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december 2010 org prep daily org prep daily december 7 2010 diastereoselective cinnamate reduction oppolzer auxiliary filed under procedures milkshake 2 48 pm 6 methoxy 2h chromene 3 carboxylic acid 12 56g 60 9 mmol suspension in anhydrous dichloromethane 100ml was combined with 7 0 ml of neat oxalyl chloride followed by 4 drops of dmf the mixture was stirred under gas outlet tube filled with drierite for 1 day by this time the gas evolution ceased the homogenous reaction mixture was evaporated to dryness the residue was briefly dried on highvac the resulting solid was crushed with a spatula and re dried on highvac for 1 day y 13 66g 100 of a yellow solid this acyl chloride readily decomposes on storage it is best kept under high vacuum while protected from a direct sunlight and used on the same day oppolzer sultam auxiliary 5 785g 26 87 mmol solid in a 0 5l flask was flushed with dry ar 60 nah in mineral oil 1 505g 37 6 mmol was added followed by anhydrous toluene 250ml gas evolution the slurry was briefly sonicated for 5 min on a sonicator bath then stirred at ambient temperature under ar for 2h45 min the mix was then cooled to 0 c a solid acyl chloride 5 983g 26 87 mmol was added in one portion the mixture was placed placed on ambient water bath and stirred vigorously for 2 hours under ar there was a delayed gas evolution accompanied by foaming at the completion of the acylation the reaction was quenched by addition of silica 50g followed by hexanes 100ml after additional 10 minutes the entire reaction mix was applied onto a column of silica 500g in hexanes ethyl acetate 10 1 then rapidly eluted with the 10 1 mix and then with hexanes ethyl acetate 7 3 mix 3l there is a risk of the product crystallizing on the column if the elution is too slow a yellow band was collected combined fractions provided upon evaporation and drying on highvac 9 965g 92 th of the chromene acylated auxiliary as a yellow fluorescent solid 1h cdcl3 400mhz 7 31 br s 1h 6 80 m 2h 6 73 d 2 4hz 1h 5 03 dd 13 6hz 1 2hz 1h 4 81 dd 14 0hz 1 2hz 1h 4 12 dd 7 6hz 4 8hz 1h 3 77 s 3h 3 54 d 13 6hz 1h 3 43 d 13 6hz 1h 2 05 m 1h 1 93 m 4h 1 43 m 2h 1 30 s 3h 1 02 s 3h note 1 the intermediate from the previous step 2 020g 5 00 mmol in a 300ml rb flask was dissolved in anh thf 50ml under ar and the solution was cooled to 50 c l selectride 1m solution in thf 6 5 ml was added dropwise with vigorous stirring over 5 min period and the reaction was then maintained at 50c for additional 45 min the reaction was quenched at 55 c by dropwise addition of 2m sulfuric acid 25 ml the cooling bath was removed and the reaction mixture was stirred at ambient temperature in an open flask for 2 hours the reaction mix was then partitioned between ether 120 ml and water 80 ml the organic phase was separated washed with water 100ml and saturated sodium bicarbonate 100ml the aqueous phases were re extracted with ether 130 ml the combined organic extracts were dried mgso4 and evaporated the evaporation residue was kept under ar note 2 until it could be purified on a column of silica 120g in ethyl acetate gradient in hexanes 0 to 30 etoac the obtained column purified material 1 57g 98 2 dr by 1h nmr was suspended in cyclohexane 60ml the slurry was refluxed for 10 min and then allowed to sit at ambient temperature overnight the solid product was collected by flitration washed with hexanes dried by suction and on highvac y 1 410g 69 5 th of a diastereomerically pure material 1h cdcl3 400mhz 6 77 d 8 9hz 1h 6 69 dd 8 9hz 3 0hz 1h 6 59 d 2 9hz 1h 4 44 ddd 10 7hz 3 3hz 2 0hz 1h 4 04 t 10 3hz 1h 3 92 t 6 3hz 1h 3 74 s 3h 3 58 m 1h 3 54 d 13 9hz 1h 3 47 d 13 9hz 1h 3 03 m 2h 2 08 m 2h 1 90 m 2h 1 41 m 2h0 1 20 s 3h 0 99 s 3h note 2 this reduced chromane auxiliary intermediate 1 410g 3 477 mmol was dissolved in thf 140 ml and the solution was cooled to 0 c water 36ml and 50 h2o2 15ml was added followed by 1m aqueous lioh 5 0ml prepared freshly from aldrich lioh monohydrate the reaction mixture was stirred at 0 c for for 20 min then quenched with 2m h2so4 1 5ml and warmed to ambient temperature the reaction mix was partitioned between ether 300 ml and water 150 ml the organic phase was washed with additional water 200ml then shaken for 5 min with 1m na2so3 200ml to convert the peroxyacid into a carboxylic acid the aqueous phases were sequentially re extracted with additional ether 300ml the combined organic phases containing a mixture of the product and the liberated auxiliary were extracted twice with 3 1 mix of water with conc aqueous ammonia 2x100ml and then with water these combined ammonia extracts were then acidified with 6m hcl 140ml with cooling on ice bath the acidified mixture was then extracted 3 times with dichloromethane 3x150ml the dichloromethane extracts were washed with water 100ml combined dried mgso4 and evaporated the residue was re crystallized from cyclohexane 60ml at reflux then kept at ambient temperature overnight the precipitated product was collected by filtration washed with hexanes 2x10ml and dried on highvac y 682mg of white cotton like fluffy needles 94 th s enantiomer 99 ee note 3 1h cdcl3 400mhz 6 77 d 8 8hz 1h 6 69 dd 8 8hz 2 8hz 1h 6 63 d 2 8hz 1h 4 39 m 1h 4 16 m 1h 3 75 s 3h 3 06 m 3h 13c cdcl3 100mhz 177 9 153 7 148 0 120 5 117 4 114 0 113 8 66 2 55 7 38 4 27 3 alpha d 27 2 04 c 0 981 chiral hplc assay chiralpak ad rh 17 to 20 mecn in water with 0 1 tfa at 75c 0 8 ml min note 1 using the same procedure oppolzer sultam auxiliary 6 238g 29 mmol with 60 nah 1 625g 40 6 mmol and acylchloride 6 967g 31 mmol provided 11 06g of the opposite enantiomer 94 5 th note 2 the l selectride reduction procedure can be difficult to manage on a large scale air oxidation of borane species that carried over into the crude product inspite the workup seems to be responsible for variable yields 40 50 on a larger scale a careful workup with perborate would probably solve this problem note 3 using the above procedure l selectride reduction of the acylated intermediate prepared from the auxiliary provided 1 210g 59 5 th of the reduced intermediate which was then hydrolyzed as above in 93 yield to provide 580mg of pure r enantiomer 99 ee note 4 a more direct approach to the optically pure chromane acid by asymmetric hydrogenation with a ru catalyst is described here comments 62 pages about milkshake about org prep daily bug report chemistry resources chemistry chemjobber in the pipeline med chemist open flask org chem portal practical fragments stellen fuer chemiker edible links serious eats links to behold idle words categories chris douglas industry life krest17 lab destruction lit highlights mechanisms procedures questions uncategorized search archives january 2026 december 2025 november 2025 october 2025 september 2025 april 2019 march 2019 december 2018 june 2018 september 2017 august 2017 march 2016 october 2015 august 2015 july 2015 june 2015 march 2015 november 2014 july 2014 may 2014 september 2013 july 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