2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-hydroxy-butanoic acid synthesis

Yield:73731-37-0 100%

Reaction Conditions:

Stage #1:L-threonine;N-(9H-fluoren-2-ylmethoxycarbonyloxy)succinimide with sodium carbonate in 1,4-dioxane;water at 20;Inert atmosphere;
Stage #2: with hydrogenchloride in water; pH=4

Steps:

(2S,3R)-Benzyl 2-amino-3-((triisopropylsilyl)oxy)butanoate (17d)
At r.t. a solution of FmocONSu (3.37 g, 10.0 mmol) in 25 mL of Dioxane¹² is added over 1h to a solution of L-threonine (1.19 g, 10.0 mmol) and Na₂CO₃ (1.06 g, 10.0 mmol) in 10 mL Dioxane and 25 mL water. The resulting suspension is stirred overnight and becomes clear. The solvent is evaporated in vacuo and the product is precipitated with 1M HCl_aq. at pH 4, filtered, washed with water and dissolved in EtOAc. The organic phase is dried (Na₂SO₄) and evaporated to yield the product quantitatively as a white solid which does not need any further purification. Under argon atmosphere Fmoc-threonine (2.67 g, 7.80 mmol) is dissolved in 32 mL dry MeOH. Then Cs₂CO₃ (1.40 g, 4.30 mmol) is added.¹¹ After 15 min the solvent is evaporated and the resulting solid is three times suspended in CH₂Cl₂ and evaporated to remove all the MeOH. The Cs-salt is then suspended in 36 mL of dry DMF under argon atmosphere and stirred with benzylbromide (1.02 mL, 1.47 g, 8.60 mmol) over night at r.t. After evaporation of the solvent in vacuo, the residue is partitioned between water and CH₂Cl₂. The water phase is subsequently extracted two times with EtOAc. The combined organic phases are dried (Na₂SO₄) and evaporated. The crude product is purified either by recrystallisation from EtOAc or by silica column chromatography (cyclohexane/EtOAc 4 : 1) to get Fmoc-threoninebenzylester (3.07 g, 7.10 mmol, 91%, R_f = 0.17 (cyclohexane/EtOAc 3 : 1)) as a white solid. The Fmoc-threoninebenzylester (2.16 g, 5.00 mmol) is dissolved in 48 mL dry CH₂Cl₂ under argon atmosphere. The solution is cooled to 0°C and NEt₃ (770 µL, 560 mg, 5.50 mmol) and Triisopropylsilyltriflat (1.42 mL, 1.61 g, 5.25 mmol) is added subsequently.¹² The mixture is allowed to warm to r.t. and is stirred 1h. Then 30 mL of dilute K₂CO₃- solution is added. The phases are separated and the water phase is extracted two times with CH₂Cl₂. The combined organic phases are dried (Na₂SO₄) and evaporated. The crude product is purified by silica column chromatography (cyclohexane/EtOAc 10 : 1) to get Fmoc(OTIPS)benzylester (2.47 g, 4.20 mmol, 84%, R_f = 0.61 (cyclohexane/EtOAc 3 : 1)) as a colourless oil. Fmoc(OTIPS)benzylester (0.87 g, 1.48 mmol) is dissolved in 7.4 mL dry CH₂Cl₂ under argon atmosphere. The solution is cooled to 0°C and 7.4 mL of 40% (v/v) Piperidine solution in dry CH₂Cl₂ are added dropwise.¹³ After 15 min of stirring at 0°C, the mixture is concentrated in vacuo at 25°C to an oil and put immediately onto the silica column (cyclohexane/EtOAc 5 : 1 + 0.5% NEt₃, elution of product with 1 : 1 + 0.5% NEt₃). Yield of the title compound 17d is 0.44 g (1.20 mmol, 81%) as a colourless oil.

References:

Loke, Inga;Park, Natja;Kempf, Karl;Jagusch, Carsten;Schobert, Rainer;Laschat, Sabine [Tetrahedron,2012,vol. 68,# 2,p. 697 - 704] Location in patent:supporting information; experimental part

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