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Synlett 2004(7): 1249-1253  
DOI: 10.1055/s-2004-822920
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

A. Jayanthia, Vedavati G. Puranikb, A. R. A. S. Deshmukh*a
a Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune - 411 008, India
b Division of Physical Chemistry, National Chemical Laboratory, Pune - 411 008, India
Fax: +91(20)25893153; e-Mail: arasd@dalton.ncl.res.in;
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Publication History

Received 30 January 2004
Publication Date:
10 May 2004 (online)

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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.

Key words

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

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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.

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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) Å3; Z = 4; Dc = 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.

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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.

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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) Å3; Z = 2; Dc = 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.

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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.

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Crystal structure data for 10: C19H23NO5, 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) Å3; Z = 4; Dc = 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.