Approach to Substituted Methylcarbapenems and Benzocarbacephems by Radical Cyclization Using Cp₂TiCl

Abstract

The reductive radical cyclization of 4-(1-methyl-2-­phenyloxiranyl)-β-lactams has been achieved using titanocene monochloride. The reaction was regioselective and diastereoselective to afford carbapenems and benzocarbacephems. A rearrangement of β-hydroxy-β-phenylketones to give benzaldehyde was observed when the nitrile function was used as radical acceptor.

radical cyclization - titanocene chloride - methylcarbapenem - benzocarbacephem antibiotics - lactams

References and Notes

<A NAME="RG06607ST-1">1</A> Gansäuer A. Bauer D. J. Org. Chem.  1998,  63:  2070 

<A NAME="RG06607ST-2">2</A> Spencer RP. Cavalloro CL. Schwartz J. J. Org. Chem.  1999,  64:  3987 

<A NAME="RG06607ST-3">3</A> Qian Y. Li G. Zheng X. Huang YZ. Synlett  1991,  489 

<A NAME="RG06607ST-4">4</A> Zhang Y. Yu Y. Bao W. Synth. Commun.  1995,  25:  1825 

<A NAME="RG06607ST-5">5</A> Jana S. Roy SC. Tetrahedron Lett.  2006,  47:  5949 

<A NAME="RG06607ST-6A">6a</A> Gansäuer A. Lauterbach T. Narayan S. Angew. Chem. Int. Ed.  2003,  42:  3687 

<A NAME="RG06607ST-6B">6b</A> Gansäuer A. Bluhm H. Chem. Rev.  2000,  100:  2771 

<A NAME="RG06607ST-6C">6c</A> Gansäuer A. Bluhm H. Pierobon M. J. Am. Chem. Soc.  1998,  120:  12849 

<A NAME="RG06607ST-6D">6d</A> Nugent WA. RajanBabu TV. J. Am. Chem. Soc.  1994,  116:  986 

<A NAME="RG06607ST-7A">7a</A> Jana S. Guin C. Roy SC. Tetrahedron Lett.  2005,  46:  1155 

<A NAME="RG06607ST-7B">7b</A> Hersant G. Ferjani MBS. Bennett SM. Tetrahedron Lett.  2004,  45:  8123 

<A NAME="RG06607ST-8A">8a</A> Fernández-Mateos A. Mateos Burón L. Martín de la Nava EM. Rabanedo Clemente R. Rubio González R. Sanz González F. Synlett  2004,  2553 

<A NAME="RG06607ST-8B">8b</A> Fernández-Mateos A. Martín de la Nava EM. Pascual Coca G. Ramos Silvo A. Rubio González R. Org. Lett.  1999,  1:  607 

<A NAME="RG06607ST-9">9</A> Fernández-Mateos A. Mateos Burón L. Rabanedo Clemente R. Ramos Silvo AI. Rubio González R. Synlett  2004,  1011 

<A NAME="RG06607ST-10A">10a</A> Ruano G. Grande M. Anaya J. J. Org. Chem.  2002,  67:  8243 

<A NAME="RG06607ST-10B">10b</A> Ruano G. Martiáñez J. Grande M. Anaya J. J. Org. Chem.  2003,  68:  2024 

<A NAME="RG06607ST-10C">10c</A> Anaya J. Fernández-Mateos A. Grande M. Martiáñez J. Ruano G. Rubio-González MR. Tetrahedron  2003,  59:  241 

<A NAME="RG06607ST-11">11</A> Monleón LM. Grande M. Anaya J. Tetrahedron  2007,  63:  3017 

<A NAME="RG06607ST-12">12</A>

The stereochemistry depicted in Schemes [1] and [3] for the oxirane ring in epoxides 1a,b, 8a,b, and 10a,b were tentatively proposed by comparison of the respective polarities and ¹H NMR data with those of pure 4-(1-methyl-2-phenyloxiranyl)-β-lactams Ia and Ib (Figure [1] ).^10b This will be described elsewhere.

Figure 1

<A NAME="RG06607ST-13">13</A>

Typical Procedure
A solution of the specific epoxide (1.0 mmol) in THF (17.0 mL) was added dropwise to a green suspension of Cp₂TiCl, generated from titanocene dichloride (548 mg, 2.2 mmol) and activated zinc granules (262 mg, 4.0 mmol), in anhyd and strictly deoxygenated THF (12.5 mL). The reaction mixture was stirred at r.t. until a color change from green to orange was observed, and then the reaction was quenched with 10% v/v aq KH₂PO₄ (30.0 mL). The aqueous phase was extracted with EtOAc and the organic combined extracts were filtered through Celite^®, dried (anhyd Na₂SO₄) and concentrated in vacuo. The crude material obtained was purified by column chromatography on silica gel.

