Synthesis of a Novel Tetrahydroxylated β-Homoproline

Abstract

A gram-scale synthesis of a novel densely functionalized and orthogonally protected β-homoproline was achieved from l-tartaric acid derived nitrone through a highly stereoselective 1,3-­dipolar cycloaddition to γ-crotonolactone as the key initial step, followed by appropriate elaboration of the adduct.

Key words

non-natural amino acid - total synthesis - nitrone - ­cycloaddition

References and Notes

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23

Data for Compound 1 (Mixture of Two Rotamers)
Yellow solid, mp 88-90 ˚C. ^¹H NMR (400 MHz, CDCl₃):
δ = 7.79-7.78 (m, 2 H), 7.68-7.60 (m, 2 H), 7.44-7.30 (m, 4 H), 4.70-4.66 (m), 4.61-4.24 (m), 4.01-3.97 (m), 3.92-3.81 (m), 3.73-3.64 (m), 3.42 (t, J = 9.5 Hz), 3.32 (t, J = 10.0 Hz), 3.26 (d, J = 11.5 Hz), 3.10 (d, J = 11.5 Hz) (for a total of 12 H), 1.40 (s), 1.33 (s), 1.32 (s), 1.29 (s) (for a total of 6 H), 1.25 (s), 1.20 (s), 1.18 (s), 1.08 (s) (for a total of 18 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 176.9, 176.8 (s, COOH), 156.4,155.1 (s, C=O Fmoc), 143.9, 143.8, 143.6, 141.4, 141.3, 141.2 (s, 4 C, Fmoc), 127.7-119.9 (d, 8 C, Fmoc), 108.3, 108.2 (s, CO acetonide), 78.4, 77.6, 76.3, 75.6, 75.5, 75.2 (d, 3 C), 74.7, 74.5, 74.4, 74.3 (s, 2 C, CO t-Bu), 68.1, 67.9, 67.5, 67.1 (t), 65.2, 64.5 (d), 54.6, 54.2 (t), 52.9, 51.7 (d), 47.1, 47.0 (d, Fmoc), 28.3, 28.2, 28.1, 28.0 (q, 6 C, t-Bu), 26.5, 26.3, 25.7, 25.5 (q, 2 C, acetonide). IR (KBr): 3600-2400 (large), 2976, 1706, 1368, 1185, 740 cm^-¹. ESI-MS: m/z (%) = 596.25 (27)[M⁺ + 1], 618.42 (100) [M⁺ + Na]. Anal. Calcd for C₃₄H₄₅NO₈ (595.72): C, 68.55; H, 7.61; N, 2.35. Found: C, 68.32; H, 7.47; N, 2.68. [α]_D ^²5 +3.27 (c 1.47, CH₂Cl₂).