Cycloadditions of Chiral Nitrones to Racemic 3-Substituted Butenes: A Direct Access with Kinetic Resolution to Enantiopure Dihydroxylated Amino Acids

Kaiss Aouadi; Sébastien Vidal; Moncef Msaddek; Jean-Pierre Praly

doi:10.1055/s-2006-951534

LETTER

Cycloadditions of Chiral Nitrones to Racemic 3-Substituted Butenes: A Direct Access with Kinetic Resolution to Enantiopure Dihydroxylated Amino Acids

Kaiss Aouadi^a,b, Sébastien Vidal^a, Moncef Msaddek^b, Jean-Pierre Praly*^a
^a Université Claude Bernard Lyon 1, CPE-Lyon, Bât. 308, Laboratoire de Chimie Organique 2 - Glycochimie, UMR-CNRS 5181, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
e-Mail: jean-pierre.praly@univ-lyon1.fr;
^b Université de Monastir, Faculté des Sciences de Monastir, Laboratoire de Synthèse Hétérocyclique et Photochimie, Avenue de l’Environnement, Monastir 5000, Tunisia

Abstract

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Abstract

1,3-Dipolar cycloadditions of racemic 3-substituted 1-butenes to nitrones derived from (-)- or (+)-menthone occurred via exo-approach of the alkene onto the nitrone’s less hindered face. This process afforded bicyclic spiroheterocycles as epimers, with selectivities £ 4:1, depending on the 3-substituent (R) on the alkene. The selectivity appeared to be influenced by hydrogen bonding (R = OH) or the bulkiness of the R group (R = OBz, Br), as a result of kinetic resolution. The cycloadducts obtained led, after a reductive step and cleavage of the chiral auxiliary, to enantiopure dihydroxylated non-natural amino acids in high overall yield.

Key words

1,3-dipolar cycloadditions - nitrones - isoxazolidines - dihydroxy amino acid - kinetic resolution

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References

References and Notes

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General Procedure: A mixture of nitrone (-)-1 (1.5 mmol) and alkene 2a-e (for nitrone/alkene ratio see Table [1] ) was stirred in toluene (10 mL) at 110 °C [monitored by TLC (CHCl₃-i-PrOH, 98:2)]. When the reaction was complete the solution was concentrated and the residue was purified by flash chromatography (CHCl₃-i-PrOH, 98:2) to afford the desired cycloadducts 3a-e and 4a-e. Cycloadduct 3a: [α]_D ²² +65 (c 1, CH₂Cl₂); white solid; mp 97-100 °C (Et₂O). ¹H NMR (CDCl₃, 300 MHz): δ = 0.80 (d, 3 H, J = 6.6 Hz, CH₃), 0.86 (d, 3 H, J = 6.9 Hz, CH₃), 0.93 (d, 3 H, J = 6.3 Hz, CH₃), 0.93 (m, 1 H), 1.11 (d, 3 H, J = 6.6 Hz, CH₃), 1.25 (t, 1 H, J = 12.3 Hz), 1.39 (m, 1 H), 1.44 (m, 1 H), 1.64 (m, 2 H), 1.83 (m, 1 H), 1.99 (m, 1 H), 2.06 (dt, 1 H, J = 3.0 Hz, J = 12.3 Hz), 2.55 (m, 2 H), 2.74 (s, 3 H, NCH₃), 3.78 (dt, 1 H, J = 3.0 Hz, J = 6.9 Hz), 3.97 (dd, 1 H, J = 3.0 Hz, J = 7.5 Hz), 4.05 (dq, 1 H, J = 3.0 Hz, J = 6.6 Hz). ¹³C NMR (CDCl₃, 75 MHz): δ = 18.4, 18.6, 22.2, 22.4, 24.1, 24.2, 25.9 (NCH₃), 29.3, 31.5, 34.5, 40.6, 47.9, 65.8, 68.0, 80.1, 88.9, 172.8 (C=O). MS (ESI): m/z = 311 [M + H]⁺. Anal. Calcd for C₁₇H₃₀N₂O₃: C, 65.77; H, 9.74; N, 9.02; O, 15.46. Found: C, 65.66; H, 9.99; N, 8.83; O, 16.01. Cycloadduct 3e: [α]_D ²² +59 (c 1, CH₂Cl₂); white crystals, mp 94-95 °C (Et₂O). ¹H NMR (CDCl₃, 300 MHz): δ = 0.81 (d, 3 H, J = 6.9 Hz, CH₃), 0.85 (d, 3 H, J = 6.9 Hz, CH₃), 0.91 (d, 3 H, J = 6.6 Hz, CH₃), 0.93 (m, 1 H), 1.26 (t, 1 H, J = 12.3 Hz), 1.38 (m, 1 H), 1.44 (m, 1 H), 1.63 (m, 2 H), 1.72 (d, 3 H, J = 6.3 Hz, CH₃), 1.82 (m, 1 H), 1.98 (m, 1 H), 2.03 (dt, 1 H, J = 2.5 Hz, J = 12.6 Hz), 2.42 (ddd, 1 H, J = 7.2 Hz, J = 12.6 Hz, J = 9.0 Hz), 2.74 (s, 3 H, NCH₃), 2.86 (ddd, 1 H, J = 1.8 Hz, J = 5.4 Hz, J = 12.6 Hz), 3.92 (m, 3 H). ¹³C NMR (CDCl₃, 75 MHz): δ = 18.4, 22.2, 22.3, 23.1, 24.1, 24.2, 25.9 (NCH₃), 29.5, 34.5, 37.8, 40.7, 48.0, 48.8, 65.7, 80.8, 89.2, 172.5 (C=O). MS (ESI): m/z = 373 [M + H]⁺, 395 [M + Na]⁺, 767 [2 M + Na]⁺. Cycloadduct 4e: [α]_D ²² +54 (c 1, CH₂Cl₂); yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ = 0.83 (d, 3 H, J = 6.6 Hz, CH₃), 0.85 (d, 3 H, J = 6.6 Hz, CH₃), 0.92 (m, 1 H), 0.93 (d, 3 H, J = 6.3 Hz, CH₃), 1.26 (t, 1 H, J = 12.3 Hz), 1.36 (m, 1 H), 1.39 (m, 1 H), 1.65 (m, 2 H), 1.67 (d, 3 H, J = 6.6 Hz, CH₃), 1.83 (m, 1 H), 2.05 (dt, 1 H, J = 2.5 Hz, J = 12.0 Hz), 2.11 (m, 1 H), 2.22 (ddd, 1 H, J = 9.0 Hz, J = 6.0 Hz, J = 12.3 Hz), 2.69 (ddd, 1 H, J = 5.1 Hz, J = 12.3 Hz), 2.75 (s, 3 H, NCH₃), 3.90 (ddd, 1 H, J = 5.1 Hz, J = 4.5 Hz), 4.02 (br d, 1 H, J = 9.0 Hz), 4.02 (dq, 1 H, J = 6.6 Hz, J = 7.2 Hz). ¹³C NMR (CDCl₃, 75 MHz): δ = 18.3, 22.3, 22.3, 22.4, 24.1, 24.3, 26.0 (NCH₃), 29.6, 34.5, 36.1, 40.6, 47.8, 48.0, 66.6, 81.2, 90.0, 172.4 (C=O). MS (ESI): m/z = 373.1 [M]⁺, 769.0 [2 M + Na]⁺. HRMS (ESI): m/z calcd for C₁₇H₂₉BrN₂O₂ [M]⁺: 373.1491; found: 373.1491.

