Stereospecific Synthesis of Aldols

Jung etaU US 5,426,206 (June 20, 1995) Assignee The Regents of the University of California Utility Stereospecific Routes to Polypropinates and Chiral 

The product from Step 1 (0.4 mmol) dissolved in 3 ml CH2CI2 was treated with DIPEA (0.59 mmol), DMAP (1 crystal), and TBSCl (0.51 mmol) and refluxed 12 hours. It was poured into 20 ml 0.2 M pH 7 phosphate buffer, extracted with petroleum ether, and isolated as a clear oil in 89.6% yield. H-NMR and IR data supplied. 

The product from Step 2 (0.46 mmol) was dissolved in 4 ml CH2CI2, treated with 100 mg of 4 A powdered molecular sieves, DIPEA (0.74 mmol), and cooled to —42°C. TBSOTf (0.68 mmol) was added dropwise, the mixture stirred 80 minutes, was then poured in 20ml diethyl ether, and shaken with 5 mis pH 5.5 buffer. The product was purified by chromatography using EtOAc/hexane/TEA, 2 97 1, and isolated in 78% yield. 

The reagent in Step 1, (E)-2-methyl -2-hexen-l-ol, was prepared using a modified Morita-Baylis-Hillman procedure with ethyl acrylate and l,4-diazabicyclo[2.2.2]octane. Other examples of the Bayliss-Hilman reaction are provided (1). The stereoisomer, (Z)-2-methyl-2-hexen-l-ol was used to prepare other aldol stereoisomers. The preparation of the (Z)-isomer is provided below by the author  

To bis(2,2,2-trifluoroethyl) ethyl 2-phosphopropinate (3.75 mmol), 18-crown-6 (10.18 mmol) in 30 ml of THE at -42 °C was added solid KHMDS (3.68 mmol). The solution was cooled to -78 °C, butyraldehyde (2.5 mmol) added dropwise, and the mixture stirred 8 hours at -78 °C and 12 hours at -20 °C. The mixture was re-cooled to -78 °C, l.OM LiBEtjH (10.0 mmol) in THF added, the reaction warned to 25°C over 4 hours, and stirred an additional 10 hours. The reaction was quenched with EtOAc and poured over distilled water. The mixture was purified chromatography on silica gel with CH2Cl2/EtOAc, 97 3, and the product isolated as an oil in 90% yield. 

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