Mono-tert-butyl succinate

The monoester of succinate was prepared as described by Srinivasan, Uttamchandani and Yao [42]: Tert-butanol (10 mL) was added to asolution of succinic anhydrate (6.04 g, 60.40 mmol), Nhydroxysuccinimid (2.53g, 22.01 mmol) and DMAP (0.88 g, 7.23 mmol) in toluene (100 mL)and the solution was heated for 48 h under reflux conditions. After cooling down to rt, twolayers formed in the reaction vessel (brown oil and clear, colourless solution). The crudesolution was diluted with EtOAc (50 mL) and washed with citric acid (10 percent, 2 × 50 mL) andbrine. The organic layer was dried over Na2SO4, the solvent evaporated and the crude productwas recrystallized from Et2O/PE (1:3, 25 mL) to yield the title compound in quantitativeyield.Succinic anhydride 7 (10 g, 100 mmol), N-hydroxysuccinimide (3.34 g, 0.30 mmol), and DMAP (1.17 g, 1.00 mmol) were dissolved in toluene (50 mL). tert-Butanol (11.7 mL, 124 mmol) and EtSuccinic anhydride (10 g, 100 mmol) was reacted with anhydrous t-butyl alcohol (17 mL) in anhydrous toluene (150 mL) in the presence of dimethylaminopyridine (1.8 g, 15 mmol), N-hydroxysuccinamide (3.45 g, 30 mmol), and trimethylamine (4.2 mL, 30 mmol) to yield the ring opened mono-tert-butylsuccinate product (4). The product was purified by ethyl acetate and water extractions followed by recrystallization of the isolated products of the organic phase in 1:3 ether:hexanes (77percent). The pure compound (4) (5.57 g, 31.9 mmol) was then reacted with tert-Butyldimethylchlorosilane (TBDMS) protected diethanolamine (24.6 mmol) in a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (6.60 g, 34.4 mmol) mediated coupling reaction in anhydrous N, N-dimethylformamide (DMF) (30 mL) overnight. The resulting product (5) was purified by removing the DMF via rotovap, performing ethyl acetate and water extractions, and further purifying the product by performing silica gel liquid column chromatography using ethyl acetate and hexanes as the mobile phase (69.8percent). Deprotection of the TBDMS groups was performed by reacting the purified product from the previous step with iodine in methanol (2percent w/v) at reflux for three hours. After reaction, NaSuccinic anhydride, 3 (5.0g, 49.96mmol) was suspended in 30mL of toluene under nitrogen atmosphere. N-Hydroxysuccinimide (1.72g, 14.98mmol), 4-(dimethylamino)pyridine (0.610g, 4.9mmol), dry tert-butyl alcohol (15mL, 150mmol), and EtTo a stirred solution of benzyl tert-butyl butanedioate (2.3 g, 8.71 mmol) in dry THF (30mL), 10percent Pd-C (0.23 g) was added and stirred under H2 atmosphere (balloon) for 16 h (TLCindicated complete consumption of starting material). The reaction mixture was filteredthrough Celite and washed with CHCh (100 mL). The filtrate was concentrated in vacuo togive crude residue which was purified by column chromatography (100-200 silica gel, 30 g, 35percent EtOAc-Hexane) to afford 4-tert-butoxy-4-oxo-butanoic acid (0.8 g, 52percent) as a colorlessoil.1H NMR [400 MHz, CDCh]: 8 2.65-2.61 (m, 2H), 2.56-2.52 (m, 2H), 1.44 (s, 9H).