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Synlett 2006(17): 2739-2742  
DOI: 10.1055/s-2006-950268
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regio- and Stereoselectivity in the Titanium-Mediated Cyclopropanation of ω-Alkenoic Diesters: Application in the Diastereoselective Synthesis of Pyrrolidinone

Jean-Marc Garnier, Mouhamad Jida, Jean Ollivier*
Laboratoire de Synthèse Organique et Méthodologie, UMR CNRS 8182, Institut de Chimie Moléculaire et des Matériaux d"Orsay, Université de Paris-Sud, Bât. 420, 91405 Orsay, France
Fax: +33(1)69156278; e-Mail: jollivie@icmo.u-psud.fr;
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Publication History

Received 26 July 2006
Publication Date:
09 October 2006 (online)

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Abstract

The titanium-mediated intramolecular cyclopropanation of ω-allylic succinates leads only to cyclopropanol, arising from exclusive reactivity of one ester function. As an extension of this methodology, the diastereoselective synthesis of highly functionalized pyrrolidinone has been realized from cheap commercially available l-aspartic acid.

Key Words

amino acids - diastereoselectivity - fused-ring system - heterocycles - regioselectivity - titanium

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General Procedure for the Intramolecular Cyclopropanation of ω-Alkenoic Diesters: To a solution of ω-alkenoic diesters (2 mmol) and titanium isopropoxide (0.6 mL, 2 mmol, 1 equiv) in anhyd THF (6 mL) was added over 4 h at r.t. under argon a solution of cyclohexyl-magnesium chloride (5.1 mL, 8 mmol, 4 equiv, 1.57 M in Et2O). After stirring for an additional hour at r.t., the dark solution was cooled at 0 °C and Et2O (25 mL) was added. The mixture was quenched by addition of a sat. NH4Cl (5 mL) solution and was stirred overnight at r.t. The white precipitate was filtered off through a plug of Celite, washed with Et2O (30 mL) and the filtrate was dried over MgSO4. After evaporation of the solvents, the residue was purified by column chromatography.

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Ethyl 1-Hydroxybicyclo[3.1.0]hexan-3-carboxylate (5a) 1H NMR (250 MHz, CDCl3): δ = 4.22 (q, J = 7.0 Hz, 2 H, cis), 4.11 (q, J = 7.0 Hz, 2 H, trans), 2.96 (t, J = 10.0 Hz, 1 H, trans), 2.95 (t, J = 10.0 Hz, 1 H, cis), 2.61 (dd, J = 5.0, 13.0 Hz, 1 H, cis), 2.60 (dd, J = 5.0, 13.0 Hz, 1 H, trans), 2.25-2.50 (m, 8 H), 2.00 (d, J = 5.0, 13.0 Hz, 1 H, cis), 1.99 (d, J = 5.0, 13.0 Hz, 1 H, trans), 1.18-1.30 (m, 2 H), 0.93 (t, J = 6.7 Hz, 3 H, cis), 0.90 (t, J = 6.7 Hz, 3 H, trans), 0.58 (dd, J = 4.5, 6.0 Hz, 1 H, trans), 0.47 (dd, J = 4.5, 6.0 Hz, 1 H, cis). 13C NMR (50 MHz, CDCl3): δ = 176.1 (cis), 175.1 (trans), 63.7 (cis), 62.6 (trans), 60.5, 40.7 (cis), 40.0 (trans), 36.4 (trans), 35.9 (cis), 30.6 (trans), 28.2 (cis), 23.8 (cis), 20.6 (trans), 17.1, 13.9 (trans), 13.1 (cis). IR (neat): 3384, 2938, 2872, 1731 cm-1. MS (EI, cis isomer): m/z (%) = 170 (24) [M+], 128 (93), 100 (100), 97 (38), 55 (44). MS (EI, trans isomer): m/z (%) = 170 (14) [M+], 97 (100), 69 (26), 55 (30), 41 (24). HRMS (cis isomer): m/z calcd for C9H14O3: 170.0942; found: 170.0944. HRMS (trans isomer): m/z calcd for C9H14O3: 170.0942; found: 170.0946.

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Molecular mechanic calculations were carried out using Spartan 04 molecular modeling software (Wavefunction, Inc. Irvine, CA.) with MMFF as the force field.

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An energy difference >3 kcal×mol-1 predicts a 100:0 selectivity.

