Synthesis of Novel Polycyclic β-Lactams from d-Glucose via Unusual ­Substrate-Controlled Radical Cyclization

Abstract

A highly stereoselective and substrate-controlled synthesis of polycyclic β-lactams from d-glucose derived chiral template via intramolecular free radical cyclization is described. The cyclization is highly substrate dependant, proceeding via 6-exo and 7-endo heptynyl type radical cyclization with the radical acceptor at N-1 and the radical progenitor on a sugar moiety, anchored to the β-lactam ring at C-4.

azetidin-2-ones - polycyclic β-lactams - radical cyclization - tributyltin hydride

References

For selected reviews, see:

<A NAME="RG00304ST-1A">1a</A> Setti EL. Micetich RG. Curr. Med. Chem.  1998,  5:  101 

<A NAME="RG00304ST-1B">1b</A> The Organic Chemistry of β-Lactams   Georg GI. VCH; New York: 1993. 

<A NAME="RG00304ST-1C">1c</A> Neuhaus FC. Georgeopapadakou NH. In Emerging Targets in Antibacterial and Antifungal Chemotherapy   Sutcliffe J. Georgeopapadakou NH. Chapman and Hall; New York: 1992. 

<A NAME="RG00304ST-1D">1d</A> Alcaide B. Almendros P. Curr. Org. Chem.  2002,  6:  245 

<A NAME="RG00304ST-2A">2a</A> Hook V. Chem. Ber.  1997,  33:  34 

<A NAME="RG00304ST-2B">2b</A> Niccolai D. Tarsi L. Thomas RJ. Chem. Commun.  1997,  2333 

<A NAME="RG00304ST-2C">2c</A> Davies J. Science  1994,  264:  375 

<A NAME="RG00304ST-2D">2d</A> Spratt BG. Science  1994,  264:  388 

<A NAME="RG00304ST-3A">3a</A> Radicals in Organic Synthesis   Renaud P. Sibi MP. Wiley-VCH; Weinheim, Germany: 2002. 

<A NAME="RG00304ST-3B">3b</A> Curran DP. Porter NA. Giese B. Stereochemistry of Radical Reactions   VCH; Weinheim: 1996. 

<A NAME="RG00304ST-3C">3c</A> Giese B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds   Pergamon; Oxford: 1986. 

<A NAME="RG00304ST-3D">3d</A> Giese B. Kopping B. Göbel J. Dickhaut G. Thoma G. Trach F. Org. React.  1996,  48:  301 

<A NAME="RG00304ST-4">4</A> Jasperse CP. Curran DP. Fevig TL. Chem. Rev.  1991,  91:  1237 

<A NAME="RG00304ST-5">5</A> Mustafi D. Makinen MW. J. Am. Chem. Soc.  1995,  117:  6739 

<A NAME="RG00304ST-6A">6a</A> Beckwith ALJ. Tetrahedron  1981,  37:  3073 

<A NAME="RG00304ST-6B">6b</A> Beckwith ALJ. Easton CJ. Lawrence T. Serelis AK. Aus. J. Chem.  1983,  36:  545 

<A NAME="RG00304ST-6C">6c</A> Dener JM. Hart DJ. Ramesh S. J. Org. Chem.  1988,  53:  6022 

<A NAME="RG00304ST-6D">6d</A> Sharma GVM. Sreenivasa Rao V. Tetrahedron Lett.  1990,  31:  4931 

<A NAME="RG00304ST-6E">6e</A> Gomez AM. Moreno E. Valverde S. Lopez JC. Tetrahedron Lett.  2002,  43:  5559 

<A NAME="RG00304ST-6F">6f</A> Gomez AM. Moreno E. Valverde S. Lopez JC. Tetrahedron Lett.  2002,  43:  7863 

<A NAME="RG00304ST-6G">6g</A> Gomez AM. Moreno E. Valverde S. Lopez JC. Tetrahedron: Asymmetry  2003,  14:  2961 

<A NAME="RG00304ST-6H">6h</A> Dupuy C. Crozet M.-P. Surzur J.-M. Bull. Soc. Chim. Fr.  1980,  361 

<A NAME="RG00304ST-6I">6i</A> Bachi MD. Frolow F. Hoornaert C. J. Org. Chem.  1983,  48:  1841 

<A NAME="RG00304ST-7A">7a</A> Bachi MD. Hoornaert C. Tetrahedron Lett.  1981,  22:  2689 

