Synthesis of 4-Dendronized β-Lactams

Abstract

The first synthesis of 4-dendronized β-lactams usingthe standard Staudinger ketene-imine cyclization is described.Both π-conjugated and Fréchet’s aromaticpolyether dendrons having imine focal points were used as startingmaterials. Exclusive cis-stereochemistrywas observed for all the β-lactams prepared.

dendrimers - β-lactams - imines - ketenes - Staudinger reaction

References

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1b Dendrimersand Other Dendritic Polymers   Fréchet JMJ. Tomalia DA. Wiley; Chichester: 2001. 

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4 For a recent review see: Gómez-Gallego M. Mancheño MJ. Sierra MA. Tetrahedron  2000,  56:  5743 

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11

RepresentativeExperimental Procedure for the Preparation of Imine 1b: A solutionof the starting aldehyde (300 mg, 0.21 mmol) and p-anisidine(51 mg, 0.41 mmol) in dry CH₂Cl₂ (10 mL) wasstirred overnight under argon at r.t. over molecular sieves (4 Å).Then, the molecular sieves were removed by filtration and the solventwas evaporated in vacuo. The residue was washed with EtOH in orderto solubilize the excess of p-anisidine,and the insoluble imine 1b was obtainedby filtration as a yellow solid (280 mg, 87% yield). Furtherpurification could be obtained by crystallization from CHCl₃/EtOH. ¹HNMR (300 MHz, CDCl₃): δ = 0.88 (t,12H, 4 × CH₃), 1.20-1.50 (m, 72 H,36 × CH₂), 1.79 (m, 8 H, 4 × CH₂),3.85 (s, 3 H, OCH₃), 3.98 (t, 8 H, J = 6.6Hz, 4 × CH₂), 6.90-7.00 (m includingA of ABq, 14 H, J = 8.7Hz, 4 × CH= and arom.), 7.14 (B of ABq, 4 H, J = 16.5 Hz,4 × CH=), 7.29 (B of ABq, 2 H, J = 8.7Hz, arom.), 7.47 (B of ABq, 8 H, J = 8.7Hz, arom.), 7.54 (s, 2 H, arom.), 7.55 (s, 4 H, arom.), 7.83 (t,1 H, J = 1.5Hz, arom.), 8.04 (d, 2 H, J = 1.5Hz, arom.), 8.47 (s, 1 H, CH=N). ¹³CNMR and DEPT (75 MHz, CDCl₃): δ = 159.1(C), 158.6 (C), 156.2 (CH), 144.2 (C), 138.2 (C), 136.9 (C), 136.4(CH), 131.2 (CH), 129.5 (C), 129.3 (CH), 127.8 (CH), 127.7 (CH),125.3 (CH), 124.6 (CH), 124.2 (C), 123.3 (C), 122.4 (CH), 114.7(CH), 114.4 (CH), 90.7 (C), 88.0 (C), 68.1 (OCH₂), 55.5(OCH₃), 31.9 (CH₂), 29.7 (CH₂),29.6 (CH₂), 29.6 (CH₂), 29.6 (CH₂),29.4 (CH₂), 29.4 (CH₂), 29.3 (CH₂),26.0 (CH₂), 22.7 (CH₂), 14.1 (CH₃).IR (KBr): ν = 1618 (C=N), 1585, 1512,1466, 1256 cm^-1. MS (FAB+): m/z= 1556.8. HRMS: m/z calcd for C₁₁₀H₁₄₁NO₅: 1556.0810.Found: 1556.0797. Anal. Calcd for C₁₁₀H₁₄₁NO₅:C, 84.84; H, 9.13; N, 0.90. Found: C, 84.47; H, 9.29; N, 0.81.

12

RepresentativeExperimental Procedure for the Preparation of β-Lactam2f: To a cooled solution (0 °C) under argon of imine 1e (100 mg, 0.06 mmol) and (+)-(S)-(4-phenyl-2-oxo-1,3-oxazolidin-3-yl)aceticacid in Et₃N
(1 mL) and dry CH₂Cl₂ (3mL) was added dropwise dichlorophenylphosphate (14 µL,0.09 mmol). The cooling bath was removed and the mixture was stirredat r.t. for 24 h. Finally, it was quenched with 1 M HCl, extractedwith CH₂Cl₂ (×3), and dried (MgSO₄).After filtration and evaporation of the solvent under reduced pressure,the crude product was purified by column chromatography (silicagel, CH₂Cl₂) to give 2f asa white solid (60 mg, 54% yield). [α]_D ²⁰ = +29.0(c 0.03, CHCl₃). ¹HNMR (500 MHz, CDCl₃): δ = 3.67 (s,3 H, OCH₃), 3.88 (dd, 1 H, J = 8.5Hz, J = 7.5 Hz,CH-O), 4.20 (t, 1 H, J = 9.0Hz, Ph-CH-N), 4.35 (dd, 1 H, J = 8.5Hz, J = 7.5Hz, CH-O), 4.54 (d, 1 H, J = 5.0Hz, H4), 4.89-5.02 (m including d, 29 H, J = 5.0Hz, H3 and 14 × CH₂), 6.47 (br s, 2 H, arom.),6.49 (d, 2 H, J = 2.0Hz, arom.), 6.56 (t, 4 H, J = 2.0Hz, arom.), 6.61 (t, 1 H, J = 2.0 Hz,arom.), 6.64 (d, 4 H, J = 2.0Hz, arom.), 6.67 (d, 8 H, J = 2.0Hz, arom.), 6.70 (A of ABq, 2 H, J = 9.0Hz, arom.), 7.08-7.11 (m, 2 H, arom.), 7.18 (B of ABq,2 H, J = 9.0Hz, arom.), 7.28-7.42 (m, 43 H, arom.). ¹³CNMR and DEPT (125 MHz, CDCl₃): δ = 160.1(C), 160.0 (C), 159.9 (C), 156.9 (C), 156.2 (C), 139.2 (C), 139.1(C), 136.7 (C), 136.5 (C), 135.2 (C), 130.8 (C), 129.3 (CH) 129.2(CH), 128.6 (CH), 128.0 (CH), 127.6 (CH), 118.4 (CH), 114.1 (CH), 106.4(CH), 106.2 (CH), 106.1 (CH), 103.1 (CH), 101.5 (CH), 101.4 (CH),70.2 (CH₂), 70.0 (CH₂), 69.9 (CH₂),69.8 (CH₂), 62.5 (CH), 61.3 (CH), 59.6 (CH), 55.3 (OCH₃).IR (KBr): ν = 1754 (C=O), 1596 cm^-1.MS (MALDI-TOF): m/z = 1922.7(M + Na), 1497.5, 1027.1. Anal. Calcd for C₁₂₃H₁₀₆N₂O₁₈:C, 77.75; H, 5.62; N, 1.47. Found: C, 77.42; H, 5.71; N, 1.43.