A Concise Organocatalytic Route to Protected (2S,4R)-4-Hydroxyornithine and (+)-Pseudohygroline

Abstract

A practical, efficient, and organocatalytic approach to the synthesis of (2S,4R)-4-hydroxyornithine and (+)-pseudohygroline is reported using proline-catalyzed sequential α-aminoxylation/α-amination reaction and Horner–Wadsworth–Emmons olefination reaction of an aldehyde as the key step.

Key words

aldehydes - amination - amino alcohols - Wittig reaction - cyclization - enantioselectivity

• References and Notes

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• 21 The ee of 7a was determined by derivatizing it with Mosher’s acid and analyzing the ¹⁹F NMR spectrum. The ee of 7b was determined by comparing its specific rotation with the literature value.^24a The diastereomeric ratios of 10 and 13 were determined using HPLC analysis (see Supporting Information).
• 22 Dibenzyl 1-{(2S,4R)-5-[(tert-Butoxycarbonyl)amino]-4-[(tert-butyldimethylsilyl)oxy]-1-hydroxypentan-2-yl}hydrazine-1,2-dicarboxylate (10) Colorless oil; yield 2.122 g (63%). [α]_D ²⁵ –9.56 (c 1.0, CHCl₃). IR (CHCl₃): ν_max = 3019, 2956, 1712, 1505, 1216 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.02 (s, 3 H), 0.90 (s, 9 H), 1.45 (s, 9 H), 1.66–1.82 (m, 2 H), 3.24–3.48 (m, 2 H), 3.90–4.15 (m, 3 H), 4.40–4.73 (m,1 H), 5.07–5.34 (m, 4 H), 6.11–6.19 (m, 1 H), 7.22–7.36 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = –4.8, –4.7, 17.9, 25.8, 28.6, 31.8, 32.6, 53.3, 62.3, 62.5, 67.9, 71.8, 71.9, 79.7, 126.4, 127.8, 128.1, 128.5, 129.3, 135.3, 135.5, 135.9, 138.1, 138.3, 155.9, 156.5, 158.1, 158.6 ppm. ESI-MS: m/z = 654.43 [M + Na]⁺. Anal. Calcd (%) for C₃₂H₄₉N₃O₈Si: C, 60.83; H, 7.82; N, 6.65. Found: C, 60.70; H, 7.91; N, 6.57. Dibenzyl 1-{(4S,6S,E)-6-[(tert-butyldimethylsilyl)oxy]-1-ethoxy-1-oxohept-2-en-4-yl}hydrazine-1,2-dicarboxylate (13) Colorless oil; yield 1.33 g (65%). [α]_D ²⁵ +2.32 (c 0.5, CHCl₃). IR (CHCl₃): ν_max = 3295, 2956, 1755, 1719, 1406, 1043 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = –0.02 (s, 3 H), 0.03 (s, 3 H), 0.85 (s, 9 H), 1.16 (d, J = 6.2 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 2 H), 1.64–1.72 (m, 2 H), 3.76–3.93 (m, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.91–5.15 (m, 5 H), 5.94 (m, 1 H), 6.57 (br s, 1 H), 6.83 (dd, J = 6.8, 15.6 Hz, 1 H), 7.31 (m, 10 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = –4.8, –4.1, 14.1, 17.9, 24.1, 29.9, 40.6, 56.5, 60.5, 67.4, 67.7, 68.3, 122.9, 128.0, 128.1, 128.3, 128.4, 135.5, 144.6, 155.3, 156.3, 166.1 ppm. ESI-MS: m/z = 607.32 [M + Na]⁺. Anal. Calcd (%) for C₃₁H₄₄N₂O₇Si: C, 63.67; H, 7.58; N, 4.79. Found: C, 63.39; H, 7.43; N, 4.92.
• 23 (2S,4R)-2,5-Bis{(tert-butoxycarbonyl)amino)-4-[(tert-butyldimethylsilyl]oxy}pentanoic Acid (12) Viscous oil; yield 42 mg (82%). [α]_D ²⁵ –34.56 (c 1, CHCl₃). IR (CHCl₃): ν_max = 3346, 2910, 1716, 1453 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 0.08 (s, 6 H), 0.88 (s, 9 H), 1.45 (s, 18 H), 1.73–1.79 (m, 2 H), 3.07–3.28 (m, 1 H), 3.55–3.80 (m, 1 H), 3.90–4.11 (m, 2 H), 5.59 (br s, 1 H), 5.74 (br s, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = –5.1, –4.7, 14.1, 18.0, 22.7, 28.3, 31.9, 42.5, 65.2, 66.4, 80.4, 163.3 ppm. ESI-MS: m/z = 485.21 [M + Na]⁺. Anal. Calcd (%) for C₂₁H₄₂N₂O₇Si: C, 54.52; H, 9.15; N, 6.05. Found: C, 54.25; H, 9.37; N, 5.75. (+)-Pseudohygroline (5a) Colorless liquid; yield 0.02 g (95%). [α]_D ²⁵ –48.12 (c 0.5, EtOH). ¹H NMR (200 MHz, CDCl₃): δ = 1.17 (d, J = 6.2 Hz, 3 H), 1.31–1.45 (m, 3 H), 1.71–1.78 (m, 2 H), 1.98–2.04 (m, 1 H), 2.31–2.40 (m, 1 H), 2.37 (s, 3 H), 2.69–2.77 (m, 1 H), 3.00–3.08 (m, 1 H), 3.87–3.96 (m, 1 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 21.9, 22.8, 29.1, 38.1, 40.6, 56.5, 67.1, 68.2 ppm. ESI-MS: m/z = 144.22 [M + H]⁺.
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