<A NAME="RG00304ST-7B">7b</A> Bachi MD. Hoornaert C. Tetrahedron Lett.  1982,  23:  2505 

<A NAME="RG00304ST-7C">7c</A> Bachi MD. Frolow F. Hoornaert C. J. Org. Chem.  1983,  48:  1841 

<A NAME="RG00304ST-7D">7d</A> Knight J. Parsons P. Southgate R. J. Chem. Soc., Chem. Commun.  1986,  78 

<A NAME="RG00304ST-7E">7e</A> Just G. Sacripante G. Can. J. Chem.  1987,  65:  104 

<A NAME="RG00304ST-7F">7f</A> Kametani T. Chu S.-D. Itoh A. Maeda S. Honda T. Heterocycles  1988,  27:  875 

<A NAME="RG00304ST-7G">7g</A> Kametani T. Chu S.-D. Itoh A. Maeda S. Honda T. J. Org. Chem.  1988,  53:  2683 

<A NAME="RG00304ST-7H">7h</A> Rocker PJ. Miller MJ. J. Org. Chem.  1995,  60:  6176 

<A NAME="RG00304ST-7I">7i</A> Bosch E. Bachi MD. J. Org. Chem.  1993,  58:  5581 

<A NAME="RG00304ST-7J">7j</A> Banik BK. Subbaraju GV. Manhas MS. Bose AK. Tetrahedron Lett.  1996,  37:  1363 

<A NAME="RG00304ST-7K">7k</A> Alcaide B. Rodriguez-Campos IM. Rodriguez-Lopez J. Rodriguez-Vicente A. J. Org. Chem.  1999,  64:  5377 

<A NAME="RG00304ST-7L">7l</A> Alcaide B. Almendros P. Aragoncillo C. Org. Lett.  2003,  5:  3795 

<A NAME="RG00304ST-7M">7m</A> Joshi SN. Puranik VG. Deshmukh ARAS. Bhawal BM. Tetrahedron: Asymmetry  2001,  12:  3073 

<A NAME="RG00304ST-7N">7n</A> Joshi SN. Phalgune UD. Bhawal BM. Deshmukh ARAS. Tetrahedron Lett.  2003,  44:  1827 

<A NAME="RG00304ST-8A">8a</A> Bose AK. Manhas MS. Hedge VR. Wagle DR. Bari SS. J. Chem. Soc., Chem. Commun.  1986,  181 

<A NAME="RG00304ST-8B">8b</A> Bose AK. Mathur C. Wagle DR. Nagui R. Manhas MS. Heterocycles  1994,  39:  491 

<A NAME="RG00304ST-8C">8c</A> Hanessian S. Desilets D. Rancourt G. Fosfin R. Can. J. Chem.  1982,  60:  2292 

<A NAME="RG00304ST-8D">8d</A> Koga K. Ikata N. Toshino O. Chem. Pharm. Bull.  1982,  30:  1929 

<A NAME="RG00304ST-8E">8e</A> Bernardo SD. Tengi JP. Sasso GJ. Weigele M. J. Org. Chem.  1985,  50:  3457 

<A NAME="RG00304ST-8F">8f</A> Arun M. Joshi SN. Puranik VG. Bhawal BM. Deshmukh ARAS. Tetrahedron  2003,  59:  2309 

<A NAME="RG00304ST-9">9</A> Furniss B. Hann Ford AJ. Smith PWG. Tatchell AR. Vogel’s Textbook of Practical Org. Chem.  1989, 5th ed. 654 

<A NAME="RG00304ST-10">10</A> Garegg PJ. Samuelsson B. J. Chem. Soc., Perkin Trans. 1  1980,  2866 

<A NAME="RG00304ST-11">11</A> Daumas M. Vo-Quang Y. Vo-Quang L. Le Goffic F. Synthesis  1989,  64 