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Ethyl 3-Oxo-4-cyclohexen-1-carboxylate (6) 1H NMR (250 MHz, CDCl3): δ = 6.95 (dt, J = 4.2, 10.0 Hz, 1 H), 6.04 (dt, J = 1.5, 10.0 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 3.10 (m, 1 H), 2.65 (m, 4 H), 1.27 (t, J = 7.2 Hz, 3 H). 13C NMR (50 MHz, CDCl3): δ = 196.9, 172.8, 147.7, 129.6, 60.9, 39.6, 27.8, 21.5, 13.9. IR (neat): 3487, 2960, 1739 cm-1. MS (EI): m/z (%) = 168 (13) [M+], 137 (66), 109 (100). HRMS: m/z calcd for C9H12O3: 170.0942; found: 170.0943.

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Disopropyl N -Allyl- N -benzylaspartate (10)
1H NMR (250 MHz, CDCl3): δ = 7.20 (s, 5 H), 5.70-5.86 (m, 1 H), 4.95-5.34 (m, 4 H), 3.98 (t, J = 7.5 Hz, 1 H), 3.89 (d, J = 14.0 Hz, 1 H), 3.57 (d, J = 14.0 Hz, 1 H), 3.38 (dd, J = 5.0, 14.2 Hz, 1 H), 3.17 (dd, J = 7.7, 14.0 Hz, 1 H), 2.84 (dd, J = 7.2, 15.7 Hz, 1 H), 2.62 (dd, J = 7.2, 15.7 Hz, 1 H), 1.34 (d, J = 6.0 Hz, 3 H), 1.32 (d, J = 6.0 Hz, 3 H), 1.26 (d, J = 6.0 Hz, 3 H), 1.25 (d, J = 6.0 Hz, 3 H). 13C NMR (62 MHz, CDCl3): δ = 171.2, 170.3, 139.5, 136.0, 128.6, 128.2, 127.0, 117.6, 68.3, 68.0, 58.6, 54.6, 54.2, 35.7, 22.3, 22.0, 21.9, 21.8. IR (neat): 3430, 2980, 1726 cm-1. MS (EI): m/z (%) = 347 (17.2) [M+], 260 (87.4), 256 (19.6), 218 (35.3), 90 (100). HRMS (ES+): m/z calcd for C20H29NO4Na: 370.1989; found: 370.1994.

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Isopropyl (1-Benzyl-4-methyl-3-oxopyrrolidin-2-yl)acetate (14)
1H NMR (360 MHz): δ = 7.28-7.35 (m, 10 H), 5.03 (sept, J = 7.2 Hz, 2 H), 4.07 (d, J = 13.0 Hz, 1 H, cis), 4.06 (d, J = 13.0 Hz, 1 H, trans), 3.43 (d, J = 13.0 Hz, 1 H, cis), 3.37 (d, J = 13.0 Hz, 1 H, trans), 3.35 (t, J = 8.6 Hz, 2 H), 2.90 (t, J = 4.5 Hz, 2 H), 2.77 (dd, J = 4.0, 15.8 Hz, 2 H), 2.69 (dd, J = 5.1, 16.2 Hz, 1 H, trans), 2.64 (dd, J = 5.1, 16.2 Hz, 1 H, cis), 2.40-2.60 (m, 2 H), 2.05 (dd, J = 9.0, 11.2 Hz, 2 H), 1.25 (d, J = 6.1 Hz, 3 H, trans), 1.22 (d, J = 7.2 Hz, 3 H, cis), 1.21 (d, J = 6.1 Hz, 3 H, trans), 1.18 (d, J = 7.2 Hz, 3 H, cis), 1.09 (d, J = 7.2 Hz, 6 H). 13C NMR (90 MHz, CDCl3): δ = 216.4 (cis), 216.3 (cis), 170.4 (cis), 170.3 (trans), 137.6 (cis), 137.5 (trans), 128.9 (trans), 128.7 (cis), 128.3 (trans), 128.1 (cis), 127.3 (trans), 127.2 (cis), 68.1 (cis), 68.0 (trans), 66.3 (trans), 65.7 (cis), 58.7 (trans), 58.4 (cis) 57.1 (trans), 56.1 (cis), 42.0 (trans), 40.5 (cis), 35.8 (trans), 35.1 (cis), 15.9 (cis), 15.8 (trans), 11.7 (cis), 11.5 (trans). IR (neat): 3493, 1758, 1731 cm-1. MS (EI, trans isomer): m/z (%) = 289 (3.7) [M+], 218 (2.7), 188 (10.9), 132 (22.0), 91 (100), 65 (10.4), 43 (44.9). MS (EI, cis isomer): m/z (%) = 289 (2.3) [M+], 230 (10.6), 248 (4.1), 212 (8.3), 132 (15.6), 91 (100), 43 (32.2). HRMS (trans isomer): m/z calcd for C17H23NO3: 289.1672; found: 289.1676. HRMS (cis isomer): m/z calcd for C17H23NO3: 289.1672; found: 289.1674.