Multigram-Scale Synthesis of IS, 2S -Cyclohex-4-ene-l,2-dicarboxylic acid

Multigram-Scale Synthesis of (IS, 2S)-Cyclohex-4-ene-l,2-dicarboxylic acid 7 

If the reaction conditions are forced (longer time, higher concentration, or temperature), some trans-esterification also takes place, yielding variable amounts of a mono tert-butylester, which can be hydrolyzed to the diacid in quantitative yield by treatment of the crade with TEA. 

The enantiomeric excess of 7 can be improved by recrystalhzation of its quinine salt, using the following procedure to a solution of 7 (74% ee, 5.12 g, 30.1 mmol, lequiv) in MeOH (36 ml) was added a solution of quinine (12.4 g in 12.8 ml of MeOH, 38.2 mmol, 1.3 equiv) and the solution was stirred at 40°C for 10min. Then, the solvent was evaporated, the residue redissolved in AcOEt (25 ml) and heated under reflux for 10 min. After coohng to room temperature, the mixture was filtered to eliminate the excess of quinine. The filtrate was evaporated and the solid (15.65 g) crystallized from MeOH (about 20 ml) to obtain the quininium salt as a white sohd. 

To recover the acid, the quininium salt was dissolved in a 10% HCl solution in water (500ml) and extracted with AcOEt (3x 240ml). The combined organic phases were washed with 10% HCl (2 x 50 ml), brine (2x 40 ml), and H2O (40 ml). The organic phase was dried with Naj SO4 and the solvent was evaporated to obtain the enantiomerically pure (lS,2S)-diacid 7 (3.7g, 82%). Quinine was recovered by treatment of the acidic water solution with NaOH. The sohd was filtered and washed with HtO. 

2 mmol) was added and the solution was stirred at 80 °C until the mixture was dear and uniform [64]. Then, the solution was cooled to room temperature and aUyl-TMS (trimethylsilyl 8.3 ml, 52 mmol) was added, followed by TMSOTf (9.6 ml, 52 mmol). The reaction was stirred for 18 h and was worked up by adding ice-cold deionized H2O (12 ml) and stirring for 10 min. Then, the solution was neutralized with EtjN and the solvent was evaporated under reduced pressure. 

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