<A NAME="RG00304ST-12">12</A>

General Procedure for the Synthesis of N -Propargyl β-Lactams (6a-c and 7a-c): To a solution of propargylamine (2 mmol) in CH₂Cl₂ (20 mL), was added an anhyd MgSO₄ (4 equiv) and a CH₂Cl₂ solution of iodoaldehyde 4 (2 mmol, in 5 mL) under argon atmosphere at r.t. and stirred for 3-4 h. The mixture was filtered through a pad of celite and the filtrate was concentrated to get the imines 5, which was found to be unstable and used immediately without further purification.
A solution of the acid chloride (phenoxy or benzyloxy or methoxyacetyl chloride, 1.5 mmol) in anhyd CH₂Cl₂ (10 mL) was added to a solution of the imine (5, 1.0 mmol) and Et₃N (4.5 mmol) in CH₂Cl₂ (20 mL) at 0 °C under argon atmosphere. It was then allowed to warm to r.t. and stirred for 15 h. The reaction mixture was then washed with water, sat. NaHCO₃ solution, and sat. brine solution. The organic layer was then dried over anhyd Na₂SO₄, and concentrated under reduced pressure to give diastereomeric mixture of cis β-lactams 6 and 7 in 1:1 ratio (40-50%). The diastereomers were separated by flash column chromatography using silica gel (230-400 mesh).
6a (Figure [4] ): White crystalline solid (mp 109-110 °C); [α]_D ²⁵ +133.0 (c = 0.93, CHCl₃). IR (CHCl₃): 1770 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.41 (s, 3 H, CH₃), 1.58 (s, 3 H, CH₃), 2.37 (t, 1 H, H₁₄), 3.97-4.06 (dd, J = 2.5, 17.9 Hz, 1 H, H₁₂), 4.10-4.15 (dd, J = 3.9, 3.9 Hz, 1 H, H₆), 4.30 (t, J = 3.9, 4.9 Hz, 1 H, H₄), 4.41-4.50 (dd, J = 2.5, 17.9 Hz, 1 H, H₁₂), 4.65 (t, J = 3.5, 3.9 Hz, 1 H, H₇), 4.70-4.78 (dd, J = 3.9, 3.9 Hz, 1 H, H₅), 5.34 (d, J = 4.9 Hz, 1 H, H₃), 5.88 (d, J = 3.5 Hz, 1 H, H₈), 7.02-7.09 (m, 3 H, aromatic), 7.29-7.37 (m, 2 H, aromatic). ¹³C NMR (50.32 MHz, CDCl₃): δ = 165.6 (C₂), 157.5 (C₁₅), 129.7 (C₁₉, C₁₇), 122.7 (C₁₈), 115.9 (C₁₆, C₂₀), 112.4 (C₉), 103.4 (C₈), 81.7 (C₇), 80.8 (C₅), 80.1 (C₃), 75.8 (C₁₄), 74.0 (C₁₃), 56.3 (C₄), 30.9 (C₁₂), 26.9 (C₁₀), 26.8 (C₁₁), 19.4 (C₆). MS (70 eV): m/z = 470 [M + 1]. Anal. Calcd for C₁₉H₂₀NO₅I: C, 48.63; H, 4.30; N, 2.98. Found: C, 48.49; H, 4.27; N, 2.80.
7a (Figure [5] ): Gummy material; [α]_D ²⁵ -13.4 (c = 1.08, CHCl₃). IR (CHCl₃): 1769 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.37 (s, 3 H, CH₃), 1.43 (s, 3 H, CH₃), 2.40 (t, 1 H, H₁₄), 3.87-4.02 (m, 2 H, H₁₂, H₆), 4.36 (t, J = 3.4, 4.9 Hz, 1 H, H₄), 4.43-4.55 (m, 2 H, H₁₂, H₇), 4.64 (t, J = 3.4, 3.4 Hz, 1 H, H₅), 5.37 (d, J = 4.9 Hz, 1 H, H₃), 5.81 (d, J = 3.4 Hz, 1 H, H₈), 7.03-7.12 (m, 2 H, aromatic), 7.31-7.37 (m, 3 H, aromatic). ¹³C NMR (50.32 MHz, CDCl₃): δ = 164.1 (C₂), 156.3 (C₁₅), 128.8 (C₁₉, C₁₇), 121.5 (C₁₈), 114.8 (C₁₆), 113.9 (C₂₀), 111.2 (C₉), 107.5 (C₈), 79.9 (C₇), 79.1 (C₅), 75.7 (C₃), 75.4 (C₁₄), 73.3 (C₁₃), 55.2 (C₄), 30.6 (C₁₂), 25.9 (C₁₀), 25.6 (C₁₁), 21.7 (C₆). MS (70 eV): m/z = 470 [M + 1]. Anal. Calcd for C₁₉H₂₀NO₅I: C, 48.63; H, 4.30; N, 2.98. Found: C, 48.82; H, 4.11; N, 2.93.

