A Stereodivergent Synthesis of Hydroxyethylene Dipeptide Isostere via Highly Diastereoselective Epoxidation

Abstract

Epoxidation of δ-amino-β,γ-unsaturated ester with tri­fluoroperacetic acid afforded its epoxide in a highly diastereo­selective manner. Subsequent stereodivergent epoxide opening reactions provided synthetic routes towards both the threo and erythro hydroxyethylene peptide isostere.

Key words

hydroxyethylene isostere - diastereoselective epoxidation - stereodivergent - epoxide ring opening

References

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19

Ene-acid 3a is available in multi-kg quantities (Z/E selectivity, 24:1; 83% ee); see ref. 20.

22

Preparation of 4a: To a stirred mixture of 3b (660 mg, 1.87 mmol), urea hydrogen peroxide (790 mg, 8.40 mmol), and Na₂HPO₄ (1.12 g, 7.89 mmol) in CH₂Cl₂ (10 mL) was added (CF₃CO)₂O (784 mg, 3.73 mmol) at 0 °C. The mixture was allowed to warm to r.t. and stirred for 4 h. The reaction mixture was washed with a sat. aq solution of NaHCO₃, a 5% solution of NaHSO₃, and finally H₂O. The separated organic layer was concentrated and MTBE (15 mL) was added to the residue. The mixture was stirred for 5 h. The solid formed was filtered and washed with MTBE (2 mL). The cake was dried over a stream of nitrogen to give 4a (615 mg, 86.1%) as a white solid; 4a t _R 31.4 min, ent -4a t _R 40.8 min (Chiralpak^® AD-H; 35 °C; 10% i-PrOH-hexane; 1 mL/min; 250 nm); ee of isolated 4a ³99.9%, while the ee of the filtrate was 50%, which reflects highly selective recrystallization. ¹H NMR (CDCl₃, 400 MHz): δ = 7.38-7.18 (10 H, m), 5.12 (1 H, d, J = 12.4 Hz), 5.09 (1 H, d, J = 12.4 Hz), 4.95 (1 H, br), 3.71 (1 H, m), 3.67 (3 H, s), 3.32 (1 H, m), 3.07 (1 H, m), 3.01 (1 H, dd, J = 8.0, 4.4 Hz), 2.85 (1 H, dd, J = 13.2, 8.0 Hz), 2.38 (1 H, dd, J = 16.8, 7.6 Hz), 2.03 (1 H, dd, J = 17.2, 4.8 Hz); ¹³C NMR (CDCl₃, 125 MHz): δ = 170.8, 155.8, 136.6, 136.5, 129.6, 128.7, 128.6, 128.2, 128.1, 127.0, 67.0, 57.6, 53.6, 52.0, 51.8, 39.5, 33.3.

25

Benzyl (1 S )-1-[(2′ S )-5′-oxotetrahydrofuran-2′-yl]-2-phenylethylcarbamate ( 6): [α]_D ²⁵ = -9.6 (CHCl₃, c 1); ¹H NMR (CDCl₃, 500 MHz): δ = 7.34-7.25 (10 H, m), 5.09 (1 H, d, J = 12.4 Hz), 5.05 (1 H, d, J = 12.4 Hz), 4.87 (d, 1 H, J = 10.0Hz), 4.48 (1 H, t, J = 7.8 Hz), 4.07 (dd, 1 H, J = 17.5, 8.7 Hz), 2.98 (1 H, dd, J = 13.3, 6.9 Hz), 2.90 (1 H, dd, J = 13.3, 8.7 Hz), 2.48 (dd, 2 H, J = 9.7, 7.4 Hz), 2.16-2.03 (2 H, m); ¹³C NMR (CDCl₃,125 MHz): δ = 177.2, 156.7, 137.1, 136.4, 129.4, 128.8, 128.6, 128.2, 128.0, 126.9, 79.9, 54.9, 39.3, 28.7, 24.1; MS: m/z = 340 [M + H].

27

Amino-ester side-product (Figure [1] ): ¹H NMR (CDCl₃, 400 MHz): δ = 7.34-7.28 (5 H, m), 3.57 (3 H, s), 3.51 (1 H, m), 3.24 (1 H, dd, J = 13.6, 5.6 Hz), 2.95 (1 H, dd, J = 13.6, 8.8 Hz), 2.32 (2 H, m), 1.95-1.69 (4 H, m); MS: m/z = 222 [M + H].

28

Lactam side-product (Figure [2] ): ¹H NMR (CDCl₃, 400 MHz): δ = 7.35-7.17 (5 H, m), 5.65 (1 H, br), 3.61 (1 H, m), 2.88 (1 H, dd, J = 13.6, 5.2 Hz), 2.62 (1 H, dd, J = 13.6, 9.2 Hz), 2.43-2.29 (2 H, m), 1.94 (2 H, m), 1.68 (1 H, m), 1.47 (1 H, m); MS: m/z = 190 [M + H] .

29

Benzyl (1 S )-1-[(2′ R )-5′-oxotetrahydrofuran-2′-yl]-2-phenylethylcarbamate ( 10): [α]_D ²⁵ = -8.6 (CHCl₃, c 0.02); ¹H NMR (CDCl₃, 400 MHz): δ = 7.37-7.18 (10 H, m), 5.04 (2 H, s), 4.66 (1 H, br), 4.40 (1 H, m), 4.05 (1 H, m), 3.03 (1 H, dd, J = 14.4, 4.4 Hz), 2.90 (1 H, m), 2.52 (2 H, m), 2.25 (1 H, m), 2.11 (1 H, m); ¹³C NMR (CDCl₃, 100 MHz): δ = 176.6, 165.9, 136.1, 132.7, 129.5, 128.8, 128.6, 128.3, 128.0, 127.0, 80.4, 60.4, 50.0, 30.9, 28.2, 24.7; MS: m/z = 340 [M + H] .