<A NAME="RG06607ST-14">14</A>

All these compounds are racemic mixtures but only one stereoisomer is depicted for simplicity. The C3-, C4- or C5-configuration for bi- or tricyclic β-lactams is based on spectroscopic data and the configuration proposed for the starting material. This will be described elsewhere.
Selected Data for Cyclization Products
Carbapenem 2: R _f = 0.50 (7:3 benzene-EtOAc). IR (neat): ν = 3500, 1774, 1755 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (3 H, s), 1.53 (3 H, s), 1.21 (3 H, d, J = 7.1 Hz), 2.73 (1 H, dq, J = 7.1, 8.7 Hz), 3.52 (3 H, s), 3.62 (1 H, dd, J = 4.0, 8.7 Hz), 4.68 (1 H, d, J = 4.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 12.5, 21.0, 23.4, 41.0, 58.9, 59.1, 64.4, 83.4, 170.9, 218.0. HRMS-FAB: m/z calcd for C₁₀H₁₅NO₃Na [M⁺ + 23]: 220.0944; found: 220.0949.
Benzocarbacephem 5: R _f = 0.28 (95:5 benzene-EtOAc). IR (neat): ν = 1759, 1685 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.26 (3 H, d, J = 6.5 Hz), 3.01 (1 H, dq, J = 6.5, 12.8 Hz), 3.68 (3 H, s), 3.98 (1 H, dd, J = 4.5, 12.8 Hz), 4.79 (1 H, d, J = 4.5 Hz), 7.21 (1 H, dt, J = 1.2, 7.9 Hz), 7.52 (1 H, dt, J = 1.4, 7.9 Hz), 7.55 (1 H, dd, J = 1.2, 7.9 Hz), 7.95 (1 H, dd, J = 1.4, 7.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 10.5, 40.5, 57.7, 59.5, 84.9, 119.4, 123.2, 124.7, 127.7, 134.9, 138.0, 163.7, 194.8. HRMS-FAB: m/z calcd for C₁₃H₁₃NO₃Na [M⁺ + Na]: 254.0788; found: 254.0795.
Benzocarbacephem 6: R _f = 0.25 (95:5 benzene-EtOAc). IR (neat): ν = 1761, 1684 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.36 (3 H, d, J = 6.6 Hz), 2.76 (1 H, dq, J = 6.6, 12.9 Hz), 3.60 (3 H, s), 3.88 (1 H, dd, J = 2.0, 12.9 Hz), 4.66 (1 H, d, J = 2.0 Hz), 7.19 (1 H, dt, J = 1.0, 7.9 Hz), 7.57 (1 H, dt, J = 1.5, 7.9 Hz), 7.65 (1 H, dd, J = 1.0, 7.9 Hz), 7.91 (1 H, dd, J = 1.5, 7.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 10.1, 43.9, 58.1, 61.4, 90.3, 118.7, 121.9, 124.5, 127.9, 135.2, 138.3, 161.3, 193.3. HRMS-FAB: m/z calcd for C₁₃H₁₃NO₃Na [M⁺ + Na]: 254.0788; found: 254.0800.
Carbapenem 9a (from enriched mixtures): ¹H NMR (400 MHz, CDCl₃): δ = 1.02 (3 H, s), 1.23 (3 H, s), 1.47 (3 H, s), 2.63 (3 H, s), 2.79 (1 H, s), 3.56 (1 H, d, J = 4.0 Hz), 4.21 (1 H, d, J = 4.0 Hz), 4.76 (1 H, s), 7.24-7.39 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 9.1, 19.3, 29.5, 58.5, 58.9, 59.1, 62.9, 82.4, 83.9, 127.5, 127.9, 141.3, 171.3.
Carbapenem 9b: R _f = 0.37 (1:1 hexane-EtOAc). IR (neat): ν = 3411, 1731 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.06 (3 H, s), 1.28 (3 H, s), 1.42 (3 H, s), 2.55 (3 H, s), 3.25 (1 H, s), 3.71 (1 H, d, J = 4.3 Hz), 4.39 (1 H, d, J = 4.3 Hz), 4.60 (1 H, s), 7.24-7.39 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 6.4, 19.1, 29.7, 52.7, 53.4, 58.7, 59.1, 59.2, 78.9, 83.6, 126.8, 128.3, 141.1, 170.6. HRMS-FAB: m/z calcd for C₁₇H₂₄NO₄ [M⁺ + 1]: 306.1700; found: 306.1722.
Carbapenem 11a (from enriched mixtures): ¹H NMR (400 MHz, CDCl₃): δ = 0.97 (3 H, s), 1.10 (3 H, s), 1.64 (3 H, s), 2.12 (1 H, br s), 3.51 (3 H, s), 4.07 (1 H, d, J = 4.5 Hz), 4.29 (2 H, d, J = 1.9 Hz), 4.75 (1 H, d, J = 4.5 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 16.3, 21.8, 23.3, 54.6, 55.7, 59.2, 65.0, 66.9, 84.7, 171.0, 221.4.
Carbapenem 11b: R _f = 0.34 (1:1 benzene-EtOAc). IR (neat): ν = 3473, 1746 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (3 H, s), 1.17 (3 H, s), 1.62 (3 H, s), 2.12 (1 H, br s), 3.51 (3 H, s), 3.61 (1 H, d, J = 11.1 Hz), 3.85 (1 H, d, J = 11.1 Hz), 4.12 (1 H, d, J = 4.5 Hz), 4.77 (1 H, d, J = 4.5 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 16.3, 21.7, 23.1, 54.6, 55.7, 59.2, 64.0, 65.2, 84.7, 171.0, 221.4. HRMS-FAB: m/z calcd for C₁₁H₁₇NO₄Na [M⁺ + 23]: 250.1055; found: 250.1050.

<A NAME="RG06607ST-15">15</A>

Conformational minima derived from analysis with CS Chem3D Pro 5.0(1999) software (CambridgeSoft Co. Cambridge, MA) using MM2 calculations.

<A NAME="RG06607ST-16">16</A> Neu HC. Novelli A. Chin N. Antimicrob. Agents Chemother.  1989,  33:  1009 

<A NAME="RG06607ST-17A">17a</A> Alcaide B. Almendros P. Curr. Org. Chem.  2002,  6:  245 

<A NAME="RG06607ST-17B">17b</A> Gómez-Gallego M. Manchedo MJ. Sierra MA. Tetrahedron  2000,  56:  5743 

<A NAME="RG06607ST-17C">17c</A> Setti EL. Micetich RG. Curr. Med. Chem.  1998,  5:  101