C₁₂H₁₃NO₃: C, 65.73; H, 5.98; N, 6.40. Found: C, 65.50; H, 6.01; N, 6.24.

16

(1S,5R)-6-Benzyl-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (8a) was synthesized from 3-hydroxymethyl-azetidin-2-one (7a) following the procedure described for compound 5a.¹⁴
8a: Thick oil, 80%; [α]_D ³⁰ -1.6 (c 0.9, CHCl₃); IR (CHCl₃): 1774 cm^-1; ¹H NMR (CDCl₃, 200 MHz): δ = 7.30-7.40 (m, 5 H), 4.34 (d, J = 9.8 Hz, 1 H), 4.21 (dd, J = 9.8, 3.1 Hz, 1 H), 3.74 (d, J = 13.5 Hz, 1 H), 3.47 (d, J = 13.5 Hz, 1 H), 2.96 (dd, J = 4.5, 3.1 Hz, 1 H), 2.72 (d, J = 4.5 Hz, 1 H); ¹³C NMR (50.32 MHz, CDCl₃): δ = 172.3, 137.0, 128.6, 127.8, 127.7, 69.5, 61.1, 42.1, 39.7; MS (70 eV): m/z = 190 (M⁺); Anal. Calcd for C₁₁H₁₁NO₂: C, 69.81; H, 5.86; N, 7.40. Found: C, 69.62; H, 5.43; N, 7.19.