An Efficient Synthesis of Azetidine-2,3-diones from l-(+)-Diethyl Tartrate

Abstract

A convenient route to enantiopure azetidine-2,3-diones is described. The chiral ketene generated from commercially available l-(+)-diethyl tartrate on Staudinger cycloaddition with different imines gave spiro-β-lactams in good yields. These spiro-β-lactams were transformed into azetidine-2,3-diones in excellent yields in a two-step process.

stereoselective synthesis - lactams - imines - cycloaddition - spiro compounds

References and Notes

For reviews on β-lactam antibiotics, see:

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24

Typical Procedure for Spiro-β-lactams 5a and 6a: A solution of acid chloride 3 (0.371 g, 1.84 mmol) in anhyd dichloromethane (10 mL) was added dropwise over a period of 20-30 min to a solution of imine 4a (0.296 g, 1.23 mmol) and triethyl amine (0.77 mL, 5.53 mmol) in anhyd dichloromethane (20 mL) at -40 °C. After the addition was complete the solution was allowed to attain r.t. and stirred for 15 h (TLC). The reaction mixture was then diluted with dichloromethane and washed with H₂O (2 × 10 mL) and sat. brine solution (10 mL). The combined organic layer was dried over anhyd Na₂SO₄, filtered and concentrated under reduced pressure to get the crude diastereomeric mixture of 5a and 6a (0.480 g, 70%). ¹H NMR of the crude product showed a 60:40 mixture of diastereomers which were separated by careful flash column chromatography [PE-EtOAc (8:2)].
(3 S ,4 S ,8 R )-1,2-Bis(4-methoxyphenyl)-6,6-dimethyl-3-oxo-5,7-dioxa-2-azaspiro[3.4]octane-8-carboxylic Acid Ethyl Ester ( 5a): yield: 42%; colorless crystals; mp 163-164 °C; [α]_D ²⁶ +1.4 (c = 2.7, CHCl₃). IR (CHCl₃): 1751, 1755 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.04 (s, 3 H, Me), 1.12 (t, J = 7.2 Hz, 3 H, OCH₂CH ₃), 1.60 (s, 3 H, Me), 3.74 (s, 3 H, Me), 3.81 (s, 3 H, Me), 4.16-4.29 (m, 2 H, OCH₂), 5.02 (s, 1 H, C8-H), 5.19 (s, 1 H, C3-H), 6.79 (d, J = 8.9 Hz, 2 H, ArH), 6.91 (d, J = 8.9 Hz, 2 H, ArH), 7.25-7.31 (m, 4 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 13.7, 25.6, 26.5, 55.1, 55.2, 61.8, 68.0, 78.1, 92.5, 113.6, 113.9, 114.1, 118.7, 124.9, 129.2, 130.3, 156.2, 159.8, 163.3, 167.9. MS: m/z = 442 [M + 1]. Anal. Calcd for C₂₄H₂₇NO₇: C, 65.29; H, 6.16; N, 3.17. Found: C, 65.18; H, 6.29; N, 3.03.
(3 R ,4 R ,8 R )-1,2-Bis(4-methoxyphenyl)-6,6-dimethyl-3-oxo-5,7-dioxa-2-azaspiro[3.4]octane-8-carboxylic Acid Ethyl Ester ( 6a): yield: 28%; brown viscous liquid; [α]_D ²⁶ -7.0 (c = 2.8, CHCl₃). IR (CHCl₃): 1751, 1755 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.06 (s, 3 H, Me), 1.11 (t, J = 7.2 Hz, 3 H, OCH₂CH ₃), 1.47 (s, 3 H, Me), 3.75 (s, 3 H, Me), 3.80 (s, 3 H, Me), 4.18-4.30 (m, 2 H, OCH ₂CH₃), 4.87 (s, 1 H, C3-H), 5.03 (s, 1 H, C8-H), 6.79 (d, J = 9.0 Hz, 2 H, ArH), 6.87 (d, J = 9.0 Hz, 2 H, ArH), 7.25-7.30 (m, 4 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 13.8, 25.6, 26.1, 55.0, 55.2, 61.7, 65.7, 77.0, 90.9, 113.1, 113.7, 114.2, 118.7, 124.5, 129.1, 130.3, 156.3, 159.7, 163.4, 167.6. MS: m/z = 442 [M + 1]. Anal. Calcd for C₂₄H₂₇NO₇: C, 65.29; H, 6.16; N, 3.17. Found: C, 65.42; H, 6.10; N, 3.25.
