Constrained Tetramic Acids,
Homostreptopyrrolidine, and their Analogues Based on Unusual Intramolecular
Wittig Olefination with Phosphorus Ylides

Andrej Ïuriš; Adam Daïch; Dušan Berkeš

doi:10.1055/s-0030-1260793

LETTER

Constrained Tetramic Acids, Homostreptopyrrolidine, and their Analogues Based on Unusual Intramolecular Wittig Olefination with Phosphorus Ylides

Andrej Ïuriš^a, Adam Daïch*^b, Dušan Berkeš*^a
^a Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
Fax: +421(2)52968560; e-Mail: dusan.berkes@stuba.sk;
^b Laboratoire de Chimie, URCOM, EA 3221, INC3M CNRS-FR 3038, UFR des Sciences et Techniques, Université du Havre, BP: 540, 25 Rue Philipe Lebon, 76058 Le Havre Cedex, France
Fax: +33(2)32744391; e-Mail: adam.daich@univ-lehavre.fr;

Abstract

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Abstract

The synthesis of bicyclic tetramic acids based on the ‘nonclassical’ intramolecular Wittig reaction catalyzed by the corresponding phosphonium salt was developed. We have found that such applications proceed smoothly with high yield with N-substituted aminobutanolides when catalyzed with hydrochloride salt of the starting aminolactones. In addition, a convenient multigram synthesis of optically pure 4-hydroxy-5-substituted pyrrolidinones, including homostreptopyrrolidine as methylene homologues of naturally occurring streptopyrrolidine, via two consecutive reduction is also developed.

Key words

intramolecular Wittig - streptopyrrolidine analogues - tetramic acid - Wittig olefination - N-debenzylation

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Referenzen

References and Notes

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General Procedure for ‘Nonclassical’ Wittig Reaction - Method B
To a mixture of lactone 9a (2.19 g, 7.78 mmol) in dry toluene (120 mL) were added subsequently the catalyst 9a˙HCl (0.124 g, 0.39 mmol) and the ylide 10 (4.608 g, 13.23 mmol). The reaction mixture was refluxed under argon atmosphere for 1 h. The solvent was then evaporated under reduced pressure, and the residue was purified by chroma-tography on silica gel column (hexane-EtOAc = 3:1) to provide the constrained tetramic acid 7a (2.33 g, 7.63 mmol, 93%) as a white solid; mp 111-113 ˚C (Et₂O-heptane), [α]_D ^²0 205.7 (c 0.32, CHCl₃). IR (KBr): ν_max = 3105, 2983 (CH), 1668 (C=O), 1644 (C=C), 1185 (COC) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.26-7.41 (m, 10 H, ArH), 5.55-5.65 (m, 1 H, H-1′, 1 H, H-2), 5.06 (s, 1 H, H-6), 4.02 (ddd, 1 H, J = 1.0, 6.6, 11.7 Hz, H-3a), 2.66 (ddd, 1 H, J = 4.4, 6.5, 10.9 Hz, H-3A), 1.93 (q, 1 H, J = 22.9 Hz, H-3B), 1.56 (d, 3 H, J = 7.3 Hz, H-2′). ^¹³C NMR (75 MHz, CDCl₃): δ = 178.7 (C-6a), 175.6 (C-5), 140.9, 137.7, 129.2, 128.9, 128.8, 127.6, 127.1, 126.2 (ArC), 91.4 (C-6), 90.8 (C-2), 59.6 (C-1′), 48.7 (C-3a), 41.3 (C-3), 18.7 (C-2′). Anal. Calcd for C₂₀H₁₉NO₂(305.14): C, 78.66; H, 6.27; N, 4.59. Found: C, 80.00; H, 6.51; N, 4.66.
Method C
To a mixture of lactone 9a (0.391 g, 1.39 mmol) in dry toluene (15 mL) were added subsequently the additive 11 (0.718 g, 1.67 mmol) and Et₃N (0.141 g, 1.39 mmol). The reaction mixture was refluxed under argon atmosphere for 2 h. The white precipitate deposited was filtered off and washed with toluene. Filtrates were then evaporated under reduced pressure, and the residue was purified by chroma-tography on silica gel column (hexane-EtOAc = 3:1) to provide the constrained tetramic acid 7a (0.401 g, 1.31 mmol, 94%) as a white solid.

General Procedure for the Reduction of Tetramic Acids 7a-h into Corresponding Compounds 12a-h
To the bicyclic tetramate 7a (2.33 g, 7.63 mmol) dissolved in EtOAc (190 mL) was added catalyst (0.47 g, 10 mol% Pd/C), and the resultant suspension was then vigorously stirred under an hydrogen atmosphere for 2 h. After the reaction was complete, the catalyst was filtered off and the product purified by flash chromatography on silica gel column (hexane-EtOAc = 4:1) to provide the sat. bicyclic lactam 12a (1.82 g, 77%); mp 52-54 ˚C (Et₂O-heptane); [α]_D ^²0
-69.3 (c 0.23, CHCl₃). IR (KBr): ν_max = 3064, 2929 (CH), 1661 (C=O), 1056 (COC) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.15-7.32 (m, 10 H, ArH), 5.53 (q, 1 H, J = 7.3 Hz, H-1′), 4.74 (dd, 1 H, J = 5.2, 10.5 Hz, H-2), 4.50 (td, 1 H, J = 5.5, 7.5 Hz, H-7), 3.86 (dd, 1 H, J = 7.4, 14.2 Hz, H-3a), 2.78 (d, 2 H, J = 5.4 Hz, H-6), 2.51 (ddd, 1 H, J = 5.3, 7.5, 12.6 Hz, H-3A), 1.84 (ddd, 1 H, J = 6.6, 10.6, 12.4 Hz, H-3B), 1.53 (d, 3 H, J = 7.3 Hz, H-2′). ^¹³C NMR (75 MHz, CDCl₃): δ = 172.6 (C-5), 140.0, 139.4, 128.7, 128.6, 128.0, 127.9, 127.5, 125.8 (ArC), 81.7 (C-2), 74.9 (C-7), 61.2 (C-1′), 50.4 (C-3a), 43.8 (C-6), 38.3 (C-3), 17.7 (C-2′). Anal. Calcd for C₂₀H₂₁NO₂ (307.16): C, 78.15; H, 6.89; N, 4.56. Found: C, 78.23; H, 7.04; N, 4.54.