<A NAME="RG00304ST-13">13</A>

Crystal structure data for 6a: C₁₉H₂₀INO₅, colorless crystals grown from i-PrOH; M = 469.26; crystal dimensions 0.43 × 0.21 × 0.14 mm; crystal system orthorhombic, space group P2₁2₁2₁; a = 8.104 (2), b = 9.166 (2), c = 26.351 (6) Å; V = 1957.4 (8) ų; Z = 4; D_c = 1.592 g/cm³; µ (MoKα) (λ = 0.7107 Å) = 1.664 mm^-1; F(000) = 936; θ = 1.55-23.27°; T = 293 (2) K; Max. and min. transmission = 0.8041 and 0.5320; Reflections collected/unique = 8515/2801 [R(int) = 0.0181]; Completeness to θ = 23.27 99.6%; Refinement method = Full-matrix least-squares on F² _; Data/restraints/parameters = 2801/0/240; Goodness-of-fit on F² = 1.156; Final R indices [I>2σ(I)]: R1 = 0.0196, wR2 = 0.0497; R indices (all data): R1 = 0.0203, wR2 = 0.0501.

<A NAME="RG00304ST-14">14</A>

General Procedure for Intramolecular Radical Cyclization of N -Propargyl β-Lactams (6a-b, and 7a-c): A solution of Bu₃SnH (0.40 mL, 1.5 mmol) and AIBN (15 mg, 0.09 mmol) in toluene (10 mL) was slowly added to a refluxing solution of β-lactam 6a-b or 7a-c (1 mmol) in toluene (20 mL) over a period of 5 h. The reaction mixture was further refluxed for 2-5 h. After completion of the reaction (TLC), the solvent was concentrated and the crude reaction mixture was purified by flash column chromatography (silica gel, petroleum ether-EtOAC) to get pure cyclized product 8a-b or 9a-c.
8a (Figure [6] ): White crystalline solid (mp 109-110 °C); [α]_D ²⁵ +42.07 (c = 2.1, CHCl₃). IR (CHCl₃): 1765 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.31-1.32 (d, 6 H, CH₃), 2.89 (d, J = 4.4 Hz, 1 H, H6), 3.72 (d, J = 14.7 Hz, 1 H, H₁₂), 3.89 (t, J = 3.4, 3.9 Hz, 1 H, H₄), 4.34 (d, J = 14.7 Hz, 1 H, H₁₂), 4.87-4.98 (m, 3 H, H₁₄, H₇), 5.24 (s, 1 H, H₅), 5.37 (d, J = 3.9 Hz, 1 H, H₃), 5.87 (d, J = 3.9 Hz, 1 H, H₈), 7.00-7.07 (m, 3 H, aromatic), 7.29-7.36 (m, 2 H, aromatic). ¹³C NMR (50.32 MHz, CDCl₃): δ = 166.3 (C₂), 156.9 (C₁₅); 137.1 (C₁₃), 129.6 (C₁₉, C₁₇), 122.6 (C₁₈), 115.5 (C₁₆, C₂₀), 113.5 (C₁₄), 111.6 (C₉), 104.6 (C₈), 81.8 (C₇), 80.5 (C₃), 75.1 (C₅), 54.9 (C₄), 47.7 (C₆), 45.4 (C₁₂), 26.4 (C₁₀, C₁₁). MS (70 eV): m/z = 344 [M + 1]. Anal. Calcd for C₁₉H₂₁NO₅: C, 66.50; H, 6.16; N, 4.10. Found: C, 66.33; H, 5.97; N, 4.24.
9a (Figure [7] ): Gummy material; [α]_D ²⁵ +25.38 (c = 1.16, CHCl₃). IR (CHCl₃): 1762 cm^-1. ¹H NMR (200 MHz, CDCl₃) δ = 1.14 (s, 3 H, CH₃), 1.27 (s, 3 H, CH₃), 2.99 (br s, 1 H, H₆), 3.86 (d, J = 19.0 Hz, 1 H, H₁₂), 4.27-4.44 (m, 4 H, H₅, H₇, H₄, H₁₂), 5.32-5.57 (m, 3 H, H₁₃, H₁₄, H₃), 5.82 (d, J = 3.0 Hz, 1 H, H₈), 6.95-7.05 (m, 3 H, aromatic), 7.28-7.32 (m, 2 H, aromatic). ¹³C NMR (75.2 MHz, CDCl₃): δ = 162.0 (C₂), 157.4 (C₁₅), 129.5 (C₁₄), 125.8 (C₁₉, C₁₇), 124.8 (C₁₃), 122.0 (C₁₈), 115.5 (C₁₆, C₂₀), 111.8 (C₈), 104.9 (C₉), 84.5 (C₇), 79.6 (C₃), 74.2 (C₅), 57.5 (C₄), 50.5 (C₆), 41.7 (C₁₂), 26.9 (C₁₀), 26.7 (C₁₁); MS (70 eV): m/z = 344 [M + 1]. Anal. Calcd for C₁₉H₂₁NO₅: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.62; H, 6.28; N, 4.20.