Typical Procedure for Diol 7a: To a solution of spiro-β-lactam 5a (0.200 g, 0.453 mmol) in dichloromethane (10 mL) was added anhyd FeCl₃ (0.147 g, 0.907 mmol) at r.t. and stirred for 2 h. After completion of the reaction (TLC) the reaction mixture was passed through a celite bed. The filtrate was concentrated in vacuo to get the crude diol 7a. The crude product was purified by column chromatography [PE-EtOAc (3:2)] to obtain pure diol 7a (0.162 g, 89%).
(3 S ,4 S )-Hydroxy-[3-hydroxy-1,2-bis(4-methoxyphenyl)-4-oxoazetidin-3-yl]acetic Acid Ethyl Ester ( 7a): yield: 89%; thick brown oil; [α]_D ²⁶ +20 (c = 1.1, CHCl₃). IR (CHCl₃): 1731, 1735, 3377 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.29 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃), 2.05 (s, 2 H, OH), 3.75 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 4.32 (quart, J = 7.1 Hz, 2 H, OCH ₂CH₃), 5.27 (s, 1 H, CHCOOEt), 5.30 (s, 1 H, C4-H), 6.79 (d, J = 9.0 Hz, 2 H, ArH), 6.91 (d, J = 8.9 Hz, 2 H, ArH), 7.21-7.30 (m, 4 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 13.9, 55.1, 55.3, 62.3, 63.3, 71.0, 86.3, 114.1, 119.0, 124.5, 129.0, 130.0, 156.3, 159.8, 164.2, 171.5. MS: m/z = 402 [M + 1]. Anal. Calcd for C₂₁H₂₃NO₇: C, 62.83; H, 5.78; N, 3.49. Found: C, 62.72; H, 5.94; N, 3.60.
(3 R ,4 R )-Hydroxy-[3-hydroxy-1,2-bis(4-methoxyphenyl)-4-oxo-azetidin-3-yl]acetic Acid Ethyl Ester ( 8a): yield: 88%; thick brown oil; [α]_D ²⁶ -25.6 (c = 2.5, CHCl₃). IR (CHCl₃): 1731, 1737, 3371 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.26 (t, J = 7.2 Hz, 3 H, OCH₂CH ₃), 2.04 (s, 2 H, OH), 3.74 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 4.30 (quart, J = 7.2 Hz, 2 H, OCH ₂CH₃), 4.63 (s, 1 H, C4-H), 5.30 (s, 1 H, CHCOOEt), 6.78 (d, J = 9.1 Hz, 2 H, ArH), 6.91 (d, J = 8.9 Hz, 2 H, ArH), 7.23-7.30 (m, 4 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 13.5, 55.2, 55.3, 61.9, 63.2, 71.1, 86.8, 114.1, 119.2, 124.5, 129.1, 130.0, 156.9, 159.7, 164.3, 171.5. MS: m/z = 402 [M + 1]. Anal. Calcd for C₂₁H₂₃NO₇: C, 62.83; H, 5.78; N, 3.49. Found: C, 62.75; H, 5.69; N, 3.32.
Typical Procedure for Dione 9a: To a solution of diol 7a (0.105 g, 0.261 mmol) in acetone-water (2:1, 6 mL) was added powdered NaIO₄ and the solution was stirred for 6-8 h. After completion of the reaction (TLC), the reaction mixture was filtered through a Büchner funnel and the residue was washed with acetone (5 mL). The combined filtrates were evaporated in vacuo to remove acetone. The residue was extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure to get the crude dione 9a as a yellow solid. The crude product was purified by column chromatography [PE-EtOAc (8:2)] to get pure dione 9a as a yellow solid (0.065 g, 84%).
(4 S )-1,4-Bis(4-methoxyphenyl)azetidine-2,3-dione ( 9a): yield: 84%; yellow solid; mp 144 °C; [α]_D ²⁶ +53.3 (c = 0.9, CHCl₃). IR (CHCl₃): 1755, 1809, 1832 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 3.79 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 5.51 (s, 1 H, C4-H), 6.85-6.94 (m, 4 H, ArH), 7.24 (d, J = 9.3 Hz, 2 H, ArH), 7.46 (d, J = 9.1 Hz, 2 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 55.2, 55.4, 74.4, 114.6, 114.8, 119.6, 123.5, 127.7, 129.8, 157.8, 160.1, 160.8, 191.1. MS: m/z = 298 [M + 1]. Anal. Calcd for C₁₇H₁₅NO₄: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.85; H, 5.19; N, 4.62.
(4 R )-1,4-Bis(4-methoxyphenyl)azetidine-2,3-dione ( 10a): yield: 85%; [α]_D ²⁶ -54.6 (c = 1.5, CHCl₃). The spectral data of 10a was identical to that of 9a. Anal. Calcd for C₁₇H₁₅NO₄: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.50; H, 5.22; N, 4.67.

