Trifluoroethanol, 2,2,2-, purification

The first problem encountered once the peptide has been successfully synthesized is that standard purification protocols fail. Although very hydrophobic peptides are soluble in acids such as TFA, these harsh conditions are not suitable for purification, because they can reduce column life times and denature native protein structures. Hence residual acid has to be removed, and many peptides can then be redissolved in mixtures of water and tert-butanol. Peptides with a strong tendency to aggregate may be dissolved either in trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), mixtures of 1-propanol and 1-butanol, 20% acetic acid or 70-90% formic acid. 

Trifluoroethanol [5n] This solvent is strongly acidic and the major impurities are water and trifluoroacetic acid. In its purification, it is dried over potassium carbonate anhydride for a night and then subjected to fractional distillation (reflux ratio 10 1) under atmospheric pressure, the middle fraction being collected. 

The submitters used 99+% 2,2,2-trifluoroethanol, and 99% triethylamine, purchased from Janssen Chimica, without purification. The checkers used the same grade materials purchased from Aldrich Chemical Company, Inc., and Eastman Kodak, respectively. 

Trifluoroethyl methacrylate (MATRIF) and 2,2,2-trifluoroethyl acrylate (ATRIF) monomers are commercially available products, but they can be synthesized from methacryloyl or acryloyle chloride and 2,2,2-trifluoroethanol in the presence of triethylamine as a base [41]. The purification of ATRIF and MATRIF monomers was carried out by distillation (at 59°C/100 mmHg and 46°C/125 mmHg, respectively). 

After acid-free cleavage from the resin 120 with 1,1,1-trifluoroethanol in CH2CI2 and chromatographic purification, building blocks 162-165 are obtained in yields of 8-40%. Although the yields of the products 162 and 164 are enhanced compared to 163 and 165 (40% 8% and 17% 12%, respectively), a completely selective synthesis does not seem to be possible by this approach. An interesting feature here was the publication of an acid-free procedure for the cleavage of amines from trityl resins and a refinement of the Kaiser test. 

The cycloaddition precursor 227 was prepared by alkylation and decarboxylation of enantiomericaUy pure (3-ketoester 225, which led to ketone 226. Chlorination of 226 was accomplished by quenching the corresponding lithium enolate with triflic chloride to afford a-chloroketone 227. Without purification, a-chloroketone 227 was treated with triethylamine in a solution of 2,2,2-trifluoroethanol and ethyl ether (1 1 mixture). This gave cycloadduct 230 as a 25 1 mixture of isomers in 74% yield from 227 after treatment of 229 with tosic acid. The exquisite stereoselectivity can be rationalized from diene endo attack on the face opposite of the methyl-bearing stereocenter of the cyclic oxyaUylic cation 228. Cycloadduct 230 was then subsequently converted into (+)-dactylol 224 over several steps. 

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