<A NAME="RG00304ST-15">15</A>

Crystal structure data for 8b: C₂₀H₂₃NO₅, colorless crystal from i-PrOH; M = 357.39; crystal dimensions 0.21 × 0.19 × 0.06 mm; crystal system monoclinic, space group P2₁; a = 9.839 (15), b = 8.148 (12), c = 11.946 (18) Å; V = 945.6 (2) ų; Z = 2; D_c = 1.255 g/cm³; µ (MoKα) (λ = 0.7107 Å) = 0.090 mm^-1; F(000) = 380; θ = 1.73-24.99°; T = 293 (2) K; Max. and min. transmission = 0.9943 and 0.9813; Reflections collected/unique = 9089/3324 [R(int) = 0.0320]; Completeness to θ = 24.99 99.8%; Refinement method = Full-matrix least-squares on F²; Data/restraints/parameters = 3324/1/237; Goodness-of-fit on F² = 1.071; Final R indices [I>2σ(I)]: R1 = 0.0497, wR2 = 0.1024; R indices (all data): R1 = 0.0584, wR2 = 0.1065.

<A NAME="RG00304ST-16">16</A>

Spectral data for hydrogenated product 10 (Figure [8] ): White crystalline solid (mp 174 °C); [α]_D ²⁵ +1.88 (c = 0.8, CHCl₃). IR (CHCl₃,): 1755 cm^-1. ¹H NMR (200 MHz, CDCl₃) δ = 1.15 (s, 3 H, CH₃), 1.25 (s, 3 H, CH₃), 1.5-1.9 (m, 4 H, H₁₃, H₁₄), 2.3-2.4 (m, 1 H, H₆), 3.1-3.2 (m, 1 H, H₁₂), 3.7-3.8 (m, 1 H, H₁₂), 4.17 (d, J = 4.3 Hz, 1 H, H₄), 4.31 (d, J = 3.6 Hz, 1 H, H₇), 4.33 (d, J = 4.3 Hz, 1 H, H₅), 5.36 (d, J = 4.3 Hz, 1 H, H₃), 5.85 (d, J = 3.6 Hz, 1 H, H₈), 6.9-7.4 (m, 5 H, aromatic). ¹³C NMR (50.32 MHz, CDCl₃): δ = 164.7 (C₂), 157.2 (C₁₅), 129.3 (C₁₉, C₁₇), 121.7 (C₁₈), 115.4 (C₂₀, C₁₆), 110.9 (C₈), 104.6 (C₉), 85.3 (C₇), 79.3 (C₃), 75.1 (C₅), 57.6 (C₄), 48.3 (C₁₂), 42.8 (C₆), 27.7 (C₁₄), 26.3 (C₁₀, C₁₁), 23.5 (C₁₃). MS (70 eV): m/z = 345 [M⁺]. Anal. Calcd for C₁₉H₂₃NO₅: C, 66.07; H, 6.71; N, 4.06. Found: C, 66.17; H, 6.87; N, 4.27.

<A NAME="RG00304ST-17">17</A>

Crystal structure data for 10: C₁₉H₂₃NO_5, colorless needles grown from i-PrOH; M = 345.38; crystal dimensions 0.47 × 0.24 × 0.19 mm; crystal system orthorhombic, space group P2₁2₁2₁; a = 5.498 (2), b = 14.423 (5), c = 21.601 (8) Å; V = 1712.9 (11) ų; Z = 4; D_c = 1.339 g/cm³; µ (MoKα) (λ = 0.7107 Å) = 0.097 mm^-1; F(000) = 736; θ = 1.70-28.22°; T = 293 (2) K; Max. and min. transmission = 0.9814 and 0.9554; Reflections collected/unique = 8380/3863 [R(int) = 0.0227]; Completeness to θ = 28.22°, 94.3%; Refinement method = Full-matrix least-squares on F² _; Data/restraints/parameters = 3863/0/247; Goodness-of-fit on F² = 0.837; Final R indices [I>2σ(I)]: R1 = 0.0374, wR2 = 0.0745; R indices (all data): R1 = 0.0584, wR2 = 0.0794.