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Synlett 2006(4): 0591-0594  
DOI: 10.1055/s-2006-932485
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of γ-Lactam Lignans via Aza-Michael Addition

Matthieu Dorbeca, Jean-Claude Florent*a, Claude Monnereta, Marie-Noëlle Ragerb, Emmanuel Bertounesque*a
a UMR 176 CNRS-Institut Curie, Section de Recherche, 26 rue d’Ulm, 75248 Paris Cedex 05, France
Fax: +33(1)2346631; e-Mail: Emmanuel.Bertounesque@curie.fr;
b Département de RMN, Ecole Nationale Supérieure de Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France
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Publication History

Received 20 December 2005
Publication Date:
20 February 2006 (online)

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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.

Key words

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

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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.

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, H3 ′′, H5 ′′), 7.47 (s, 1 H, H5), 6.55 (d, 2 H, J = 9.2 Hz, H2 ′′, H6 ′′), 6.33 (s, 2 H, H2 ′, H6 ′), 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, OMe4 ′), 3.80 (s, 6 H, OMe3 ′ ,5 ′), 3.63 (m, 1 H, H11a), 3.49 (s, 3 H, CO2Me), 3.48 (m, 1 H, H11b), 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, H3 ′′, H5 ′′), 7.79 (d, J = 9.3 Hz, 2 H, H2 ′′, H6 ′′), 7.48 (s, 1 H, H5), 6.73 (s, 1 H, H8), 6.27 (s, 2 H, H2 ′, H6 ′), 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, H11a), 4.01 (m, 1 H, H11b), 3.81 (s, 3 H, OMe4 ′), 3.76 (s, 6 H, OMe3 ′,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/H2 ′,6 ′, and H3/H2 ′,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