Sample purchased from Acros Organics.

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General Procedure: A suspension of cycloadduct 3a-d or 4a-d (100 mg) and Pd(OH)₂/C (20%, 15 mg) was stirred in MeOH (10 mL) at r.t. under H₂ (1 atm). When the reaction was complete (TLC) (CHCl₃-i-PrOH, 98:2), the mixture was filtered over Celite, concentrated, and purified by flash chromatography (CHCl₃-i-PrOH, 98:2) to afford the desired spiro-imidazolidinones 5a, 5b, 5d or 6a, 6b, 6d. Imidazolidinone 5a: [α]_D ²² +13 (c 1, CH₂Cl₂); colorless oil. ¹H NMR (CDCl₃, 300 MHz): δ = 0.87 (d, 3 H, J = 6.9 Hz, CH₃), 0.89 (d, 3 H, J = 6.9 Hz, CH₃), 0.90 (m, 1 H), 0.93 (d, 3 H, J = 6.3 Hz, CH₃), 1.16 (d, 3 H, J = 6.3 Hz, CH₃), 1.38 (m, 2 H), 1.50 (m, 2 H), 1.58 (t, 1 H, J = 6.9 Hz), 1.68 (m, 2 H), 1.76 (m, 1 H), 1.81 (m, 1 H), 1.88 (ddd, 1 H, J = 2.1 Hz, J = 3.9 Hz, J = 13.1 Hz), 2.17 (br s, 1 H, OH), 2.76 (s, 3 H, NCH₃), 3.72 (m, 2 H), 3.83 (m, 1 H), 5.57 (br s, 1 H, NH). ¹³C NMR (CDCl₃, 75 MHz): δ = 17.5, 18.4, 22.1, 22.2, 23.9, 24.6, 25.4 (NCH₃), 28.8, 34.0, 34.4, 46.6, 48.0, 58.3, 70.1, 73.4, 81.3, 174.6 (C = O). MS (ESI): m/z = 313 [M + H]⁺, 647.0 [2 M + Na]⁺. HRMS (CI, isobutane): m/z calcd for C₁₇H₃₂N₂O₃ [M + H]⁺: 313.2491; found: 313.2490.

Typical Procedure: A solution of 1,3-imidazolidinone 5a (100 mg) and AcOH (25 mL) in aq HCl (3 N, 30 mL) was stirred at 80 °C for 2 h. The reaction mixture was then evaporated to dryness and LiOH·H₂O (200 mg) in THF-H₂O (1:1, 10 mL) was added. The resulting mixture was stirred at r.t. for 2 h, then concentrated to dryness and purified by reverse-phase flash chromatography (C₁₈) to afford the desired amino acid 7. [α]_D ²² -23 (c 1, H₂O); white solid; mp 194-195 °C (MeOH). ¹H NMR (D₂O, 300 MHz): δ = 1.12 (d, 3 H, J = 6.6 Hz, CH₃), 1.73 (m, 2 H, H-3), 3.50 (dd, 1 H, J = 4.8 Hz, J = 7.8 Hz, H-2), 3.65 (m, 1 H, H-4), 3.71 (m, 1 H, H-5). ¹³C NMR (D₂O, 75 MHz): δ = 17.0 (CH₃), 35.7 (C-3), 53.4 (C-2), 70.8 (C-5), 72.5 (C-4), 181.3 (C=O). MS (ESI, negative mode): m/z = 162 [M - H]^-. HRMS (CI, isobutane): m/z calcd for C₆H₁₃NO₄ [M + H]⁺: 164.0923; found: 164.0919.

Crystallographic data for 3a, 3e, and 4a have been deposited with the Cambridge Crystallographic Data Centre, under the following reference numbers: CCDC 606452 (3a); CCDC 601858 (3e); CCDC 606451 (4a). Copies of these data can be obtained on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk).

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