A Practical Approach for Enantio- and Diastereocontrol in the Synthesis of 2,3-Disubstituted Succinic Acid Esters: Synthesis of the pan-Notch Inhibitor BMS-906024

Abstract

An oxidative intermolecular enolate heterocoupling reaction was employed for the synthesis of anti-2,3-disubstituted succinic acid mono- and differentially protected diesters. Tactical approaches to access all the diastereomers are discussed. The method was applied to the synthesis of a potent anticancer agent, BMS-906024.

Key words

oxidative enolate coupling - chiral succinic acid - pan-Notch Inhibitor BMS-906024

• References and Notes

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• 9 Five separate vessels, all appropriately dried, were set up as follows: 1) a flask fitted with a stir bar to be used to prepare LDA, purged with N₂; 2) a flask containing bis(2-ethylhexanoyloxy)copper, placed under vacuum for several hours to remove oxygen, then purged with N₂; 3) a flask of appropriate size (this will be the main reaction flask, the larger the better for efficient heat transfer later in the procedure was found to be ideal) equipped with a stir bar was charged with LiCl, placed under vacuum then dried with a heat gun until all traces of water were removed, then purged with N₂; 4) a flask charged with the amide starting material, purged with N₂; 5) a flask equipped with a stir bar was charged with the ester starting material, purged with N₂. Procedure A 0.5 M solution of LDA was prepared by the addition of a solution of 2.5 M n-BuLi in hexanes (14.7 mL, 36.8 mmol) to a cold (–78 °C) solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under N₂. The solution was stirred at 0 °C for 15 min. A solution of (S)-4-isopropyl-3-(5,5,5-trifluoropentanoyl)oxazolidin-2-one (2.45 g, 9.2 mmol) in toluene (15.3 mL) was added with stirring to dry LiCl (1.96 g, 46.2 mmol). The mixture was cooled to –78 °C, and the freshly prepared 0.5 M solution of LDA (21.0 mL, 10.5 mmol) was added. The reaction mixture was stirred at –78 °C for 10 min, at 0 °C for 10 min, and cooled to –78 °C. Meanwhile, the freshly prepared 0.5 M solution of LDA (37.0 mL, 18.5 mmol) was added to a cold (–78 °C) solution of tert-butyl 5,5,5-trifluoropentanoate (3.41 g, 16.1 mmol) in toluene (15.3 mL). After 25 min of stirring at –78 °C, this reaction mixture was transferred via cannula into the cold (–78 °C) LiCl/enolate solution. After an additional 5 min of stirring at –78 °C, solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel through a funnel, and the flask was rapidly recapped with a septum. The vessel was immediately removed from the cold bath and immersed into a warm (40 °C) water bath with rapid swirling. The reaction mixture changed from the initial turquoise to a dark green then to a brown color. After 20 min of stirring, the reaction mixture was poured into 5% aq NH₄OH (360 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0–60% EtOAc in hexanes, RediSep silica gel, 120 g). Concentration of appropriate fractions provided the product tert-butyl (2S,3R)-6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate (2.87 g, 66%) as a pale yellow oil. ¹H NMR indicated that the product was a 1.6:1 mixture of diastereomers, as determined by integration of the multiplets at 2.74 and 2.84 ppm. ¹H NMR (400 MHz, CDCl₃): δ = 4.43–4.54 (2 H, m), 4.23–4.35 (5 H, m), 4.01 (1 H, ddd, J = 9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J = 10.29, 6.27, 4.02 Hz), 2.37–2.48 (2 H, m), 2.20–2.37 (3 H, m), 1.92–2.20 (8 H, m), 1.64–1.91 (5 H, m), 1.47 (18 H, s), 0.88–0.98 (12 H, m).
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• 12 To a cold (–78 °C), stirred solution of DIPA (1.7 mL, 11.9 mmol) in THF (19 mL) under nitrogen was added a 2.5 M solution of n-BuLi in hexanes (4.8 mL, 12.0 mmol). The reaction mixture was stirred at –78°C for 5 min, then at 0 °C for 15 min, and transferred via cannula dropwise (over 25 min) to a cold (–78 °C) solution of a 1.7:1 ratio for 3-(tert-butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid (1.99 g, 5.4 mmol) in THF (18 mL). The mixture was stirred at –78 °C for 15 min, then at 24 °C for 15 min, and again at –78°C for 15 min. A 1 M solution of diethylaluminum chloride in hexanes (11.4 mL, 11.4 mmol) was added dropwise via syringe, and stirring was con­tinued at –78 °C for 10 min, at 24 °C for 15 min, and again at –78 °C for 15 min. MeOH (25 mL) was rapidly added, and the flask was swirled vigorously while warming to room temperature. The reaction mixture was concentrated to ca. 25% of the original volume. EtOAc (100 mL), aq 1 M HCl (50 mL), and ice (75 g) were added. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organics were washed with a solution of a mixture of KF (2.85 g) in water (75 mL) and aq 1 M HCl (13 mL), then subsequently washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure to provide the product (2R,3S)-3-(tert-butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid (2.13 g, >99%) as a pale yellow oil. Relative integration of the t-Bu peaks in ¹H NMR established a 9:1 ratio for the anti/syn diastereomers, respectively. anti-Isomer: ¹H NMR (400 MHz, CDCl₃): δ = 2.64–2.76 (2 H, m), 2.04–2.35 (4 H, m), 1.88–2.00 (2 H, m), 1.71–1.83 (2 H, m), 1.48 (9 H, s).
• 13 The residue was purified by flash chromatography using a Teledyne ISCO CombiFlash Rf system with an external ELS detector, and a gradient from 60–100% toluene and hexane.
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