Bicyclic Lactams Derived from Serine or Cysteine and 2-Methylpropanal

Abstract

Bicyclic lactams may be prepared from serine or cysteine and 2-methylpropanal; the resulting S,N-heterocycles are more stable than the corresponding O,N-heterocycles but both are synthetic intermediates capable of further elaboration.

Key words

lactams - antibiotics - cyclisation - heterocycles

• References

• 1 Bagum H, Christensen KE, Genov M, Pretsch A, Pretsch D, Moloney MG. J. Org. Chem. 2019; 84: 10257
• 2a Bagum H, Christensen KE, Pretsch A, Genov M, Pretsch D, Moloney MG. Tetrahedron 2019; 75: 130561
• 2b Josa-Cullere L, Moloney MG, Thompson AL. Synlett 2016; 27: 1677
• 3 Andrews MD, Brewster AG, Crapnell KM, Ibbett AJ, Jones T, Moloney MG, Prout K, Watkin D. J. Chem. Soc., Perkin Trans. 1 1998; 223
• 4a Panduwawala TD, Iqbal S, Tirfoin R, Moloney MG. Org. Biomol. Chem. 2016; 14: 4464
• 4b Panduwawala TD, Josa-Cullere L, Kuprov I, Odell B, Moloney MG, Claridge TD. W. J. Org. Chem. 2016; 81 (10) 4142
• 5 Lazar L, Fulop F. Eur. J. Org. Chem. 2003; 3025
• 6a Lazar L, Goblyos A, Martinek TA, Fulop F. J. Org. Chem. 2002; 67 (14) 4734
• 6b Fulop F, Mattinen J, Pihlaja K. Tetrahedron 1990; 46: 6545
• 6c Fulop F, Pihlaja K, Mattinen J, Bernath G. J. Org. Chem. 1987; 52: 3821
• 7 Seebach D, Aebi JD. Tetrahedron Lett. 1984; 25: 2545
• 8 Jeong Y.-C, Anwar M, Nguyen TM, Tan BS. W, Chai CL. L, Moloney MG. Org. Biomol. Chem. 2011; 9: 6663
• 9 Fulop F, Pihlaja K, Neuvonen K, Bernath G, Argay G, Kalman A. J. Org. Chem. 1993; 58: 1967
• 10 Dieckmann Cyclisation:³ To a solution of N-acyl oxazolidine or thiazolidine 5a,b (1.0 equiv) in anhydrous THF was added potassium tert-butoxide (1.05 equiv). The mixture was heated at reflux for 3 h. The reaction mixture was partitioned between Et₂O and water, the aqueous phase was acidified with 2 M aqueous HCl and the mixture was extracted with EtOAc. The organic layer was washed with a 1 M aqueous solution of NaH₂PO₄ and brine, dried over anhydrous Na₂SO₄ filtered and concentrated under reduced pressure to give the methyl ester tetramic acids 6a–e. Synthesis of Mesylate:¹⁶ Tetramic acid 6a–e (1.0 quiv) was dissolved in CH₂Cl₂ under a nitrogen atmosphere. Methanesulfonyl chloride (1 equiv) and DIPEA (2 equiv) were added to this solution. The resulting mixture was stirred for 2–6 h at room temperature until total consumption of the starting material. The reaction mixture was washed with 5% HCl, 5% NaHCO₃, and brine, dried over MgSO₄, and filtered. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether as eluants to give pure mesylates 7a,c Representative reaction: Tetramic acids (6d + 6e, 2.32 g, 8.55 mmol) was reacted with MsCl (0.66 mL, 8.55 mmol) and DIPEA (2.9 mL, 17.1 mmol) in CH₂Cl₂ (85 mL). Purification by flash column chromatography (20–30% EtOAc in petroleum ether) furnished pure mesylates 7d and 7e. Yield: 61% (1.82 g); colourless oil; R_f (40% EtOAc in Petrol) 0.37; [α]_D ²⁵ +235.0 (c 1.0 in ­CH₂Cl₂). IR: 2960 (C-H), 2935 (C-H), 1747 (C=O), 1713 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.87 (d, J = 6.6 Hz, 3 H, CH(CH ₃)), 1.02 (d, J = 6.6 Hz, 3 H, CH(CH ₃)), 1.78–1.84 (m, 1 H, CH(CH₃)₂), 1.85 (s, 3 H, C(7)CH₃), 2.84 (d, J = 11.1 Hz, 1 H, C(4)H _AH_B), 3.23 (s, 3 H, OSO₂CH₃), 3.58 (d, J = 11.1 Hz, 1 H, C(4)H_A H _B), 3.76 (s, 3 H, CO₂CH₃), 4.70 (s, J = 9.7 Hz, 1 H, C(2)H). ¹³C NMR (100 MHz, CDCl₃): δ = 8.6 (C(7)CH₃), 19.6, 20.2 (CH(CH₃)₂), 35.2 (C(4)), 36.9 (CH(CH₃)₂), 39.5 (OSO₂CH₃), 53.7 (CO₂ CH₃), 66.8 (C(2)), 78.2 (C(5)), 124.0 (C(7)), 154.0 (CO₂CH₃), 168.4 (C(8)), 171.4 (C(6)). MS (ESI+): m/z (%) = 372.0 (100, [M + Na]⁺); HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₃H₁₉NNaO₆S₂: 372.0546; found: 372.0547. Suzuki coupling:¹⁷ A mixture of 1,4-bis(diphenylphosphino)butane (0.06 equiv) and bis(benzonitrile)palladium(II) chloride (0.05 equiv) in anhydrous toluene was stirred at room temperature under a nitrogen atmosphere for 30 minutes to form a creamy orange slurry of [1,4-bis(diphenylphosphino)butane]palladium(II) chloride. Mesylate (1.0 equiv), boronic acid (1.05–1.8 equiv), ethanol (7.0 equiv), 1 M aqueous sodium carbonate solution (9–18 equiv) and anhydrous toluene were added to the catalyst and the mixture was heated at reflux for 3–30 hours. After cooling, water was added, and the mixture was diluted with ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried, filtered and evaporated in vacuo to furnish the crude product, which was then purified by flash column chromatography. Typical reaction: Mesylate 7a (210 mg, 0.66 mmol) was reacted with 4-methoxyphenylboronic acid (150 mg, 0.98 mmol), PdCl₂(dppb), and 1 M aqueous Na₂CO₃ solution (0.62 mL, 5.94 mmol) in ethanol (0.27 mL, 4.62 mmol) and toluene (12 mL) for 6 h. PdCl₂(dppb) was prepared from (C₆H₅)₂P(CH₂)₄P(C₆H₅)₂ (16.9 mg, 0.04 mmol) and (C₆H₅CN)₂PdCl₂ (12.6 mg, 0.022 mmol) in toluene (2 mL). Yield: 47% (102 mg); yellow solid; mp 90–92 °C; R_f (30% EtOAc in petrol): 0.25; [α]_D ²⁵ +138.9 (c 1.0 in CH₂Cl₂). IR: 2954 (C-H), 2868 (C-H), 1743 (C=O), 1712 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (dd, J = 8.9, 6.8 Hz, 6 H, HC(CH ₃)₂), 1.80 (dq, J = 6.8, 5.6 Hz, 1 H, (HC(CH₃)₂), 3.48 (d, J = 8.3 Hz, 1 H, C(4)H _AH_B), 3.59 (s, 3 H, CO₂CH₃), 3.77 (s, 3 H, OCH₃), 4.84 (d, J = 5.6 Hz, 1 H, C(2)H), 5.02 (d, J = 8.3 Hz, 1 H, C(4)H_A H _B), 6.19 (s, 1 H, C(7)H), 6.86 (d, J = 8.9 Hz, 2 H, C(3′)H), 7.31 (d, J = 8.9 Hz, 2 H, C(2′)H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.1, 17.1 (HC(CH₃)₂), 33.2 (HC(CH₃)₂), 53.3 (CO₂ CH₃), 55.5 (OCH₃), 70.3 (C(4)), 76.8 (C(5)), 93.5 (C(2)), 114.7 (C(3′)), 119.0 (C(7)), 122.5 (C(1′)), 128.8 (C(2′)), 159.3 (C(6)), 161.9 (C(4′)), 170.1 (CO₂CH₃), 177.5 (C(8)). MS (ESI+): m/z (%) = 332.1 (30, [M + H]⁺); HRMS ([ESI]⁺): m/z [M + H]⁺ calcd for C₁₈H₂₂NO₅: 332.1493; found: 332.1493.
• 11 Seebach D, Sting AR, Hoffmann M. Angew. Chem. Int. Ed. Engl. 1996; 35: 2708
• 12 Low-temperature single-crystal X-ray diffraction data were collected with a (Rigaku) Oxford Diffraction SuperNova diffractometer. Raw frame data were reduced using CrysAlisPro and the structures were solved using ‘Superflip’.¹⁸ before refinement with CRYSTALS¹⁹ as per the Supporting Information (CIF). CCDC 1961419, 1961420, 1961421 contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 13 Corey EJ, Reichard GA. J. Am. Chem. Soc. 1992; 114: 10677
• 14 Jeong Y.-C, Moloney MG. Synlett 2009; 2487
• 15a Dyer J, Keeling S, King A, Moloney MG. J. Chem. Soc., Perkin Trans. 1 2000; 2793
• 15b Bailey JH, Cherry DT, Crapnell KM, Moloney MG, Shim SB, Bamford M, Lamont RB. Tetrahedron 1997; 53: 11731
• 16 Li W.-R, Lin ST, Hsu N.-M, Chern M.-S. J. Org. Chem. 2002; 67: 4702
• 17 Jones K, Keenan M, Hibbert FA. Synlett 1996; 509
• 18 Palatinus L, Chapuis G. J. Appl. Crystallogr. 2007; 40: 786
• 19a Parois P, Cooper RI, Thompson AL. Chem. Cent. J. 2015; 9: 1
• 19b Cooper RI, Thompson AL, Watkin DJ. J. Appl. Crystallogr. 2010; 43: 1100