Synthesis of γ-Lactam Lignans via Aza-Michael Addition

Abstract

The synthesis of γ-lactam lignans from thuriferic acid via Michael addition of substituted anilines under basic conditions, ­followed by lactam ring closure, is described.

lignans - lactams - Michael additions - thuriferic acid - privileged structure

References and Notes

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22

To avoid the formation of the protonated β-amino ketones 6 as by-products, CDCl₃ over K₂CO₃ must be used.

23 For the synthesis of 4-hydroxy-3-methyl-6,7-(methylene-dioxy)-1-(3,4,5-trimethoxyphenyl)-2-naphthoic acid (7, R = H, Figure 2) from thuriferic acid, see: Ogiku T. Yoshida Si. Ohmizu H. Iwasaki T. J. Org. Chem.  1995,  60:  4585 

24 For the synthesis of oxime derivatives from 4-ketolignans lacking the lactone ring, see: Gordaliza M. Castro MA. Miguel del Corral JM. López-Vázquez ML. García PA. San Feliciano A. García-Grávalos MD. Broughton H. Tetrahedron  1997,  53:  15743 

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27

Synthesis of 6 and 3; General Procedure To a solution of the methyl ester of thuriferic acid 5 (50 mg, 0.117 mmol) in anhyd THF (2 mL) were added Et₃N and the aniline at r.t. (Table [1] ). The reaction mixture was then heated at 65 °C for the reaction time indicated, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (cyclohexane-EtOAc, 5:2) to give the desired β-amino ketones 6. This compound (0.165 mmol, 1 equiv) was diluted in DMF (2.5 mL) and a 1 M solution of t-BuOK in t-BuOH (1 M; 16.5 µL, 0.1 equiv) was added at r.t. The mixture was stirred for 20 min then the pH was adjusted to 7 by the addition of aq NH₄Cl. The mixture was extracted with EtOAc (3 × 20 mL), the combined organic phases were dried over MgSO₄, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (cyclohexane-EtOAc, 3:1) to furnish the γ-lactam lignans 3.
Compound 6i: Yellow powder; yield: 31%; mp 194 °C; [α]_D ²⁰ -84 (c 0.19, CHCl₃). IR: 3400-3300, 2940, 1734, 1671, 1601, 1506, 1480 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.07 (d, 2 H, J = 9.2 Hz, H_{3 ′′}, H_{5 ′′}), 7.47 (s, 1 H, H₅), 6.55 (d, 2 H, J = 9.2 Hz, H_{2 ′′}, H_{6 ′′}), 6.33 (s, 2 H, H_{2 ′}, H_{6 ′}), 6.29 (s, 1 H, H₈), 6.00 (m, 2 H, OCH₂O), 5.19 (br s, 1 H, NH), 4.36 (d, 1 H, J = 10.7 Hz, H₁), 3.86 (s, 3 H, OMe_{4 ′}), 3.80 (s, 6 H, OMe_{3 ′ ,5 ′}), 3.63 (m, 1 H, H_11a), 3.49 (s, 3 H, CO₂Me), 3.48 (m, 1 H, H_11b), 3.24 (dd, 1 H, J = 12.9, 10.7 Hz, H₂), 3.19 (m, 1 H, H₃). ¹³C NMR (75 MHz, acetone-d ₆): δ = 195.8, 174.0, 155.8, 155.5, 154.4, 149.2, 143.7, 139.6, 139.1, 138.5, 128.4, 127.7, 112.9, 110.0, 108.6, 106.7, 104.1, 61.5, 57.4, 54.0, 53.1, 50.9, 50.0, 43.7. MS (DCI, NH₃): m/z = 565 [M + H]⁺.
Compound 3i: Yellow powder; yield: 65%; mp 235-240 °C; [α]_D ²⁰ -110 (c 0.34, CHCl₃). IR: 2940, 1716, 1670, 1597, 1521, 1481 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.22 (d, J = 9.3 Hz, 2 H, H_{3 ′′}, H_{5 ′′}), 7.79 (d, J = 9.3 Hz, 2 H, H_{2 ′′}, H_{6 ′′}), 7.48 (s, 1 H, H₅), 6.73 (s, 1 H, H₈), 6.27 (s, 2 H, H_{2 ′}, H_{6 ′}), 6.04 (m, 2 H, OCH₂O), 4.81 (d, J = 1.7 Hz, 1 H, H₁), 4.38 (d, J = 9.7 Hz, 1 H, H_11a), 4.01 (m, 1 H, H_11b), 3.81 (s, 3 H, OMe_{4 ′}), 3.76 (s, 6 H, OMe_{3 ′,5 ′}), 3.40 (dd, J = 7.6, 1.7 Hz, 1 H, H₂), 3.29 (m, 1 H, H₃). ¹³C NMR (75 MHz, CDCl₃): δ = 193.9, 172.3, 153.7, 153.5, 144.1, 143.6, 139.6, 138.1, 137.0, 126.9, 124.5, 118.6, 109.3, 105.8, 104.6, 102.0, 60.6, 56.0, 50.5, 43.3, 42.9, 39.5. MS (DCI, NH₃): m/z = 533 [M + H]⁺, 550 [M + NH₄]⁺.

28

The 2,3-cis stereochemistry of 3a-i was deduced from the J _1,2 and J _2,3 coupling constants (1.7 and 7.6 Hz, respectively for 3i) and was confirmed from NOESY correlations of H₂/H₃, H₂/H_{2 ′,6 ′}, and H₃/H_{2 ′,6 ′}. Molecular modeling [Insight II, Discover, MD simulations (300 K), cff 91, ε = 4.8 for CDCl₃] provided a unique global minimum conformation for 3i which fitted the NOE data (Figure [3] ).

Figure 3

29 Uneyama K. Watanabe H. Tetrahedron Lett.  1991,  32:  1459 

30 Del Corral JMM. Gordaliza M. Castro MA. López-Vázquez ML. García-Grávelos MD. Broughton HB. San Feliciano A. Tetrahedron  1997,  53:  6555