<A NAME="RB06411ST-30">30</A> Niwa H. Okamoto O. Miyachi Y. Uosaki Y. Yamada K. J. Org. Chem. 1987, 52: 2941

General Procedure for the Reduction of Bicycles 7a-h into Corresponding Tetramic Acids 13a-h
To the bicyclic tetramate 7a (1.013 g, 3.3 mmol) dissolved in MeOH (50 mL) was added catalyst (0.203 g, 10 mol% Pd/C), and the resultant suspension was then vigorously stirred under an hydrogen atmosphere for 4 h. After the reaction was complete, the catalyst was filtered off and the product purified by flash chromatography on silica gel column (hexane-EtOAc = 4:1) to provide the 5-arylalkyltetramic acid 13a (0.648 g, 64%) as colorless oil; [α]_D ^²0 11 (c 0.42, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.01-7.35 (m, 10 H, ArH), 5.70 (q, 1 H, J = 7.3 Hz, H-1′′), 3.58 (dd, 1 H, J = 2.9, 6.7 Hz, H-5), 3.05 (s, 1 H, H-3), 2.68 (ddd, 2 H, J = 4.1, 11.4, 13.7 Hz, H-2′A), 2.38 (ddd, 1 H, J = 6.6, 11.3, 13.4 Hz, H-2′B), 2.13 (dddd, 2 H, J = 3.1, 6.6, 11.2, 14.3 Hz, H-1′A), 1.80-1.92 (m, 1 H, H-1′B), 1.73 (d, 3 H, J = 7.3 Hz, H-2′′). ^¹³C NMR (75 MHz, CDCl₃): δ = 207.0 (C-4), 169.2 (C-2), 140.0, 138.0, 128.9, 128.6, 128.3, 128.2, 127.6, 126.4 (ArC); 65.6 (C-5), 50.9 (C-1′′), 41.8 (C-3), 33.3 (C-2′), 29.5 (C-1′), 18.4 (C-2′′).

<A NAME="RB06411ST-32">32</A> For a recent paper stating on this equilibrium, see: Storgaard M. Dörwald FZ. Peschke B. Tanner D. J. Org. Chem. 2009, 74: 5032 ; and the references cited therein

General Procedure for the Debenzylation Process
A solution of 12a (1.591 g, 5.16 mmol) in dry THF (30 mL) was added to liquid NH₃ (40 mL) at -78 ˚C. Small pieces of Na (15-20 equiv) were added until the reaction mixture remained blue, and the mixture was stirred at -78 ˚C. After 30 min of the reaction, the solution was then quenched with aq NH₄Cl. The residual ammonia was evaporated, and the mixture was extracted three times with Et₂O. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel column (MeOH-EtOAc = 1:10) to provide ultimately (4S,5S)-4-hydroxy-5-phenyl-ethylpyrrolidin-2-one (8a) in yield 80% (0.85 g); mp 104-106 ˚C (Et₂O); [α]_D ^²0 -18.4 (c 0.114, MeOH). ^¹H NMR (300 MHz, CDCl₃): δ = 7.14-7.30 (m, 5 H, H-Ar), 4.25 (t,
1 H, J = 4.3 Hz, H-4), 3.52 (dd, 1 H, J = 7.0, 11.7 Hz, H-5), 2.67 (t, 2 H, J = 7.2 Hz, H-2′), 2.53 (dd, 1 H, J = 5.8, 17.2 Hz, H-3A), 2.28 (dd, 1 H, J = 1.4, 17.2 Hz, H-3B), 1.91-2.05 (m, 1 H, H-1′A), 1.80-1.90 (m, 1 H, H-1′B). ^¹³C NMR (75 MHz, CDCl₃): δ = 176.8 (C-2), 141.1, 128.5, 128.3, 126.1 (ArC), 68.6 (C-4), 59.2 (C-5), 41.0 (C-3), 32.3 (C-2′), 30.4 (C-1′).

Synthesis of Products 14
By using same procedure such as from the substrate 12g as starting material, the expected (2R,3aS,7S)-2-tert-butyl-hexahydrofuro[3,2b]-pyrrol-5-one (14g) was isolated in 73% yield; mp 145-147 ˚C (Et₂O); [α]_D ^²0 13.5 (c 0.1, MeOH). ^¹H NMR (300 MHz, CDCl₃): δ = 4.74 (t, 1 H, J = 5.6 Hz, H-7), 4.31 (t, 1 H, J = 5.5 Hz, H-3a), 3.78 (dd, 1 H, J = 4.8, 10.9 Hz, H-2), 2.40-2.68 (m, 2 H, H-6), 1.86 (dd, 1 H, J = 4.8, 13.2 Hz, H-3A), 1.40-1.49 (m, 1 H, H-3B), 0.88 (s, 9 H, H-2′′). ^¹³C NMR (75 MHz, CDCl₃): δ = 177.7 (C-5), 85.5 (C-2), 59.6 (C-7), 51.1 (C-3a), 38.9 (C-6), 34.1 (C-3), 32.9 (C-1′′), 25.9 (C-2′′).