Attaching Metal-Containing Moieties to β-Lactam Antibiotics: The Case of Penicillin and Cephalosporin

Abstract

Procedures for the preparation of transition metal complexes having intact bicyclic cepham or penam systems as ligands have been developed. Starting from readily available 4-azido-2-azetidinones, a synthetic approach has been tuned using a copper-catalyzed azide-alkyne cycloaddition between 3-azido-2-azetinones and alkynes, followed by methylation and transmetalation to Au(I) and Ir(III) complexes from the mesoionic carbene Ag(I) complexes. This methodology was applied to 6-azido penam and 7-azido cepham derivatives to build 6-(1,2,3-triazolyl)penam and 7-(1,2,3-triazolyl)cepham proligands, which upon methylation and metalation with Au(I) and Ir(III) complexes yielded products derived from the coordination of the metal to the penam C⁶ and cepham C⁷ positions, preserving intact the bicyclic structure of the penicillin and cephalosporin scaffolds. The crystal structure of complex 28b, which has an Ir atom directly bonded to the intact penicillin bicycle, was determined by X-ray diffraction. This is the first structural report of a penicillin-transition-metal complex having the bicyclic system of these antibiotics intact. The selectivity of the coordination processes was interpreted using DFT calculations.

Scheme 1. Schematic Mode of Action of β-Lactam Cleavage by a Dizinc mβl

Figure 1

6-APA and 7-ACA antibiotics show the skeleton numbering.

Scheme 2. Some Examples of Syntheses of Metallo-β-Lactams

Scheme 3. Synthesis of 3-Azido-2-azetidinones 7

Scheme 4. Syntheses of β-Lactam MIC–Au(I) Complexes 12

Figure 2

ORTEP view of complex trans-12b (ellipsoids at 40%; H atoms have been omitted for clarity except those bonded to C9 and C11). Selected interatomic distances (Å) and angles (°): C1–N1 1.367(5), C1–C2 1.380(5), C1–Au1 1.980(4), C2–N3 1.362(5), C3A–N3 1.468(4), C9–N1 1.455(4), C9–C10 1.548(5), C9–C11 1.568(5), C10–O1 1.211(4), C10–N4 1.358(5), C11–N4 1.494(4), Au1–Cl1 2.2817(9), N1–N2 1.337(4), N2–N3 1.318(4); N1–C1–C2 102.3(3), N1–C1–Au1 125.3(3), C2–C1–Au1 132.4(3), N3–C2–C1 107.4(3), N1–C9–C10 115.8(3), N1–C9–C11 116.8(3), C10–C9–C11 86.0(3), O1–C10–N4 133.2(4), O1–C10–C9 135.7(3), N4–C10–C9 91.1(3), N4–C11–C9 85.5(3), C1–Au1–Cl1 178.5(2), N2–N1–C1 114.9(3), N3–N2–N1 103.0(3), N2–N3–C2 112.4(3), C10–N4–C11 96.2(3).

Scheme 5. Syntheses of β-Lactam MIC–Ir(III) Complexes 13 and 14

Scheme 6. Synthesis of β-Lactam MIC–Pd(II) Complex 15

Figure 3

ORTEP view of compound 18b (ellipsoids at 40%; H atoms have been omitted for clarity except those bonded to C1 C9, C11, and C15). Selected interatomic distances (Å) and angles (°): C1–N1 1.352(3), C1–C2 1.371(3), C2–N3 1.370(3), C9–N1 1.445(3), C9–C10 1.556(3), C9–C11 1.562(3), C10–O1 1.197(3), C10–N4 1.385(3), C11–N4 1.467(3), C11–S1 1.810(2), C12–C15 1.576(3), C12–S1 1.856(2), C15–N4 1.447(3), C15–C16 1.519(3), C16–O2 1.205(3), C16–O3 1.343(2), N1–N2 1.353(3), N2–N3 1.312(3); N1–C1–C2 104.6(2), N3–C2–C1 108.3(2), N1–C9–C10 113.5(2), N1–C9–C11 116.8(2), C10–C9–C11 85.0(2), O1–C10–N4 132.2(2), O1–C10–C9 136.5(2), N4–C10–C9 91.3(2), N4–C11–C9 88.0(2), N4–C11–S1 105.7(1), C9–C11–S1 120.2(1), C14–C12–C15 113.8(2), C15–C12–S1 105.7(1), N4–C15–C12 106.3(2), C1–N1–N2 111.0(2), C1–N1–C9 127.3(2), N2–N1–C9 121.3(2), N3–N2–N1 107.0(2), N2–N3–C2 109.1(2).

Scheme 7. Syntheses of Proligands 19 Derived from 6-APA

Scheme 8. Syntheses of Proligands 20 and 21 Derived from 7-ACA

Scheme 9. Synthesis of C⁶–Ir(III) Complexes with a Penam Bicyclic System

Figure 4

ORTEP view of complex 28b (ellipsoids at 40%; H-atoms have been omitted for clarity, except those bonded to C1, C11, and C15). Selected interatomic distances (Å) and angles (°): C1–N1 1.35(1), C1–C2 1.38(1), C2–N3 1.37(1), C3A–N3 1.47(1), C9–N1 1.47(1), C9–C10 1.54(1), C9–C11 1.57(1), C9–Ir1 2.122(9), C10–O1 1.21(1), C10–N4 1.39(1), C11–N4 1.47(1), C11–S1 1.835(9), C12–C15 1.57(1), C12–S1 1.861(8), C15–N4 1.44(1), C15–C16 1.53(1), C16–O2 1.19(1), C16–O3 1.35(1), C24–C28 1.44(1), C24–Ir1 2.159(8), C25–Ir1 2.136(9), C26–Ir1 2.223(9), C27–Ir1 2.224(8), C28–Ir1 2.146(9), Cl1–Ir1 2.437(2), Cl2–Ir1 2.406(2), N1–N2 1.31(1), N2–N3 1.33(1); N1–C1–C2 105.6(8), N3–C2–C1 104.4(8), N1–C9–C10 110.9(7), N1–C9–C11 111.9(7), C10–C9–C11 84.1(6), N4–C10–C9 92.9(7), N4–C11–C9 88.4(6), N4–C11–S1 104.8(5), C14–C12–S1 108.4(7), C15–C12–S1 104.5(6), N4–C15–C12 107.0(7), N2–N1–C1 113.1(7), C9–N1–C1 125.1(7), N2–N1–C9 121.8(7), N3–N2–N1 104.3(7), N2–N3–C2 112.5(7), C10–N4–C15 127.8(7), C10–N4–C11 93.4(6), C15–N4–C11 117.5(6).

Scheme 10. Syntheses of C7–Ir(III) Complexes with a Cepham Bicyclic System

Scheme 11. Synthesis of Complex 30

Scheme 12. 1,3-H Shift to Form the Carbene Proligand in the Four-Membered Ring from the Initial Deprotonation of the 1,2,3-Triazolium Salt

Scheme 13. Computed Relative Gibbs Energies for the Pairs of Carbene Complexes 28b–28b′ and 31–31′

Scheme 14. Computed Relative Gibbs Energies for (a) Carbenes Derived from 6-(1,2,3-Triazolyl)penam 32 and 32′ and (b) Carbenes Derived from 6-(1,2,3-Triazolyl)-2-azetidinone 33 and 33′