Diastereoselective Cyclization of γ-δ Epoxyketones with (-)-Phenylglycinol: Synthesis of Both Enantiomers of cis-5-Alkyl-2-hydroxymethyl Pyrrolidines

José M. Andrés; Ignacio Herráiz; Rafael Pedrosa; Alfonso Pérez-Encabo

doi:10.1055/s-2004-830867

LETTER

Diastereoselective Cyclization of γ-δ Epoxyketones with (-)-Phenylglycinol: Synthesis of Both Enantiomers of cis-5-Alkyl-2-hydroxymethyl Pyrrolidines

José M. Andrés, Ignacio Herráiz, Rafael Pedrosa*, Alfonso Pérez-Encabo
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47002-Valladolid, Spain
e-Mail: pedrosa@qo.uva.es ;

Abstract

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Abstract

A novel condensation of (-)-phenylglycinol with γ,δ-epoxyketones is reported for the preparation of both enantiomers of cis-5-alkyl-2-hydroxymethyl pyrrolidines. The required epoxy-derivatives were easily prepared by epoxidation of the corresponding γ,δ-unsaturated ketones. Condensation with (-)-phenylglycinol is regiospecific and stereoselective, giving only two of the four possible diastereomers. The stereochemistry of the cyclization products is dictated by the configuration of C-2 in the N-unsubstituted oxazolidine formed as intermediate.

Key words

1,2-aminoalcohols - asymmetric Synthesis - cyclizations - oxazolidines - pyrrolidines

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References

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Experimental Procedure: To a solution of epoxyketone (3.0 mmol) in CHCl₃ (3 mL), cooled to 0 °C was added
(-)-phenylglycinol (0.41 g, 3.0 mmol) in CHCl₃ (3 mL) and MgSO₄ (0.2 g). The mixture was stirred at that temperature for 2 h and then warmed to r.t. and stirred for additional 13 h. The mixture was filtered, the solvent concentrated and the residue was purified by flash chromatography (silca gel, EtOAc-hexane 1:4, v/v).

Spectroscopic data for compounds: 2a: [α]_D ²⁵ +27.2 (c 0.7, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.50 (s, 3 H), 1.60-1.73 (m, 1 H), 1.81-1.89 (m, 1 H), 1.96-2.09 (m, 2 H), 2.60 (br s, 1 H), 2.78 (dd, J = 5.0, 10.4 Hz, 1 H), 2.97-3.08 (m, 2 H), 3.98 (dd, J = 7.9, 9.9 Hz, 1 H), 4.13 (dd, J = 6.1, 7.9 Hz, 1 H), 4.62 (dd, J = 6.1, 9.9 Hz, 1 H), 7.25-7.5 (m, 5 H). ¹³C NMR (75 MHz, CD₃Cl): δ = 25.9, 27.3, 37.9, 59.7, 64.2, 64.3, 67.0, 106.5, 128.1, 128.5 (2 C), 128.9 (2 C), 135.4. Compound 2b: [α]_D ²⁵ +7.3 (c 0.6, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, J = 6.5 Hz, 3 H), 1.20-1.57 (m, 10 H), 1.58-1.73 (m, 2 H), 1.74-1.91 (m, 2 H), 1.92-2.15 (m, 2 H), 2.45 (br s, 1 H), 2.72 (dd, J = 4.7, 10.4 Hz, 1 H), 2.98 (dd, J = 3.7, 10.4 Hz, 1 H), 3.05-3.15 (m, 1 H), 4.0 (dd, J = 7.9, 10.0 Hz, 1 H), 4.11 (dd, J = 6.1, 7.8 Hz, 1 H), 4.60 (dd, J = 6.1, 10.0 Hz, 1 H), 7.25-7.52 (m, 5 H). ¹³C NMR (75 MHz, CD₃Cl): δ = 14.1, 22.6, 25.2, 27.3, 29,3, 30.0, 31.8, 35.6, 39.2, 59.4, 63.8, 64.5, 66.6, 108.7, 128.2, 128.5 (2 C), 128.9 (2 C), 135.2. Compound 3a: [α]_D ²⁵ -97.8 (c 0.7, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.48 (s, 3 H), 1.75-1.86 (m, 1 H), 1.92-2.11 (m, 3 H), 2.21-2.27 (m, 1 H), 3.10-3.15 (m, 1 H), 3.26-3.35 (m, 2 H), 3.83 (t, J = 8.6 Hz, 1 H), 4.05 (t, J = 7.6 Hz, 1 H), 4.34 (dd, J = 6.1, 8.6 Hz, 1 H), 7.23-7.40 (m, 5 H). ¹³C NMR (75 MHz, CD₃Cl): δ = 26.8, 27.2, 37.8, 63.2, 69.9, 70.8, 73.5, 105.8, 126.5 (2 C), 127.4, 128.7 (2 C), 141.6. Compound 3b: [α]_D ²⁵ -70.6 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃) δ = 0.90 (t, J = 6.5 Hz, 3 H), 1.29-1.61 (m, 11 H), 1.69-1.78 (m, 1 H), 1.81-1.93 (m, 1 H), 1.95-2.12 (m, 3 H), 2.27 (br s, 1 H), 3.13 (tq, J = 5.7 Hz, 1 H), 3.25-3.38 (m, 2 H), 3.76 (t, J = 8.7 Hz, 1 H), 4.08 (dd, J = 7.2, 8.4 Hz, 1 H), 4.33 (dd, J = 7.2, 8.7 Hz, 1 H), 7.24-7.40 (m, 5 H). ¹³C NMR (75 MHz, CD₃Cl): δ = 14.1, 22.6, 25.0, 26.9, 29.2, 29.9, 31.8, 35.0, 39.2, 63.3, 69.7, 71.0, 73.2, 108.2, 126.5 (2 C), 127.4, 128.7 (2 C), 141.7.

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Data for N-Boc Pyrrolidines: 5a: [α]_D ²⁵ -9.9 (c 1.2, CHCl₃). ent-5a: [α]_D ²⁵ +9.95 (c 1.3, CHCl₃). N-Boc derivatives of (2 R ,5 R )-5-heptyl-2-hydroxymethyl pyrrolidine: [α]_D ²⁵ +4.1 (c 0.8, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, J = 6.2 Hz, 3 H), 1.25 (m, 10 H), 1.44 (s, 9 H), 1.51-1.65 (m, 3 H), 1.82-1.97 (m, 3 H), 3.51 (t, J = 8.6 Hz, 1 H), 3.67 (t, J = 8.4 Hz, 1 H), 3.72-3.89 (m, 1 H), 3.90-4.01 (m, 1 H), 5.12 (br s, 1 H). ¹³C NMR (75 MHz, CD₃Cl): δ = 14.1, 22.6, 26.5, 26.8, 28.4 (3 C), 28.9, 29.2, 29.5, 31.8, 35.4, 59.2, 61.1, 68.8, 80.2, 157.4. N-Boc derivatives of (2 S ,5 S )-5-heptyl-2-hydroxymethyl pyrrolidine: [α]_D ²⁵ -4.0 (c 0.9, CHCl₃).

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