25

X-ray Data for 5a and 8b: Single crystals of the 5a and 8b were grown by slow evaporation of the solution mixture in EtOAc and PE. The X-ray data of 5a-8b were collected on a SMART APEX CCD single crystal X-ray diffractometer with omega and phi scan mode and different number of scans and exposure times for different crystals using λ(MoK_α) = 0.71073 Å radiation at T = 293 (2) K with oscillation/frame = -0.3°, maximum detector swing angle = -30.0°, beam center = (260.2, 252.5), in plane spot width = 1.24. All the data were corrected for Lorentzian, polarization and absorption effects using SAINT and SADABS programs. The crystal structures were solved by direct method using SHELXS-97 and the refinement was performed by full matrix least squares of F ² using SHELXL-97. [33]
Crystal Data for 5a (C ₂₄ H ₂₇ NO ₇ ): M = 441.47; crystal dimensions: 0.52 × 0.47 × 0.33 mm, multirun data acquisition. Total scans = 3, total frames = 1818, exposure/frame = 10.0 s/frame, range = 1.98°-27.00°, completeness to of 27.0°: 100.0%. Crystals belonged to monoclinic, space group P2₁/c, a = 10.8952(5) Å, b = 23.954(1) Å, c = 9.4343(5) Å, β = 109.280(3)°, V = 2324.1(2) ų, Z = 4, D_c = 1.262 mg/m³, µ (MoK_α) = 0.093 mm^-1, T = 293(2) K, 16695 reflections measured, 4083 unique [I > 2σ(I)], R value = 0.0482, wR ² = 0.1268. X-ray analysis revealed the stereochemistry at C(3) and C(4) positions. The supplementary crystallographic data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.uk/data_request/cif. Please quote the reference number CCDC 647625.
Crystal Data for 8b (C ₂₀ H ₂₁ NO ₆ ): M = 371.38; crystal dimensions: 0.51 × 0.11 × 0.03 mm, hemisphere data acquisition. Total scans = 3, total frames = 1271, exposure/frame = 15.0 s/frame, range = 2.07°-24.99°, completeness to of 24.99º: 99.4%. Crystals belonged to monoclinic, space group P2₁, a = 11.324(1) Å, b = 5.3940(7) Å, c = 15.822(2) Å, β = 98.893(3)°, V = 954.8(2) ų, Z = 2, D_c = 1.292 mg/m³, µ (MoK_α) = 0.096 mm^-1, T = 293(2) K, 4764 reflections measured, 2759 unique [I >2σ(I)], R value = 0.0696, wR ² = 0.1552. X-ray analysis revealed the stereochemistry at C(3) and C(4) positions. The end atom C(19) had positional disorder. The supplementary crystallographic data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.uk/data_request/cif. Please quote the reference number CCDC 647624.

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